The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for isatuximab (Sarclisa®; Sanofi), previously known as SAR650984.

The CHMP recommends isatuximab in combination with pomalidomide (Pomalyst®; Celgene/Bristol-Myers Squibb) and dexamethasone (pom-dex) for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide (Revlimid®; Celgene/Bristol-Myers Squibb) and a proteasome inhibitor such as bortezomib (Velcade®; Takeda) and have demonstrated disease progression on the last therapy.

Following this positive review, the European Commission will review the CHMP recommendation and a final decision on the Marketing Authorisation Application for isatuximab in the European Union is expected in the coming months.

Isatuximab, developed in collaboration with ImmunoGen, was designated as an orphan medicine during its development.

A Significant Burden
Although considered a rare disease, multiple myeloma is the second most common hematologic malignancy, [1] with more than 138,000 new diagnoses worldwide every yearly.[2]

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In Europe, approximately 39,000 patients are diagnosed with multiple myeloma each year.[3] Despite available treatments, multiple myeloma remains an incurable malignancy and is associated with a significant patient burden. Since multiple myeloma does not have a cure, most patients will relapse. The disease is generally associated with significant morbidity due to its end-organ destruction. As a result, the disease represents a major unmet medical need.

Multiple myeloma is a disease of the older population and its incidence in the African American population is twice that of the European American population. However, improvements in the treatment of the disease in the past couple of decades, beginning with the use of autologous stem cell transplantation followed by availability of novel treatments such as immunomodulatory drugs (ImIDs) and proteasome inhibitors (PIs) has transformed the natural history of the disease leading to longer survival times. [1]

The CHMP positive opinion is based on data from ICARIA-MM study (NCT02990338), the first multicenter, multinational, randomized, open-label, two-arm, Phase III trial to evaluate an anti-CD38 monoclonal antibody (mAB) in combination with pom-dex.

The trial was conducted at 102 sites in Europe, North America, Asia, Australia, and New Zealand.

The study included 307 patients with relapsed and refractory multiple myeloma who had received at least two prior therapies including lenalidomide and a proteasome inhibitor. Patients were randomized (1:1) to receive either isatuximab-irfc with pomalidomide and low-dose dexamethasone (Isa-Pd,154 patients) or pomalidomide and low-dose dexamethasone (Pd, 153 patients).

In the ICARIA-MM study, isatuximab added to pom-dex (isatuximab combination therapy; n=154) demonstrated a statistically significant improvement of progression-free survival (PFS) with a median PFS of 11.53 months compared to 6.47 months with pom-dex alone (n=153; HR 0.596, 95% CI: 0.44-0.81, p=0.0010).

The combination therapy also demonstrated a significantly greater overall response rate (ORR) compared to pom-dex alone (60.4% vs. 35.3%, p<0.0001). In additional analyses, the isatuximab combination therapy compared to pom-dex alone showed a treatment benefit consistent across select subgroups reflective of real-world practice, including patients with high-risk cytogenetics, those aged 75 years and older, patients with renal insufficiency, and patients who were refractory to lenalidomide.

Adverse reaction
The most common adverse reactions (all grades occurring in 20% or more of patients) in patients who received isatuximab combination therapy were neutropenia (96%), infusion-related reactions (39%), pneumonia (31%), upper respiratory tract infection (57%) and diarrhea (26%). Serious adverse reactions that occurred in more than 5% of patients who received Sarclisa combination therapy included pneumonia (25.3%) and febrile neutropenia (12.3%). Permanent discontinuation of Sarclisa combination therapy due to an adverse reaction (Grades 3-4) occurred in 7% of patients, and 3% of patients discontinued due to an infusion-related reaction.

“Relapsed and refractory multiple myeloma is a complicated disease that continuously develops resistance to treatment, creating a significant need for continued innovation,” noted John Reed, M.D., Ph.D., Sanofi’s Global Head of Research & Development.

“This positive CHMP opinion [..] brings us closer to our ambition to deliver a new treatment option for patients in Europe with relapsed and refractory multiple myeloma.”

Mechanism of Action
CD38 is a transmembrane glycoprotein that highly and uniformly expressed on multiple myeloma cells and cell surface receptors, making it a potential target for antibody-based therapeutics such as isatuximab.

Isatuximab is an IgG1-derived monoclonal antibody (ATC code: L01XC38) that binds to a specific epitope on the CD38 receptor on multiple myeloma cells. It is designed to work through many mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activity. The clinical significance of these findings is under investigation.

Ongoing clinical studies
Isatuximab continues to be evaluated in multiple ongoing Phase III clinical trials in combination with current standard treatments across the multiple myeloma treatment continuum. It is also under investigation for the treatment of other hematologic malignancies and solid tumors.

Sanofi’s isatuximab will be available in 100mg/5mL and 500mg/25mL single-dose vials for IV infusion.

FDA Approval
Earlier this month, on March 2, 2020, isatuximab was approved by the U.S. Food and Drug Administration (FDA) in combination with pomalidomide and dexamethasone (pom-dex) for the treatment of adults with relapsed and refractory multiple myeloma who had have received at least two prior therapies including lenalidomide and a proteasome inhibitor. In the United States, the generic name for isatuximab is isatuximab-irfc, with irfc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration.

In the United States, the launch price for isatuximab, which will be available in 100mg/5mL and 500mg/25mL single-dose vials for IV infusion, was has set at U.S. $ 650.00 per 100 mg vial and U.S. $ 3,250.00 per 500 mg vial. This represents a per infusion costs of U.S. $ 5,200.00 for an average patient treated in the United States. Based on the standard protocol, isatuximab is dosed every week for four weeks, and then every two weeks.

Sanofi did not disclose the pricing of the drug in Europe, which is based on reimbursement in each European member state.

According to analysts at the Jefferies Financial Group, isatuximab is expected to reach sales of more than U.S. $ 1 billion. However, the same anaylsts are concerned that the drug may struggle to catch up with daratumumab (Darzalex®; Janssen Biotech), also an anti-CD38 drug, which was initially approved in 2015 and reached sales of nearly U.S. $ 3 billion in 2019.

Isatuximab is one of many multiple myeloma treatment options approved recently approved by reglators in the United States and Europe. With the potential approval novel therapies in the (near) future, including GSK’s , investigational antibody-drug conjugate (ADC) belantamab mafodotin, also known as GSK2857916, a humanized, afucosylated, IgG1 anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F (MMAF), the number of novel drugs designed to treat multiple myeloma is growing exponentially.

Clinical trials
Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients (ICARIA-MM) – NCT02990338

[1] Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016;43(6):676–681. doi:10.1053/j.seminoncol.2016.11.004
[2] International Myeloma Foundation. Myeloma Action Month. Online. Last accessed Match 26, 2020
[3] João C, Costa C, Coelho I, Vergueiro MJ, Ferreira M, da Silva MG. Long-term survival in multiple myeloma. Clin Case Rep. 2014;2(5):173–179. doi:10.1002/ccr3.76

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