FDA Issues Complete Response Letter for Long-Acting Form of Glatiramer Acetate for Relapsing Multiple Sclerosis

According to an announcement, the FDA has issued a complete response letter (CRL) for Viatris and Mapi Pharma’s investigational agent GA Depot, a long-acting, once-monthly glatiramer acetate (GA Depot) solution as a potential treatment for patients with relapsing forms of multiple sclerosis (MS). The companies are reviewing the content of the CRL and will be determining the next steps to advance this treatment for patients with MS.¹

The agency originally accepted the new drug application (NDA), which comprised of data from a phase 3, multinational, double-blind, placebo-controlled study (NCT04121221) of GA Depot in November 2023. In the trial, treatment with GA Depot led to statistically significant reduction of annualized relapse rate (ARR) relative to placebo (P = .0066) over a 52-week period. Findings from the study were strengthened by MRI end points as well.²

In the study, 1016 patients with relapsing-remitting MS and active secondary progressive MS aged 18-55 were randomly assigned to 40 mg of GA Depot or placebo, via intramuscular injection, once every 4 weeks for a total of 13 doses. At 52 weeks, patients on the therapy demonstrated 28.5% reduction in cumulative new enhancing T1 lesions (P = .0083) and a 17.3% reduction of cumulative number of new or newly enlarging hyperintense T2 lesions (P = .0305). Additionally, treatment with the therapy resulted in consistently and statistically significant (P = .0193) reductions in mean Expanded Disability Status Scale (EDSS) scores.

READ MORE: Glatiramer Acetate Depot Demonstrates Sustained Longterm Safety Profile as Potential MS Therapy

The safety profile of GA Depot was consistent throughout its clinical program. In the phase 3 study, investigators observed a higher incidence of treatment-emergent adverse events among those on GA Depot; however, most were injection site reactions that were mainly mild in nature. Compliance was high in the study (99%), with 93.4% of patients who continued on to the 52-week, open-label extension (OLE).

More recently, at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 29 to March 2, in West Palm Beach, Florida, investigators presented data from the OLE, with GA Depot demonstrating a safe and tolerable profile. Overall, 625 patients completed the OLE period (81.9%), 332 of these who previously received placebo (pGA Depot) and 347 who continued to receive GA Depot (cGA) treatment. Between both groups, the number of events/exposures to treatment-emergent AEs in the OLE were lower for those in the cGA Depot group compared with the GA Depot group during the placebo-controlled period (2.46 person-years [PYs] vs 5.89 PYs).³

Additional data from the OLE showed that the incidence of TEAEs leading to early discontinuation, which included ISRs, was lower in the cGA Depot group (8 patients, 2.3%) than in the pGA Depot group (20 patients, 4.8%). Regardless of whether patients stayed on treatment or switched from placebo, there were no clinically meaningful changes in physical examinations, serum biochemistry values, hematology values, vital signs, and ECG.

GA Depot is also currently being investigated in a phase 2 study of patients with primary progressive MS (NCT03362294), a form of the disease that has limited approved therapeutic option. At the 2022 Consortium of Multiple Sclerosis Centers Annual Meeting, 1-year interim data from the trial suggested that the agent is safe and effective for this patient population, based on the low rate of AEs detected and the stable EDSS for both men and women. In total, 69.2% of individuals treated with glatiramer acetate depot had no evidence of progression. On MRI analysis, patients had –0.89% change in brain volume from baseline to 1 year and –0.34% change from 6 months to 1 year. Similarly, these patients saw a –2.59% and –1.31% change in cortical volume from the same time points, respectively.⁴

REFERENCES
1. Viatris and Mapi Pharma Statement Regarding New Drug Application for GA Depot. News Release. Viatris. Published March 11, 2024. Accessed March 11, 2024. https://newsroom.viatris.com/press-releases?item=123816
2. Miller AE, Popper L, Berger JR, et al. Results of a Phase III, Multinational, Double Blind, Placebo-Controlled Study in Subjects with Relapsing Forms of Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of GA Depot, a Long-Acting IM Injection of Glatiramer Acetate, Administered Once Every Four Weeks. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P087.
3. Miller A, Wynn D, Weinstock-Guttman B, et al. Safety and tolerability of glatiramer acetate depot: results of phase 3 open label period. Presented at: 2024 ACTRIMS Forum; February 29-March 2; West Palm Beach, FL. Abstract P100.
4. Fletcher S, Kimelman NB, Danon U, et al. Glatiramer acetate depot (extended release) phase 2a study in patients with primary progressive multiple sclerosis: safety and efficacy 1 year interim snapshot analysis. Presented at: CMSC Annual Meeting; June 1-4, 2022; National Harbor, MD.