The Rise of BCMA CAR-T Therapies in Multiple Myeloma: Who Will Emerge as Best-in-Class?

The development prospects of BCMA CAR-T products have attracted much attention. Their application in the field of hematological tumor treatment is gradually becoming a reality, and innovative attempts in the treatment of autoimmune diseases have also painted a new growth blueprint for the market.

However, despite the market's high expectations for the future of BCMA CAR-T products, it is still difficult to predict which product will ultimately become the industry "ceiling."

Efficacy and safety are key indicators for evaluating these products, and different products perform differently in these aspects. This means that the competitive landscape of the market will be determined by the clinical trial results and patient feedback of the products.

Who will eventually dominate this market remains to be revealed over time. At present, many strong players have emerged in China, with a greater chance of winning.

Taking IASO Bio as an example, since the one-year anniversary of its listing, with the continuous release of clinical data, its product Equecabtagene Autoleucel (trade name: Carvykti) is gradually demonstrating the potential to become a "Best-in-Class" (BIC) candidate.

/ 01 / Efficacy is deep and long-lasting

The most core competitiveness of CAR-T products is undoubtedly the remarkably outstanding efficacy. In terms of objectives, it involves two aspects: rapid and deep remission as well as long-lasting effects. To put it simply, it means both excellent treatment outcomes and prolonged durability. This is exactly the characteristic of Equecabtagene Autoleucel.

1) Rapid and profound relief effects

In terms of remission, the most core observation indicators are the combination of CR (Complete Remission) rate and MRD (Minimal Residual Disease) negative rate.

CR is defined as negative serum and urine immunofixation electrophoresis, disappearance of soft tissue plasmacytomas, and plasma cells < 5% in bone marrow (BM) aspirate. As the name suggests, the higher the CR rate, the more significant the treatment effect.

And MRD refers to minimal residual disease. During or after treatment, the amount of malignant tumor cells remaining in a cancer patient's body may be very small, but they can still potentially cause a recurrence of cancer. Therefore, MRD negativity means that the treatment has achieved a very deep response.

Whether it is CR or MRD, they both directly predict the patient's progression-free survival (PFS) and overall survival (OS). In particular, regarding MRD, at the FDA's third Oncologic Drugs Advisory Committee (ODAC) meeting held in April this year, after oncology experts reviewed data supporting the use of surrogate endpoints for the approval of multiple myeloma drugs, all 12 members voted unanimously to support the use of MRD as a surrogate endpoint to expedite the approval of new therapies for multiple myeloma.

Specifically, for Icarus Bio's equecabtagene autoleucel, it has demonstrated unique advantages globally in terms of both the CR rate and the MRD negativity rate.

Latest data from the registrational clinical trial FUMANBA-1 of IASO Bio's equecabtagene autoleucel:As of December 31, 2022, among 103 evaluable subjects, the rate of stringent complete response/complete response (sCR/CR) was 77.7%.

In terms of CAR-T products already on the market globally, this figure already ranks first. However, in the FUMANBA-1 clinical trial, patients who had previously received CAR-T therapy were included.If this group is excluded, the sCR/CR rate reaches 82.4% among the 91 subjects without a prior history of CAR-T treatment.

And,The MRD negativity rate after Icarus treatment also leads the industry: Among 91 subjects without a history of CAR-T treatment, the MRD negativity rate reached 97.8%, and 100% of patients in complete remission achieved MRD-negative status., indicating a more significant trend in PFS benefit。

More notably, IASO Bio's product has a lower dosing regimen, yet the median time to response (TTR) is only 15 days, and the median time to complete remission (TTCR) is just 95 days, both shorter than other similar products in terms of onset and time to achieve complete remission.

These data undoubtedly demonstrate the rapid and potent tumor-killing efficacy of Equecabtagene Autoleucel in the treatment of multiple myeloma.

2) Lasting efficacy

In addition to focusing on in-depth relief, another dimension we need to pay attention to is whether the efficacy is sufficiently long-lasting.

Currently, multiple myeloma remains incurable, and existing drugs have limitations such as insufficient treatment durability, significant side effects, and the need for long-term medication. CAR-T products, which have emerged as wonder drugs for cancer, naturally need to demonstrate more persistent efficacy, which is fundamental to their competitiveness.

In terms of the durability of efficacy, the irreplaceable gold standards are naturally PFS and OS. However, the issue is that the median PFS of standard treatment has exceeded 6 years, and the median OS is over 10 years. Consequently, new treatments require longer follow-up periods to demonstrate statistically significant differences in PFS. Including the patient enrollment period and follow-up time, it may even exceed 10 years.

Due to the relatively short time since the introduction of CAR-T products and the varying clinical progress of different CAR-T products, there is a lack of long-term PFS and OS data.In this regard, we can make corresponding observations through the PFS rate and OS rate of specific cycles.

For example, the 12-month PFS rate is an observation index. This index refers to the proportion of patients who have not experienced disease progression within one year.According to the FUMANBA-1 clinical trial, the 12-month PFS rate of Ixcellen (Equecabtagene Autoleucel) was as high as 85.5%.

In addition to the PFS rate, the MRD negativity rate at specific time points also provides us with an excellent observation window. As mentioned earlier, MRD is an indicator reflecting tumor recurrence. Maintaining a long-term MRD negativity rate suggests that the CAR-T product has an exceptionally durable effect.

From the clinical data of IASO Bio's equecabtagene autoleucel, the PFS rate is highly consistent with the MRD-negative rate.The 12-month sustained MRD negativity rate of this product reached 81.7%.

These data provide strong support for the competitiveness of IASO Bio's equezelcel in the multiple myeloma treatment field. Of course, it is important to note that apart from PFS and MRD negativity rates, long-term survival rates are also crucial indicators for evaluating treatment efficacy. Future long-term follow-up data will further validate the efficacy and safety of equezelcel, benefiting patients and...HealthcareProfessionals provide more comprehensive decision-making basis.

3) Deep Response in Refractory Patients

Deep and lasting therapeutic effects are undoubtedly the treatment goals of all CAR-T products. However, beyond that, we also need to observe the versatility of CAR-T products—whether they can deliver therapeutic benefits to more patients.

The core reason is that, due to objective factors, some patients have limited therapeutic effects from CAR-T products and are referred to as "refractory patients."

For example, tumor burden can affect the efficacy of CAR-T therapy. In multiple myeloma patients, the accumulation of free BCMA (sBCMA) may "compete" with BCMA expressed on the surface of myeloma cells, thereby reducing the killing effect of BCMA-targeted therapies, including BCMA CAR-T, on myeloma cells. It can also influence the pharmacokinetics and pharmacodynamics of BCMA CAR-T, such as increasing BCMA CAR-T exhaustion. Currently, all CAR-T products approved by the FDA have reported that high baseline levels of sBCMA impact their therapeutic efficacy, significantly reducing PFS and/or the complete response rate.

Currently, not all CAR-T products will be affected. At the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in 2024, IASO Bio presented data showing that its product, Equecabtagene Autoleucel, was unaffected by sBCMA levels.

As shown in the figure above, there were no significant differences in the overall response rate (ORR), complete response rate (CR), minimal residual disease (MRD) negativity rate in the total population, and 18-month progression-free survival rate (PFS) between the high and low baseline sBCMA groups after infusion.

In this regard, Professor Luogui Qiu from the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, and Professor Chunrong Li from Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, stated that Idecabtagene Vicleucel can overcome the influence brought by baseline sBCMA, providing more significant and durable relief for patients. This includes patients with higher baseline sBCMA levels and those whose efficacy of other BCMA CAR-T or BCMA-targeted treatments is affected by sBCMA, making it a more universal choice for all multiple myeloma patients.

In fact, according to the 2023 ASH Annual Meeting data, other baseline characteristics were similar to the entire FUMANBA-1 population, further suggesting the potential for higher versatility of Icaritin.

/ 02 / Safety Far Ahead

In the competition of CAR-T products, safety is a crucial factor. For BCMA CAR-T products, the importance of safety is reflected in two aspects.

On the one hand, it is the feasibility of frontline treatment. In the field of cancer treatment, the safety of BCMA CAR-T products will directly affect whether they can be used as a frontline treatment option.

On the other hand, it is the foundation of treatment for autoimmune diseases. For autoimmune diseases, patients often have long treatment cycles, which requires therapies to not only be effective but also have sustained safety and tolerability, ensuring that patients can benefit in the long term without being affected by severe side effects.

In addition to its efficacy, which combines depth, breadth, and durability, IASO Bio's product also leads the way in terms of safety.

1) A lower proportion of Grade 3 or higher CRS, ICANS

An important indicator for measuring the safety of CAR-T products,The proportion of Grade 3 or higher CRS (Cytokine Release Syndrome) and ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome).

Since the clearance of tumor cells by CAR-T cells involves the release of a large number of cytokines, it can strongly activate the immune system in the body, which easily leads to CRS.

Meanwhile, if cerebral CRS or abnormal expansion of CAR-T cells in the cerebrospinal fluid occurs, it is also likely to cause ICANS.

CRS and ICANS are the most common toxic side effects of CAR-T cell therapy, which may endanger the patient's life if not controlled.

Although timely clinical detection and early intervention can prevent tragedies, the challenge lies in ensuring timely detection and early intervention, as this requires extremely high medical standards. A CAR-T product with a lower incidence of Grade 3 or higher CRS and ICANS would be more competitive.In fact, a lower incidence of Grade 3 or higher CRS and ICANS is precisely a characteristic of IASO Bio's product.

According to the Fumanba-1 study, only 1% of patients experienced Grade 3 or higher CRS, which is the lowest level among currently marketed similar products. Additionally, only two patients treated with Idecabtagene Vicleucel exhibited ICANS reactions, both of which were below Grade 3 in severity.

This indicates that Icarus Bio's Equecabtagene Autoleucel has a significant advantage in terms of safety, and may become the preferred treatment choice for doctors and patients.

2) "0" Rare Complications

For BCMA CAR-T products, in addition to the related toxic side effects that occur during treatment, there are also some rare complications that require long-term tracking. In terms of real-world research, there are two types of phenomena that need long-term attention.

First, whether there are treatment-related motor/neurological side effects, especially Parkinson's disease. In real-world studies, cases of induced Parkinson's disease have been observed in currently marketed BCMA CAR-T products.

Second, whether treatment-related secondary tumors have occurred. It is not new that CAR-T products may cause secondary tumors. Last November, the FDA announced it was investigating marketed CAR-T products to determine whether they could lead to T-cell malignancies in extremely rare cases, which plunged the market into panic.

Of course, for now, not all CAR-T products will lead to the aforementioned rare cases.For example, in the Chinese population of subjects in the registration study, no movement/cognitive disorders, no Parkinson's disease, and no secondary tumors were found with Idecabtagene Vicleucel.

The above positive results indicate that Icarus is a potentially safer treatment option.

/ 03 / Birth Determines Destiny

Whether in terms of safety or therapeutic efficacy, Idecabtagene Vicleucel has demonstrated extremely prominent advantages, which is not surprising. It is inevitable that there are performance differences between different CAR-T products.

As the saying goes, birth determines destiny. Globally, differences in technological levels among enterprises lead to variations in their sequence designs, directly impacting their core competitiveness.

From the molecular structure perspective, Idecabtagene Vicleucel, which demonstrated advantages in the MAIC analysis, possesses three major breakthrough structural advantages.

First, its design of full-epitope antibodies, which involves the synergistic interaction of light-chain and heavy-chain antibodies, is consistent with human natural antibodies. This design can form a more stable and compact extracellular antibody structure, specifically and tightly binding to the BCMA antigen on the surface of multiple myeloma cells. It also mediates the rapid activation and transduction of cellular signals, inducing stronger tumor-killing capabilities.

Second, the dissociation kinetics are very close to those of healthy human T-cell receptors (TCR) (6 minutes).This behavior, which is highly similar to that of a normal human body, not only enhances tumor-killing efficiency and alleviates depth but also reduces self-exhaustion.This is beneficial for IASO Bio in the body.Rapid, thorough tumor killing and持久地发挥免疫监视作用，降低复发的风险。

In contrast, other BCMA CAR-T products, such as Zevor-cel, have a lower dissociation constant, resulting in a longer dissociation time (approximately 45 minutes). This prolonged binding time may inhibit the continuous killing activity of individual CAR-T cells, affect tumor-killing efficiency, and potentially lead to further exhaustion or even death of CAR-T cells, shortening their persistence in patients and possibly reducing the depth of response and long-term efficacy.

This might explain why the dosage of Zevor-cel is approximately twice that of Eque-cel, but the latter demonstrates a high CR rate and high PFS rate in the Chinese patient population, reflecting the excellent tumor-killing ability and long-term efficacy of individual Eque-cel cells.

Third, the use of low immunogenicity fully human antibodies makes it less likely to produce anti-drug antibodies (ADAs) that could affect the long-term survival of CAR-T cells after infusion. At 3 months post-infusion of Equecabtagene Autoleucel, the ADA was only 1.3%, indicating the characteristic of persistent durability due to its low immunogenicity.

Data show that the median persistence time of IASO Bio's CAR-T product in patients is 419 days, surpassing the critical threshold of 280 days, which has been proven to significantly improve the overall survival (OS) rate for patients with multiple myeloma.

It is precisely the advantage of molecular design that makes equecabtagene autoleucel appear more promising in the field of oncology and become the first cell therapy product globally to be applied to autoimmune diseases. In the clinical trials of four indications, including myasthenia gravis, conducted by Wuhan Tongji Hospital for neuro-autoimmune diseases, it has achieved a breakthrough curative effect on advanced autoimmune patients, freeing them from conventional drug treatments such as hormone therapy.

Although the long-term market position of Idecabtagene Vicleucel among BCMA CAR-T products remains to be seen, it has already demonstrated to the market the importance of in-depth technological expertise in an era of rapid technological advancement. In the future, companies that will dominate the BCMA CAR-T field will undoubtedly be those that continuously invest in technological innovation and possess core technological advantages.

       Title: The Era of BCMA CAR-T Therapy in Multiple Myeloma – Who Will Become the Best in Class?