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FDA Issues Complete Response Letter for GA Depot in Relapsing Multiple Sclerosis

On 11th March 2024, Viatris Inc. announced that the U.S Food and Drug Administration (FDA) had issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for Glatiramer Acetate (GA) Depot 40mg.1 The FDA declined to approve the long-acting, intramuscular agent for the treatment of relapsing types of multiple sclerosis (RMS), despite Phase III data where the drug demonstrated comparable efficacy to existing GA formulations. Despite the setback, the accumulated evidence indicates that GA Depot holds promise as a more convenient treatment option for patients with RMS. Therefore, the company intends to resubmit the application with additional requirements specified by the FDA.

RMS & Glatiramer Acetate

The term RMS is used to describe both relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) with superimposed relapses, which develop when immune cells breach the blood-brain barrier, initiating attacks on the myelin sheath surrounding neurons.2 For approximately 30 years, GA has served as a disease-modifying therapy for patients with RMS, acting through numerous immunomodulatory mechanisms, including inhibition of the T-cell response to myelin antigens through T-cell receptor antagonism and MHC binding.3 Until now, GA has been administered through self-subcutaneous injection three times a week or once daily, however, GA Depot introduces microspheres via intramuscular (IM) injection for a gradual release of GA molecules into the circulation over approximately 30 days.4

GA Depot was developed with the vision of providing patients with RMS a more convenient monthly injection. This initiative aims to enhance their quality of life, whilst minimizing the occurrence of treatment-emergent adverse events (TEAEs).

“The monthly administration of GA Depot should offer patients a much more preferable schedule than current regimens of GA, a long-standing pillar in the treatment of MS, and lead to improved patient satisfaction and medication adherence” -Aaron Miller, MD, Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, & Principal Investigator.4

Phase III Trial Results 

The regulatory application, which the FDA agreed to review last August, was backed by data from a Phase 3 clinical trial (NCT04121221) involving 1,016 adults, aged 18-55, with RRMS or active SPMS.5 The double blind, placebo-controlled study examined the efficacy, safety, and tolerability of GA Depot. Participants received either 40mg of GA Depot or matching placebo, administered once every four weeks for a total of 52 weeks (13 IM injections).5  The primary endpoint was the annualized relapse rate (ARR), with secondary endpoints including changes in T1 and T2 lesions in the brain. 

The results, presented at the AAN meeting in April 2023, confirmed that the study achieved its primary endpoint.6 GA Depot demonstrated a statistically significant 30.1% reduction in the ARR compared to placebo (p=0.0066), aligning with the efficacy levels seen in other GA formulations. Notably, patients treated with GA Depot experienced an average of 0.18 relapses during the trial, while those on placebo averaged 0.26 relapses.6 The secondary endpoints achieved in the study include a statistically significant reduction of both new T1 enhancing lesions (28.5%, p=0.0083), and new or newly enlarging hyperintense T2 lesions (17.3%, p=0.0305), indicating less disease activity. Treatment with GA Depot was also associated with reductions in the number of injection site reactions (ISRs) in comparison to other GA products. 

Following on from this study, 93% of the participants transitioned to the 52-week open label extension study, where all subjects received 40mg of GA depot once every 4 weeks.7 In data recently presented at the ACTRIMS Forum 2024, treatment-emergent adverse events (TEAEs) were mostly mild or moderate in the 625 patients who completed the open label period.7The incidence of TEAEs was lower in the open-label phase compared to the placebo-controlled phase in those initially randomized to GA Depot, indicating reduced side effects with continued use. In both groups, no clinically meaningful changes were seen in physical examinations, serum biomarkers, or ECG.

Continued research and development

No details of the reasons outlined by the FDA in the CRL have been disclosed. Viatris and Mapi Pharma say they are committed to addressing the FDA’s concerns and plan to resubmit the application with additional requirements.

Despite the setback, ongoing research initiatives, including a Phase IIa trial (NCT03362294) for primary progressive MS (PPMS), underscore the commitment to advancing MS treatment options. In this trial, 30 subjects will receive either 40mg or 25mg of GA Depot once a month for approximately 3 years, with the primary focus on evaluating safety and efficacy endpoints.8 In 2022, a scheduled one-year interim analysis disclosed that GA Depot demonstrated safety and that patient disability was stable, with No Evidence of Progression (NEP) observed in 69.2% of the patients.8

Written by Mary Kelly

Reviewed by Juliet Lawrence

References:

  1. Viatris. Viatris and Mapi Pharma Statement Regarding New Drug Application for GA Depot. [Press Release]. 11 Mar 2024. Accessed 11 Mar 2024.
  2. European Medicines Agency. Clinical investigation of medicinal products for the treatment of multiple sclerosis. EMA/CHMP/771815/2011. 2015.
  3. Schrempf W, Ziemssen T. Glatiramer acetate: mechanisms of action in multiple sclerosis. Autoimmun Rev. Aug 2007;6(7):469-75.
  4. Mapi Pharma Ltd. Mapi Pharma Announces Positive Top-Line Results from GA Depot Phase III Trial for Relapsing forms of Multiple Sclerosis (RMS). [Press release]. 21 Sep 2022. Accessed 11 Mar 2024.
  5. ClinicalTrials.gov. A Study to Assess Efficacy, Safety and Tolerability of Monthly Long-acting IM Injection of GA Depot in Subjects With RMS (NCT04121221). Oct 2019. Accessed March 11, 2024.
  6. Miller A, Popper L, Berger J, et al. Results of a Phase III, Multinational, Double-blind, Placebo-controlled Study in Subjects with Relapsing Forms of Multiple Sclerosis (RMS) to Assess the Efficacy, Safety, and Tolerability of GA Depot, a Long-Acting IM Injection of Glatiramer Acetate, Administered Once Every Four Weeks (P6-3.014). Neurology. Apr 2023; 100(17_supplement_2).
  7. Miller A, Wynn D, Weinstock-Guttman B, et al. Safety and Tolerability of Glatiramer Acetate Depot: Results of Phase III Open Label period [Conference poster]. Presented at the ACTRIMS Forum 2024, 29 Feb-2 Mar, 2024, West Palm Beach, FL.
  8. ClinicalTrials.gov. Safety and Efficacy of Monthly Long-acting IM Injection of 25mg or 40 mg GA Depot in Subjects With PPMS (NCT03362294). Dec 2017. Accessed 11 Mar, 2024.
  9. 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 the CMSC Annual Meeting; June 1-4, 2022; National Harbor, MD.