Innovative Breakthrough Amid Life-or-Death Urgency: Isatuximab Emerges as a Game-Changer in Multiple Myeloma Therapy
Sanofi
Pharmaceutical R&D Developer
In the field of cancer treatment, multiple myeloma (MM) has always been a fortress that needs continuous攻克, and it is also a popular area for new drug development.
In recent years, CD38 monoclonal antibodies have emerged as a significant advancement, demonstrating treatment advantages both as monotherapy and in combination regimens for newly diagnosed multiple myeloma (NDMM) patients in first-line induction and for relapsed or refractory multiple myeloma (RRMM) patients.
Recently, at the American Society of Clinical Oncology (ASCO) Annual Meeting and the European Hematology Association (EHA) Annual Meeting, Sanofi announced two significant research advancements, further fueling the CD38 track for MM.
Among them, the IMROZ Phase 3 clinical study for NDMM patients unsuitable for transplantation has demonstrated the potential of Isatuximab as a "first-in-class" combination therapy. Its combination with bortezomib, lenalidomide, and dexamethasone (VRd) reduces the risk of relapse or death by 40%. The complete data was simultaneously published in The New England Journal of Medicine. Based on this study, the U.S. Food and Drug Administration (FDA) has granted Isatuximab priority review status.
Another real-world study for RRMM patients, the IsaFiRsT study, is the first to evaluate the combination therapy of Isatuximab with Pomalidomide and Dexamethasone (Isa-Pd) in Chinese patients, serving as an innovative drug registration study. The study met its primary endpoint, with an Objective Response Rate (ORR) reaching 82.6%.
These two research achievements are not far away from Chinese patients. According to the query on the CDE official website, Sanofi's new generation of CD38 monoclonal antibody drug Isatuximab has submitted two indications for market application in China and has been accepted by the National Medical Products Administration (NMPA), covering NDMM and RRMM patients. Chinese patients are expected to have access to innovative treatment options, and the CD38 treatment landscape will be completely reshaped.
MM Patients Await with Bated Breath, Innovative Therapies Offer "Lifesaving Hope"
Multiple myeloma is a malignant clonal plasma cell proliferative disease that leads to extensive bone destruction, accompanied by lytic lesions, osteopenia, and pathological fractures, known as the "bone-eating" blood disease.
According to statistics, there are approximately 1.6 multiple myeloma patients per 100,000 people in China, with the incidence rate increasing annually.1`, and the age of onset is lower compared to the global average.`2. At the same time, multiple myeloma is still an incurable malignant hematological tumor, and patients will eventually face the dilemma of recurrence.3. The more times of clinical recurrence, the greater the difficulty of treatment, and the shorter the progression-free survival and post-relapse survival time for patients.4-5In other words, patients are always staring into the "abyss" of recurrence, where each episode can be life-threatening, urgently demanding more innovative and high-quality drugs and solutions.
Therefore, for RRMM patients, it is necessary to switch to drugs with new mechanisms to avoid drug resistance. Currently, the treatment options in later lines are still very limited, and patients urgently need more innovative drugs to expand treatment options. For NDMM patients, the first-line treatment regimen must strive to extend the time to first relapse and prolong progression-free survival (PFS), creating a better time window for later-line treatments and avoiding situations where no effective drugs are available in the later stages.
Among the numerous targets in multiple myeloma, CD38 still occupies a central position mainly due to its mechanistic advantages. CD38 is a transmembrane glycoprotein with extracellular enzymatic activity and also functions as a receptor and adhesion molecule. CD38 is expressed at low levels on normal lymphocytes, myeloid cells, and non-hematopoietic tissue cells, but is highly expressed on plasma cells and MM cells, making the CD38 molecule an ideal target for MM treatment.
In 2015, the world's first CD38 antibody, daratumumab, was approved by the U.S. FDA for marketing to treat patients with relapsed and refractory multiple myeloma. Following its market launch, the drug’s sales steadily increased, reaching $9.744 billion globally in 2023, demonstrating the significant application potential of the CD38 target in the MM field.
In 2020, Sanofi's CD38 monoclonal antibody Isatuximab was approved by the FDA for marketing. In the United States and the European Union, Isatuximab had been granted orphan drug designation for the treatment of relapsed or refractory multiple myeloma (RRMM). Currently, this drug has been approved for two indications.
China Real-World Study ORR Reaches 82.6%, Innovative Model Accelerates Accessibility
Under the significant unmet needs of MM patients, innovation in research and development along with acceleration have become key terms. Therefore, at the 2024 European Hematology Association (EHA) Annual Meeting, the latest progress of Sanofi's IsaFiRsT study was highly anticipated for its labels as a "real-world study," "targeting Chinese patients," and "serving as an innovative drug registration study."
In recent years, to promote the entry of advanced international drugs and medical devices into the Chinese market for the benefit of patients, the National Medical Products Administration (NMPA) has actively explored the application of Real-World Evidence (RWE) in the review and approval of drug and device products. As China's only "medical special zone," the Lecheng Pilot Zone has become a "policy highland," conducting cutting-edge research on the application of real-world data internationally, accumulating experience and exploring methods for the reform of drug and device review and approval systems in China.
Real-world studies, starting from clinical practice and focusing on patient needs, are playing an increasingly important role in the field of drug development and regulation. They demonstrate innovative value in promoting registration, access, and other aspects, opening up a unique "accelerated channel" for innovative products. Isatuximab is one of the three pilot drugs conducting clinical real-world data research in the Lecheng International Medical Tourism Pilot Zone.
This study enrolled a total of 24 patients with RRMM (median age of 62 years) who had previously received ≥2 lines of therapy (including lenalidomide and proteasome inhibitors) and had measurable serum or urine M protein (91.7% of the patients were resistant to PIs, 95.8% were resistant to lenalidomide, 91.7% were double-resistant, and 91.7% were resistant to their last line of prior treatment). These patients were treated with Isa-Pd until disease progression or the occurrence of unacceptable toxicity.
As of November 12, 2023, the primary endpoint ORR was achieved. At a median follow-up of 8.41 months, the median progression-free survival (PFS), overall survival (OS), and duration of response (DoR) were not reached.
Data show that Isa-Pd achieved an ORR of 82.6% in Chinese patients with RRMM, consistent with the results of the global Phase III ICARIA-MM study. Additionally, no new safety signals were identified, and overall adverse reactions were manageable.
Based on this real-world research project, Sanofi has submitted the marketing application for Isatuximab, which was accepted by the NMPA in December 2023. It is intended for use in combination with pomalidomide and dexamethasone to treat adult patients with multiple myeloma who have received at least two prior therapies (including lenalidomide and a proteasome inhibitor). This is the first hematology oncology drug to utilize real-world data from Lecheng to receive marketing authorization acceptance from the National Medical Products Administration.
Isa-VRd Combination Therapy: A First-in-Class Approach for Frontline Treatment of MM
If the later-line treatment of MM extends the "lifeline" of patients, then the first-line treatment will seize the golden window for patient survival. Despite the current application of various new therapies and drugs, challenges remain as none can avoid disease recurrence caused by clonal evolution or minimal residual disease (MRD). As the disease progresses, each recurrence becomes more aggressive, and the remission periods achieved by new therapies gradually shorten.
Therefore, first-line treatment becomes the new "main battlefield." The treatment plan must strive to extend the time of the first recurrence and prolong PFS, creating a better time window for subsequent treatments while avoiding the situation of having no available drugs in later stages.
Sanofi's Phase 3 IMROZ Study Data on Isatuximab for Newly Diagnosed Transplant-Ineligible Multiple Myeloma Patients Presented at ASCO Offers a Potential "First-in-Class" Combination Therapy Answer.
The study results showed that the IMROZ study met the primary endpoint (progression-free survival) and multiple secondary endpoints, with good safety and no new safety signals observed, as follows:
Compared with standard treatment VRd (bortezomib, lenalidomide, and dexamethasone) alone, the risk of disease progression or death was reduced by 40% in patients treated with Isatuximab-VRd. At 60 months, the estimated PFS was 63.2% for patients treated with Isatuximab-VRd, compared to 45.2% for those treated with VRd.
Among patients treated with Isatuximab-VRd, 74.7% achieved complete response, compared to 64.1% of those treated with VRd.
Among patients treated with Isatuximab-VRd, 55.5% achieved minimal residual disease (MRD)-negative complete response, compared to 40.9% of those treated with VRd.
Among patients treated with Isatuximab-VRd, 46.8% maintained MRD for 12 months or longer, compared to only 24.3% of patients treated with VRd.
Besides the achievement of the primary endpoint of PFS, it is worth mentioning the secondary endpoint of MRD-negative complete response. In the field of MM treatment, achieving undetectable minimal residual disease (uMRD) is one of the initial goals advocated to reach, especially for high-risk MM patients, where achieving deep remission is more critical. This promotes conversion to longer PFS and OS, playing a positive role in the dynamic risk stratification and treatment guidance for MM patients.
Sanofi News stated, "The IMROZ results demonstrate the potential for Isatuximab to become a 'cornerstone' of first-line treatment, possibly improving the long-term prognosis of multiple myeloma, an incurable disease. If successfully approved, Isatuximab will also become the first CD38 monoclonal antibody to be used in combination with standard therapy for the treatment of NDMM patients who are not eligible for transplant."
Based on this research data, in May this year, the U.S. FDA accepted the supplemental Biologics License Application (sBLA) for Isatuximab in combination with VRd for the treatment of newly diagnosed multiple myeloma patients who are not eligible for transplant, and granted it priority review. In China, on May 21, the NMPA also accepted the marketing application for this indication, marking the second indication for Isatuximab to have its marketing application accepted by the NMPA.
Summary
As a highly heterogeneous hematological malignancy, the multiple myeloma drug market still has a significant amount of unmet clinical needs. According to China's first "Quality of Life Survey Report for Multiple Myeloma Patients," nearly 50% of patients indicated that current treatments fail to meet their expectations regarding overall treatment efficacy and survival benefits, and they hold high hopes for new therapeutic approaches.
The CD38 target has shown promising therapeutic prospects in the field of multiple myeloma. With Daratumumab already established in China, Sanofi's CD38 monoclonal antibody drug Isatuximab could play a significant role in addressing the large unmet demand. The two recent clinical studies published by Sanofi sufficiently demonstrate Isatuximab’s potential in NDMM and RRMM, as well as Sanofi's commitment to accelerating access through innovative pathways.
We look forward to the approval and market launch of Isatuximab in China, which will bring more treatment options and survival hope to NDMM and RRMM patients in China. With the addition of another key player in the CD38 field, the entire MM treatment landscape is also set to undergo significant changes.
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Editor: Liuli
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