■Other pipeline trends for Synbio Pharmaceuticals＜4582＞

1. “Treaxine (R)” (generic name: bendamustine hydrochloride)

“Treaxine (R)” is an anticancer drug for malignant lymphoma. Malignant lymphoma is a disease in which lymphocytes, which are a type of white blood cell, become cancerous (tumours) and form lumps (tumors) in lymph nodes or organs, and also occurs from lymph nodes distributed throughout the body and organs other than lymph nodes (stomach, intestines, thyroid, spinal cord, lungs, liver, skin, eyes, etc.). It is the most common disease among blood cancers, and the number of cases per year in Japan exceeds 30,000, and the number of patients requiring treatment is expected to increase moderately as the elderly population increases. Malignant lymphoma is mainly divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), and NHL accounts for about 90% of cases in Japan. Also, depending on the rate at which symptoms progress, they are classified as low grade, medium grade, and high malignancy, and there are various disease types.

(1) Expansion of indications

The company has been working to gradually expand indications as a sales strategy for “treaxine (R).” Starting with obtaining sales approval for recurrent and intractable low-grade non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL) in 2010/10, sales approval for chronic lymphocytic leukemia (CLL) was obtained in 2016/8, and untreated (initial treatment) low-grade NHL/MCL was obtained in December of the same year. Also, in 2018/7, a combination therapy (BR therapy) of “treaxine (R)” and rituximab was newly included in the hematopoietic tumor treatment guidelines issued by the Japanese Society of Hematology, and it was recommended as a standard treatment option for all approved indications, and “treaxine (R)” was positioned as standard therapy for malignant lymphoma in both name and reality.

In addition, for CD20 positive follicular lymphoma (FL), which is a representative histological type of low-grade NHL, partial change approval relating to combination not only with rituximab but also with a novel anti-CD20 antibody preparation was obtained in 2018/7, and combination therapy with obinutuzumab*1 was added as a treatment option, and approval for partial changes related to pretreatment for tumor-specific T-cell infusion therapy*2 was obtained in 2019/3, the first CAR-T therapy*3 “kimria (R) infusion It is now possible to use “treaxine (R)” as a pretreatment for “intravenous injection*4.”

*1 Obinutuzumab (“Gazaiba (R)”: distributor Chugai Pharmaceutical ＜4519＞): Similar to rituximab recommended by domestic and international treatment guidelines as a therapeutic agent for NHL, it is a sugar chain modified type II anti-CD20 monoclonal antibody that binds to CD20, which is a protein expressed on B cells other than stem cells and plasma cells, and directly attacks and destroys target B cells and the immune system in the body.

*2 Tumor-specific T cell infusion therapy: A therapy in which cancer patients' own T cells (a type of lymphocyte) are artificially imparted with cancer specificity outside the body, amplified, and then administered to the patient.

*3 CAR-T therapy (chimeric antigen receptor T cell therapy): Among tumor-specific T cell infusion therapy, a therapy in which a gene encoding a chimeric antigen receptor (CAR) that combines the antigen binding site of an antibody that recognizes membrane antigens on tumor cells and the intracellular domain of the T cell receptor is introduced into T cells and amplified and injected.

*4 Kymuria (R) intravenous infusion (generic name chisagenlecle eucel: distributor Novartis Pharma Co., Ltd.): This is the first CAR-T therapy approved in Japan, and manufacturing and sales approval was obtained in 2019/3 using recurrent and refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) and recurrent and refractory CD19 positive DLBCL as indications.

Furthermore, in March 2021, sales approval for recurrent and refractory DLBCL*1 was obtained, and in addition to BR therapy, a combination therapy (P-BR therapy) of poratuzumab vedotin*2 and BR therapy, which Chugai Pharmaceutical was developing, was approved, so the number of target patients also expanded significantly compared to the past. It is thought that BR therapy and P-BR therapy, which have few side effects and are highly effective, will spread as standard therapies in the future. Note, whether to choose BR therapy or P-BR therapy will be determined by the doctor depending on the patient's symptoms, gene type, etc.

*1 The standard treatment for untreated DLBCL is a combination of rituximab and chemotherapy, but approximately 40% of patients have recurred. Also, implementation of autologous hematopoietic stem cell transplantation (ASCT: autologous stem cell transplantation) is recommended as one treatment for recurrent and refractory DLBCL, but relief chemotherapy before ASCT is not effective in about half of them, and ASCT cannot be performed. Furthermore, there are many patients who are not eligible for ASCT due to age or complications, etc., and standard treatment has not yet been established.

*2 Polatuzumab vedotin: An anti-CD79b antibody drug complex developed by Roche using ADC (Antibody-Drug Conjugate: Antibody-Drug Conjugate: Antibody-Drug Conjugate) technology of Seattle Genetics＜SGEN＞ in the United States, in which a humanized anti-CD79b monoclonal antibody is combined with a tubulin polymerization inhibitor with a linker. CD79b protein is specifically expressed in many B cells, making it a promising target for developing new treatments. Polatuzumab vedotin binds to CD79b while suppressing effects on normal cells, and is thought to destroy B cells by delivered chemotherapeutic agents.

Furthermore, sales of RTD formulations, which are liquid types of “treaxine (R),” began in January 2021, and all switches from FD formulations were completed in December of the same year. Also, sales approval was obtained for RI administration in 2022/2, and 90% of the total was switched to RI administration as of the end of 2023/12. This is because RI administration can greatly reduce the burden on health care workers and patients by shortening the intravenous infusion time from the conventional 60 minutes to 10 minutes.

(2) Effects of generic drugs

In February 2022, it was announced that 4 companies (Towa Pharmaceutical ＜4553＞, Pfizer Inc.), Meiji Seika Pharma Co., Ltd., and Koisei Co., Ltd.) have obtained sales approval for generic pharmaceuticals using RTD formulations as starting drugs. Also, it was announced that of these, Towa Pharmaceutical and Pfizer obtained sales approval for RI administration in November of the same year. Following the fact that Towa Pharmaceutical began sales in 2022/6, Pfizer began sales in December of the same year. Although there was almost no impact on the sales side until 2022, the company's market share, which was over 90% as of 2023/1, fell to about 60% in December of the same year, and market share gradually eroded. In addition to the fact that drug prices had a large drug price difference of about 43% of the starting product, it seems that the fact that Pfizer started sales had an impact. Nonetheless, compared to cases of other anticancer drugs, the rate of decline in market share since generic products were released has moderated. It is thought that an extensive network has been built with KOLs and hematology health care workers from all over the country, and that the latest information has been provided by holding seminars on a regular basis, etc., and the high level of safety as a starting product has been evaluated. Also, although there is a large difference in drug prices, the company sees that the price of anticancer drugs is in the low price range, and the priority of drug prices is relatively low as a purchase standard for medical institutions.

In addition, the company filed a lawsuit against the two companies that sold generic pharmaceuticals with the Tokyo District Court in 2022/12 to cancel manufacture and sale of generic pharmaceuticals and claim for damages based on patent infringement in collaboration with Eagle, which is the license source, but it seems that it will take some time for the final judgment results to come out, and the company assumes that market share for “treaxin (R)” will continue to decline moderately in the future.

(Author: FISCO Visiting Analyst Joe Sato)