Background Analysis: US FDA Advisory Committee to Review GSK’s Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma – JUL 14, 2020 (ODAC)

Announcement

The US FDA has scheduled a meeting of the Oncologic Drugs Advisory Committee (ODAC) for Tuesday, July 14, 2020. The committee will discuss a biologic license application for belantamab mafodotin, submitted by GlaxoSmithKline Intellectual Property Development Ltd. England (GSK). The proposed indication is for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

Due to the impact of this COVID-19 pandemic, all meeting participants will be joining this advisory committee meeting via an online teleconferencing platform. The meeting presentations will be heard, viewed, captioned, and recorded via this online teleconferencing platform.

Clinical Background

Belantamab mafodotin is a potential first-in-class, humanized, anti-BCMA (antibody drug conjugate against B-cell maturation antigen). The BLA is primarily based on results of the pivotal trial, named DREAMM-2 (DRiving Excellence in Approaches to Multiple Myeloma). DREAMM-2 is an open-label, phase 2 trial investigating the safety and efficacy of two doses of belantmab mafodotin, 2.5 mg/kg or 3.4 mg/kg every three weeks, in a population of patients with relapsed/refractory multiple myeloma (RRMM) who are refractory to a proteasome inhibitor (PI) and an immunomodulatory agent and have failed prior treatment with an anti-CD38 antibody (ClinicalTrials.Gov Identifier: NCT03525678).

On December 16, 2019, GSK reported that 30 of the 97 patients (31%) in the 2.5 mg/kg arm of the DREAMM-2 trial achieved an overall response. Regarding safety, the company said the three most commonly reported grade 3 or 4 adverse events (AEs) in the 2.5 mg/kg arm were keratopathy (27%), thrombocytopenia (20%) and anemia (20%). Corneal events leading to treatment discontinuation affected 1% of patients in the 2.5 mg/kg cohort.

On May 27, 2020, GSK reported that follow-up data demonstrated an overall response rate (ORR) that was consistent with what was reported earlier, with an ORR of 32% (31 out of 97 patients). Of these 97 patients, the majority (58%) had a very good partial response or greater, including two stringent complete responses and five complete responses. The company also reported that the data for the 2.5 mg/kg dosing regimen showed a median duration of response (DoR) of 11 months (95% Confidence Interval (CI), 4.2–not reached) and a median overall survival (OS) of 14.9 months (95% CI, 9.9–not reached). Regarding safety, the company said that no new safety signals were identified. They most commonly reported grade 3 or higher AEs (occurring in more than 10% of patients), in patients receiving the 2.5 mg/kg dose regimen, were keratopathy/microcyst-like epithelial changes (MECs) (46%), thrombocytopenia (22%), anemia (21%), lymphocyte count decreased (13%) and neutropenia (11%). The company noted that the first event of keratopathy (MECs), characterized as changes in the corneal epithelium as seen on eye examination which can manifest with or without symptoms, had resolved in 77% of patients in the 2.5 mg/kg arm at time of data cut-off, and no permanent loss of vision has been reported to date.

Of note, an expanded access program for belantamab mafodotin is available to eligible US patients with multiple myeloma (ClinicalTrials.gov Identifier: NCT03763370).

Regulatory Considerations

The potential ocular risks associated with the use of belantamab mafodotin in the proposed patient population, relative to the demonstrated benefit, is likely to be the main focus of the ODAC’s discussion. Hal Barron, Chief Scientist at GSK, responded to a question on the topic of potential ocular risks associated with the drug on an April 29, 2020 conference call about the company’s Q1 results. He stated as follows:

The data in this heavily pre-treated, refractory, relapsed patient population from DREAMM-2 was very robust and we see the benefit outweighing the adverse events experienced, particularly of the ocular events seen in the program.

What we have noticed, and discussed with all of you on the call before, is that these ocular adverse events are unique. Although they were well-managed in the clinical programs, it is important to us to make sure that myeloma experts and eyecare professionals in the real world are able to work together to ensure that the drug is used safely in patients. Of course, we are open to any approach that ensures that patient safety is well-handled.

In addition to managing it well, we also have – as alluded to earlier – the opportunity to do more dose exploration when belantamab is added on to standard of care therapies or other active medicines. It is possible that the dose needed would be lower and therefore managing these unique adverse events through dose reduction is possible. In addition, we are evaluating various schedules that might enable that.

Lastly, the one combination that I have mentioned, and this is part of an ongoing proof of concept study – and Andrew (Questioner from Citi), I think you are aware of this study – and there is really interesting data with a gamma secretase inhibitor, in a small number of patients, and much support from preclinical data, looking at inhibiting gamma secretase to prevent the clipping of the BCMA off the plasma cell. In CAR-T therapy, this has resulted in a very high response rate and, again, a small number of patients, and we are cautiously optimistic that that combination may even be a third avenue by which we can lower the dose and, in addition, manage the ocular adverse events. Again, we are continuing to believe the benefit seen in the 2.5mg/kg, three week-dose in DREAMM-2 outweighs the adverse events, but we take that seriously and we are looking at ways to optimise the drug’s use in the real world.

Regulatory Background

US Regulatory Background

August 2020 – PDUFA date

January 21, 2020 – GSK announced the FDA’s acceptance of the BLA for priority review (BLA #761158).

Ex-US Regulatory Background

February 3, 2020 - GSK announced the European Medicines Agency’s (EMA’s) acceptance of a marketing authorization application (MAA) for accelerated assessment.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: GlaxoSmithKline Drug Name: belantamab mafodotin Drug Class: anti-BCMA Indication: multiple myeloma

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.