Replimune · RP1 · Apr 2026
What did the FDA's second letter object to?
A unanimous finding that the data were insufficient, three deficiencies in the single-arm trial, and early Phase 3 data the FDA called insufficient.
EphemerisX Research · Published · 2 source documents · 1 min read
Short answer
The FDA's second letter concluded the data were insufficient to show effectiveness, and set out three deficiencies in the RPL-001-16 trial.
What the evidence shows
The review team, supervisory leadership and Oncology Center of Excellence experts unanimously determined data presented are insufficient to conclude substantial evidence of effectiveness
FDA · Apr 10, 2026 · p. 1.
The letter gives three deficiencies in RPL-001-16. Response rate and duration of response were not reliably assessed, could be artifactually increased, and may not be reproducible
FDA · Apr 10, 2026 · p. 5; comparing response rates cross-trial is challenging due to the heterogeneity of the patient populations
FDA · Apr 10, 2026 · p. 5; and it remains unclear whether the observed responses in RPL-001-16 are due to nivolumab alone
FDA · Apr 10, 2026 · p. 6. The early Phase 3 data submitted with the resubmission were insufficient to support an efficacy claim
FDA · Apr 10, 2026 · p. 4.
To address them, the company must conduct and provide the results from adequate and well-controlled clinical trial(s)
FDA · Apr 10, 2026 · p. 6. Its 8-K: Replimune disagrees with the FDA about whether the data set, upon which breakthrough therapy designation was awarded, is sufficient
8-K · Apr 13, 2026.
Follow the thread
- What did Replimune resubmit in October 2025, and what did the FDA make of it?Phase 3 data “insufficient”
- Why did a different FDA team review the resubmission?“Unanimously determined”
- How did Replimune's 8-K describe the FDA's second letter?Responses “not reliably assessed”
- What changed between the FDA's first and second letters?The early Phase 3 analysis
This investigation connects to
- What happens after a second FDA Complete Response Letter?Cross-investigation · Divergent outcome · with Aldeyra Therapeutics, CorMedix, Outlook Therapeutics, Verrica Pharmaceuticals
- How did two programs move forward after repeat FDA letters without running a new trial?Cross-investigation · Comparable evidence · with Outlook Therapeutics
- When is one trial enough? How the FDA weighed the evidence in three programsCross-investigation · Comparable evidence · with Aldeyra Therapeutics, Outlook Therapeutics
The documents, by date
The passages quoted
FDA Complete Response Letter, April 10, 2026 · page 1
This BLA resubmission primary clinical review team, supervisory leadership in the Office of Therapeutic Products, and subject matter experts from Oncology Center of Excellence unanimously determined data presented are insufficient to conclude substantial evidence of effectiveness of vusolimogene oderparepvec for treatment of unresectable advanced cutaneous melanoma.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 4
This data is insufficient to support an efficacy claim.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 5
However, comparing response rates cross-trial from RPL-001-16 to historical controls is challenging due to the heterogeneity of the patient populations in RPL-001-16 and the historical controls (e.g., the type of prior therapy received, such as single agent anti-PD-1 or combination checkpoint inhibitor, duration of prior therapy, setting of prior anti-PD-1 therapy [adjuvant vs. advanced/metastatic setting], extent of disease at baseline).Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 5
Given these issues, the reported response rate and duration of response from RPL-001-16 were not reliably assessed, could be artifactually increased, and may not be reproducible.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 6
Thus, it remains unclear whether the observed responses in RPL-001-16 are due to nivolumab alone.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 6
To address these deficiencies, you must conduct and provide the results from adequate and well-controlled clinical trial(s) which demonstrate substantial evidence of effectiveness.Open at the source →
Replimune Form 8-K, filed April 13, 2026
Replimune disagrees with the FDA about whether the data set, upon which breakthrough therapy designation was awarded, is sufficient to allow this promising medicine to be made available to advanced cancer patients.Open at the source →