Other pipeline developments for Shionogi Pharma (4582).
"Treaxine(R)" (generic name: bendamustine hydrochloride).
"Treaxine(R)" is an anticancer agent for malignant lymphomas. Malignant lymphoma is a disease in which lymphocytes, a type of white blood cell, become cancerous (tumor) and form lumps (tumors) in lymph nodes and organs, and can occur from lymph nodes and organs other than lymph nodes such as the stomach, intestines, thyroid gland, spinal cord, lungs, liver, skin, and eyes that are distributed throughout the body. It is the most common disease among blood cancers, with an annual incidence of over 30,000 in Japan, and the number of patients requiring treatment is expected to gradually increase with the increase in the elderly population. Malignant lymphomas are mainly divided into Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), of which about 90% are NHL in Japan. In addition, it is classified into low malignancy, medium malignancy, and high malignancy depending on the progression rate of symptoms, and there are various types of the disease.
(1) Expansion of indications: The company has been working to expand its indication for "Treaxine (R)" as a sales strategy. Starting with the approval for non-Hodgkin's lymphoma (low malignancy grade) and mantle cell lymphoma (MCL) in October 2010, it obtained sales approval for chronic lymphocytic leukemia (CLL) in August 2016, and for untreated (initial treatment) low-malignancy NHL/MCL in December of the same year. In addition, in July 2018, the Japanese Society of Hematology issued guidelines for the treatment of hematopoietic tumors, which included the combination therapy of "Treaxine (R)" and rituximab (BR therapy) as a choice of standard treatment for all approved indications. Thus, "Treaxine (R)" has now been positioned as the standard therapy for malignant lymphoma in name and reality. In addition, in July 2018, it obtained partial changes in approval concerning the combined use with not only rituximab but also a new anti-CD20 antibody preparation for follicular lymphoma (FL), which is a representative tissue type of low-malignancy NHL, and it was added as a treatment option. In March 2019, it obtained partial changes in approval for pretreatment of tumor-specific T-cell infusion therapy, and the use of "Treaxine (R)" became possible as pretreatment for the first CAR-T therapy in Japan, "Kymriah(R) intravenous drip injection" for recurrent and refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) and recurrent and refractory CD19-positive DLBCL.
Novartis AG has been working to expand the indications for "Treaxine(R)" as a sales strategy
In addition to the above, in March 2021, it obtained sales approval for recurrence-resistant DLBCL. With the approval of P-BR therapy, a combination therapy of Obinutuzumab and BR therapy, which was being developed by Chugai Pharmaceutical Co., Ltd., the target patient population has expanded significantly compared to the past. It is expected that in the future, the side-effect-free and highly effective BR therapy and P-BR therapy will penetrate as standard therapies. It will be up to the doctor to decide whether to choose BR therapy or P-BR therapy based on the patient's symptoms and genetic type.
※1Obinutuzumab ("Gazyva(R)": sold by Chugai Pharmaceutical Co., Ltd. <4519>): a type II anti-CD20 monoclonal antibody that binds to CD20, a protein expressed on B-cells other than stem cells and plasma cells, similarly to rituximab, which is recommended in treatment guidelines for NHL in Japan and abroad, and directly attacks and destroys target B-cells along with the immune system in the body.
※2Tumor-specific T-cell infusion therapy: a therapy in which a patient's T-cells (a type of lymphocyte) are artificially given cancer specificity outside of the body, amplified, and then administered to the patient.
※3Chimeric antigen receptor T-cell therapy: a therapy in which a chimeric antigen receptor (CAR) that combines the antigen binding site of an antibody that recognizes membrane antigens on tumor cells with the intra-cellular domain of a T-cell receptor is introduced into T-cells, amplified, and infused. It is one of the tumor-specific T-cell infusion therapies.
※4Kymriah(R) Intravenous Infusion (generic name: tisagenlecleucel; manufacturer: Novartis Pharma K.K.): the first CAR-T therapy approved in Japan, which was approved for the indication of recurrent/refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) and recurrent/refractory CD19-positive DLBCL in March 2019.
Its indication for salvage therapy for recurrent/refractory DLBCL was also approved in March 2021. In addition to the BR therapy, P-BR therapy, a combination therapy of Polatuzumab vedotin, which is a development of Chugai Pharmaceutical Co., Ltd., was approved, further expanding the target patient population. It is expected that in the future, side effect-free and highly effective BR therapy and P-BR therapy will become widely used as standard therapies. It will be up to the doctor to decide whether to choose BR therapy or P-BR therapy based on the patient's symptoms and genetic type.
Standard treatment for untreated DLBCL is combination therapy with rituximab and chemotherapy, but about 40% of patients relapse. Autologous stem cell transplantation (ASCT) is recommended as one of the treatment options for relapsed/refractory DLBCL, but about half of them have not been able to receive ASCT due to the lack of effectiveness of rescue chemotherapy prior to ASCT. Furthermore, many patients are not eligible for ASCT due to factors such as age and comorbidities, and standard treatment has not yet been established.
Polatuzumab vedotin: an anti-CD79b antibody-drug conjugate developed by Roche using ADC (Antibody-Drug Conjugate) technology from Seattle Genetics＜SGEN＞, which links a humanized monoclonal anti-CD79b antibody with a tubulin polymerization inhibitor via a linker. CD79b protein is specifically expressed in many B cells and is considered a promising target for developing new therapies. Polatuzumab vedotin is thought to bind to CD79b while suppressing its impact on normal cells, and destroy B cells with the delivered chemotherapy agent.
As of December 2023, RTD formulation of "Trexin(R)" has completely shifted from FD formulation since its release in January 2021. In addition, it has obtained sales approval for RI administration in February 2022, with 90% of overall shifting to RI administration by the end of December 2023. RI administration is expected to greatly reduce the burden on medical personnel and patients by shortening the infusion time from the conventional 60 minutes to 10 minutes.
(2) Impact of generic drugs
In February 2022, four companies (Toa Pharmaceutical＜4553＞, Pfizer Inc., Meiji Seika Pharma Co., Ltd., and Kowa Sei Co., Ltd.) announced the acquisition of marketing approval for generic drugs with RTD formulations as generic drugs with RTD formulation as their reference drug. In addition, Toa Pharmaceutical and Pfizer obtained sales approval for RI administration in November of the same year. Toa Pharmaceutical began selling it in June 2022, followed by Pfizer in December of the same year. Although there was almost no impact on sales in 2022, share of the company, which was over 90% in January 2023, has gradually declined to about 60% by December of the same year. This was partly due to the significant price difference with the reference drug, as well as the impact of Pfizer's launch. However, compared to other anticancer drugs, the rate of decline in sales after the launch of generic versions has been relatively slow. This is thought to be due to the company's extensive network of KOLs and hematologists across the country, where periodic seminars are held to provide the latest information, as well as the high safety of the reference drug as a branded product. In addition, although the price difference is large, the price of the anticancer drug is relatively low, and the importance of pricing as a purchasing criterion for medical institutions is relatively low, which is also recognized by the company.
The company has filed a lawsuit with the Tokyo District Court in December 2022 against the two companies that launched generic drugs based on the patent infringement together with Eagle, the licenser, seeking an injunction and damages for the manufacture and sale of generic drugs, but it is expected to take some time for the final judgment to be made, and the company anticipates that the share of "Trexin (R)" will continue to decline gradually in the future.
(Written by FISCO guest analyst, Jo Sato)