Executive summary

SymBio in-licenses drugs for development and sale

SymBio Pharmaceuticals Ltd. is a specialty pharmaceutical company that buys the right to develop and commercialize drug candidates, conducts clinical trials, and obtains manufacture and marketing approval in order to address the underserved medical needs of patients. With its main focus on the areas of oncology, hematology, and rare diseases, the company typically seeks in-licensing opportunities for niche markets from pharmaceutical and biotech companies based in the US or EU.

Notably, the company does not conduct basic research and outsources preclinical/clinical development, employing a fabless in-licensing approach. Using its proprietary in-house “search engine,” the company identifies, assesses and in-licenses only quality drug candidates having proof-of-concept established in human subjects. The company first screens third-party drug candidates being tested in clinical trials, then presents the in-licensing opportunities to its Scientific Advisory Board for further assessment of the science behind each molecule, preclinical/clinical data, target market, and the feasibility of receiving marketing approval from Japanese regulatory authorities.

According to the company, the typical development timeline of an oncology drug in Japan from preclinical studies to marketing approval is about 10 to 17 years. However, the company secured marketing approval for its first oncology drug under development in Japan, Treakisym®, in only five years after in-licensing the drug. Within three years of its launch, Treakisym® captured more than 50% of the non-Hodgkin’s lymphoma (NHL) and mantle cell lymphoma (MCL) market in Japan.

As of February 2021, the company had obtained approval for and launched Treakisym® (anticancer agent for hematologic malignancies) for the indications of relapsed or refractory low-grade NHL and MCL, untreated (first-line treatment) and relapsed or refractory low-grade NHL and MCL, and chronic lymphocytic leukemia (CLL). Treakisym® is listed in the Practical Guidelines for Hematological Malignancies 2018 edited and published by Japanese Society of Hematology as the standard treatment for relapsed or refractory low-grade B-cell NHL, MCL, and CLL, and as first-line treatment for low-grade NHL.

The company obtained manufacturing and marketing approval for the ready-to-dilute (RTD) liquid formulation of Treakisym® and began sales in January 2021. Unlike the lyophilized (freeze-dried [FD]) powder formulation of Treakisym®, the RTD formulation eliminates the need for troublesome manual dissolution, thereby reducing burdens placed on medical personnel. The re-examination term for the lyophilized formulation of Treakisym® ends in 2020, but by launching the RTD formulation to which SymBio has exclusive rights, the company can extend the product life cycle of Treakisym® until 2031.

Drugs in the development pipeline include Treakisym® for the indication of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), rapid infusion (RI) administration of Treakisym®, rigosertib (anticancer agent for myelodysplastic syndromes) IV and oral formulations, and the antiviral drug brincidofovir. With regard to Treakisym® indicated for refractory or relapsed DLBCL, in March 2021 the company obtained approval for the combination therapies of Treakisym® with rituximab, and with rituximab and polatuzumab vedotin.

Earnings

FY12/20 sales were JPY3.0bn (+5.3% YoY). Product sales totaled JPY3.0bn (+5.9% YoY) and royalty revenue totaled JPY10mn (JPY26mn in FY12/19). The operating loss totaled JPY4.5bn (operating loss of JPY4.3bn). The company also reported a recurring loss of JPY4.6bn (recurring loss of JPY4.4bn) and a net loss of JPY4.1bn (net loss of JPY4.4bn).

The company’s FY12/21 forecast calls for sales of JPY9.2bn (+206.4% YoY), operating profit of JPY1.4bn (operating loss of JPY4.5bn in FY12/20), recurring profit of JPY1.4bn (recurring loss of JPY4.6bn), and net income of JPY1.1bn (net loss of JPY4.1bn). The company expects increased product sales in Japan due to the move to sell Treakisym® in-house, and to turn profitable at all levels on the back of sales growth and improved profit margins.

In its medium-term plan (FY12/21–FY12/23), with the aims of achieving sales growth and higher profit margins, SymBio projects sales of JPY12.4bn and net income of JPY1.8bn in FY12/23. The company expects higher sales from increased market penetration of Treakisym® for approved indications, as well as anticipated approval of additional indication of Treakisym® for relapsed or refractory DLBCL.

SymBio aims to turn profitable in FY12/21. To this end, the company intends to build its own sales structure, obtain approval for and switch to Treakisym® liquid formulations, and obtain approval for the additional indication of Treakisym® for relapsed or refractory DLBCL. Shared Research understands that the first two of these measures (own sales structure and approval/switch to Treakisym® liquid formulations) are key to improvement in gross profit and GPM, which in turn will help the company achieve profitability in FY12/21. As of February 2021, the company was on track to moving into the black, having established its own sales structure and commenced sales of Treakisym® liquid formulations. SymBio also filed for approval of the additional indication of Treakisym® for relapsed or refractory DLBCL in May 2020.

Strengths and weaknesses

Shared Research thinks SymBio’s strengths include its unique drug candidate selection process, strong product development team, and business strategy focusing on niche markets. Weaknesses include its dependence on a single individual and product (see Strengths and weaknesses).

Key financial data

Recent updates

Obtained approval to extend the expiration date of Treakisym® Injection (RTD formulation)

On November 24, 2021, SymBio Pharmaceuticals Ltd. announced that it obtained approval to extend the expiration date of Treakisym® Injection (RTD formulation).

The company obtained approval to make a partial change to the approved matters of Treakisym® Injection 100mg/4ml (ready-to-dilute [RTD] formulation), aimed at extending the expiration date of the drug to 30 months based on the results of long-term stability tests. 

SymBio announced final results of phase III trial in Japan for Treakisym® used in combination with rituximab as treatment for r/r DLBCL

SymBio Pharmaceuticals Ltd. announced the final results of the phase III trial in Japan for Treakisym® used in combination with rituximab (BR therapy) as treatment for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).
   

The company announced the final results of a phase III trial in Japan for its anticancer agent Treakisym® used in BR therapy to treat r/r DLBCL.

The company conducted the phase III trial and its long-term follow-up study to obtain approval for use of Treakisym® in BR therapy for r/r DLBCL, and the final results were presented at the 83rd Annual Meeting of the Japanese Society of Hematology in September 2021. The phase III trial confirmed the efficacy of BR therapy as demonstrated in the phase II trial (conducted in Japan and Korea), and the regulatory approval was granted in March 2021.

Final main efficacy evaluation results of phase III trial and long-term follow-up study (38 cases) 

• Response rate (complete or partial response [CR+PR]): 76.3%
• Complete response (CR): 47.4%
• Median overall survival: 29.2 months 
  

Initiation of controls on shipments of Treakisym® lyophilized injection formulation

SymBio Pharmaceuticals Ltd. announced that it will initiate controls on shipments of Treakisym® lyophilized
injection formulation. 

In January 2021, SymBio commenced manufacture and sale of a ready-to-dilute (RTD) formulation of Treakisym® intravenous fluid in quantities of 100mg/4ml, as a successor to the lyophilized (freeze-dried [FD]) powder formulation of Treakisym® 100mg. Although the company is still manufacturing and selling both the RTD and FD formulations as of September 2021, it is actively converting the market from FD to RTD.

However, SymBio has announced that it will initiate controls on shipments of the FD formulation, to avoid a potential stockout arising from delays in the migration from FD to RTD. 

The company has sufficient inventory to ensure stable supply of RTD. In addition, in May 2021 SymBio submitted a partial change application with respect to its marketing authorization for the RTD liquid formulation to add rapid infusion (RI) administration.  

As of September 2021, there is no change to the company’s full-year FY12/21 earnings forecast in relation to the controls on shipments.

UCSF Brain Tumor Center initiates studies to investigate new indications for brincidofovir IV

SymBio Pharmaceuticals Ltd. announced that the University of California San Francisco (UCSF) Brain Tumor Center initiated studies to investigate new indications for brincidofovir IV.

The company announced that the Brain Tumor Center, Department of Neurological Surgery, UCSF, initiated preclinical studies to investigate antitumor effects of brincidofovir IV against brain tumor.

Trends and outlook

Quarterly trends and results

Cumulative Q3 FY12/21 results

• Sales: JPY5.6bn (+138.1% YoY)
• Operating profit: JPY424mn (loss of JPY3.1bn in cumulative Q3 FY12/20)
• Recurring profit: JPY414mn (loss of JPY3.2bn in cumulative Q3 FY12/20)
• Net income: JPY325mn (loss of JPY2.7bn in cumulative Q3 FY12/20) 
  

Sales increased YoY in cumulative Q3 (January–September) FY12/21, largely due to the transfer of sales from Eisai Co., Ltd. to the company’s own sales force. The business alliance agreement with Eisai for Treakisym® expired on December 9, 2020, and SymBio began independently marketing Treakisym® in Japan on December 10. This allows the company to receive not only the gross profit it received previously (the company’s sales to Eisai minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source the product).

However, there were headwinds such as the clearance of market inventory of the FD formulation sold by Eisai prior to the switch to the company’s own sales force in December 2020, delays in medical care due to the COVID-19 outbreak from late 2020, and constraints on sales activities due to tighter restrictions on facilities visits.

In Q3, sales of Treakisym® for the indication of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) accelerated. This was partially because the backlog of delayed medical treatments cleared on COVID-19 measures, including vaccinations for the elderly. Other factors included the March 2021 approval of BR-therapy and P-BR therapy to treat r/r DLBCL, and Chugai Pharmaceutical's polatuzumab vedotin being added to the NHI drug list in May 2021. 

Gross profit was JPY4.0bn (+562.4% YoY), and GPM was 72.9% (+46.7pp YoY). The company attributes the GPM rise to the shift to its own marketing system and the launch of Treakisym® Ready-to-dilute (RTD) formulation in January 2021. In cumulative Q3, sales of Treakisym® lyophilized formulations surpassed those of Treakisym® RTD formulations.

Profits at the operating profit level down grew on reduced SG&A expenses and sales growth, and the company achieved profitability in cumulative Q3. SG&A expenses decreased 3.5% YoY to JPY3.6bn

R&D expenses decreased 26.3% YoY to JPY1.3bn. This included expenses for conducting clinical trials of intravenous formulations of Treakisym® and brincidofovir.

Excluding R&D expenses, SG&A expenses rose 16.3% YoY to JPY2.3bn. The switch to in-house sales drove up the cost of sales.

Q3 FY12/21 (July–September 2021) results

In Q3 FY12/21 (July–September 2021), sales were JPY2.4bn (+147.6% YoY), gross profit was JPY1.8bn (+530.6% YoY), the GPM was 73.6% (+44.7pp YoY), and operating profit was JPY619mn (JPY1.3bn loss in Q3 FY12/20). The company turned profitable at OP level in Q2 and further increased OP in Q3.

Versus Q2 FY12/21, sales were up JPY680mn, gross profit up JPY506mn, the GPM up 0.3pp, and operating profit up JPY603mn.

Factors that contributed to sales growth were as follows. In Q2, sales were impacted by clearance of unsold inventory of lyophilized formulations sold by Eisai prior to December 2020, but this was no longer a factor in Q3. In March 2021, BR therapy was approved for r/r DLBCL while Chugai Pharmaceutical received approval for the combination of polatuzumab vedotin + BR therapy (P-BR therapy). In Q3, sales of Treakisym® used in BR and P-BR therapies for the for the r/r DLBCL treatment increased.  

The GPM rose QoQ, because the switch from the lyophilized formulation to the RTD formulation of Treakisym® progressed faster in Q3 than in Q2.

Progress in cumulative Q3 versus full-year FY12/21 company forecast

When reporting Q2 FY12/21 results, 1H sales fell short of the company forecast, but the company left its full-year forecast unchanged, because it expects higher sales in 2H than in 1H, and thinks the full-year forecast is achievable. Reasons for the company's expectation of profit growth in 2H versus 1H are as follows.

In 1H FY12/21, the impact of the clearance of unsold inventory of the lyophilized formulation of Treakisym® sold by Eisai totaled around JPY400mn. The clearance was completed in 1H and will have no impact on 2H results.

Patients cut back on hospital visits in 1H because of COVID-19, but the company expects this pattern to change in 2H as more seniors are vaccinated and likely to resume hospital visits.

The company received approval for BR therapy indicated for r/r DLBCL in March 2021, while Chugai Pharmaceutical received approval for polatuzumab vedotin + BR therapy indicated for r/r DLBCL. These approvals were granted about three months earlier than the company expected at the beginning of FY12/21. The company targets JPY2.6bn in sales of Treakisym® indicated for r/r DLBCL on a NHI drug reimbursement price basis, but Shared Research understands that sales may exceed this target because of the earlier-than-expected approval timing. The company recorded sales of Treakisym® indicated for r/r DLBCL in the second half of Q2 and expects this sales to increase in 2H.

The company forecasts a higher GPM in 2H as the switch from the lyophilized formulation to the RTD formulation of Treakisym® progresses.

Cumulative Q3 sales were 60.7% of full-year FY12/21 company forecasts while operating profit came in at 31.2%. It is our understanding that Q3 earnings are in line with company expectations for 2H. Q4 sales and operating profit are projected to exceed Q3 levels as higher vaccination rates help reduce patient hesitancy for doctor consultations, progress is made switching to the higher-margin RTD formulation, and increases in SG&A expenses are curbed. 

Overview of business progress

In FY12/21, progress in main businesses are as follows:

In October 2021, Dr. Carolyn Yanavich was appointed Vice President, and Head of Project Management and Clinical Operations of SymBio Pharma USA. 

In September 2021, results of the domestic phase III trial evaluating TREAKISYM in combination with Rituximab for treatment of relapsed and refractory diffuse large B-cell lymphoma were disclosed. The phase III and follow-up studies demonstrated a response rate (complete response and partial response [CR+PR]) of 76.3%, complete response rate (CR) of 47.4%, and median overall survival of 29.2 months. 

In September 2021, the company announced plans to adjust shipments of lyophilized TREAKISYM. As of September 2021, SymBio manufactures and markets both the RTD and FD formulations while it looks to switch FD to RTD. Adjustments to FD shipments are being made because of potential stockout. 

In September 2021, the company initiated a pre-clinical study to investigate the anti-tumor effect of brincidofovir IV on brain tumors at the Brain Tumor Center, Department Neurological Surgery, University of California, San Francisco.

In September 2021, the company concluded a joint research agreement with the National Cancer Centre Singapore to explore the anti-tumor effects of brincidofovir IV in Epstein-Barr (EB) virus positive lymphoma and its mechanism of action. 

In August 2021, the company announced it had started administration to the first patient enrolled (FPI) in the Phase II clinical trial of antiviral drug brincidofovir (IV forumulation).

Also in August 2021, the company concluded a joint research agreement with Kyoto University regarding the mechanism of effect of bendamustine, under development as an anticancer agent indicated for DLBCL.

In July 2021, the company concluded a joint research agreement with the General Surgical Science Department, Gunma University Graduate School of Medicine regarding the exploration of new indications for bendamustine and rigosertib, which are under development as anticancer agents.

In June 2021, Chimerix, Inc. (licensor of brincidofovir) obtained FDA approval of brincidofovir tablets and oral suspensions as antiviral formulations for the treatment of smallpox.

In May 2021, SymBio submitted approval application for Treakisym® rapid infusion (RI) liquid formulation.

In April 2021, the company obtained approval of Treakisym® ready-to-dilute (RTD) liquid formulation for use in combination with rituximab and in combination with rituximab and polatuzumab vedotin for the treatment of refractory or relapsed diffuse large B-cell lymphoma (r/r DLBCL).

In March 2021, the company obtained approval of Treakisym® for use in combination with rituximab, and in combination with rituximab and polatuzumab vedotin for the treatment of r/r DLBCL.

In January 2021, the company launched Treakisym® RTD liquid formulation.

Domestic

Preparations for in-house sales organization begin

The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expired in December 2020, and the company switched to in-house sales for domestic sales of Treakisym®.

The company has thus far deployed a nationwide network of marketing representatives as well as hematology experts to cover each region to establish a highly productive internal sales organization capable of making proposals that fit the needs of each region. With the termination of its alliance agreement with Eisai, in September 2020, the company concluded a basic agreement with Suzuken Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to achieve nationwide distribution. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, under management by S.D. Collabo Co., Ltd.

During cumulative Q3, in January 2021, the company launched sales of the ready-to-dilute (RTD) formulation of Treakisym®, for which it obtained manufacturing and marketing approval in September 2020.

On March 23, 2021, the company obtained approval of a partial change to the manufacturing and marketing authorization for bendamustine-rituximab combination therapy (BR therapy) and bendamustine-rituximab-polatuzumab vedotin combination therapy (P-BR therapy) to treat r/r DLBCL patients. This enabled conventional lyophilized (freeze-dried [FD]) powder formulation of Treakisym® to be used in BR therapy right away. In April 2021, the company obtained approval of Treakisym® ready-to-dilute (RTD) liquid formulation for use in BR therapy and P-BR therapy for the treatment of r/r DLBCL. In May 2021, Chugai Pharmaceutical's polatuzumab vedotin was added to the NHI drug price list, enabling Treakisym® to be used in P-BR therapy.

Stable product supply

With the launch of sales of Treakisym® RTD formulation in January 2021, the company now markets both Treakisym® in both RTD formulation and FD formulation.

SymBio imports FD formulation Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma) and Treakisym® RTD formulation from Eagle Pharmaceuticals Inc.

On the quality control front, the company conducts secondary packaging and quality screening on imported batches of both the FD and RTD formulations of TREAKISYM® to maintain stable quality.

On the supply front, the company is striving to replace the FD formulation of TREAKISYM® with RTD formulation in the market, but the current conversion rate is behind plan. Due to the possibility of the FD formulation being out of stock, SymBio began controlling shipments of FD from September 21, 2021. The company has secured sufficient quantities of the RTD formulation to ensure stable supply.

Treakisym® (SyB L-0501[FD formulation]/SyB L-1701 [RTD formulation]/SyB L-1702 [RI administration]; generic name: bendamustine hydrochloride or bendamustine hydrochloride hydrate, product name: Treakisym®)

The anticancer agent Treakisym® is used to treat malignant lymphomas, indicated for untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL and MCL (October 2010), and chronic lymphocytic leukemia (August 2016).

The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for Hematological Malignancies 2018 published by Japanese Society of Hematology as a standard treatment option, which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for lymphatic cancer.

Also, SymBio obtained approval for the partial revision to the marketing authorization of Treakisym® in July 2018. Treakisym® can now be used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicular lymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for the partial revision to its application to use Treakisym® as a pretreatment agent in tumor-specific T cell infusion therapy. This allows Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor T-cell (CAR-T) therapy approved in Japan. Growing use of Treakisym® as a pretreatment agent in regenerative medicine has solidified its positioning as standard therapy for malignant lymphomas.

In the phase III clinical study of Treakisym® administered in BR therapy targeting r/r DLBCL, the company filed for approval for partial revision to manufacturing and marketing authorization in May 2020 and obtained that approval in March 2021. In April 2021, it obtained approval for partial revision to manufacturing and marketing authorization of Treakisym® RTD liquid formulation for use in BR and P-BR therapy as treatment for r/r DLBCL. The company has conducted a follow-up study with overall survival as the primary endpoint, because evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in BR therapy is crucial for establishing Treakisym® as a treatment for DLBCL. It is now making preparations to publicize the results of that study. 

In response to Chugai's June 2020 filing for manufacturing and marketing approval of combination therapy of polatuzumab vedotin + BR therapy (P-BR therapy) to treat r/r DLBCL, SymBio submitted a filing for Treakisym® + polatuzumab vedotin + rituximab in July 2020 and received approval in March 2021. Polatuzumab vedotin was included in the NHI price list from May 2021, at which time it became possible to use Treakisym® in P-BR therapy. Prior to this, there were no effective treatments for this indication so multi-drug regimens comprised of different anticancer agents were used as rescue chemotherapy. Accordingly, there was strong demand for development of an effective and safe treatment option. As BR therapy was already used to treat r/r DLBCL in Europe and the US, patient groups and related academic societies submitted a request to MHLW for an accelerated approval in Japan.

The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in September 2017 for the RTD and rapid infusion (RI) formulations of Treakisym® (the RI formulation reduces administration time). Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company launched it in January 2021. The company has concluded clinical trials to confirm safety of the RI formulation and applied for approval in May 2021. Unlike the current FD formulation, the RTD formulation reduces the workload of medical professionals, because it eliminates the need for troublesome manual dissolution. The RI formulation can be administered in just 10 minutes, versus 60 minutes for the current FD and RTD formulation. This reduces the burden on patients and healthcare professionals, providing significant value added. 

Rigosertib Sodium (SyB L-1101 [IV]/SyB C-1101 [oral]; anticancer agent; generic name: rigosertib Sodium)

Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japan and is looking to apply the knowledge gleaned from additional analysis of the INSPIRE study to rigosertib development going forward.

Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination with azacytidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety among Japanese patients, SymBio began a phase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019.

The company said it would conduct joint research into Treakisym® and rigosertib with the University of Tokyo's Institute of Medical Science and Gunma University regarding efficacy of using the two compounds in combination or with existing drugs and also explore new indications.

Antiviral drug SyB V-1901 (generic name: brincidofovir）

In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug in intravenous and oral forms). The company acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox.

The company has concluded that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. In March 2021, the company submitted of an investigational new drug (IND) application to the Food and Drug Administration (FDA) of the US with the goal of obtaining permission for the launch of a phase II clinical trial for a phase II clinical trial of BCV IV as a treatment for adenovirus infections that primarily occur in children (although also in adults). In April 2021, the company received granted fast track designation from the FDA and on August 16, 2021, the investigational drug was administered to the first patient enrolled (first patient in [FPI]) in the clinical trial.

Based on safety and efficacy data acquired from its study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow the market for and maximize the business value of BCV. Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of BCV Oral against dsDNA viruses, raising expectations for its potential as a safe and effective therapy to prevent and treat a range of viral infections in patients receiving hematopoietic stem cell transplantation.

Chimerix announced in December 2020 that the FDA had accepted its new drug application (NDA) for BCV as a medical defense against smallpox and that it had received FDA approval in June 2021. Further, through joint research with the National Cancer Centre Singapore and University of California San Francisco Brain Tumor Center, SymBio is investigating new indications for BCV. 

Overseas

The company’s US-based wholly-owned subsidiary SymBio Pharma USA, Inc. appointed Dr. Carolyn Yanavich as its Vice President, and Head of Project Management and Clinical Operations on October 11, 2021, and launched full-scale operations aimed at accelerating global development of antiviral drug brincidofovir toward commercialization. 

In-licensing of drug candidates

The company is currently focusing on unrolling global development plans for the antiviral drug brincidofovir it in-licensed in September 2019, but also constantly looking into multiple licensing deals and looking for and evaluating promising new in-licensing drug candidates.

Full-year company forecast

Earnings outlook

The company’s FY12/21 forecast calls for sales of JPY9.2bn (+206.4% YoY), operating profit of JPY1.4bn (operating loss of JPY4.5bn in FY12/20), recurring profit of JPY1.4bn (recurring loss of JPY4.6bn), and a net income of JPY1.1bn (net loss of JPY4.1bn). 

The company expects increased product sales in Japan due to the move to sell Treakisym® in-house and obtaining approval for, and beginning sales of Treakisym® for the additional indication of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). 

Sales increase resulting from move to sell Treakisym® in-house: The business alliance agreement with Eisai for Treakisym® expired on December 9, 2020, and SymBio began independently marketing Treakisym® in Japan on December 10. Switching from marketing through Eisai (based on the marketing agreement with Eisai) to doing its own marketing meant that products are shipped to pharmaceutical wholesalers instead of to Eisai. This allows the company to receive not only the gross profit it received previously (the company’s sales to Eisai minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source the product). 

Obtaining approval for, and beginning sales of Treakisym® for the additional indication of relapsed or refractory DLBCL: The company targets sales of JPY2.6bn on an NHI drug reimbursement price basis for Treakisym® indicated for DLBCL.

The company expects to turn profitable at all profit levels on the back of sales growth.

It forecasts gross profit of JPY7.0bn (+702.6% YoY) with a GPM of 76.0% (+47pp YoY). The increase in gross profit is due to higher sales and GPM. The GPM rise is due to starting in-house sales of Treakisym® and switching to the RTD formulation of the product.▷ It forecasts gross profit of JPY7.0bn (+702.6% YoY) with a GPM of 76.0% (+47pp YoY). The increase in gross profit is due to higher sales and GPM. The GPM rise is due to starting in-house sales of Treakisym® and switching to the RTD formulation of the product.  

GPM rise due to starting in-house sales of Treakisym®: As noted above, switching from marketing through Eisai (based on the marketing agreement with Eisai) to doing its own marketing meant that products are shipped to pharmaceutical wholesalers instead of to Eisai. This allows the company to receive not only the gross profit it received previously (the company’s sales to Eisai minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source the product). Before December 9, 2020, the company was selling the lyophilized formulation of Treakisym® to Eisai at a GPM of around 30%. Shared Research understands that from December 10 onward, by doing its own marketing, the GPM on Treakisym® would go up to around 70%. 

GPM rise due to switching from the lyophilized formulation to the RTD formulation of Treakisym®: The company sourced the lyophilized formulation of Treakisym® from Astellas Deutschland, but the liquid formulations (RTD formulation and RI administration) are supplied by Eagle Pharmaceuticals. The company commented that the GPM on liquid formulations of Treakisym® will be higher than the GPM on the lyophilized formulation. By the end of 2021, the company targets an RTD product sales share of 91% of total Treakisym® sales. 

SymBio expects SG&A expenses of JPY5.6bn (+4.1% YoY).

The company plans R&D expenses of JPY2.0bn (-10.9% YoY). It will proceed with development of Treakisym® for the indication of relapsed or refractory DLBCL, Treakisym® liquid formulations, and rigosertib, as well as antiviral drug brincidofovir. The company made a milestone payment on obtaining approval of the RTD formulation of Treakisym® in FY12/20, but no milestone payments are expected in FY12/21. 

SG&A expenses excluding R&D expenses are estimated to be JPY3.6bn (+15.1% YoY). The company will reinforce its in-house sales structure and prepare to expand its business overseas so that it can turn profitable in FY12/21 and sustain earnings expansion thereafter.

The main pipeline development plans are as follows.

Treakisym®

The company targets Treakisym® sales of JPY11.3bn in FY12/21 on an NHI drug reimbursement price basis (JPY8.0bn in FY12/20).

Sales growth of Treakisym® for approved indications: The company targets Treakisym® sales of JPY4.1bn as first-line therapy for low-grade non-Hodgkin’s lymphoma and JPY4.6bn for other indications (NHI reimbursement price basis) in FY12/21.

Sales growth of Treakisym® for added indication: SymBio applied for approval of the additional indication of relapsed or refractory DLBCL for Treakisym® in May 2020, and expects to obtain approval and launch in Q2 FY12/21. The company targets Treakisym® sales of JPY2.6bn for the indication of DLBCL. 

Extended product life cycle: The company began sales of the RTD formulation of Treakisym® in Q1 FY12/21. By the end of 2021, the company targets a 91% sales share of the RTD formulation of total Treakisym® sales. It plans to begin sales of the RI formulation in 1H FY12/22. 

Oral rigosertib and rigosertib injection

SymBio is continuing to develop intravenous rigosertib formulation. Onconova, the licensor of anticancer drug rigosertib, announced in August 2020 that its global phase III trial (INSPIRE study) in patients with higher-risk myelodysplastic syndromes (higher-risk MDS) intolerant of treatment with hypomethylating agents failed to meet its primary endpoints. SymBio engages in clinical development of rigosertib in Japan, and plans to use the knowledge obtained from genomic analysis of the INSPIRE study in future development of rigosertib. 

Antiviral drug brincidofovir

Regarding the intravenous formulation of brincidofovir (BCV IV), after a review at the global advisory board held in February 2020, the company concluded that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. As of February 2021, the company was preparing to begin clinical trials of the liquid formulation of BCV for dose determination in children. 

Long-term outlook

Medium-term plan (FY12/21–FY12/23)

SymBio announced a three-year medium-term plan for FY12/21 through FY12/23 along with the FY12/20 results. 

Targets in medium-term plan (FY12/21–FY12/23)

Sales

SymBio expects product sales of Treakisym® to account for the bulk of sales. 

Product sales targets reflect the recent pace of market penetration and sales trends, which feed into the company’s revised sales growth rates calculated over the medium-term plan period. 

Sales through FY12/20 were booked based on product shipment sales to the sales distributor, Eisai. From FY12/21 onward, sales will be booked on product shipment sales to pharmaceutical wholesalers from the company’s own in-house sales organization.

In estimating sales from FY12/21 onward, SymBio disclosed targets assuming increased product sales of Treakisym® as it expects to gain approval of the drug as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in Q2 FY12/21. 

Transition to in-house sales structure

SymBio has entrusted Treakisym® sales to Eisai until end-FY12/20. During this period, product shipments to Eisai are being booked as sales. However, Eisai’s exclusive sales period expires in FY12/20, and from FY12/21 SymBio will switch to selling Treakisym® in-house. Up to and including FY12/20, Shared Research assumes that the price of shipments to Eisai will be around 50% of the NHI drug price. With the transition to an in-house sales structure in FY12/21, though, Shared Research thinks the price that SymBio charges to wholesalers will rise to roughly 90% of the NHI drug price. Thus even if volume remains largely unchanged, the company expects higher selling prices to drive sharp YoY sales growth in FY12/21.

Based on data supplied by Eisai, sales of Treakisym® were JPY7.7bn (+6.3% YoY) in FY03/20. In contrast, SymBio’s product sales stood at JPY2.8bn in FY12/19. The fiscal year ends of the two companies differ by three months, SymBio’s product sales include overseas sales, and at Eisai, there is a time lag between product procurement and sales. Broadly speaking, however, we can infer that Eisai’s gross profit is roughly Eisai’s sales minus SymBio’s sales, so once SymBio begins its own sales of Treakisym®, it is our understanding that the company will be gaining the equivalent of Eisai’s portion of gross profit.

As noted, the company plans to shift to its own sales organization and switch product shipments from Eisai to pharmaceutical wholesalers in FY12/21. In the run-up to this it will be necessary to reduce Eisai’s inventories toward the end of FY12/20. Sales of Treakisym® based on an NHI drug price should remain solid, reflecting actual market demand, but SymBio plans to stop shipping to Eisai with a target date of end-1H FY12/20. It expects FY12/20 sales to decline by a commensurate amount.

Addition of an indication of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL)

The company plans to seek approval of the additional indication of r/r DLBCL for Treakisym® in Q2 FY12/21. It aims to commence sales of Treakisym® for this indication in Q3 FY12/21, with a view to growing Treakisym® product sales in FY12/21 onward. The company says that its sales target range for FY12/22 is based on an estimated market penetration rate due to the additional indication.

As reference for the anticipated impact of adding the indication of r/r DLBCL, the company estimates that the number of patients being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients with untreated low-grade NHL and MCL is 6,967, for a total of 16,303. For these indications, SymBio’s FY12/19 sales target was JPY10.1bn on an NHI drug price basis. By comparison, the company estimates that the number of Japanese patients with r/r DLBCL is 18,672.

In FY12/21, the company targets Treakisym® sales (on an NHI drug reimbursement price basis; same below) of JPY11.3bn (JPY8.0bn in FY12/20), breaking down into JPY8.7bn for approved indications and JPY2.6bn for the DLBCL indication. 

Treakisym® indicated for DLBCL will begin contributing to earnings in FY12/21. The full-year contribution of this product (indicated for DLBCL) in FY12/22 and FY12/23, as well as its higher market penetration rate will likely boost overall sales.

Gross profit under the medium-term plan

The FY12/21 full-year forecast calls for a rise in GPM to 76.0% (+47pp YoY), which is due to starting in-house marketing of Treakisym® and switching to the RTD formulation of the product. The company assumes that progress in switching to liquid formulations of Treakisym® during the medium-term plan period will gradually raise the GPM. 

Based on historical performance, Shared Research understands that the gross profit margin was about 30% for Treakisym® shipments to Eisai prior to December 10, 2020. As outlined earlier, on December 10, 2020, SymBio transitioned to in-house sales of Treakisym®, rather than entrusting them to Eisai. The company now ships Treakisym® to pharmaceutical wholesalers instead of to Eisai. The gross profit earned prior to the transition remains, but is augmented by the gross profit that had previously gone Eisai’s way (difference between the procurement price paid by Eisai and the price on shipments from Eisai to wholesalers). Shared Research estimates that the transition to in-house sales will lift SymBio’s gross profit margin to around 70%. 

SymBio is likely to further boost the gross profit margin by procuring Treakisym® from a different source. The company procures lyophilized Treakisym® from Astellas Deutschland, but procures the liquid formulations (RTD and RI formulations) from Eagle Pharmaceuticals. The company expects GPM to be higher for the liquid formulations than for the lyophilized product. The company targets 91% sales share of the RTD formulation of total Treakisym® sales at end-FY12/21 and 95% at end-FY12/22. 

SG&A expenses under the medium-term plan

The company expects a gradual increase in SG&A expenses, including milestone payments and clinical trial expenses. SG&A expenses are largely broken down to R&D spending and other SG&A expenses.

The company calculated R&D expenses based on the latest development plans for its existing pipeline comprising Treakisym®, rigosertib, and antiviral drug brincidofovir. 

The company forecasts R&D expenses of JPY2.0bn (-10.9% YoY) in FY12/21. It made a milestone payment of around JPY500mn for the RTD formulation of Treakisym® in FY12/20 after obtaining approval, but plans no milestone payment in FY12/21. 

The company plans milestone payments for Treakisym® RTD formulation and antiviral drug brincidofovir in FY12/22 and FY12/23. It also expects an increase in clinical trial expenses for brincidofovir in FY12/22 onward. 

The company does not assume any upfront payments for in-licensing drug candidates outside its existing pipeline after brincidofovir, an antiviral drug, although it will continue to evaluate and investigate them.

Other SG&A expenses comprise primarily Treakisym® sales and marketing, production and distribution, business development, and management related costs. From FY12/21, SymBio assumes costs associated with operating its own sales organization for sales of Treakisym®. It forecasts an increase primarily in personnel expenses due to a higher medical representative headcount and higher expenses due to more activities. The company forecasts JPY3.6bn (+15.1% YoY) in SG&A expenses other than for R&D in FY12/21, assuming an increase in sales promotion and other expenses. It does not anticipate a large increase in expenses in FY12/22 onward, having established its own sales structure.

Net income

In the previous medium-term plan announced in February 2020, the company forecast net income exceeding recurring profit in FY12/21 and FY20/22 to reflect the reduction in loss carried forward from FY12/21 onward on tax effect accounting. Heeding the advice of accounting auditors, the new medium-term plan was formulated by removing income taxes adjustment factors for FY12/21 onward. 

Personnel plans

SymBio completed the formation of its 62-member nationwide sales structure in FY12/20. It plans to allocate the bare minimum of necessary personnel in other parts of the organization and is budgeting for personnel expenses accordingly. The company plans to increase personnel expenses for global expansion of brincidofovir, an antiviral drug, and reflected this in personnel expenses.

Funding plans

Regarding funding plans, the company will work toward strengthening its financial base so that it can respond in a flexible and nimble way to the need for funds according to business developments.

Shared Research thinks that once the company has turned profitable at net income level in FY12/21, there will be no need to raise funds through the issue of shares. In December 2020, SymBio concluded a JPY3.0bn syndicated loan (committed credit line) agreement with MUFG Bank, Ltd. as the arranger and agent to have a flexible funding structure in place. 

Business

Business description

SymBio obtains rights to develop and market new drug candidates from biotech companies in the US and EU

President and CEO, Fuminori Yoshida, established SymBio in March 2005 to address underserved medical needs in Japan and the Asia Pacific region, with main focus on oncologic, hematologic and autoimmune diseases. The company aspires to be a leading specialty pharmaceutical company in the Asia Pacific region. Its strategic approach to drug development negates the need for costly and time-consuming investment in earlier-stage R&D activities with an in-house search and evaluation team to identify and assess only quality drug candidates having proof-of-concept established in human subjects.

Strategy Overview (details to follow)

Post proof-of-concept: The company reduces product development risk by focusing on drug candidates undergoing clinical development with preclinical/clinical data establishing safety and efficacy in human subjects.

Screening: The company uses an in-house search and evaluation team to screen and evaluate drug candidates having a high unmet medical in Japan and other Asia Pacific markets with the potential to secure marketing approval in a shorter clinical development period. A select number of drug candidates will then undergo rigorous review by the company’s Scientific Advisory Board (SAB).

Fabless: The company outsources preclinical/clinical studies and manufacturing to reduce fixed costs.

Niche market: The company targets drugs with the potential to receive orphan drug designation and thus, secure a longer marketing exclusivity period due to high unmet medical needs—including oncology, hematology, and rare diseases—and smaller patient populations. Larger pharmaceutical companies may be reluctant to develop drugs in niche markets due to limited sales potential—SymBio sees an opportunity to avoid intense competition in the marketplace by focusing on the development of orphan or ‘orphan-like’ drugs.

Global expansion: The company identifies and capitalizes on opportunities to grow sales by acquiring the right to develop drug candidates in Japan and other international markets.

The company have in-licensed new drug candidates after rigorously evaluating them.

According to the company, the development of a drug—from preclinical studies to approval—usually takes 10 to 17 years. A newly developed chemical compound has a 1/100,000 chance of securing regulatory approval. By contrast, the company’s first product, Treakisym®, received approval for domestic production only five years after signature of the License Agreement. The company achieved sales of JPY4.2bn in Japan in the third year after launch (FY12/13), equivalent to a market share of over 50%.

An example of the company’s ability to identify and pursue quality in-licensing opportunities with proof-of-concept established is the license agreement signed for the development and commercialization right to rigosertib—currently in joint global phase III clinical trials. In July 2011, once phase II clinical trials in the US established the drug’s proof-of-concept, SymBio secured an exclusive right to all indications for rigosertib in Japan and South Korea from Onconova within seven months from the initial meeting between the two companies. The following year, Baxter International Inc. entered into an agreement with Onconova for the commercialization rights to rigosertib in Europe with a USD50mn upfront payment and USD337.5mn in pre-commercial milestones tied to MDS and pancreatic cancer indications (in addition to an existing equity investment with Onconova of USD55mn), a market that is approximately twice the size of Japan.

Products under development: Treakisym® (FD), Treakisym® (RTD formulation and RI administration), rigosertib (injection and oral), and brincidofovir

Additional indications for Treakisym®

For patients that have developed resistance to other drugs, Treakisym® is safer and more efficacious than existing treatments. As outlined below, the company has gained approval in Japan for the indications of refractory or relapsed low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma, chronic lymphocytic leukemia, and first-line treatment of low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma.

Refractory or relapsed low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma: After designation as an orphan drug (drug for the treatment of rare diseases), Treakisym® won marketing approval for this indication in October 2010.

Chronic lymphocytic leukemia: SymBio received approval for this to be added as indication for Treakisym® in August 2016.

First-line treatment of untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma: The company gained approval for this to be added as indication for Treakisym® in December 2016.

As of February 2021, phase III clinical trials for the fourth indication of relapsed or refractory DLBCL had been completed, with the trial confirming a positive overall response rate (the primary endpoint of the study) exceeding expectations (November 2019). The company filed for manufacture and marketing approval in May 2020 and expects to obtain approval in 1H FY12/21.

Treakisym® (RTD formulation and RI administration)

In September 2017, Eagle Pharmaceuticals and SymBio concluded a license agreement that licenses to SymBio rights to develop, market, and sell Eagle’s bendamustine hydrochloride ready-to-dilute (RTD) formulation and rapid infusion (RI) administration products in Japan. Securing products to replace existing freeze-dried (FD) product (whose exclusive sales rights in Japan expire in 2H 2020) had been a priority for the company. SymBio obtained approval for the RTD formulation in September 2020, and launched the product in January 2021. For the RI administration, the company concluded clinical trials aimed at confirming the drug’s safety and in May 2021, submitted an approval application. 

With this, it aims to promote a switch in clinical settings from the current lyophilized powder formulation to RTD and RI formulations that lighten the workload for medical professionals, at the same time curtailing uptake of Treakisym® generics (filing for approval of generics will be possible from 2H 2020, although Shared Research believes that even if generics launch it will not be until around 2022). Because it has exclusive rights to sell the RTD and RI formulations in Japan, SymBio will be able to extend Treakisym®’s product lifecycle until 2031.

Rigosertib

Rigosertib is a treatment for myelodysplastic syndromes (MDS). According to the company, rigosertib may be used alone or—due to its safety—in combination with other anticancer drugs. The drug is being developed in both intravenous (IV) and oral forms.

In February 2014, Onconova completed phase III clinical trials of rigosertib (injection) in patients with relapsed or refractory MDS in Europe, and its efficacy was proven in subgroup analysis. SymBio also completed patient registration for phase I domestic clinical trials in January 2015. 

In August 2015, Onconova initiated global phase III clinical trials for patients with higher-risk MDS who had failed to respond to the standard therapy with hypomethylating agents (HMAs) or relapsed in more than 20 countries, and announced in August 2020 that they had failed to meet the primary endpoints in comparison with physician’s choice. In Japan, the company conducted joint global phase III clinical trials in cooperation with Onconova. SymBio says it will utilize the knowledge obtained from additional analysis of the global phase III clinical trials in future development of rigosertib.

For the oral form of the drug, Onconova completed phase I/II clinical trials targeting first-line treatment of higher-risk MDS, which suggested efficacy and safety of rigosertib-azacitidine combination therapy. SymBio initiated the phase I clinical trial of rigosertib monotherapy for higher-risk MDS in Japan in June 2017 and completed patient enrollments in June 2019.

Brincidofovir

Brincidofovir is an antiviral drug formed by conjugating a lipid chain (hexadecyloxypropyl, or HDP) of specified length to cidofovir (an antiviral drug already approved and marketed in the EU and the US, but not approved in Japan). It has a novel mechanism of action, which is attributed to its being a lipid conjugate, and can be taken up into cells with enhanced efficiency compared to cidofovir (i.e., brincidofovir has higher cell membrane permeability). Once inside a cell, brincidofovir transforms into a direct-acting agent and inhibits viral replication, demonstrating high antiviral effect. It is also easy to use as it has a low risk of nephrotoxicity, which is a side effect of cidofovir, hence making brincidofovir a novel, highly active anti-multiviral drug. It is expected to become an effective treatment for a wide spectrum of infectious diseases caused by DNA viruses, including cytomegalovirus (CMV) and other herpes viruses, adenoviruses, BK virus, papillomaviruses, and smallpox virus.

In September 2019, SymBio entered an exclusive global license agreement with Chimerix Inc. for brincidofovir. As a result, the company acquired exclusive worldwide rights to develop, market, and manufacture brincidofovir for all indications except smallpox. As of February 2021, the company was preparing for dose determination trials of brincidofovir liquid formulation targeting adenovirus infection in children. 

Revenue source: Treakisym® sales

Revenue mainly comes from product sales of Treakisym®. Operating losses have persisted since the company’s founding with the exception of FY12/08 when the company booked operating profit due to a one-time contract payment from Eisai for an exclusive domestic right to sell Treakisym®.

For FY12/21, the company expects JPY1.4bn operating profit (versus a JPY4.5bn operating loss in FY12/20) and JPY1.1bn net income (net loss of JPY4.1bn in FY12/20). The company began in-house sales of Treakisym® in December 2020 and sales of the RTD formulation in January 2021. It also expects to obtain approval for the additional indication of relapsed or refractory DLBCL in FY12/21, which are all factors expected to contribute toward sales growth and GPM improvement. The company therefore forecasts a turn to profitability at operating profit level in FY12/21.

Over the course of the medium-term plan (FY12/21–FY12/23), the company targets operating profit of JPY2.1bn in FY12/23 and expects to continue posting operating profit over the medium term thereafter.

Business strategy

Unlike conventional pharmaceutical companies, SymBio does not conduct basic research or develop its own drug candidates in labs or clinics. Rather, it in-licenses drug candidates from pharmaceutical and biotech companies based in the US or EU.

The company focuses on developing drugs that have strong safety and efficacy data in clinical trials, providing an opportunity to develop new drugs more likely to succeed and secure regulatory approval with the use of bridging data whenever possible to shorten development timelines. Because the company does not conduct basic research, the company can obtain approval and start selling a drug within five to six years of securing the development and commercialization right. The company increases the chance that drug candidates it in-licenses will be approved in the future through an effective in-house screening process and rigorous evaluation by the company’s Scientific Advisory Board.

The overall aim is to reduce development risk, streamline expenses, and expand revenue opportunities. This hinges on the following five strategies, namely post proof-of-concept, screening, fabless, niche market, and global expansion.

Post-POC strategy: SymBio targets compounds with an established proof-of-concept

The pharmaceutical business requires substantial financial commitment in terms of upfront investment, not to mention the number of years of development required in order to realize a return on the investment and the high risk of failure in clinical studies from phase I through III. According to the company, the probability of a chemical compound having a signal with pharmacological activity in a particular disease being approved as a drug is 1/20,000 to 1/25,000, and only 15–20% of drugs that manage to enter the marketplace achieve profitability for the sponsor.

Given the high rate of attrition of drug candidates in clinical development, SymBio reduces development risk by only targeting quality drug candidates undergoing clinical development with proof-of-concept (confirming efficacy and safety of a new drug candidate through administration to animals or humans) established in human subjects and/or market sales. NDA filings that use clinical data generated overseas can expedite product development in Japan and other parts of Asia, slashing development costs and improving the overall success rate.

Screening strategy: independent search network plus evaluation experience

Identify candidate drugs by utilizing independent search network and evaluation experience

The company identifies quality chemical compounds owned by pharmaceutical and biotech companies in the US or EU using a proprietary “search engine” and rigorous evaluation process. These candidates are first screened in-house by the search and evaluation team, whose members have extensive product development experience working at various pharmaceutical and biotech companies.

Onsite due diligence

After a select team visits the potential licensor to conduct due diligence, a decision is made regarding whether to pursue the in-licensing opportunity based on the results of onsite due diligence and input from the company’s SAB members.

Evaluation by a panel of pharmaceutical experts

The final in-licensing candidate will be determined by the Scientific Advisory Board after rigorous evaluation by external experts involved in therapeutic research in related fields.

Only a few new drug candidates have met the company’s stringent criteria since its foundation

The company has in-licensed only a few new drug candidates that have met its stringent criteria. The first was Treakisym®, which the company currently sells in Japan (as of February 2021). Clinical trials for additional Treakisym® indications are underway, as are preparations to file for approval of the RI formulation of the drug. The company is also developing intravenous and oral formulations of rigosertib and antiviral drug brincidofovir.

Scientific Advisory Board

The Scientific Advisory Board is comprised of former directors of pharmaceutical companies, researchers, and doctors, and meets three times a year. Typically, the SAB panel evaluates two to three drug candidates that have been selected via the company’s in-house screening process. This in-house screening of only those drug candidates having proof-of-concept established in human subjects with supportive efficacy and safety data followed by SAB assessment enables the company to reduce development risk and to pursue only those opportunities having the best chance of reaching the marketplace.

Fabless strategy with a lean management team

SymBio seeks to reduce costs and raise profits by finding the right partner(s) to develop and commercialize drugs nimbly and efficiently through flawless execution.  Specifically, the company designs clinical trial protocols and whenever possible, will participate in global phase III studies being conducted by its partner(s) overseas with the aim of shortening development timelines in Japan.

It may be possible to file NDAs in Japan using foreign data to support or “bridge” data generated in Japanese clinical trials, thereby avoiding the need to complete domestic phase II and/or phase III studies for marketing approval.The company uses its well-established network for bendamustine to coordinate with medical professionals, outsourcing routine development duties. Production is also outsourced either to the company that originally granted the product license, or to other domestic or foreign manufacturer(s). The company began in-house sales in Japan of Treakisym® on December 10, 2020, taking over from Eisai, which marketed the product until December 9, 2020.

Niche markets: oncology, hematology, and rare diseases

SymBio focuses on drugs for underserved medical needs—even when the market may be as small as JPY10bn—rather than focusing on blockbuster drugs with sales in the hundreds of billions of yen. It aims to take advantage of therapeutic areas that tend to be overlooked in the pharmaceutical industry and thus, lack effective drugs. Specifically, the company specializes in therapeutic areas with high barriers to entry, such as oncology, hematology, and rare diseases.

According to the company, globally Japan has the third largest oncology market after the US and EU, and the market is expected to continue to expand due to Japan’s aging population. However, regarding the type of tumors that anticancer drugs can effectively treat, there is a considerable range of indications with a limited number of patients who will benefit from approved cancer treatments, particularly in the elderly population where the occurrence of serious adverse events can be prohibitive. As a result, barriers to entry are high—developing cancer drugs for niche markets is especially difficult and requires a high level of expertise. 

Concerns about having sufficient profit margins from marketed drugs to fund large operations means that major pharmaceutical companies may be reluctant to target indications with limited patient numbers for development, presenting an opportunity with fewer competitors in the marketplace for smaller and more specialized pharmaceutical companies such as SymBio. The company can also increase value added of niche disease areas by additional indications and putting new products on the market. For example, its first in-house proprietary drug Treakisym® has gained over 50% market share three years after going on sale. In July 2018, Treakisym® was newly included as a standard option for first-line treatment of low-grade NHL and mantle cell lymphoma in the Guidelines for Hematological Malignancies 2018 issued by the Japan Society of Hematology in July 2018.

Strategy for global expansion

The company is seeking to develop new drugs that are complementary to Treakisym® and rigosertib to sell in China/Hong Kong, Taiwan, South Korea, and Singapore, as well as in Japan. Also, it acquired exclusive worldwide rights to develop, manufacture, and market brincidofovir.

Pipeline

As of February 2021, the main drugs for which SymBio was preparing to file for approval or in the development pipeline were as follows:

Treakisym®, for the indication of relapsed or refractory DLBCL (aggressive NHL): Completed enrollment of patients for the phase III clinical trial (April 2019). Filed for approval in May2020. Expects to obtain approval and begin sales in FY12/21.

Treakisym®, clinical trials of the RI formulation: Initiated clinical trials in November 2018. Plans to file for approval in FY12/21 and begin sales in FY12/22 

Rigosertib (intravenous formulation), for the indication of relapsed or refractory higher-risk MDS: Conducting additional analysis of global phase III clinical trial results 

Rigosertib (oral formulation), for the indication of higher-risk MDS: Completed patient enrollment for the phase I clinical trial in June 2019, and completed global phase I/II clinical trials of the combination therapy with azacitidine. Preparing for phase I clinical trial of the combination therapy with azacytidine. 

Antiviral drug brincidofovir: Preparing to begin phase II clinical trials of brincidofovir (liquid formulation) targeting adenovirus infection in children

SyB L-0501 (generic name: bendamustine HCI, product name: Treakisym®)

SyB L-0501 (Treakisym®) or bendamustine hydrochloride is an anticancer agent. It is used as a treatment for low-grade NHL, MCL, MM and CLL.

According to the company, no cross-resistance (resistance to drugs with a similar structure or action as the study drug) has been shown for this drug, which means it is safer and more efficacious than existing treatments for target indications. In October 2010, SymBio received regulatory approval in Japan to market the drug for relapsed or refractory low-grade NHL and MCL. Eisai has been selling the drug since its launch in December 2010. The company received permission to add CLL as an indication for Treakisym® in August 2016, and first-line treatment of low-grade NHL and MCL in December 2016. As of February 2021, the company had filed for approval of Treakisym® for the additional indication of relapsed or refractory DLBCL (aggressive NHL; May 2020).

Lymphatic cancer

Lymphatic cancer, a malignant growth of lymphocytes in white blood cells

Lymphatic cancer is a malignant growth of lymphocytes in white blood cells. It causes inflammation of the lymphatic nodes. The most common symptom is a painless lump or swelling in one or more lymph nodes, usually in the neck, armpit or groin. In lymphatic cancer, the lump or swelling grows persistently without decreasing in size, also spreading to other parts of the body and eventually presenting as generalized symptoms, including fever, weight loss, and night sweats. Other symptoms can include widespread itching and skin rash, as well as airway obstruction, interrupted blood flow, and numbness arising from pressure of swollen lymph nodes on the respiratory tract, blood vessels, and spinal cord.

Lymphatic cancer is divided into Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Among the Japanese population, only 4% of lymphatic malignancies are HL. About 70–80% of NHL cases affect B-cells; the remaining 20–30% affect T/NK cells. According to the Japanese Association of Clinical Cancer Centers (JACCC), the five-year relative survival rates for lymphatic malignancies (among patients diagnosed between 2001 and 2005) are as outlined in the table below. In Hodgkin’s lymphoma (all cases) the five-year relative survival rate was 76.0%, as compared with 68.3% for non-Hodgkin’s lymphoma (all cases).

Method of treatment determined by grade; separate clinical trials required for each disease subtype

Physicians examine tissue and determine the method of treatment depending on the type of cancerous cells observed: they look at the grade (high, intermediate, or low, depending on the aggressiveness of the disease) and clinical staging, which shows to what extent the cancer has spread. To gain approval to manufacture and sell pharmaceuticals, companies must conduct separate clinical trials for each disease subtype. Clinical trial subjects are categorized as either treatment-naïve, or relapsed/refractory (patients who have received treatment in the past, which has proven ineffective).

Treakisym® in-licensed from Astellas; developed jointly with Eisai in Japan; sold in-house from December 2020

In December 2005, SymBio signed a license agreement for the exclusive right to bendamustine in Japan with Astellas Deutschland GmbH (“Astellas”), a subsidiary of Astellas Pharma Inc. The company entered into a second license agreement with Astellas in March 2007 to extend its exclusive development and commercialization right for bendamustine to China/Hong Kong, Taiwan, South Korea, and Singapore.

In August 2008, SymBio granted Eisai Co., Ltd. the co-development and exclusive marketing right for Treakisym® in Japan. Under the agreement, SymBio receives one-time payments from Eisai as well as milestone payments based on the clinical trial stage for a particular indication, plus revenues after supplying Treakisym® to Eisai. Eisai shoulders half of the development costs for Treakisym®, including labor costs for researchers and outsourcing costs for clinical trials (see the Earnings structure section). The marketing agreement with Eisai expired in December 2020, after which SymBio began to independently market Treakisym® in Japan.

SymBio has granted exclusive marketing rights for Treakisym® to InnoPharmax, Inc. in Taiwan, Cephalon, Inc. in China, and Eisai in South Korea and Singapore. In return, SymBio receives one-time milestone payments, and books revenue from the sale of the drug to these companies.

Approved for relapsed or refractory low-grade NHL, MCL in October 2010

In October 2010, five years after acquiring the right to Treakisym®, SymBio received marketing approval in Japan for relapsed or refractory low-grade NHL and MCL. In FY12/16—six years after the domestic launch of the drug in December 2010—Treakisym® sales reached JPY4.7bn on an NHI drug price basis.

According to the company, Japan has about 4,700 patients who suffer from relapsed or refractory NHL and MCL. SymBio thinks annual Treakisym® sales could reach JPY4.5–5.0bn.

Treakisym®: additional indications, RTD, RI, and oral formulations

Approval as the first-line treatment for untreated low-grade NHL, MCL in December 2016, and for additional indication of CLL in August 2016

In December 2016, Treakisym® was approved in Japan as the first-line treatment for low-grade NHL/MCL. It was approved for CLL in August 2016. 

The company filed for the approval of Treakisym® for the additional indication of relapsed or refractory DLBCL (aggressive NHL) in May 2020.

Treakisym® indicated for untreated low-grade NHL and MCL

According to the company, R-CHOP therapy—a combination of rituximab with CHOP chemotherapy drugs (cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (oncovin), and prednisolone)—was standard first-line treatment for low-grade NHL and MCL in Japan prior to December 2016. In December 2016, Treakisym® won approval for the additional indication of first-line treatment of low-grade NHL and MCL, and subsequently in July 2018, Treakisym® was newly included as a standard option for first-line treatment of low-grade NHL and MCL in the Guidelines for Tumors of Hematopoietic and Lymphoid Tissues 2018 issued by the Japan Society of Hematology.

In Phase III clinical trials conducted overseas, rituximab in combination with Treakisym® (bendamustine hydrochloride; BR therapy) demonstrated safety and efficacy superior to those of the standard R-CHOP therapy for previously untreated low-grade B-cell NHL. These findings were presented at the American Society of Hematology Annual Meeting in December 2012. Based on these results, the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend the use of BR therapy as first-line therapy for patients with untreated low-grade NHL.

These comparative studies were conducted at 81 facilities in Germany, in patients who were newly diagnosed between September 2003 and August 2008 with stage III or IV low-grade NHL or MCL. The studies compared R-CHOP therapy with the combination therapy of bendamustine-rituximab (BR) (bendamustine is marketed as Levact®, Ribomustin®, or Ribovact® in Europe). A total of 275 patients underwent R-CHOP therapy, while 274 underwent the BR therapy. The median observation period was 45 months. Clinical results showed that the median progression-free survival was 69.5 months for the BR group and 31.2 months (p<0.0001) for the R-CHOP group, demonstrating greater statistical significance for the BR therapy. Comparison of overall survival and safety between the two groups also showed superior results for the BR group.

Treakisym® approved in December 2016 for untreated low-grade NHL and MCL

In December 2016, SymBio received marketing approval of Treakisym® in Japan, for untreated low-grade NHL and MCL. Shared Research believes this shift will gain support from the aforementioned data demonstrating that BR therapy is more efficacious than R-CHOP therapy, and inclusion of BR therapy as a standard treatment option in the Guidelines for Tumors of Hematopoietic and Lymphoid Tissues 2018.

Untreated low-grade NHL and MCL: patient population and estimated sales

SymBio estimates that there are 6,967 first-line low-grade NHL and MCL patients in Japan. Although fewer than the number of patients with relapsed or refractory low-grade NHL and MCL, the company expects higher market penetration amid the trend of switching from R-CHOP to BR therapy. Treakisym® sales could reach JPY5.0–7.0bn as the Japanese population continues to age.

Treakisym® indicated for chronic lymphocytic leukemia (CLL)

Additional indication of CLL approved in August 2016

In Japan, SymBio obtained approval for the additional indication of CLL for Treakisym® in August 2016.

Potential patient population, estimated sales

SymBio estimates that there are about 656 CLL patients in Japan. Shared Research estimates that sales could reach JPY300mn–JPY350mn. This estimate is based on Treakisym® sales per patient with relapsed or refractory low-grade NHL or MCL.

Treakisym® indicated for relapsed or refractory DLBCL (aggressive NHL)

Diffuse large B-cell lymphoma (DLBCL), or aggressive NHL, progresses rapidly but recovery may be expected in patients for whom anticancer drugs are effective. R-CHOP is the standard therapy for relapsed or refractory DLBCL, the most common type of NHL.

But according to the company, 40% of untreated patients treated with R-CHOP relapse or become refractory, and only patients who are 65 or younger can undergo chemotherapy at higher doses together with autologous stem cell transplants. Because the majority of relapsed or refractory DLBCL patients are elderly, physicians must consider potential side effects when selecting a suitable treatment. Weaker patients—due to age or other illnesses—have limited choices for treatment, and there is a need for a safer, more efficacious method of treatment such as Treakisym®.

R&D status: approval application of Treakisym® for the indication of relapsed or refractory DLBCL

Results of phase III clinical trials in patients with relapsed or refractory DLBCL

Following consultations with the Pharmaceuticals and Medical Devices Agency (PMDA), the company commenced phase III clinical trials of Treakisym® in combination with rituximab (BR therapy) for relapsed or refractory DLBCL. The objective of the study was to examine the efficacy and safety of BR therapy, with the overall response rate (ORR; antitumor effect) as the primary endpoint. Enrollment of 60 patients was completed in April 2019. The following results of the clinical trial (main efficacy evaluation results in 38 cases) were presented at the Japanese Society of Medical Oncology Annual Meeting 2021 held in February 2021.

• Response rate (CR+PR): 76.3%
• Complete response (CR): 47.4%
• Median overall survival: 29.2 months 
  

* CR (complete response) = disappearance of all signs of cancer in response to treatment. Also known as complete remission.
* PR (partial response) = the cancer partly responded to treatment, but has not disappeared. Also known as partial remission. 

Based on these results the company filed for approval of Treakisym® to make BR therapy possible for the treatment of relapsed or refractory DLBCL. The company expects to obtain approval for this indication and begin sales in FY12/21. 

Potential use of Treakisym® as pretreatment agent for CAR-T therapy

In April 2018, Novartis Pharma K.K. applied in Japan for approval of the chimeric antigen receptor T-cell (CAR-T) therapy CTL019 (US product name: Kymriah®), for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in patients aged 25 years or younger and relapsed or refractory DLBCL. In May 2018, Novartis obtained approval in the US for use of CTL019 to treat adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy. Since the use of CTL019 is limited to adult patients for whom two or more lines of therapy have proved ineffective, Shared Research understands that CTL019 is different from Treakisym® and that the two companies do not compete in this area. In September 2018, the company applied for a partial change to the approved matters of Treakisym® to enable its use as a pretreatment agent for CTL019 targeting relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adults.

Patient population, estimated sales

According to SymBio, the number of relapsed or refractory diffuse large B-cell lymphoma (DLBCL; aggressive NHL) patients in Japan is approximately 18,672. We estimate annual peak sales for the indication (NHI drug reimbursement price basis) at JPY8.0–10.0bn.

Concluded license agreement for RTD and RI formulations of bendamustine hydrochloride (marketed as Treakisym® in Japan) in September 2017

In September 2017, Eagle Pharmaceuticals and SymBio concluded a license agreement that licenses to SymBio rights to develop, market, and sell Eagle Pharmaceuticals’ bendamustine hydrochloride ready-to-dilute (RTD) and rapid infusion (RI) products (marketed in the US by Teva Pharmaceutical Industries as BENDEKA®) in Japan. Under the terms of this agreement, SymBio will pay Eagle Pharmaceuticals a USD12.5mn upfront payment and a milestone payment upon approval. The company will also pay additional milestone payments on the achievement of cumulative sales thresholds and royalties on future sales of licensed bendamustine products.

RTD and RI products do not require reconstitution; RI product can be administered in one sixth of the time as FD product

The FD powder injection product currently available must be reconstituted manually before administration by intravenous infusion. Since RTD and RI products are already liquidized, they do not require the time-consuming process of reconstitution and substantially reduce the workload of healthcare professionals. RI products also do not require reconstitution and can be administered by intravenous infusion in 10 minutes instead of 60 minutes for FD powder injection and RTD products, which reduces stress on patients.

Life cycle of Treakisym® can be extended until 2031

The re-examination term for the FD formulation of Treakisym® ends in 2020, after which generics can be manufactured and sold. SymBio believes that by selling the RTD and RI formulations of the product that offer the advantages of reducing healthcare professionals’ workload and stress on patients after 2020, it can extend the exclusive sales period until 2031. This increases the possibility of prolonging the life cycle of Treakisym® and limiting the spread of generics.

Bendamustine hydrochloride RTD and RI injection products are marketed in the US by Teva Pharmaceutical Industries as BENDEKA®, which has 97% share of the US bendamustine market within two years after its sales.

R&D status: obtained approval in September 2020 for RTD formulation and preparing for approval application of RI formulation

The company obtained approval for the bendamustine hydrochloride RTD formulation in September 2020. As of February 2021, it was preparing to file for approval of the RI formulation.

Clinical trials are required for the RI formulation because the administration time is different from the FD formulation. In November 2018, the company began a clinical trial of Treakisym® RI formulation in 36 patients. It plans to launch the RI formulation in 1H FY12/22.

Treakisym® as a pretreatment agent for a regenerative medicine product (CAR-T cell therapy)

In September 2018, the company applied for a partial change to the approved matters of anticancer drug Treakisym® to enable its use as a pretreatment agent for regenerative medical products.

In April 2018, Novartis Pharma K.K. filed for manufacture and marketing approval for the first chimeric antigen receptor T-cell (CAR-T) therapy (CTL019) in Japan for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in patients aged 25 years or younger and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adult patients. If the therapy is approved, Treakisym® can be used as a pretreatment agent for CAR-T therapy for the treatment of ALL and DLBCL. Further, the approval would mark the addition of regenerative medicine as a new area of indication for Treakisym®. 

SyB L-1101 (injection)/ SyB C-1101 (oral) (generic name: rigosertib)

Rigosertib is an anti-cancer agent under development by Onconova Therapeutics, Inc. in the US and EU for the treatment of myelodysplastic syndromes (MDS) and solid tumors. According to SymBio, rigosertib has high safety profile and can be used in combination with other anticancer drugs. It is provided in injection and oral formulations.

Myelodysplastic Syndromes (MDS)

MDS is a refractory disease with a poor prognosis and progression to acute myeloid leukemia (AML) in approximately 30% of cases. It leads to abnormalities in hematopoietic stem cells that produce blood cells, resulting in a lack of blood. Blood cells produced this way are abnormally shaped. This change in the cells is called dysplasia. 

The disease typically leads to frequent anemia with some patients dying from infection or bleeding due to the reduction in blood cells. The average survival period is about three to five years, with some patients surviving 10 years or longer. It is still not clear what environmental or genetic factors are responsible for the occurrence of MDS, although those who have received radiation treatment or taken anticancer drugs may have a higher risk of developing the disease (source: Japan Adult Leukemia Study Group: JALSG).

The seriousness of MDS is determined with the use of the International Prognostic Scoring System (IPSS). The IPSS score is calculated based on the ratio of myeloblasts (immature blood cells) in the bone marrow, chromosome analysis, and the results of a general laboratory blood test. The risk level is assessed based on the number of years that the patient is expected to live, disease progression, and the probability that the disease may lead to acute myeloid leukemia. Risk categories: low, intermediate-1, intermediate-2, and high. Lower-risk MDS refers to low and intermediate-1 patients, while higher-risk MDS refers to intermediate-1 and high in the IPSS risk categories.

Acquired rights from Onconova to develop and market rigosertib in Japan, South Korea

In July 2011 SymBio bought exclusive rights to develop and sell the intravenous (IV) and oral forms of rigosertib in Japan and Korea following completion of Onconova’s phase II US clinical trial for the IV form (upfront payment of JPY800mn, Shared Research estimate).

 In September 2012, Baxter International Inc. acquired exclusive rights to develop and sell rigosertib in Europe. It paid an upfront payment of USD50mn, for a total licensing fee including milestone payments of USD565mn.

Development status of rigosertib

As of February 2021, SymBio was developing the IV form of rigosertib for the indication of relapsed or refractory higher-risk MDS, and the oral form for higher-risk MDS.

Onconova has been conducting joint global phase III clinical trials in over 20 countries since August 2015 for the intravenous form of rigosertib in higher-risk MDS patients who had failed to respond to or relapsed after prior therapy with hypomethylating agents (HMAs). In the Japanese market, the company has been conducting the joint global phase III clinical trials in cooperation with Onconova since December 2015. In August 2020, Onconova announced that the global phase III trial of rigosertib (IV) failed to meet its primary endpoints. Onconova is performing additional analysis of the results. The company commented that it is looking to apply the knowledge gleaned from additional analysis of the study to rigosertib development going forward.

Onconova completed phase I/II clinical trials in the US for the oral form of rigosertib as first-line treatment for higher-risk MDS (in combination with azacitidine), which demonstrated safety and efficacy of the combination therapy. SymBio restarted phase I clinical trials of the oral formulation of rigosertib monotherapy in Japan in June 2017 and completed patient enrollment in June 2019, to verify the tolerability and safety of the study drug in Japanese patients. After establishing safety in phase I clinical trials, the company plans to resume the trial of rigosertib in combination with azacitidine and participate in global clinical trials of the combination therapy planned by Onconova in higher-risk MDS patients.

Rigosertib injection in patients with higher-risk refractory or relapsed MDS 

Higher-risk MDS (patients in the Intermediate-2 risk and High-risk groups based on International Prognostic Scoring System) is likely to cause a decline in blood cells or lead to leukemia. Treatment may involve stem cell transplants, depending on the patient’s age, condition, and the compatibility of the donor. In the US and Europe, Vidaza (azacitidine) and Dacogen (decitabine) are standard drug therapies for this treatment. In Japan, Vidaza (being marketed by Nippon Shinyaku) is also administered in cases where stem cell transplants are not used. (for Vidaza, see Market and value chain)

However, some cases of higher-risk MDS show resistance to standard treatment with hypomethylating agents (HMAs) such as Vidaza and Dacogen, including relapse following treatment. The most advanced research being conducted for rigosertib was for the treatment of patients with higher-risk MDS who had progressed on, failed or relapsed after prior therapy with HMAs. According to the company, no drugs had been approved for the treatment of post-HMA higher-risk MDS patients as of February 2021.

R&D status: global phase III studies underway in patients with relapsed higher-risk MDS following HMA therapy 

Phase III clinical trials in patients with relapsed or refractory higher-risk MDS 

In February 2014, Onconova completed its phase III ONTIME clinical trial for the intravenous form of the drug in MDS patients in the US who showed resistance to standard treatment with HMAs, or who experienced recurrence of the disease after treatment with HMAs.

Of the 299 patients enrolled in the phase III clinical trial, 199 were administered rigosertib and 100 were placed in the control group. The overall survival (OS) period for those who received rigosertib was 8.2 months, while OS for the control group (BSC) was 5.8 months. However, with a p-value of 0.27, there was no statistically significant difference between the two groups.

Among patients whose condition had deteriorated or not responded to previous treatment using hypomethylating agents (184 of 299 people, or 62%), the overall survival period for higher-risk MDS patients who received rigosertib was 8.5 months, while for those in the control group (BSC) it was 4.7 months. The p-value was 0.022, showing a statistically significant difference. The hematological toxicity of the conventional anticancer agent was approximately 60%. With rigosertib, toxicity of Grade 3 or above did not exceed 7%, and non-hematological toxicity did not exceed 3%, confirming safety of the drug.

Phase III clinical trials in patients with higher-risk MDS for whom HMA therapy was ineffective or who relapsed after treatment 

In August 2015, Onconova submitted plans to US Food and Drug Administration (FDA) and regulatory agencies in England, Germany, and Australia for global phase III comparative trials of rigosertib for patients who did not see results from low methylation, or experienced higher-risk refractory or relapsed MDS following HMA treatment. These global trials are currently ongoing.

In August 2020, Onconova announced that the primary endpoint (overall survival compared with physician’s choice [PC] treatment) was not met in the phase III clinical trial. More specifically, the primary endpoint of the trial was overall survival, comparing IV rigosertib plus best supportive care to PC plus best supportive care. Onconova also analyzed a pre-specified subgroup of very high risk (VHR-MDS) patients. Results of the trial demonstrated that in the intent-to-treat analysis patients given IV rigosertib achieved overall survival of 6.4 months, versus 6.3 months for PC (p=0.33) in the overall HR-MDS population. There was also no significant difference in overall survival between the two study arms in the VHR-MDS subgroup. Onconova is conducting further analysis.

SymBio responsible for operation of global phase III clinical trials in Japan

The company has been conducting the global phase III clinical trials in Japan since December 2015. The first patient was registered in July 2016 and 48 patients had been registered as of end December 2019 versus the target of 50. Regarding Onconova’s August 2020 announcement regarding not meeting primary endpoints of its phase III clinical trial, SymBio commented that it is looking to apply the knowledge gleaned from additional analysis of the study to rigosertib development going forward. 

Oral rigosertib in patients with higher-risk MDS

R&D status: phase I/II clinical trials underway

Onconova, the anticancer drug rigosertib’s licensor, presented phase II clinical trial data on oral rigosertib for patients with higher-risk myelodysplastic syndromes (MDS) at the 58th American Society of Hematology (ASH) Annual Meeting held in December 2016.

The data on the efficacy and safety of oral rigosertib and azacitidine combination for 33 MDS patients (20 HMA naïve; 13 HMA resistant) was presented at the poster presentation, “Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study.” The complete remission (CR) rate among HMA-naïve patients was higher (35%) and responses occurred more rapidly and durably with the oral rigosertib combination compared to the single-agent azacitidine. The median duration of CR was eight months, comparing very favorably to the historic duration of CR of 3.2 months with single-agent azacitidine.

As of February 2021, Onconova was making efforts toward finalizing the design for a pivotal phase III oral rigosertib/azacitidine combination trial for the first-line treatment of higher-risk MDS.

Phase I clinical trials in Japan

The company began the domestic phase I clinical trial of oral rigosertib to confirm the safety of the drug at high doses (a requirement for phase II clinical trials conducted by Onconova in the US for the indication of first-line treatment for relapsed or refractory higher-risk MDS). The patient enrollment for the study was completed in June 2019. After establishing safety in the phase I clinical trial, the company plans to resume the trial of the drug in combination with azacitidine and participate in global clinical trials conducted by Onconova. In December 2019, Onconova issued a press release announcing it was considering a phase II/III adaptive trial for untreated high-risk MDS patients based on data presented at the 61st American Society of Hematology Annual Meeting and Exposition held in December 2019.

Exploring new indications

In January 2021, the company entered into a joint research agreement with the Institute of Medical Science, the University of Tokyo (IMSUT) to explore potential new indications for bendamustine and rigosertib. 

Under this agreement, SymBio will undertake joint research with Professor Toshio Kitamura, from the Division of Cellular Therapy within IMSUT’s Advanced Clinical Research Center, using bendamustine and rigosertib in combination or with other approved drugs to explore efficacy and new indications. The joint research will analyze the epigenetic control of various tumor cells to explore as-yet-unknown pharmacological effects of bendamustine and rigosertib, analyzing their effects when used in combination and with other approved drugs.

Professor Kitamura is an accomplished researcher and has a large network of researchers and physicians in the areas of hematopoietic stem cell differentiation and hematopoietic tumors such as leukemia. 

He is also studying molecular mechanisms in the development of hematopoietic tumors caused by epigenetic abnormalities, looking to develop novel therapies using hematopoietic tumor models. SymBio will leverage its experience in winning early approval for proprietary anticancer drugs in collaborating with IMSUT to search for new indications for bendamustine and rigosertib.

Patient population, estimated sales

According to SymBio estimates, patients with lower-risk MDS in Japan number about 7,800, with 3,200 MDS patients classified as higher-risk.

Nippon Shinyaku Co., Ltd. (TSE1: 4516) has been selling azacitidine in Japan as first-line therapy for MDS under the product name Vidaza since March 2011. According to Nippon Shinyaku, sales of Vidaza were JPY15.7bn in FY03/20 (+8.3% YoY) and forecast to reach JPY16.0bn in FY03/21. Shared Research thinks that sales of the intravenous and oral forms of rigosertib could match or exceed sales of Vidaza, used for patients who have not received treatment with Vidaza or in combination therapy with Vidaza.

SyB V-1901 (antiviral drug, brincidofovir)

In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. for the antiviral drug brincidofovir (SyB V-1901). The company acquired exclusive global rights to develop, manufacture, and market brincidofovir for all diseases except smallpox. Under the terms of the agreement, the company will pay Chimerix an upfront payment of USD5mn, milestone payments on future developments of USD180mn, and royalties on the product sales. Brincidofovir differs from other candidates in SymBio’s pipeline in that it targets the global market and that the company had acquired not only development and marketing rights but also manufacturing rights to the drug.

According to the company, Chimerix had been developing oral formulation of brincidofovir, but suspended development due to the failure of the phase III clinical trial. SymBio determined that the failure of the oral formulation was due to its low intestinal absorption rate and side effects arising from toxicity, and thought that it could circumvent such problems if it worked on developing brincidofovir as an intravenous formulation. The company commented that one of the reasons it entered the license agreement with Chimerix was the latter’s policy of focusing on cancer.

Mechanism of action and target indications of brincidofovir

Brincidofovir is an antiviral drug formed by conjugating a lipid chain (hexadecyloxypropyl, or HDP) of specified length to cidofovir (antiviral drug already approved and marketed in the EU and the US, but not approved in Japan). As a lipid conjugate, it has a novel mechanism of action and can be taken up by cells at enhanced efficiency compared to cidofovir (i.e., brincidofovir has higher cell membrane permeability). Once inside a cell, brincidofovir transforms into a direct-acting agent and inhibits viral replication, demonstrating high antiviral efficacy. It is also easy to use as it has a low risk of nephrotoxicity, which is a side effect of cidofovir, hence making it a novel, highly active anti-multiviral drug. It is expected to become an effective treatment against a wide array of infectious diseases caused by DNA viruses, including cytomegalovirus (CMV) and other herpes viruses, adenoviruses, BK virus, papillomaviruses, and smallpox virus.

Development status: preparing to begin phase II clinical trials in the US and Europe

The US-based phase I clinical trial of intravenous formulation of brincidofovir was completed. No serious side effects were observed in the study.

After a review at the global advisory board held in February 2020, the company concluded that it would prioritize global development of brincidofovir (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. Based on safety and efficacy data acquired from its study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow the market for and maximize the business value of brincidofovir. As of February 2021, the company was in preparation to initiate a dose-finding study of the liquid formulation of brincidofovir in pediatric patients. 

Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of the oral formulation of brincidofovir, raising expectations for the potential of the liquid formulation as a safe and effective therapy to prevent and treat a range of viral infections in patients receiving hematopoietic stem cell transplantation. 

Hematopoietic stem cell transplantation is one of the therapies aimed at completely curing diseases such as blood cancer and immunodeficiency disorders that are difficult to treat with conventional chemotherapy. In Japan, there are about 4,000 patients who have undergone allogeneic hematopoietic stem cell transplantation, and about 60% of them have contacted viral hemorrhagic cystitis (vHC) or HHV-6 encephalitis. For vHC, cidofovir is used as first-line treatment in the EU and US. For encephalitis, foscavir and denocin are designated as the first-line drugs, and cidofovir as the second-line drug.

Earnings structure

Sales

The company’s sales are made up of product sales and royalty revenue. Per the above table, most of the sales through FY12/19 have originated from Eisai. The company began own sales of Treakisym® from December 10, 2020 and recorded sales to non-Eisai partners of JPY441mn in FY12/20.

Product sales

Product sales are revenue from selling Treakisym®. The company began booking product sales in FY12/10, when it obtained approval for Treakisym® and started selling the anticancer agent in December 2010. ThroughFY12/16, the company booked sales of Treakisym® indicated for relapsed or refractory low-grade NHL and MCL.

In FY12/17, the company booked sales of additional indications of untreated low-grade NHL and MCL, resulting in a strong sales YoY.

FY12/19 product sales declined YoY. A lyophilized injection formulation of Treakisym® imported from Astellas Deutschland GmbH, a consolidated subsidiary of Astellas Pharma, was found to contain impurities and appearance defects, and as a result, shipments of Treakisym® 100mg to Japan distributor Eisai were postponed. Consequently, booking of some product sales was delayed until the following fiscal year, resulting in a YoY decline in sales.

Royalty revenue

Royalty revenue includes one-time contract payments and milestone payments.

CoGS

old refers to procurement costs for drugs. SymBio purchases lyophilized Treakisym® from Astellas Deutschland GmbH. Before December 2019, Astellas supplied Treakisym® to the company for about 70% of SymBio’s wholesale price to Eisai. As noted above, the company began own sales of Treakisym® on December 10, 2020. This allows the company to receive not only the gross profit it received previously, but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source the product). Shared Research understands that this is a factor that contributes to higher GPM.

SymBio sources the RTD formulation of Treakisym® from US company Eagle Pharmaceuticals. According to the company, its GPM on the RTD formulation is higher than for lyophilized Treakisym®.

SG&A expenses

Personnel and R&D are the main SG&A expenses.

Personnel expenses

Personnel expenses consist of directors’ remuneration as well as expenses for personnel involved in such tasks as marketing, searching for in-licensing candidates and general administration. Personnel expenses have been trending upward in line with additions to the pipeline and business expansion.

R&D expenses

R&D expenses include personnel expenses for R&D staff as well as clinical trial outsourcing expenses and upfront payments accompanying product in-licensing. R&D expenses fluctuate depending on the progress of clinical trials and new license agreements from in-licensing activities. According to the company, in-licensing expenses are between JPY500mn and JPY1bn per drug, and domestic clinical trials cost between JPY1bn and JPY2bn.

Eisai paid half of the development costs for the Treakisym® freeze-dried (FD) formulation in Japan.

Strengths and weaknesses

Strengths

Unique candidate selection process: SymBio makes decisions on in-licensing new drug candidates based on an initial assessment and screening process by its in-house search and evaluation team. The final decision is made by the company after evaluation by a team of medical experts—the Scientific Advisory Board (SAB). President Yoshida’s extensive range of contacts in the pharmaceutical industry built during his tenure at Amgen Japan and Amgen Inc. is a significant hurdle for competitors attempting to emulate the quality of the company’s search and evaluation team, SAB panel and selection process.

Strong product development: Treakisym® (bendamustine hydrochloride)—the first drug the company developed—received marketing approval in Japan just five years after the license agreement was signed with Astellas. Treakisym®, launched by the company in December 2010, is being used by a number of Japanese physicians and is considered to be an essential drug for the treatment of relapsed or refractory low-grade NHL and MCL. The company’s success with Treakisym® demonstrates its strong product development capabilities and nimbleness.

Strong share in niche markets: SymBio focuses on niche markets for rare oncologic and hematologic diseases and rare diseases. The company takes advantage of a less competitive environment by developing drugs for indications that serve a limited number of patients and require a high degree of in-house expertise. Thus, the company has succeeded in securing more than 50% of the target market for Treakisym® in relapsed or refractory low-grade NHL and MCL in the third year after launch.

Weaknesses

Dependence on a single individual: Founding President and CEO, Fuminori Yoshida, has played a central role in all aspects of SymBio’s management since its foundation. If for any reason Mr. Yoshida is unable to perform his duties, this could have an impact on company operations.

Dependence on a single product: As of February 2021, Treakisym® accounted for all product sales of the company. SymBio is a biotech startup whose strength lies in having brought a pharmaceutical product to market, but its dependence on a single product raises the risk of earnings volatility. Sales and gross profit declined in FY12/19 and FY12/20 due to contamination and irregular appearance of lyophilized Treakisym® imported from Astellas Deutschland GmbH, which led to a temporary slump in product sales.

Market overview

Lymphatic cancer: patient population, market size, treatment drugs

Morbidity of lymphatic cancer

In 2017, the number of people diagnosed with lymphatic cancer in Japan was 34,571 (+1.0% YoY; average annual increase in past 10 years is 6.3%), according to “Cancer statistics and cancer registration in Japan” complied by the Center for Cancer Control and Information Services. Of these, 27,887 (+1.3% YoY), or 80.7% (80.4% in the previous year), were 60 years or older.

 Of the 977,393 (-1.8% YoY) people diagnosed with cancer, those diagnosed with lymphatic cancer accounted for only 3.5% (3.4% in the previous year), but their number increased 84.1% between 2007 and 2017 versus a 38.8% increase in the number of people newly diagnosed with cancer.

Treakisym® market potential and patient population

The company estimates that the number of patients being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients with untreated low-grade NHL and MCL is 6,967. On an NHI drug reimbursement price basis, Treakisym® sales reached JPY8.5bn in FY12/18 (JPY7.6bn in FY12/17).

The company estimates that the number of Japanese patients with relapsed or refractory DLBCL for which the company is considering application for approval of an additional indication is 18,672.

Drugs competing with Treakisym®

As of February 2015, these include rituximab and ibritumomab tiuxetan.

Rituximab (product name: Rituxan)

The drug, co-developed by the US companies IDEC Pharmaceuticals and Genentech, Inc. received US approval in November 1997 as the world’s first monoclonal antibody.

Rituxan consists of a portion of both mouse antibody and IgG, a human antibody. It attaches itself to the CD20 antigen that appears on B cells in the body and fights tumors through complement-dependent cytotoxicity and antibody‐dependent cell‐mediated cytotoxicity effects (source: Chugai, Zenyaku Kogyo). 

In Japan, Zenyaku Kogyo and Chugai have been jointly selling the drug since September 2001. Chugai’s Rituxan sales were JPY7.2bn (-39.5% YoY) in FY12/20.

Ibritumomab tiuxetan (product name: Zevalin)

Like Rituxan, the antibody drug Zevalin targets CD20 antigen on B cells. It combines the antibody with a radioactive substance and attacks B cells with radiation. The treatment is only available at medical institutions authorized to handle radioactive elements.

Zevalin was approved in January 2008 as a treatment for refractory lymphatic cancer (low-grade B-cell NHL). It is sold by Fujifilm RI Pharma Co., Ltd., a subsidiary of Fujifilm Holdings Corporation.

Patient population, treatment drugs for MDS 

MDS patient population estimated at 11,000

A high proportion of people aged 60 or older suffer from MDS. The number of patients totaled 9,000 in 2008, with 2,781 deaths from the disease according to Japan’s Ministry of Health, Labour and Welfare (MHLW). 

SymBio estimates that there are currently about 11,000 MDS patients in Japan amid a larger elderly population. Even though the number of patients continues to rise, there is a high unmet medical need in Japan with no efficacious treatment available.

Drugs competing with rigosertib

According to the company, as of February 2021, Nippon Shinyaku Co., Ltd.’s Vidaza was the only IV drug approved in Japan for the main indication of MDS.

Azacitidine (product name: Vidaza)

Vidaza, developed by Pharmion Corporation (now Celgene Corporation) in the US, is a treatment for first-line intermediate and higher-risk MDS. Nippon Shinyaku Co., Ltd. signed a license agreement with Pharmion in 2006 to sell this drug in Japan, obtaining marketing approval in January 2011 following the completion of domestic clinical trials. 

In addition to killing cancerous cells, azacitidine inhibits DNA methylation. It becomes efficacious after use for three to six months, with bone marrow suppression as the main side effect (a decline in white blood cells and platelets). However, while the use of hypomethylating agents such as azacitidine and decitabine (Dacogen) in the treatment of MDS has improved the outcome of patients who tend to have very poor survival, about half of MDS patients do not respond, progress, or relapse at different times after their response on these HMAs, followed by an extremely poor prognosis.

According to Nippon Shinyaku, Vidaza is the only approved drug in Japan for the first-line treatment of higher-risk MDS, with no efficacious treatment available once patients treated with Vidaza relapse. Nippon Shinyaku booked Vidaza sales of JPY15.7bn (+8.3% YoY) in FY03/20 and expects sales of JPY16.0bn in FY03/21. 

Historical performance

1H FY12/21 results

• Sales: JPY3.1bn (+131.3% YoY)
• Operating loss: JPY195mn (loss of JPY1.8bn in 1H FY12/20)
• Recurring loss: JPY204mn (loss of JPY1.9bn in 1H FY12/20)
• Net loss: JPY206mn (loss of JPY1.9bn in 1H FY12/20) 
  

Sales increased YoY in 1H, largely due to the transfer of sales from Eisai Co., Ltd. to the company’s own sales force. The business alliance agreement with Eisai concerning the marketing of Treakisym® expired on December 9, 2021, and the company began its own marketing in Japan on December 10, 2021, starting shipments to pharmaceutical wholesalers instead of Eisai. This allowed the company to receive not only the gross profit it received previously (the company’s sales to Eisai minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source the product).

However, there were negative factors for Treakisym® sales, such as the impact of clearance of unsold inventory of lyophilized formulations sold by Eisai prior to December 2020, delays in treating patients after the COVID-19 outbreak starting in late 2020, and tightened restrictions on visiting facilities limiting sales activities.

From Q3 onward, the company says that it expects sales of drugs targeting relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) to accelerate. The backlog of delayed medical treatments should clear as measures to combat COVID-19, including vaccinations for the elderly, progress. Other factors include the March 2021 approval of BR-therapy and Pola-BR therapy to treat r/r DLBCL, and Chugai Pharmaceutical's polatuzumab vedotin being added to the NHI drug list in May 2021. 

Gross profit was JPY2.3bn (+589.5% YoY), and GPM was 72.3% (+48.0pp YoY). The company attributes the GPM rise to the shift to its own marketing system and the launch of Treakisym® Ready-to-dilute (RTD) formulation in January 2021. In 1H, sales of Treakisym® lyophilized formulations surpassed those of Treakisym® RTD formulations.

Although SG&A expenses increased in 1H, losses at the operating profit/losses level down narrowed thanks to the effect of sales growth, and the company recorded operating profit in Q2 (April–June 2021). SG&A expenses increased 13.8% YoY to JPY2.5bn and R&D expenses increased 9.4% YoY to JPY912mn. 

R&D expenses were JPY912mn (+9.4% YoY). The company incurred clinical trial expenses for the IV formulations of Treakisym® and brincidofovir.

SG&A expenses other than R&D expenses were JPY1.6bn (+16.6% YoY). Sales expenses associated with the transition to its own sales system increased.

Q2 FY12/21 (April-June 2021) results

In Q2 FY12/21, sales were JPY1.7bn (+113/3% YoY), gross profit was JPY1.3bn (+525.5% YoY), the GPM was 73.3% (+48.3pp YoY), and operating profit was JPY16mn (JPY878mn loss in Q2 FY12/20). The company turned profitable at OP level.

Versus Q1 FY12/21, sales were up JPY306mn, gross profit up JPY255mn, the GPM up 2.2pp, and operating profit up JPY226mn.

Factors that contributed to sales growth were as follows. In Q1, sales were impacted by clearance of unsold inventory of lyophilized formulations sold by Eisai prior to December 2020, but this effect faded in Q2. In March 2021, approval was granted for Treakisym® in combination with rituximab for the indication of r/r DLBCL (BR therapy). In Q2, the company recorded sales of Treakisym® for the indication of r/r DLBCL.

The GPM rose QoQ, because the switch from the lyophilized formulation to the RTD formulation of Treakisym® progressed faster in Q2 than in Q1.

June 2021 results

The company commented that it turned profitable on a monthly basis in June 2021. Sales were JPY706mn (+298.3% YoY), gross profit was JPY523mn (+881.6% YoY), the GPM was 74.1% (+44.1pp YoY), and operating profit was JPY85mn (JPY324mn loss in June 2020).

Sales in June 2021 surpassed the average monthly sales in Q2 FY12/21 and the GPM was also higher than the monthly average in Q2. Sales were higher in June than in April and May, because the company recorded sales of Treakisym® targeting r/r DLBCL. GPM rose especially in the latter half of Q2 thanks to the switch to the RTD formulation. 

Progress in 1H versus full-year FY12/21 company forecast

In 1H FY12/21, sales were 34.4% of the full-year forecast, while the company posted a JPY195mn operating loss versus the full-year forecast of JPY1.4bn profit. Although 1H sales fell short of the company forecast, the company left its full-year forecast unchanged, because it expects higher sales in 2H than in 1H, and thinks the full-year forecast is achievable. Reasons for the company's expectation of profit growth in 2H versus 1H are as follows.

In 1H FY12/21, the impact of the clearance of unsold inventory of the lyophilized formulation of Treakisym® sold by Eisai totaled around JPY400mn. The clearance was completed in 1H and will have no impact on 2H results.

Patients cut back on hospital visits in 1H because of COVID-19, but the company expects this pattern to change in 2H as more seniors are vaccinated and likely to resume hospital visits.

The company received approval for BR therapy indicated for r/r DLBCL in March 2021, while Chugai Pharmaceutical received approval for polatuzumab vedotin + BR therapy indicated for r/r DLBCL. These approvals were granted about three months earlier than the company expected at the beginning of FY12/21. The company targets JPY2.6bn in sales of Treakisym® indicated for r/r DLBCL on a NHI drug reimbursement price basis, but Shared Research understands that sales may exceed this target because of the earlier-than-expected approval timing. The company recorded sales of Treakisym® indicated for r/r DLBCL in the second half of Q2 and expects this sales to increase in 2H.

The company forecasts a higher GPM in 2H as the switch from the lyophilized formulation to the RTD formulation of Treakisym® progresses.

Business progress

In August 2021, the company announced it had started administration to the first patient enrolled (FPI) in the Phase II clinical trial of antiviral drug brincidofovir (IV forumulation).

Also in August 2021, the company concluded a joint research agreement with Kyoto University regarding the mechanism of effect of bendamustine, under development as an anticancer agent indicated for DLBCL.

In July 2021, the company concluded a joint research agreement with the General Surgical Science Department, Gunma University Graduate School of Medicine regarding the exploration of new indications for bendamustine and rigosertib, which are under development as anticancer agents.

Chimerix Inc., the licensor of antiviral drug brincidofovir, obtained approval from the US Food and Drug Administration (FDA) in June 2021 for antiviral drug brincidofovir tablets and oral formulation as a treatment for smallpox.

In May 2021, the company filed for approval of of Treakisym® Rapid Infusion (RI) formulation.

In April 2021, the company received approval for the RTD formulation of Treakisym® in combination with rituximab, and for the RTD formulation of Treakisym® in combination with rituximab and polatuzumab vedotin for the indication of r/r DLBCL.

In March 2021, the company received approval for Treakisym® in combination with rituximab, and for Treakisym® in combination with rituximab and polatuzumab vedotin for the indication of r/r DLBCL.

In March 2021, the company filed an Investigational New Drug (IND) application of brincidofovir IV formulation for a Phase II clinical trial targeting adenovirus infection in children.

In January 2021, the company began sales of the read-to-dilute (RTD) liquid formulation of Treakisym®.

Domestic

Preparations for in-house sales organization begin

The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expired in December 2020, and the company switched to in-house sales for domestic sales of Treakisym®.

The company has thus far deployed a nationwide network of marketing representatives as well as hematology experts to cover each region to establish a highly productive internal sales organization capable of making proposals that fit the needs of each region. With the termination of its alliance agreement with Eisai, in September 2020, the company concluded a basic agreement with Suzuken Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to achieve nationwide distribution. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, under management by S.D. Collabo Co., Ltd.

During 1H, in January 2021, the company launched sales of the ready-to-dilute (RTD) formulation of Treakisym®, for which it obtained manufacturing and marketing approval in September 2020.

On March 23, 2021, the company obtained approval of a partial change to the manufacturing and marketing authorization for bendamustine-rituximab combination therapy (BR therapy) and bendamustine-rituximab-polatuzumab vedotin combination therapy (Pola-BR therapy) to treat r/r DLBCL patients. This enabled conventional lyophilized (freeze-dried [FD]) powder formulation of Treakisym® to be used in BR therapy right away. In April 2021, the company obtained approval of Treakisym® ready-to-dilute (RTD) liquid formulation for use in BR therapy and Pola-BR therapy for the treatment of r/r DLBCL. In May 2021, Chugai Pharmaceutical's polatuzumab vedotin was added to the NHI drug price list, enabling Treakisym® to be used in Pola-BR therapy.

Stable product supply

With the launch of sales of Treakisym® RTD formulation in January 2021, the company now markets both Treakisym® in both RTD formulation and FD formulation.

SymBio imports FD formulation Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma) and Treakisym® RTD formulation from Eagle Pharmaceuticals Inc. In 1H, secondary packaging and quality tests were applied to imported batches, resulting in stable quality, and as of May 2021, inventories had maintained proper levels to enable stable product supply.

On the supply front, the company is aiming for 91% completion of the switchover from the FD formulation to the RTD formulation of Treakisym®.

Treakisym® (SyB L-0501[FD formulation]/SyB L-1701 [RTD formulation]/SyB L-1702 [RI formulation]; generic name: bendamustine hydrochloride or bendamustine hydrochloride hydrate, product name: Treakisym®)

The anticancer agent Treakisym® is used to treat malignant lymphomas, indicated for untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL and MCL (October 2010), and chronic lymphocytic leukemia (August 2016).

The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for Hematological Malignancies 2018 published by Japanese Society of Hematology as a standard treatment option, which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for lymphatic cancer.

Also, SymBio obtained approval for the partial revision to the marketing authorization of Treakisym® in July 2018. Treakisym® can now be used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicular lymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for the partial revision to its application to use Treakisym® as a pretreatment agent in tumor-specific T cell infusion therapy. This allows Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor T-cell (CAR-T) therapy approved in Japan. Growing use of Treakisym® as a pretreatment agent in regenerative medicine has solidified its positioning as standard therapy for malignant lymphomas.

In the phase III clinical study of Treakisym® administered in BR therapy targeting r/r DLBCL, the company filed for approval for partial revision to manufacturing and marketing authorization in May 2020 and obtained that approval in March 2021. In April 2021, it obtained approval for partial revision to manufacturing and marketing authorization of Treakisym® RTD liquid formulation for use in BR and Pola-BR therapy as treatment for r/r DLBCL. The company has conducted a follow-up study with overall survival as the primary endpoint, because evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in BR therapy is crucial for establishing Treakisym® as a treatment for DLBCL. It is now making preparations to publicize the results of that study. Also, after Chugai Pharmaceutical Co., Ltd. applied for manufacture and marketing approval for polatuzumab vedotin in combination with BR therapy to treat r/r DLBCL in June 2020, the company applied for approval for partial revision to manufacturing and marketing authorization for Treakisym® in Pola-BR therapy and obtained approval in March 2021. Polatuzumab vedotin was added to the NHI drug price list in May 2021, and now Treakisym® may be used in Pola-BR therapy. Previously there were no effective treatments for the additional indication of r/r DLBCL, which was usually treated by a combination of anticancer agents as salvage chemotherapy, so development of a highly effective but safe new drug was sought after. Since BR therapy is already being used in the West to treat r/r DLBCL, patient organizations and related academic societies petitioned MHLW so that it could be used in Japan as soon as possible.

The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in September 2017 for the RTD and rapid infusion (RI) formulations of Treakisym® (the RI formulation reduces administration time). Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company launched it in January 2021. The company has concluded clinical trials to confirm safety of the RI formulation and applied for approval in May 2021. Unlike the current FD formulation, the RTD formulation reduces the workload of medical professionals, because it eliminates the need for troublesome manual dissolution. The RI formulation can be administered in just 10 minutes, versus 60 minutes for the current FD and RTD formulation. This reduces the burden on patients and healthcare professionals, providing significant value added. Multiple patent protections in the form of a liquid product license will enable the extension of the product life of Treakisym® to 2031.

Rigosertib Sodium (SyB L-1101 [IV]/SyB C-1101 [oral]; anticancer agent; generic name: rigosertib Sodium)

Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japan and is looking to apply the knowledge gleaned from additional analysis of the INSPIRE study to rigosertib development going forward.

Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination with azacytidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety among Japanese patients, SymBio began a phase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019.

The company said it would conduct joint research into Treakisym® and rigosertib with the University of Tokyo's Institute of Medical Science regarding efficacy of using the two compounds in combination or with existing drugs and also explore new indications.

Antiviral drug SyB V-1901 (generic name: brincidofovir）

In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug in intravenous and oral forms). The company acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox.

The company has concluded that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. In March 2021, the company submitted of an investigational new drug (IND) application to the Food and Drug Administration (FDA) of the US with the goal of obtaining permission for the launch of a phase II clinical trial for a phase II clinical trial of BCV IV as a treatment for adenovirus infections that primarily occur in children (although also in adults). In April 2021, the company received granted fast track designation from the FDA.

Based on safety and efficacy data acquired from its study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow the market for and maximize the business value of BCV. Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of BCV Oral against dsDNA viruses, raising expectations for its potential as a safe and effective therapy to prevent and treat a range of viral infections in patients receiving hematopoietic stem cell transplantation.

Chimerix announced in December 2020 that the FDA had accepted its new drug application (NDA) for BCV as a medical defense against smallpox and that it had received FDA approval in June 2021. 

Overseas

The company marketed SyB L-0501 in China and Hong Kong, and product sales were in line with the company’s plans.

In-licensing of drug candidates

The company is currently focusing on unrolling global development plans for antiviral drug brincidofovir it in-licensed in September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drug candidates.

Q1 FY12/21 results

• Sales: JPY1.4bn (+157.6% YoY)
• Operating loss: JPY211mn (loss of JPY962mn in Q1 FY12/19)
• Recurring loss: JPY4.6bn (loss of JPY991mn in Q1 FY12/19)
• Net loss: JPY4.1bn (loss of JPY992mn in Q1 FY12/19) 
  

Sales increased 157.6% YoY to JPY1.4bn, largely due to the transfer of sales from Eisai Co., Ltd. to the company’s own sales force. The business alliance agreement for Treakisym® concluded with Eisai expired on December 9, 2020, and SymBio started independently marketing Treakisym® in Japan on December 10, 2020. With this change, the product is shipped to pharmaceutical wholesalers instead of to Eisai. This allows the company to receive not only the gross profit it received previously (the company’s sales to Eisai minus cost of sales), but also the gross profit earned by Eisai through December 9, 2020 (i.e., the difference between the shipment price from Eisai to pharmaceutical wholesalers and the price Eisai paid the company to source the product).

Earnings were partially hindered by medical care delays due to the COVID-19 outbreak since late 2020 and constraints on sales activities due to tighter restrictions on facilities visitations, but considering the clearance of market inventory of the lyophilized (freeze-dried [FD]) powder formulation of Treakisym® sold by Eisai prior to the switch to the company’s own sales force in December 2020, demand for Treakisym® was strong in Q1.

For Q2, although there are lingering impacts of the clearance of market inventory distributed prior to the switch to the company’ own sales force, there will be minimal impact on sales overall, and the company says that it anticipates sales growth on the additional indications for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) that were approved on March 23, 2020.

Gross profit was JPY1.0bn (+690.9% YoY), and GPM was 71.1% (+47.9pp YoY). The company attributes GPM growth to the shift to its own marketing system and the launch of Treakisym® Ready-To-Dilute (RTD) formulation in January 2021. In Q1, sales of Treakisym® lyophilized formulations surpassed those of Treakisym® RTD formulations

Although SG&A expenses increased, losses at the operating profit level on down shrank thanks to the effect of sales growth. SG&A expenses increased 12.0% YoY to JPY1.2bn.

R&D expenses increased 8.0% YoY to JPY473mn. This included expenses for conducting clinical trials of Treakisym® and brincidofovir injections. 

Excluding R&D expenses, SG&A expenses rose 14.7% YoY to JPY747mn. The switch to in-house sales drove up the cost of sales. Yet, the results were below the company’s forecast for SG&A expenses (excluding R&D expenses) of JPY3.6bn (+15.1% YoY), as the shift to online sales activities and other factors curbed the expenses.

Overview of business progress

In FY12/21, progress in main businesses are as follows:

In June 2021, Chimerix, Inc. (licensor of brincidofovir) obtained FDA approval of brincidofovir tablets and oral suspensions as antiviral formulations for the treatment of smallpox.

In May 2021, SymBio submitted approval application for Treakisym® rapid infusion (RI) liquid formulation.

In April 2021, the company obtained approval of Treakisym® ready-to-dilute (RTD) liquid formulation for use in combination with rituximab and in combination with rituximab and polatuzumab vedotin for the treatment of refractory or relapsed diffuse large B-cell lymphoma (r/r DLBCL).

In March 2021, the company obtained approval of Treakisym® for use in combination with rituximab, and in combination with rituximab and polatuzumab vedotin for the treatment of r/r DLBCL.

In March 2021, the company submitted an Investigational New Drug (IND) application for phase II clinical study of brincidofovir injection in pediatric patients with adenovirus infections. 

In January 2021, the company launched Treakisym® RTD liquid formulation.

Domestic

Preparations for in-house sales organization begin

The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expired in December 2020, and the company switched to in-house sales for domestic sales of Treakisym®. 

The company has thus far deployed a nationwide network of marketing representatives as well as hematology experts to cover each region to establish a highly productive internal sales organization capable of making proposals that fit the needs of each region. With the termination of its alliance agreement with Eisai, in September 2020, the company concluded a basic agreement with Suzuken Co., Ltd and Toho Pharmaceutical Co., Ltd for the procurement and sale of pharmaceuticals to achieve nationwide distribution. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, under management by S.D. Collabo Co., Ltd. 

During Q1, in January 2021, the company launched sales of the ready-to-dilute (RTD) formulation of Treakisym®, for which it obtained manufacturing and marketing approval in September 2020.

On March 23, 2021, the company obtained approval of a partial change to the approved matters of the lyophilized (freeze-dried) powder formulation of Treakisym® for use in bendamustine-rituximab combination therapy (BR therapy) and in bendamustine-rituximab-polatuzumab vedotin combination therapy (Pola-BR therapy) to treat r/r DLBCL patients. The lyophilized powder formulation of Treakisym® can be used in BR therapy (120mg/sqm as bendamustine hydrochloride) right away, and it can also be used in Pola-BR therapy (90mg/sqm as bendamustine hydrochloride) once polatuzumab vedotin is added to the NHI drug price list (listed in May 2021) .

On April 28, 2021, the company obtained approval of a partial change to the approved matters of Treakisym® RTD liquid formulation for use in BR and Pola-BR therapy as treatment for r/r DLBCL.

Stable product supply

With the launch of sales of Treakisym® RTD formulation in January 2021, the company now markets both Treakisym® in both RTD formulation and lyophilized powder formulation.

SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma) and Treakisym® RTD formulation from Eagle Pharmaceuticals Inc. In Q1, secondary packaging and quality tests were applied to imported batches, resulting in stable quality, and as of May 2021, inventories had maintained proper levels to enable stable product supply.

On the supply front, the company is aiming for 91% completion of the switchover from the lyophilized formulation to the RTD formulation of Treakisym®.

Anticancer agents: (SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI] (generic name: bendamustine hydrochloride, product name: Treakisym®)

The anticancer agent Treakisym® is used in malignant lymphomas, indicated for untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL and MCL (October 2010), and chronic lymphocytic leukemia (August 2016). 

The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for Hematological Malignancies 2018 published by Japanese Society of Hematology as a standard treatment option, which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for lymphatic cancer. 

Also, SymBio obtained approval for partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicular lymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for partial change to the approved matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion therapy. This allows Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor T-cell (CAR-T) therapy approved in Japan. Growing use of Treakisym® as a pretreatment agent in regenerative medicine has solidified its positioning as standard therapy for malignant lymphomas.

In the phase III clinical study of Treakisym® administered in BR therapy for the treatment of r/r DLBCL, the company submitted an application for partial change to approved matters in May 2020 and obtained approval in March 2021. In April 2021, it obtained approval for a partial change to the approved matters of Treakisym® RTD liquid formulation for use in BR and Pola-BR therapy as treatment for r/r DLBCL. The company has conducted a follow-up study with overall survival as the primary endpoint, because evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in BR therapy is crucial for establishing Treakisym® as a treatment for DLBCL. It is now making preparations to publicize the results of that study. Also, after Chugai Pharmaceutical Co., Ltd. applied for manufacture and marketing approval for polatuzumab vedotin in combination with BR therapy to treat r/r DLBCL in June 2020, the company applied for approval for a partial change to the approved matters of Treakisym® for use in Pola-BR therapy and obtained approval in March 2021. With the approvals obtained by Chugai and SymBio, once polatuzumab vedotin is added to the NHI drug price list, Treakisym® will be able to be used in Pola-BR therapy. At present there are no effective treatments for the additional indication of r/r DLBCL, which is usually treated by a combination of anticancer agents as salvage chemotherapy, so development of a highly effective but safe new drug would be ideal. Since BR therapy is already being used in the West to treat r/r DLBCL, patient organizations and related academic societies have petitioned MHLW so that it can be used in Japan as soon as possible.

The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in September 2017 for the RTD and rapid infusion (RI) formulations of Treakisym® (the RI formulation reduces administration time). Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company launched it in January 2021. The company has concluded clinical trials to confirm safety of the RI formulation and applies for approval in May 2021. Unlike the current lyophilized powder formulation, the RTD formulation reduces the workload of medical professionals, because it eliminates the need for troublesome manual dissolution. The RI formulation can be administered in just 10 minutes versus 60 minutes for the current lyophilized injection and RTD formulation. This reduces the burden on patients and healthcare professionals, providing significant value added. Multiple patent protections in the form of a liquid product license will enable the extension of the product life of Treakisym® to 2031.

Anticancer agents: SyB L-1101 [IV]/SyB C-1101 [oral] (generic name: rigosertib sodium)

Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japan and is looking to apply the knowledge gleaned from additional analysis of the INSPIRE study to rigosertib development going forward. 

Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination with azacytidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of the high-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients, SymBio began a phase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019. 

Antiviral drug: SyB V-1901 (generic name: brincidofovir）

In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug in intravenous and oral forms). The company acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox. 

The company has concluded that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. In March 2021, the company submitted of an investigational new drug (IND) application to the Food and Drug Administration (FDA) of the US with the goal of obtaining permission for the launch of a phase II clinical trial for a phase II clinical trial of BCV IV as a treatment for adenovirus infections that primarily occur in children (although also in adults). In April 2021, the company received granted fast track designation from the FDA.

Based on safety and efficacy data acquired from its study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow the market for and maximize the business value of BCV. Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of BCV Oral against dsDNA viruses, raising expectations for its potential as a safe and effective therapy to prevent and treat a range of viral infections in patients receiving hematopoietic stem cell transplantation. 

Chimerix announced in June 2021 that the FDA approved BCV tablets and oral suspensions in adult and pediatric patients including neonates for the treatment of smallpox. 

Overseas

company marketed SyB L-0501 in China and Hong Kong, and product sales were in line with the company’s plans.

In-licensing of drug candidates

The company is currently focusing on unrolling global development plans for antiviral drug brincidofovir it in-licensed in September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drug candidates.

Full-year FY12/20 results

• Sales: JPY3.0bn (+5.3% YoY)
• Operating loss: JPY4.5bn (loss of JPY4.3bn in FY12/19)
• Recurring loss: JPY4.6bn (loss of JPY4.4bn in FY12/19)
• Net loss: JPY4.1bn (loss of JPY4.4bn in FY12/19) 
  

Sales increased YoY, as the company booked sales of Treakisym®. Sales declined 32.1% YoY to JPY1.4bn in 1H (January–June 2020), but were up 95.3% YoY to JPY1.6bn in 2H (July–December 2020). Through 1H, there was a high defect rate and unreliable delivery of multiple batches of lyophilized formulations of Treakisym® (supplied by Astellas Deutschland), reflected in the YoY sales decline. Sales recovered sharply YoY in 2H, because the defect rate improved and the company sold inspected products. 

The business alliance agreement with Eisai for Treakisym® expired on December 9, 2020, and SymBio began independently marketing Treakisym® in Japan on December 10. Sales broke down by customer were as follows: Eisai, JPY2.5bn (-10.1% YoY); Suzuken Group, JPY126mn (JPY0mn in FY12/19); and Toho Pharmaceutical JPY120mn (JPY0mn in FY12/19). 

Based on Treakisym® sales data from Eisai, which marketed the product until December 9, 2020, revenue from Treakisym® was JPY7.7bn (+6.3% YoY) in FY03/20. Total sales from Q4 FY03/20 through Q3 FY03/21 (January–December 2020) came to JPY6.9bn (JPY7.5bn for the same period a year earlier). 

Gross profit was JPY867mn (+0.2% YoY) and GPM on product sales was 28.8% (-1.0pp YoY). The CoGS ratio rose in 1H due to strengthened inspection procedures for lyophilized formulation of Treakisym® (two visual inspections), valuation loss on inventories (JPY69mn versus JPY188mn a year earlier), and higher transportation costs. The inventory valuation loss was related to quality defects of Treakisym®. 

The GPM improved from 24.2% in 1H to 33.0% in 2H. The company booked a valuation loss on inventories in 1H, but none in 2H. Shared Research understands that beginning its own marketing of Treakisym® in Q4 also contributed to the GPM improvement. 

SG&A expenses increased 4.0% YoY to JPY5.4bn. Although the company reduced R&D and administrative expenses by JPY900mn, SG&A expenses increased overall due to upfront spending to establish its own sales structure. 

R&D expenses declined 7.2% YoY to JPY2.3bn. This included expenses for conducting clinical trials of intravenous formulations of Treakisym® and rigosertib. The company also recorded a milestone payment of roughly JPY500mn on obtaining marketing approval for the RTD formulation of Treakisym®. 

Excluding R&D expenses, SG&A expenses rose 14.0% YoY to JPY3.1bn. The company incurred upfront expenses to establish its own sales organization. 

Losses expanded across the board despite higher sales due to an increase in SG&A expenses. The difference between recurring loss and net loss is attributable to a JPY525mn settlement payment booked as extraordinary gains. 

Business progress updates

Major business developments in FY12/20 were as follows. 

The business alliance agreement with Eisai for Treakisym® expired on December 9, 2020, and SymBio began independently marketing Treakisym® in Japan on December 10. 

In September 2020, the company obtained approval for the RTD formulation of Treakisym®. It began sales in January 2021. 

Also in September 2020, the company completed observation of all patients enrolled in a clinical trial of the RI formulation of Treakisym®. The company plans to apply for approval on completion of the clinical trial, targeting approval in 2H FY12/22.

In August 2020, Onconova, the licensor of anticancer drug rigosertib, announced that its global phase III trial (INSPIRE study) addressing higher-risk myelodysplastic syndromes (higher-risk MDS) intolerant of treatment using hypomethylating agents failed to meet its primary endpoints. SymBio engages in clinical development of rigosertib in Japan, and plans to use the knowledge obtained from genomic analysis of the INSPIRE study in future development of rigosertib. 

In August 2020, the company decided to develop intravenous formulation of antiviral drug brincidofovir (SyB V-1901, BCV IV) globally (mainly in Japan, the US, and Europe) for adenovirus (AdV) infections occurring after hematopoietic stem cell transplantation. Shared Research understands this is the first time the company has conducted global new drug development independently.

In July 2020, the Court of Arbitration delivered a ruling in The Medicines Company (MDCO) arbitration case. The court did not grant damage claims made against MDCO but ordered MDCO to pay 50% of costs incurred by SymBio (USD4.95mn) in the arbitration proceedings, including attorney fees.

In July 2020, the company applied for a partial change to the approved matters of Treakisym® for use in combination with polatuzumab vedotin and rituximab targeting patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

In May 2020, the company submitted an application for partial change to the approved matters of BR therapy (combination of anticancer agents Treakisym® and rituximab) to enable its use for r/r DLBCL.

Domestic

Preparations for in-house sales organization begin

The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expired in December 2020. The company therefore began preparations to build an in-house sales organization for domestic sales of Treakisym®. 

In FY12/21, the company has deployed a nationwide network of 53 marketing representatives as well as nine hematology experts to cover each region to establish a highly productive internal sales organization capable of making proposals that fit the needs of each region.

To establish a nationwide distribution structure, in September 2020, the company concluded a basic agreement with Suzuken Co., Ltd (Suzuken Group) and Toho Pharmaceutical Co., Ltd (a consolidated subsidiary of Toho Holdings Co., Ltd.; Kyoso Mirai Group) for the procurement and sale of pharmaceuticals. SymBio is using Suzuken Group and Kyoso Mirai Group as its sole distributors after the marketing agreement with Eisai expired. The company has established two distribution centers, one in Eastern Japan and the other in Western Japan, under management by S.D. Collabo Co., Ltd.  

SymBio has thus completed building its in-house sales organization, and transitioned to in-house sales of Treakisym® in December 2020 after expiry of the business alliance agreement with Eisai.

Stable product supply

SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma). Treakisym® inventories were substantially depleted in 1H relative to year-ago levels, but inventory levels recovered in 2H as secondary packaging and quality tests were applied to some batches of Treakisym® 100mg vials imported from Astellas Deutschland.

In September 2020, the company obtained manufacturing and marketing approval for liquid formulations of Treakisym® (RTD formulation) under license from Eagle Pharmaceuticals with plans to begin sales in January 2021. Import and shipments to the sole distributors of the Treakisym® (RTD formulation) began in Q4 FY12/20 (October–December 2020).

Anticancer agents: SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI] (generic name: bendamustine hydrochloride, product name: Treakisym®)

The anticancer agent Treakisym® is used to treat malignant lymphomas, indicated for untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL and MCL (October 2010), and chronic lymphocytic leukemia (August 2016). 

The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for Hematological Malignancies 2018 published by Japanese Society of Hematology as a standard treatment option, which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for lymphatic cancer. 

Also, SymBio obtained approval for the partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicular lymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for the partial change to the approved matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion therapy. This allows Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor T-cell (CAR-T) therapy approved in Japan and on the NHI drug price list from May 2019. Growing use of Treakisym® as a pretreatment agent in regenerative medicine has solidified its positioning as standard therapy for malignant lymphomas.

In the phase III clinical study of Treakisym® in BR therapy conducted in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), an additional indication following the above approved ones, results showed that the response rate (primary endpoint) was better than expected. Based on this, the company submitted an application for partial change to approved matters in May 2020. It is currently conducting a follow-up study with overall survival as the primary endpoint, because evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in combination with rituximab is crucial for establishing Treakisym® as a treatment for DLBCL. Also, after Chugai Pharmaceutical Co., Ltd. applied for manufacture and marketing approval for polatuzumab vedotin in combination with BR therapy to treat r/r DLBCL in June 2020, the company submitted an application for partial change to the approved matters of Treakisym® for use in combination with polatuzumab vedotin and rituximab. If the new drug applications by Chugai and SymBio are approved and polatuzumab vedotin is added to the NHI drug price list, Treakisym® can be used with polatuzumab vedotin in combination with BR therapy. At present there are no effective treatments for the additional indication of r/r DLBCL, which is usually treated by a combination of anticancer agents as salvage chemotherapy, so development of a highly effective but safe new drug would be ideal. Since BR therapy is already being used in the West to treat r/r DLBCL, patient organizations and related academic societies have petitioned MHLW so that it can be used in Japan as soon as possible.

The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in September 2017 for the RTD and RI formulations of Treakisym®. Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company plans to launch it in January 2021. The company is conducting clinical trials to confirm safety of the RI formulation and plans to apply for approval in FY12/21. Unlike the current lyophilized powder formulation, the RTD formulation reduces the workload of medical professionals, because it eliminates the need for troublesome manual dissolution. The RI formulation can be administered in just 10 minutes versus 60 minutes for the current lyophilized injection and RTD formulation. This reduces the burden on patients and healthcare professionals, providing significant value added. Multiple patent protections in the form of a liquid product license will enable the extension of the product life of Treakisym® to 2031.

Anticancer agents: SyB L-1101 [injection]/SyB C-1101 [oral] (generic name: rigosertib sodium)

Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japan and is looking to apply the knowledge gleaned from additional analysis of the INSPIRE study to rigosertib development going forward. 

Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination with azacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of the high-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients, SymBio began a phase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019. 

Antiviral drug, SyB V-1901 (generic name: brincidofovir）

In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for brincidofovir (SyB V-1901), an antiviral drug in intravenous and oral forms). The company acquired exclusive global rights to develop, manufacture, and market brincidofovir for all diseases except smallpox. 

After a review at the global advisory board held in February 2020, the company concluded that it would prioritize global development of brincidofovir IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. Based on safety and efficacy data acquired from its study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow the market for and maximize the business value of brincidofovir. The company is presently in preparation to initiate a dose-finding study of the liquid formulation of brincidofovir in pediatric patients slated to begin in December 2021.

Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of brincidofovir oral against dsDNA viruses. Brincidofovir IV is also expected to become a safe and effective therapy to prevent and treat a range of viral infections in patients receiving hematopoietic stem cell transplantation. 

Chimerix announced in December 2020 that the FDA had accepted its new drug application (NDA) for brincidofovir as a medical defense against smallpox. The FDA has approved priority review for BCV under the Prescription Drug User Fee Act (PDUFA) and set the date for completing the review (PDUFA date) at April 7, 2021. 

SyB P-1501, transdermal pain management system 

Regarding SyB P-1501 licensed by The Medicines Company (marketed as IONSYS in the US), the company initiated an arbitration against The Medicines Company (MDCO), under the rules of the International Chamber of Commerce, seeking damages of USD82mn arising from MDCO’s repudiation of the license agreement. SymBio argued that MDCO’s failure to provide sufficient assurance to the company regarding the performance of obligations under the license agreement in light of its decision to withdraw from business activities relating to SyB P-1501 in the European and US markets was a material breach of the license agreement. In September 2020, SymBio announced it had received the arbitration judgment and although the Court of Arbitration did not award damages sought by the company, it did order MDCO to pay 50% of legal costs (about USD5mn) sought by the company. 

Overseas

The company marketed SyB L-0501 in South Korea, Taiwan, and Singapore, and product sales were in line with the company’s plans.

In-licensing of drug candidates

The company is currently focusing on unrolling global development plans for antiviral drug brincidofovir it in-licensed in September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drug candidates.

Cumulative Q3 FY12/20 results

• Sales: JPY2.3bn (+16.2% YoY)
• Operating loss: JPY3.1bn (loss of JPY3.5bn in Q3 FY12/19)
• Recurring loss: JPY3.2bn (loss of JPY3.6bn in Q3 FY12/19)
• Net loss: JPY2.7bn (loss of JPY3.6bn in Q3 FY12/19) 
  

Overview

In cumulative Q3 FY12/20, sales increased YoY, as the company booked sales of Treakisym®. Sales were JPY1.4bn (-32.1% YoY) in 1H and JPY972mn in Q3 (versus sales of JPY3mn in Q3 FY12/19), representing YoY growth on a cumulative Q3 basis. A large defect ratio in multiple batches of lyophilized Treakisym® formulations imported from Astellas Deutschland and unstable deliveries continued in 1H, resulting in lower YoY sales. The defect ratio improved and selling inspected products led to higher YoY sales in Q3.

Based on data supplied by Treakisym® distributor Eisai, sales of Treakisym® were JPY7.7bn (+6.3% YoY) in FY03/20. Sales were solid on a quarterly basis at JPY1.6bn in Q4 FY03/20 (January–March 2020) versus JPY1.4bn in Q4 FY03/19, JPY1.9bn in Q1 FY03/21 (April–June 2020) versus JPY2.0bn in Q1 FY03/20, and JPY1.7bn in Q2 FY03/21 (July–September 2020) versus JPY2.1bn in Q2 FY03/20. 

Gross profit was JPY611mn (+8.5% YoY) and the GPM on product sales was 26.2% (-1.8pp YoY). The cost ratio increased due to strengthened inspection procedures for lyophilized formulation of Treakisym® (two visual inspections), valuation loss on inventories (JPY69mn versus JPY188mn a year earlier), and higher transportation costs. The inventory valuation loss was related to quality defects of Treakisym®. However, GPM was 28.9% in Q3, an improvement over 24.2% in 1H. Although the company booked an inventory valuation loss in 1H, it did not book a loss in Q3, leading to an improved cost ratio.

SG&A expenses declined 8.4% YoY to JPY3.8bn.

R&D expenses declined 11.5% YoY to JPY1.7bn. This included expenses for conducting clinical trials of intravenous formulations of Treakisym® and rigosertib.

Excluding R&D expenses, SG&A expenses fell by 5.6% YoY to JPY2.0bn. The company incurred development costs for its in-house sales organization.

Losses narrowed across the board on higher sales and lower SG&A expenses. The difference between recurring and net losses is attributable to a JPY525mn settlement payment booked as extraordinary gains.

Business progress updates

Major business developments in cumulative Q3 FY12/20 were as follows.

In September 2020, the company obtained approval for the RTD formulation of Treakisym®. It plans to begin sales in January 2021.

Also in September 2020, the company completed observation of all patients enrolled in a clinical trial of the RI formulation of Treakisym®. The company plans to apply for approval on completion of the clinical trial, targeting approval in 2H FY12/22.

In August 2020, Onconova, the licensor of anticancer drug rigosertib, announced that its global phase III trial (INSPIRE study) addressing higher-risk myelodysplastic syndromes (higher-risk MDS) intolerant of treatment using hypomethylating agents failed to meet its primary endpoints. SymBio engages in clinical development of rigosertib in Japan, and plans to use the knowledge obtained from genomic analysis of the INSPIRE study in future development of rigosertib.

In August 2020, the company decided to develop intravenous formulation of antiviral drug brincidofovir (SyB V-1901, BCV IV) globally (mainly in Japan, the US, and Europe) for adenovirus (AdV) infections occurring after hematopoietic stem cell transplantation. Shared Research understands this is the first time the company has conducted global new drug development independently.

In July 2020, the Court of Arbitration delivered a ruling in The Medicines Company (MDCO) arbitration case. The court did not grant damage claims made against MDCO but ordered MDCO to pay 50% of costs incurred by SymBio (USD4.95mn) in the arbitration proceedings, including attorney fees.

In July 2020, the company applied for a partial change to the approved matters of Treakisym® for use in combination with polatuzumab vedotin and rituximab targeting patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

In May 2020, the company applied for a partial change to the approved matters of BR therapy (combination of anticancer agents Treakisym® and rituximab) to enable its use for r/r DLBCL.

In May 2020, an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab) results for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of the European Hematology Association scheduled to be held in June 2020.

Domestic

Preparations for in-house sales organization begin

The business alliance agreement between SymBio and Eisai Co., Ltd. under which Eisai acts as a sales agent expires in December 2020. The company plans to transition to its in-house sales organization for domestic sales of Treakisym® in January 2021. This should facilitate a move into the black from FY12/21 and ongoing profit growth thereafter and lay the groundwork for future business development.

In Q3, the company has started work on transferring marketing operations from Eisai, and as planned, has deployed a nationwide network of 51 marketing representatives as well as six hematology experts to cover each region.

In September 2020, the company concluded a basic agreement with Suzuken Co., Ltd (hereafter, Suzuken Group) and Toho Pharmaceutical Co., Ltd (a consolidated subsidiary of Toho Holdings Co., Ltd., hereafter Kyoso Mirai Group) for the procurement and sale of pharmaceuticals. SymBio will use Suzuken Group and Kyoso Mirai Group as its sole distributors once the marketing agreement with Eisai expires. The company will have two distribution centers, one in Eastern Japan and the other in Western Japan, under management by S.D. Collabo Co., Ltd.

Stable product supply

SymBio imports lyophilized Treakisym® for injection from Astellas Deutschland (consolidated subsidiary of Astellas Pharma), which is marketed in Japan by sales agent Eisai. Treakisym® inventories were substantially depleted in 1H relative to year-ago levels, but inventory levels were recovering as of Q3 as secondary packaging and quality tests were applied to some batches of Treakisym® 100mg vials imported from Astellas Deutschland while shipments to Eisai were on track with plan.

Anticancer agents: SyB L-0501[lyophilized injection]/SyB L-1701 [RTD]/SyB L-1702 [RI] (generic name: bendamustine hydrochloride, product name: Treakisym®)

Approved indications

The anticancer agent Treakisym® is used for the indications of untreated low-grade non-Hodgkin’s lymphoma and mantle cell lymphoma (marketing approval obtained in December 2016), refractory or relapsed low-grade NHL and MCL (October 2010), and chronic lymphocytic leukemia (August 2016). 

The combination therapy of Treakisym® and rituximab (BR therapy) was newly included in the Practical Guidelines for Hematological Malignancies 2018 edited and published by Japanese Society of Hematology as a standard treatment option, which applies to all of the approved indications. This has seen Treakisym® establish its position as a standard treatment for lymphatic cancer. 

Also, SymBio obtained approval for the partial change to the approved matters of Treakisym® in July 2018. Treakisym® can now be used in combination with new anti-CD20 antibodies and not just rituximab for the treatment of CD20-positive follicular lymphoma, the most common histological type of low-grade NHL. This allows the company to provide patients a new treatment option: combination therapy with obinutuzumab. In March 2019, SymBio obtained approval for the partial change to the approved matters of Treakisym® to enable its use as a pretreatment agent in tumor-specific T cell infusion therapy. This allows Treakisym® to be used as a pretreatment agent for Kymriah® intravenous infusion, which was the first chimeric antigen receptor T-cell (CAR-T) therapy approved in Japan and on the NHI drug price list from May 2019.

Relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL)

In the phase III clinical study of Treakisym® administered in combination with rituximab (BR therapy) targeting relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), an additional indication following the above approved ones, results showed that the response rate (primary endpoint) was better than expected. Based on this, the company applied for a partial change to approved matters in May 2020. It is currently conducting a follow-up study with overall survival as the primary endpoint, because evaluating the survival data (e.g., overall survival and progression-free survival) for Treakisym® administered in combination with rituximab is crucial for establishing Treakisym® as a treatment for DLBCL. 

In May 2020, an abstract on analysis of phase III BR therapy (combination of anticancer agents Treakisym® and rituximab) results for treatment of relapsed or refractory diffuse large B-cell lymphoma was adopted for the 25th Congress of the European Hematology Association scheduled to be held in June 2020. The company noted the main results of the phase III (38 patients) trial analysis were as follows:

Overall response rate (ORR) was 76% and complete response (CR) rate was 47%.

<By gene activity pattern>

• GCB type: ORR of 83%, CR rate of 67%
• Non-GCB type: ORR of 78%, CR rate of 39% 
  

<By age group>

• Under 65 years of age: ORR of 86%, CR rate of 71%
• 65 to 75 years old: ORR of 75%, CR rate of 45%
• Over 75 years of age: ORR of 73%, CR rate of 36% 
  

As reference for the anticipated impact of adding the indication of r/r DLBCL, the company estimates that the number of patients being treated for relapsed or refractory low-grade NHL and MCL in Japan is 9,336 and the number of patients with untreated low-grade NHL and MCL is 6,967, for a total of 16,303. For these indications, distributor Eisai booked sales of JPY8.0bn in FY03/20. By comparison, the company estimates that the number of Japanese patients with r/r DLBCL is 18,672.

Also, after Chugai Pharmaceutical Co., Ltd. applied for manufacture and marketing approval for polatuzumab vedotin in combination with BR therapy to treat r/r DLBCL in June 2020, the company applied for a partial change to the approved matters of Treakisym® for use in combination with polatuzumab vedotin and rituximab. If the new drug applications by Chugai and SymBio are approved and polatuzumab vedotin is added to the NHI drug price list, Treakisym® can be used with polatuzumab vedotin in combination with BR therapy. At present there are no effective treatments for the additional indication of r/r DLBCL, which is usually treated by a combination of anticancer agents as salvage chemotherapy, so development of a highly effective but safe new drug would be ideal. Since BR therapy is already being used in the West to treat r/r DLBCL, patient organizations and related academic societies have petitioned MHLW so that it can be used in Japan as soon as possible. 

Treakisym® liquid formulations (RTD/RI) 

The company concluded an exclusive licensing agreement in Japan with Eagle Pharmaceuticals (based in New Jersey, US) in September 2017 for the RTD and RI formulations of Treakisym®. 

Manufacturing and marketing approval of the RTD formulation was obtained in September 2020, and the company plans to launch it in Q1 FY12/21. 

SymBio commenced a clinical trial for the RI formulation in November 2018 primarily to confirm safety, and the follow-up period for all patients enrolled in the trial was completed in September 2020 (LPLV: Last Patient Last Visit). The company will apply for approval without delay after the end of the clinical trial of the RI formulation and aims to begin sales in 2H FY12/22. The RI formulation can be administered in just 10 minutes versus 60 minutes for the current lyophilized injection and RTD formulation. This reduces the burden on patients and healthcare professionals, providing significant value added. 

Multiple patent protections in the form of a liquid product license (for RTD and RI formulations) will enable the extension of the product life of Treakisym® to 2031. The RTD and RI formulations were launched in the US market from January 2016 and had captured a 40% share of the bendamustine market within four months of commercialization, rising to over 90% within 12 months. The company looks for an even more rapid switch from the lyophilized powder to liquid formulations in Japan.

Treakisym® lifecycle management strategy

As noted above, SymBio anticipates Treakisym® sales will expand on the back of increased sales for already approved indications and contributions from the new indication of r/r DLBCL. Treakisym® is designated as a treatment for rare diseases and the re-examination period ends in 2020, so the launch of liquid Treakisym® (RTD and RI formulations) will extend the product life until 2031.

In addition, SymBio is slated to take over domestic marketing of Treakisym® in January 2021. Shared Research thinks this could lead to higher profit margins for SymBio as it may be able to pocket gross profits booked by Eisai (difference between Eisai’s procurement price and delivery price to drug wholesalers). We further believe gross profit margins could rise following transition to liquid Treakisym® owing to a change in suppliers. The lyophilized powder formulation of Treakisym® is supplied by Astellas Deutschland whereas the RTD and RI formulations are supplied by Eagle Pharmaceuticals. The company is also considering in-house production of liquid Treakisym® as a future possibility.

Anticancer agents: SyB L-1101 [IV]/SyB C-1101 [oral] (generic name: rigosertib Sodium)

Rigosertib injection 

Onconova Therapeutics, Inc., the licensor, conducted a global phase III trial (INSPIRE study) across more than 20 countries addressing higher-risk myelodysplastic syndromes (higher-risk MDS) with overall survival as the primary endpoint. The target is patients who do not respond to the current standard treatment with hypomethylating agents, relapse after treatment under the current standard of care, or are intolerant to hypomethylating agents. In August 2020, Onconova announced a comparator trial to physicians’ choice of treatment failed to achieve the primary endpoint. The company leads clinical trials conducted in Japan and is looking to apply the knowledge gleaned from genomic analysis of the INSPIRE study to rigosertib development going forward. 

Oral rigosertib 

Regarding the oral formulation of rigosertib, Onconova completed a phase I/II clinical trial for the drug used in combination with azacitidine, whose results suggested the efficacy and safety of the combination therapy. To verify the tolerability and safety of the high-dose oral formulation of rigosertib as an initial treatment for higher-risk MDS among Japanese patients, SymBio began a phase I clinical trial in Japan in June 2017 and completed patient enrollment in June 2019. 

Antiviral drug to treat infections: SyB V-1901 (generic name: brincidofovir)

In September 2019, SymBio concluded an exclusive global license agreement with Chimerix Inc. (hereafter Chimerix) for brincidofovir (SyB V-1901, hereafter BCV IV and BCV Oral), an antiviral drug for the treatment of infections in intravenous and oral forms). The company acquired exclusive global rights to develop, manufacture, and market BCV for all diseases except smallpox. 

After a review at the global advisory board held in February 2020, the company concluded that it would prioritize global development of BCV IV (mainly in Japan, the US, and Europe) to treat adenovirus (AdV) infections in patients receiving hematopoietic stem cell transplantation to address an unmet medical need. Based on safety and efficacy data acquired from its study, the company plans to review the drug’s efficacy against dsDNA viral infections in patients receiving hematopoietic stem cell transplantation and extend its target indications to include multiviral infections. By exploring the potential for expanding target disease areas to viral infections related to organ transplants (including kidney transplants), the company aims to grow the market for and maximize the business value of BCV. The company is presently in preparation to initiate a dose-finding study of the liquid formulation of BCV in pediatric patients slated to begin in December 2021.

Clinical trials by Chimerix have demonstrated superior, broad-spectrum antivirus activity of BCV Oral against dsDNA viruses, raising expectations for its potential as a safe and effective therapy to prevent and treat a range of viral infections in patients receiving hematopoietic stem cell transplantation. 

SyB P-1501, transdermal pain management system

Regarding SyB P-1501 licensed by The Medicines Company, the company initiated an arbitration against The Medicines Company (MDCO), under the rules of the International Chamber of Commerce, seeking damages of USD82mn arising from MDCO’s repudiation of the license agreement. SymBio argued that MDCO’s failure to provide sufficient assurance to the company regarding the performance of obligations under the license agreement in light of its decision to withdraw from business activities relating to SyB P-1501 in the European and US markets was a material breach of the license agreement. In September 2020, SymBio announced it had received the arbitration judgment and although the Court of Arbitration did not award damages sought by the company, it did order MDCO to pay 50% of legal costs (USD4.95mn) sought by the company. 

Overseas

The company marketed SyB L-0501 in South Korea, Taiwan, and Singapore, and product sales were in line with the company’s plans.

In-licensing of drug candidates

The company is currently focusing on unrolling global development plans for antiviral drug brincidofovir it in-licensed in September 2019. It is constantly looking into multiple licensing deals and looking for and evaluating promising in-licensing drug candidates.

Income statement

See the Earnings Structure section for more information about specific items (from total sales to recurring profit) on the company’s income statement. Regarding non-operating profit/loss, extraordinary gain/loss, corporate income tax, etc., extraordinary gain of JPY529mn in FY12/20 mainly comes from the booking of JPY525mn in settlement payment. 

Historical forecast accuracy

Balance sheet