Sanofi's CD38 Antibody Sarclisa Combination Therapy Demonstrates Significant Improvement in Progression-Free Survival and Deep Responses in Phase III Trial for Relapsed Multiple Myeloma

June 10, 2020 News /BioValleyBIOON/ -- Sanofi recently announced the Phase III IKEMA study of Sarclisa (isatuximab), a CD38-targeted antibody drug, for the treatment of relapsed and/or refractory multiple myeloma (MM)Clinical Trialpositive results. The results showed that, compared with carfilzomib (Kyprolis®) plus dexamethasone (Kd), the Sarclisa plus carfilzomib and dexamethasone (S-Kd) regimen significantly 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%).

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 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 during treatment. 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.

On May 12 this year, Sanofi announced that the IKEMA trial had met its primary endpoint at the first pre-planned interim analysis: compared with the standard-of-care regimen Kd, the triple-drug regimen of Sarclisa plus carfilzomib and dexamethasone (S-Kd) significantly prolonged progression-free survival (PFS) and significantly reduced the risk of disease progression or death.

The detailed data released show that, compared with the Kd group (n=123), the S-Kd group (n=179) had 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 progression-free survival (median PFS: not reached vs. 19.15 months). Compared with Kd, the S-Kd regimen demonstrated consistent treatment effects across multiple subgroups.

Regarding 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 CR 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 level 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 Trialsconsistent with the safety profile of Sarclisa observed in China, no new safety signals were identified.

The aforementioned trial results will be presented at the European Hematology Association (EHA) Virtual Congress (EHA25) on June 14 and will serve as the basis for global regulatory submissions later this year.

Philippe Moreau, MD, from the Department of Hematology at Nantes University Hospital in France, stated: “In the Phase III IKEMA trial, the S-Kd regimen reduced the risk of disease progression or death by 47% compared with the Kd regimen. These results suggest that Sarclisa has the potential to become the new standard of care for the clinical treatment of relapsed multiple myeloma.”

John Reed, M.D., Global Head of Research and Development at Sanofi, stated, “This is the second Phase III trial demonstrating that adding Sarclisa to the standard of care regimen yields superior efficacy compared with the standard of care alone. These results further substantiate the potential of this anti-CD38 monoclonal antibody to deliver meaningful clinical benefits for patients. We believe Sarclisa has the potential to become the preferred anti-CD38 therapy for multiple myeloma. We look forward to the futureClinical Trialresults to understand the impact of Sarclisa in the early stages of the disease.”

Multiple Myeloma (MM) is the second most common hematologic malignancy, with new cases worldwide annuallyDiagnosisCases exceed 138,000. In Europe, 39,000 cases are diagnosed annually; in the United States, 32,000 cases are diagnosed annually. Despite available treatments, MM remains an incurable malignancyTumor, associated with a significant burden on patients. As multiple myeloma (MM) is incurable, most patients will eventually relapse and become refractory to currently available therapies.

The active pharmaceutical ingredient of Sarclisa, isatuximab, is an IgG1 chimeric monoclonal antibody that targets a specific epitope on the CD38 receptor of 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 for solid tumors.

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

Sarclisa Receives Regulatory Approval Based on Data from the Pivotal Phase 3 ICARIA-MM Study. This was the first Phase 3 study to demonstrate positive results for Sarclisa in combination with standard of care, enrolling patients with relapsed and refractory multiple myeloma who were particularly difficult to treat and had a very poor prognosis (having received a median of 3 prior anti-myeloma therapies), thereby reflecting real-world clinical practice. The results showed that, in this patient population, Sarclisa combined with pom-dex significantly prolonged progression-free survival (median PFS: 11.53 months vs. 6.47 months), reduced the risk of disease progression or death by 40% (HR=0.596; 95% CI: 0.44-0.81; p=0.0010), and significantly improved the overall response rate (ORR: 60.4% vs. 35.3%, p<0.0001) compared to standard of care (pomalidomide + dexamethasone, pom-dex). Treatment benefits were observed across all subgroups, including patients aged ≥75 years, those with renal impairment, and those with lenalidomide-refractory disease.

Following its market launch, Sarclisa will become the first direct competitor to Johnson & Johnson’s blockbuster CD38-targeted therapy, Darzalex, which was launched in 2015 and achieved global sales of $2.998 billion in 2019, representing a 48.0% year-over-year increase. Analysts at Jefferies, a Wall Street investment bank, project that Sarclisa’s annual peak sales will exceed $1 billion after its commercialization.

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 malignancyTumorGlobally, the number of new cases exceeds 1.38 million annually. For most patients, multiple myeloma (MM) remains incurable, indicating a significant unmet medical need in this field. (Bioon.com)

Original Source: Sarclisa® (isatuximab) combination therapy demonstrated superior progression-free survival and clinically meaningful depth of response in patients with relapsed multiple myeloma