In a remarkable turnaround, Replimune has reversed the fortune of its melanoma therapy, winning FDA approval after two prior rejections and agency leadership shakeups.
Thursday, the FDA granted accelerated approval to Replimune’s engineered viral immunotherapy Tudriqev (vusolimogene oderparepvec) in combination with Bristol Myers Squibb’s Opdivo for adults with unresectable advanced cutaneous melanoma whose disease progressed on prior anti-PD-1 therapy.
The go-ahead is supported by results from the phase 1/2 Ignyte trial, in which the combo delivered a 24.2% objective response rate and a median duration of response of 14.1 months among 91 efficacy-evaluable patients.
The green light marks a dramatic regulatory turnaround for Massachusetts-based Replimune following two high-profile FDA rejections accompanied by intense debate over the interpretability of the drug’s clinical data. Former FDA Commissioner Marty Makary, M.D., previously defended the agency’s decision to reject Tudriqev, as The Wall Street Journal’s editorial board used the case to criticize his leadership.
The approval comes shortly after an FDA advisory committee voted 10 to 3 in favor of the drug’s profile, even though the FDA’s reviewers had raised significant concerns about the trial results. The agency had questioned that, without a comparator arm, the contribution of Tudriqev, previously known as RP1, couldn’t be isolated from Opdivo. Because the drug is injected directly into the tumor, the FDA also raised doubts about its systemic treatment effect.
Although external advisors to the FDA shared some of the agency’s concerns, they also believed that Replimune has shown enough data to support an approval. For example, even after excluding patients without enough tumor lesions to assess systemic response, the drug’s response rate remains notably above historical experience in this patient population.
“This is a transformative moment for Replimune, marking years of pioneering research to bring Tudriqev to patients desperately in need of new treatment options for advanced melanoma,” Sushil Patel, Ph.D., CEO of Replimune, said in an Aug. 6 statement, as he also thanked the FDA for “recognizing the urgency to get this therapy to patients.”
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Thursday’s approval, though hard-won, does not mean Replimune’s fate has completely reversed. Because the approval was granted under the accelerated pathway based on surrogate endpoints, Replimune remains on the hook to confirm Tudriqev’s clinical benefit in a confirmatory trial, which currently looks to be the ongoing phase 3 Ignyte-3 study.
The trial, which compares the Tudriqev-Opdivo cocktail against physician’s choice of therapy, has enrolled about a third of its target population, with a readout from its primary endpoint of overall survival expected in 2030, Replimune management said on an investor call Thursday. As Leerink analysts pointed out in an Aug. 6 note, Replimune will need those randomized overall survival data to secure approvals outside the U.S.
Before that, Leerink Partners analysts projected “strong demand for the regimen given its relative ease of access and benign safety profile,” according to an Aug. 3 note. Most treatment-related adverse reactions observed so far from the combo were grade 1 and 2 and transient.
Another option for post-PD-1 cutaneous melanoma, Iovance Biotherapeutics’ cell therapy Amtagvi, comes with a cumbersome treatment process with logistical challenges and potentially intense side effects from various components of the therapy.
“Tudriqev is an off-the-shelf treatment, practically for everyday clinical practice, that minimizes logistical complexity and treatment delays, and ensures that patients with aggressive disease receive immediate care,” Replimune’s chief medial officer, Kostas Xynos, M.D., Ph.D. said on the Thursday call.
Roughly 10,000 advanced melanoma patients a year in the U.S. who progress on a PD-1-containing regimen could be candidates for Tudriqev plus Opdivo, according to Replimune. For the launch, the company will adopt a phased approach, initially targeting 200 accounts, which together represent about 30% of the national melanoma patients treated annually. That will be followed by another 250 accounts to cover just over 50% of the pool before adding 750 accounts to reach about 80%, Patel said on the call.
In their Aug. 3 note, Leerink analysts put their peak sales estimate for Tudriqev at $618 million on an un-risk-adjusted basis, below the Wall Street consensus of $971 million on a risk-adjusted basis. The Leerink team cited operational uncertainties because Replimune needs to rebuild its manufacturing and commercial infrastructure. The company had laid off most of its staffers earlier this year amid the regulatory fallout.
Replimune has assembled about a third of its commercial team so far, eventually targeting about 50 staffers in that organization, including some 20 sales representatives, Patel said. Some employees who were let go earlier have come back, he added.
The positive side is, as Patel noted, the high-profile regulatory back-and-forth has increased public awareness of Tudriqev.
“One of the benefits of the adcomm was just the tremendous public and physician support and awareness it’s created for RP1,” Patel said. “And I think when you listen to the open public forum, it was very clear that this is a treatment that patients very much need and physicians want.”
Editor's Note: The story was updated 9:30 a.m. ET on Aug. 7 with additional information from an Replimune investor call and a note from Leerink on Aug. 6.