Over a 3.5-year treatment period, the risk of serious infections or malignancies, few of which were previously reported, did not increase with additional ofatumumab exposure.
Stephen L. Hauser, MD
Published in the Multiple Sclerosis Journal, findings from the open-label, phase 3b ALITHIOS trial (NCT03650114), showed that treatment with ofatumumab (Kesimpta; Novartis), an FDA-approved disease-modifying agent for relapsing multiple sclerosis (MS), was well-tolerated, with no new safety risks identified for up to 3.5 years of exposure.1
The overall safety population included 1969 patients, of whom 1292 were in the continuous ofatumumab group and 677 in the newly switched ofatumumab group. In total, 83.8% (n = 1650) of the safety population had at least 1 adverse event (AE), most of which were mild to moderate in severity, with 11.0% of patients reporting grade 3 or 4 AEs in the continuous group and 5.3% in the newly switched group. Notably, the nature and frequency of the most common AEs were comparable with those reported in ASCLEPIOS I/II (NCT02792218; NCT02792231), the trials, which ofatumumab’s approval was based on.
Lead investigator Stephen L. Hauser, MD, professor of neurology, and director, UCSF Weill Institute for Neurosciences, and colleagues concluded that these findings are supportive of a favorable benefit-risk profile of ofatumumab for patients with relapsing MS, including those early in their disease. They will continue to conduct postmarketing surveillance through ALITHIOS to identify any new safety signals until it concludes in 2029.
Previously reported at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, the safety analysis set consisted of patients who received at least 1 dose of 20-mg subcutaneous ofatumumab either continuously or newly switched. The continuous ofatumumab group included those in ASCLEPIOS I/II (up to 30 months), APLIOS (NCT03560739; 12 weeks), and APOLITOS (NCT03249714; up to 72 weeks; including patients who switched from placebo to ofatumumab in the APOLITOS open-label extension) and then who continued in ALITHIOS.
The Mapi Pharma treatment, administered intramuscularly at 40 mg, reduced annualized relapse rates among a population of patients with relapsing multiple sclerosis. Secondary outcomes are still being analyzed.
In total, 5.8% (n = 115) of the overall safety population discontinued treatment, 6.9% (n = 89) of which were on continuous treatment, and 3.8% (n = 26) in the newly switched group. Reduced immunoglobulin (IgG) levels, found in 46.1% of those who discontinued, accounted for the highest rates. Systematic infusion-related reactions (IRRs), occurred in 24.8% of the observed dataset, 26.0% of which were among those on continuous treatment, and 22.6% of which among those who switched. Systemic IRRs mainly occurred after the first ofatumumab injection, at a rate of 18.2%, but continued to drop markedly for subsequent injections, which was consistent with ASCLEPIOS I/II.
General infections, which mainly consisted of nasopharyngitis, upper respiratory tract infection, urinary tract infection, and COVID-19, occurred in 54.3% (n = 1070) of the cohort, with an exposure-adjusted incidence rate per 100 patient-years of 44.1 (95% CI, 41.5-46.8). There were no opportunistic infections, hepatitis B reactivation, or progressive multifocal leukoencephalopathy events identified. Serious infections, reported in 2.9% (n = 58) of the safety population, was similar to that of ASCLEPIOS I (2.6%) and ASCLEPIOS II (2.5%).
Throughout the study, 4 women in ASCLEPIOS I/II and 10 women in ALITHIOS were exposed to ofatumumab during the first trimester of pregnancy. Of these pregnancies, 6 resulted in early termination, 1 resulted in early intrauterine fetal demise at approximately 8.5 weeks gestation, 3 resulted in live birth, and 4 pregnancies were ongoing at data cutoff. All the live births had no birth defects, congenital anomalies, hematological abnormalities, or serious infections since cut-off date of April 21, 2021.
Both groups showed levels of serum IgG throughout the treatment period that remained stable above the LLN of 5.65 g/L, as well as decreased IgM levels that remained above the LLN of 0.40 g/L. Those treated with continuous ofatumumab had percent changes of +1.1% and –47% in IgG and IgM, respectively, at week 168. In the overall safety population, 1.5% (n = 30) of patients had IgG levels below LLN and 23.1% had IgM levels below the LLN at least once post-baseline.
