Sanofi's CD38-Targeting Antibody Sarclisa Receives EU Approval for Second Combination Therapy in Relapsed Multiple Myeloma

April 20, 2021 News /BioValleyBIOON/ -- Sanofi recently announced that the European Commission (EC) has approved the CD38-targeted antibody drug Sarclisa (isatuximab), in combination with carfilzomib (Kyprolis®) and dexamethasone (Kd regimen), for the treatment of adult patients with relapsed multiple myeloma (MM) who have received at least one prior therapy. In terms of U.S. regulatory approval, the Sarclisa + Kd regimen was granted approval in March 2021.FDAApproved.

Notably, this marks the second indication for Sarclisa approved in the EU for the treatment of relapsed multiple myeloma (MM), and the second time within less than a year that the EU has approved Sarclisa in combination with standard regimens for relapsed or refractory MM. In June 2020, Sarclisa received its initial EU approval, in combination with pomalidomide and dexamethasone (pom-dex), for adult patients with relapsed and refractory MM who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and demonstrated disease progression on or after the last therapy.

This latest approval is based on the Phase III IKEMAClinical Trialsresults. The data showed that, in patients with relapsed multiple myeloma (MM) who had previously received 1–3 lines of therapy, treatment with the Sarclisa + carfilzomib + dexamethasone (S-Kd) regimen significantly prolonged progression-free survival (PFS), reduced the risk of disease progression or death by 47%, and demonstrated clinically meaningful deep responses (minimal residual disease [MRD] negativity rate: 29.6% vs. 13%) compared to the carfilzomib + dexamethasone (Kd) regimen.

Dr. Philippe Moreau of the Hematology Department at Nantes University Hospital in France stated, “Since there is no cure for multiple myeloma and patients frequently experience disease relapse, we must persist in seeking additional treatment options. Nearly 30% of patients treated with the Sarclisa regimen achieved deep remission. This new therapeutic regimen has the potential to become the standard of care for patients with relapsed multiple myeloma, providing them with another treatment option at an early stage of disease progression.”

SanofiTumorPeter Adamson, Head of Global Development for Pediatric Innovations, stated: “The EU approval of Sarclisa in combination with the carfilzomib and dexamethasone (Kd) regimen means that patients with multiple myeloma in Europe can now receive Sarclisa in combination with two standard treatment regimens. The carfilzomib and dexamethasone (Kd) combination represents an important standard of care. Results from the Phase 3 IKEMA trial demonstrated that adding Sarclisa to this regimen reduced the risk of disease progression or death by nearly half, a finding that laid the foundation for this significant EU approval.”

Mechanism of Action of Isatuximab (Image source: aacrjournals.org)

IKEMA (NCT03275285) is a randomized, multicenter, open-label Phase IIIClinical TrialA total of 302 patients with relapsed and/or refractory multiple myeloma (MM), who had previously received 1–3 prior anti-myeloma therapies, were enrolled across 69 clinical centers in 16 countries. During the trial, Sarclisa was administered via intravenous infusion at a dose of 10 mg/kg once weekly for the first four weeks, followed by once every two weeks thereafter; carfilzomib was administered at a dose of 20/56 mg/m² twice weekly, and dexamethasone was given at standard doses throughout the treatment period. The primary endpoint of the IKEMA trial was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), rate of very good partial response or better (≥VGPR), minimal residual disease (MRD), complete response rate (CR), overall survival (OS), and safety.

The results showed that the study met its primary endpoint: compared with the Kd group (n=123), the S-Kd group (n=179) demonstrated a 47% reduction in the risk of disease progression or death (HR=0.531, 99% CI: 0.318–0.889, p=0.0007) and significantly prolonged PFS (median PFS: not reached vs. 19.15 months). Compared with Kd, the S-Kd regimen showed consistent treatment effects across multiple subgroups.

Secondary Endpoints: There was no statistically significant difference in overall response rate (ORR) between the S-Kd group and the Kd group (86.6% vs 82.9%; p=0.1930). The complete response (CR) rate was 39.7% in the S-Kd group versus 27.6% in the Kd group. The very good partial response (VGPR) rate was 72.6% in the S-Kd group versus 56.1% in the Kd group. The MRD-negative complete response rate was 29.6% in the S-Kd group versus 13% in the Kd group, indicating that nearly 30% of patients in the S-Kd group had no detectable multiple myeloma cells by next-generation sequencing at a sensitivity of 1 in 100,000. At the time of the interim analysis, overall survival (OS) data were immature.

In this study, the safety and tolerability of Sarclisa were consistent with those observed in otherClinical TrialThe safety profile of Sarclisa observed in was consistent, and no new safety signals were identified.

Multiple Myeloma (MM) is the second most common blood cancer, with new cases worldwide each yearDiagnosisThere are over 130,000 cases. In Europe, approximately 39,000 cases are diagnosed annually; in the United States, approximately 32,000 cases are diagnosed annually. Despite available treatments, MM remains an incurable malignancy.Tumor, which is associated with a significant burden on patients. Since multiple myeloma (MM) is incurable, most patients will eventually experience relapse and no longer respond to currently available therapies. Relapsed MM refers to the recurrence of cancer after treatment or during a period of remission. Refractory MM refers to cancer that does not respond to treatment or no longer responds.

The active pharmaceutical ingredient of Sarclisa, isatuximab, is an IgG1 chimeric monoclonal antibody that targets a specific epitope of the CD38 receptor on plasma cells. It triggers multiple unique mechanisms of action, including the induction of programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly expressed on multiple myeloma (MM) cells and serves as a cell-surface receptor target for antibody-based therapies in MM and other malignancies. In both the United States and the European Union, isatuximab has been granted orphan drug designation for the treatment of relapsed or refractory multiple myeloma (R/R MM). Currently, Sanofi is also evaluating isatuximab for the treatment of other hematologic malignancies.Tumorand the potential in solid tumors.

In March 2020, Sarclisa received U.S.FDAApproved in combination with pomalidomide and dexamethasone (pom-dex) for adult patients with relapsed/refractory multiple myeloma (RRMM) who have previously received at least two therapies, including lenalidomide and a proteasome inhibitor. In early June 2020, the Sarclisa plus pom-dex regimen also received approval from the European Commission (EC).

Sarclisa is the first direct competitor to Johnson & Johnson’s blockbuster CD38-targeted therapy Darzalex, which was launched in 2015. With indications spanning first- to fourth-line treatment, Darzalex has become a cornerstone of clinical practice, achieving global sales of $4.19 billion in 2020, a 39.8% increase from the previous year. Analysts at Jefferies, a Wall Street investment bank, predict that Sarclisa’s annual peak sales will exceed $1 billion following its market launch.

Currently, Sanofi is advancing multiple Phase III clinical studies to evaluate isatuximab in combination with currently available standard therapies for the treatment of patients with RRMM or newDiagnosisof MM patients. MM is the second most common hematologic malignancyTumor, globally, the number of new cases exceeds 1.38 million annually. For most patients, MM remains incurable, indicating a significant unmet medical need in this field. (Bioon.com)

Original source: European Commissionapproves second indication of Sarclisa® (isatuximab) for relapsed multiple myeloma