Sanofi recently announced the positive results of the phase III IKEMA clinical trial of the CD38 targeting antibody drug Sarclisa (isatuximab) for the treatment of relapsed and/or refractory multiple myeloma (MM). The results show that compared to carfilzomib (Kyprolis®) + dexamethasone (Kd), the Sarclisa + carfilzomib + dexamethasone (S-Kd) scheme significantly reduces the risk of disease progression or death by 47%. It also shows clinically significant deep relief (minor residual disease [MRD] negative rate: 29.6% vs 13%).
IKEMA (NCT03275285) is a randomized, multicenter, open-label phase III clinical trial enrolling 302 patients with relapsed and/or refractory multiple myeloma (MM) in 69 clinical centers in 16 countries. The patient had previously received 1-3 anti-myeloma therapies. During the trial, Sarclisa was infused intravenously at a dose of 10 mg/kg, once a week for four weeks, and then infused once every other week. Carfilzomib was dosed at 20/56 mg/m2 twice a week. The standard dose was used during treatment Dexamethasone. The primary endpoint of the IKEMA trial is progression-free survival (PFS). Secondary endpoints include overall response rate (ORR), good partial response or better response (≥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 reached its primary end point in the first pre-planned mid-term analysis: compared with the standard care plan Kd, the three-drug regimen of Sarclisa + carfilzomib + dexamethasone ( S-Kd) significantly prolong PFS, significantly reduce the risk of disease progression or death.
The detailed data released this time showed that compared with the Kd group (n=123), the S-Kd group (n=179) reduced the risk of disease progression or death by 47% (HR=0.531, 99%CI: 0.318-0.889, p = 0.0007), PFS significantly prolonged (median PFS: did not reach vs. 19.15 months). Compared with Kd, the S-Kd regimen showed consistent treatment effects in multiple subgroups.
Secondary endpoint: There was no statistically significant difference in ORR between the S-Kd group and the Kd group (86.6% vs 82.9%; p=0.1930). The complete remission rate (CR) was 39.7% in the S-Kd group and 27.6% in the Kd group. The VGPR of the S-Kd group was 72.6%, and the Kd group was 56.1%. The MRD-negative complete remission rate in the S-Kd group was 29.6% and that in the Kd group was 13%, indicating that nearly 30% of patients in the S-Kd group could not detect multiple myeloma cells at 1/100000 sensitivity using next-generation sequencing. At mid-term analysis, the overall survival (OS) data is not yet mature.
In this study, Sarclisa's safety and tolerability were consistent with the safety characteristics of Sarclisa observed in other clinical trials, and no new safety signals were observed.
The above test results will be announced at the Virtual Congress of the European Society of Hematology (EHA) (EHA25) on June 14, and will serve as the basis for the submission of global regulatory applications later this year.
Philippe Moreau, MD, Department of Hematology, Nantes University Hospital, France, said: "In the phase III IKEMA trial, the S-Kd protocol reduced the risk of disease progression or death by 47% compared to the Kd protocol. These results indicate that Sarclisa has potential Become a new standard for clinical treatment of recurrent multiple myeloma."
John Reed, MD, Sanofi’s global head of research and development, said: “This is the second phase III trial to prove that when Sarclisa is added to the standard care plan, the efficacy is better than the standard care plan. These results further prove that this anti-CD38 single Anti-potential has the potential to have a meaningful impact on patients. We believe that Sarclisa has the potential to become the first anti-CD38 therapy for multiple myeloma. We look forward to the results of future clinical trials to understand Sarclisa's impact in the early stages of the disease."
Multiple myeloma (MM) is the second most common blood cancer, with more than 138,000 newly diagnosed cases worldwide each year. In Europe, 39,000 cases are diagnosed each year; in the United States, 32,000 cases are diagnosed each year. Despite the available treatments, MM is still an incurable malignant tumor and is associated with a severe burden on patients. Because MM cannot be cured, most patients will eventually relapse and no longer respond to the currently available therapies.
Sarclisa's active pharmaceutical ingredient isatuximab is an IgG1 chimeric monoclonal antibody that targets specific epitopes on the CD38 receptor of plasma cells and can trigger a variety of unique mechanisms of action, including the promotion of programmed tumor cell death (apoptosis) and immunity Regulate activity. CD38 is expressed at high levels on multiple myeloma (MM) cells and is a cell surface receptor target for antibody therapy in MM and other malignant tumors. In the United States and the European Union, isatuximab has been granted orphan drug status for the treatment of relapsed or refractory multiple myeloma (R/R MM). Currently, Sanofi is also evaluating the potential of isatuximab in the treatment of other hematological malignancies and solid tumors.
In March this year, Sarclisa was approved by the US FDA to combine pomalidomide and dexamethasone (pom-dex) for RRMM adults who have previously received at least 2 therapies (including lenalidomide and proteasome inhibitors) patient. Earlier this month, Sarclisa's joint pom-dex program was also approved by the European Commission (EC).
Sarclisa received regulatory approval based on data from the key Phase III ICARIA-MM study. This is the first phase III study to evaluate the positive results of Sarclisa combined with standard care programs, and it enrolls patients with relapsed and refractory multiple myeloma that are particularly difficult to treat and have a poor prognosis (median of anti-myeloma therapy received 3 types), reflecting the real world clinical practice. The results showed that in these patients, the combined treatment of Sarclisa and pom-dex significantly prolonged the progression-free survival of the disease compared to standard care (pomidol + dexamethasone, pom-dex) (median PFS: 11.53 Months vs 6.47 months), the risk of disease progression or death was significantly reduced by 40% (HR=0.596; 95%CI: 0.44-0.81; p=0.0010), and the overall response rate was significantly improved (ORR: 60.4% vs 35.3%, p <0.0001), and showed therapeutic benefits in various subgroups, including patients ≥75 years of age, patients with renal insufficiency, and refractory patients with lenalidomide.
Sarclisa will become the first direct competitor of Johnson & Johnson's heavyweight CD38 targeted drug Darzalex after its launch. The latter was launched in 2015, with global sales reaching US$2.998 billion in 2019, an increase of 48.0% from the previous year. Wall Street Investment Bank Jefferies analysts expect Sarclisa’s annual sales peak to exceed $1 billion after its listing.
Currently, Sanofi is advancing multiple phase III clinical studies to evaluate isatuximab in combination with currently available standard therapies for the treatment of RRMM patients or newly diagnosed MM patients. MM is the second most common malignant tumor of the blood system, with more than 1.38 million patients worldwide each year. For most patients, MM is still incurable, so there is a significant unmet medical need in this area.