What is the potential for BMS BCMA targeted therapy before GSK?

Today, BMS and Bluebird Bio jointly announced the re-submission of BCMA CAR-T's listing application to the FDA.
the month, GlaxoSmithKline's (GSK) BCMA antibody-coupled drug was approved by the FDA's Oncology Drug Advisory Committee (ODAC) with a 12-0 vote.
addition, BCMA CAR-T therapy, developed by Nanjing Legend and Janssen, a unit of Johnson and Johnson, plans to submit a listing application in the US later this year.
these advances means that the world's first BCMA treatment is out there.
BCMA has been one of the most popular targets in recent years, with more than 60 pipelines developed worldwide and the second most popular clear target after cell therapy relay CD19.
In addition to the leading GSK, BMS, Nanjing Legend / Yang Sen, etc. , a group of Chinese upstates are lying out, by Koji Biology, Reindeer Medical, Xinda Bio, Yuxi Bio and other companies developed BCMA targeted therapy has been on the international stage.
With the maturity of technologies such as dual-specific T-cell joints (BiTE), CAR-T therapies, and antibody coupling drugs (ADCs), innovative therapies in the field of BCMA are transforming the paradigm for the treatment of patients with multiple myeloma (MM).
ideal target B-cell mature antigen (BCMA), also known as TNFRSF17 or CD269, is a member of the tumor necrotogenic pathogenic complex (TNFR) super family.
BCMA is mainly expressed in mature B lymphocytes and plasma cells and is largely d'detected in other normal human cells.
when combined with ligation B cell activation factor (BAFF) and induced proliferation ligation (APRIL), it activates the two signaling path path paths, NF-B and JNK, and is a necessary survival signal to maintain the survival, differentiation and maturation of myeloma cells.
signaling path path in the maturation of P-B cells (Photo Source: Resources) Compared to other popular targets such as PD-1/PD-L1, PCSK9, BCMA targeted therapy is impressive because it focuses only on MM as a disease.
is also one of the biggest features of BCMA, expressed in all MM cells, is the ideal antigen target for the treatment of MM.
MM is the second most common malignant tumor of the blood system after non-Hodgkin's lymphoma.
despite significant advances in protease inhibitors, immunomodulation drugs and CD38 targeted antibodies in recent years, almost all patients eventually relapse.
according to a 2019 review published in The Reviews Drug Discovery, it is considered an incurable disease with a five-year survival rate of about 50 percent and is expected to reach a global market share of $29 billion by 2027.
is clear that the urgent need for new drugs in this area is far from being met.
the advantages and limitations of the three innovative therapies, there are currently more than 60 active research and development projects targeting BCMA.
of these, most are CAR-T cell therapy, followed by dual-specific T-cell joints (BiTE) and antibody coupling drugs (ADCs).
different types of innovative therapies have potential advantages and limitations.
CAR-T therapy: This type of therapy targets MM cells by engineering the patient's T-cells in-body to express CAR that is specific to BCMA.
The most obvious advantage is that modified CAR-T cells can amplification in the human body after a single infusion, which may give the body long-lasting immunity to cancer cells, meaning that patients are expected to achieve one-time drug treatment and "cure."
but its limitations are the complexity of the pre-manufacturing process, which typically takes weeks from the collection of cells in the patient's body to the final return.
another potential risk is that a patient's pre-treatment before cell therapy, lymphatic excision, may have an impact on complementary therapy after cell therapy fails.
different BCMA dual-specific antibodies (Photo Source: Resources) BiTE: BiTE: BiTE, most of which are currently clinically developed to target BCMA.
one end binds to the BCMA antigen and the other end binds to the CD3 subject on the surface of the T cell, which collects the T cells around the tumor cells, which in turn kills the tumor cells.
these antibodies are smaller than conventional antibodies, but have excellent activity.
clinical trials conducted in the united States have shown that adverse events after BiTE treatment have infection and cytokine release syndrome, although the rate and severity are lower than in CAR-T products.
limitations of this type of therapy are that the half-life is shorter than the full-length antibody and requires intravenous infusion, which cannot be amplified and persisted in the body.
ADC: These therapies link anti-BCMA antibodies to cytotoxic agents and kill cancer cells by targeting BCMA for cytotoxic agent-specific feeds into MM cells.
car-T therapy, ADCs do not need to collect samples from patients to produce personalized therapies, and are easier to scale up to commercial levels without complex production and treatment options.
like Bite, it can induce immunogenic responses to myeloma cells, which can help promote long-lasting endogenetic anti-tumor activity.
, ADC induces cell death even when the immune system is depleted, and therefore may provide activity in patients with the weakest immunity.
, however, the safety of such products depends largely on the cytotoxic agents used, and the premature release of toxins will have an impact on healthy cells.
two of the world's products are about to go on sale, it is reported that the world has two BCMA targeted therapies in the United States to submit a new drug market application.
one of the antibody-coupled drugs developed for GSK to target BCMA, belantamab mafodotin, and the other for BMS, the targeted BCMA CAR-T therapy idecabtagene vicleucel.
recent developments, the first BCMA targeted therapy is coming.
Belantamab mafodotin is one of GSK's key research and development projects and has been recognized by the FDA as a breakthrough therapy.
comes after the product obtained positive results in a critical Phase 2 clinical trial called DRAMM-2 and supported GSK's application for a biological product license (BLA) by the end of 2019, which the FDA subsequently granted priority review eligibility.
July 14, GSK announced that the FDA Oncology Drug Advisory Committee (ODAC) voted 12-0 to support candidate drugs that benefit more than risk in treating patients with relapsed/refractic multiple myeloma.
It's worth noting that the product was approved in a clinical trial in China in May this year for the use of combined boronazome and dexamisong for the treatment of adult patients with multiple myeloma who have received at least one previous treatment.
targeting BCMA's ADC (Photo: Resources) Idecabtagene vicleucel (ide-cel, a.k.a. bb2121) is a CAR-T therapy for targeting BCMA developed by BMS and Bluebird Bio.
today, the two companies resubmit their listing applications to address unsolved regulatory requirements filed by the FDA in May 2020 after the initial BLA filing in March 2020.
the application, based on positive results from a key one-arm, open-label Phase 2 trial called KarMMa, ORR reached 73.4 percent and full remission rate (CR) 31.3 percent among a total of 128 patients who were able to evaluate efficacy.
approved, the idecabtagene vicleucel is expected to be the first CAR-T treatment to target BCMA.
, Nanjing Legend, Koji Bio and other Chinese companies have emerged in China, BCMA targeted therapies are also sought after by many biopharmaceutical companies and research institutions, and mostly focus on CAR-T therapies.
incomplete statistics, there are more than 10 targeted BCMA CAR-T therapies in the clinical development stage.
Among them, BCMA targeted therapies from Nanjing Legend, Koji Bio, Reindeer Medical/Cyda Bio, Syrhma Bio, Sibiman Biology, etc., have been presented at the annual meeting of the American Society of Hematology (ASH), which has attracted the attention of the industry for their excellent early clinical data.
legend: The company has teamed up with Jansen to develop a CAR-T therapy JNJ-4528 (LCAR-B38M) targeted at BCMA.
, the product has been presented at several international conferences with excellent data and has been recognized as a breakthrough therapy in the United States.
the latest JNJ-4528 data, 25 of the 29 patients treated achieved complete remission while maintaining an objective remission rate of 100%.
, the product is currently being studied for the one-arm phase 2 open phase of the treatment of patients with recurring or recurring multiple myeloma in China.
, according to the Nanjing Legendary prospecto, the product will be submitted to the U.S. in the second half of this year.
Cozi Bio: CT053 is an all-human BCMA CAR-T cell product developed by Kozi Bio, which has been awarded the FDA's Advanced Therapy for Regenerative Medicine (RMAT), Orphan Medicine Qualification, EMA's Priority Drug Qualification (PRIME) and Orphan Drug Qualification.
According to data presented by Koji Bio at the 2019 ASH Annual Meeting, 24 patients with relapsed/difficult-to-treat multiple myeloma were treated with CT053, and the subjects were likely to achieve partial remission and above 2-4 weeks after CT053 infusion, with ORR reaching 87.5%, a complete remission rate of 79.2% and a medium PFS of 16.6 months.
currently, registered clinical studies of the product in the United States and Canada have been initiated.
BCMA CAR-T Therapy (Photo Source: Resources) Reindeer Medical/Cynda Bio: The two companies have jointly developed an all-human source BCMA CAR-T (IBI326), which was developed to transsection auto-T cells using romvirus as a gene vector.
early studies have shown that the product has strong and fast efficacy and has outstanding response durability.
according to data released at the 2019 ASH Annual Meeting, the product treats patients with relapsed/resoicative MM with ORR up to 100% in assessable patients (17 cases), 70.6% achieves complete remission, and 88.2% of patients receive very good partial remission (VGPR) or better outcomes.
, the product is currently conducting Phase 1b/2 clinical trials in China.
: Dual CAR-BCMA-19 (GC012) is a research CAR-T cell therapy developed by the company to treat patients with BCMA-positive or/and CD19-positive recurrence/refractic MM by expressing biantibodies on the same T-cell targeting BCMA and CD19 antigens.
in vitro and in vitro have shown that the product can effectively remove MM tumor cells.
human trials showed good safety and responsiveness.
the findings were presented at the 2019 ASH annual meeting.
it is worth mentioning that the fasTCAR™ technology has also been successfully applied to Dual CAR-BCMA-19, which is expected to enhance the proliferation of T cells in the human body, improve tumor damage and tissue migration.
Sibiman Bio: The company developed car-T therapy C-CAR008, which targets BMCA, to blend antibody fragments targeted at BMCA with the CD3ζ/4-1BB signal domain, and has been shown to be effective in removing BCMA-positive tumor cells in in vitro and in vivo trials.
Preliminary trial results of this product were announced at the ASH Annual Meeting last year, in the treatment of relapse /resoic MM phase 1 dose increment trial, 5 patients with assessable efficacy after 2 weeks of treatment began to improve symptoms, after 4 weeks of treatment, 1 patient reached complete remission, 3 patients reached very good partial remission.
addition, Hengrun Dasheng's anti-human BCMA T cell injection has been clinically approved in China for the treatment of BCMA-positive recurring/refractic multiple myeloma.
in the research product IM21 is targeted at BCMA chimed antigen subject T cell injection, is currently in the exploratory clinical research stage.
addition, Sonic Pharmaceuticals is also expanding the field, with its CAR-T cell therapy product, which targets BCMA, scheduled to launch Phase 1 in 2020.
Opportunities and challenges coexist Although most BCMA targeted therapies are primarily studied in people with relapsed or resuscable multiple myeloma (RRMM), the excellent clinical data observed so far suggest that if these therapies are used as an earlier treatment option for MM patients, they may have a transformative effect on the treatment paradigm of multiple myeloma.
there are still many unknowns to be solved in this area.
such as targeted immunotherapy, including BCMA targeted drugs, may be affected by antigen escape mechanisms.
how to target BCMA drugs with other drugs with different mechanisms of action in order to achieve optimal results.
addition, further evaluation is necessary for BCMA targeted treatment in patients with unsealed clinical needs (e.g. MM high-risk patients, elderly and infirm patients, or patients with kidney failure).
references: s1. Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol. 2002;2(7):465-475. doi:10.1038/nri844 .