Replimune Approval Document Highlights Reviewer Objections
Last week’s accelerated approval of Replimune’s Tudriqev (vusolimogene oderparepvec-wtpg) came despite significant concerns about the reliability of efficacy results from the company’s Phase 1/2 IGNYTE trial. The genetically modified oncolytic viral therapy’s approval covers its use in combination with Bristol Myers Squibb's Opdivo (nivolumab) for treating adult patients with unresectable advanced cutaneous melanoma who experienced disease progression on a programmed death receptor-1 (PD-1)-blocking antibody-based regimen.
According to a just-released approval summary document, FDA’s primary clinical review team did not recommend approval because Replimune’s second resubmission did not address deficiencies cited in two earlier Complete Response Letters. However, FDA’s Office of Therapeutic Products and Office of Clinical Evaluation recommended approval after considering the totality of evidence, the unmet medical need, and input from an FDA advisory committee.
The Cellular, Tissue, and Gene Therapies Advisory Committee voted 10-3 on 7/30 that the IGNYTE efficacy results were evaluable and clinically meaningful. Committee members acknowledged substantial methodological limitations but pointed to tumor shrinkage in both injected and non-injected lesions, durable responses in some patients and the lack of effective treatment options for patients whose melanoma has progressed after anti-PD-1 therapy.
Replimune reported that the IGNYTE study’s 140-patient anti-PD-1-refractory melanoma cohort had an objective response rate of 33.6%, including 23 complete responses and 24 partial responses, with a median duration of response of 24.8 months, according to the approval document. FDA’s reanalysis, however, included only 91 patients with at least one non-injected lesion and produced an objective response rate of 24.2% and median duration of response of 14.1 months.
FDA’s document identified five methodological issues that it said could artificially inflate the reported response rate and duration of response. More than half of responders had all target lesions injected or lacked measurable target lesions at baseline; 14 patients received treatment beyond investigator-determined progression; 115 invasive procedures were performed on tumor lesions in responders before response assessments; pathological findings were used to reclassify responses in at least seven patients; and 13 responding patients had multiple consecutive non-evaluable assessments, creating uncertainty about disease progression and response duration.
FDA said continued approval would depend on confirmation of clinical benefit in the ongoing IGNYTE-3 Phase 3 trial. The randomized, controlled trial is comparing Tudriqev plus nivolumab with physician’s choice in approximately 400 patients with advanced cutaneous melanoma who have progressed on anti-PD-1 and anti-CTLA-4 therapy. Overall survival is the primary endpoint. Replimune is required to complete the study by September 2030 and submit the final report by March 2031.
In addition to the clinical postmarketing requirement, Replimune agreed to four chemistry, manufacturing and controls commitments addressing lot-release criteria, manufacturing-related testing, in-use stability and leachables data.