Replimune · RP1 · Jul 2025 → Apr 2026
What changed between the FDA's first and second letters?
One deficiency is new in the second letter; two carried over; the Phase 3 trial moved from design to early data.
EphemerisX Research · Published · 3 source documents · 1 min read
Short answer
One deficiency is new in the second letter: how tumor responses were assessed. Two concerns carried over, and the Phase 3 question moved from trial design to early data.
What the evidence shows
Letter 1 does not mention injected lesions, RECIST, surgery, biopsies or duration of response. FDA · searched The second says over half (53%) of patients with objective response did not have noninjected target lesions
FDA · Apr 10, 2026 · p. 4, and that at the September 2025 Type A meeting the FDA had communicated the response criteria were not consistent with RECIST v1.1
FDA · Apr 10, 2026 · p. 4.
Two concerns appear in both letters: the heterogeneity of the RPL-001-16 trial patient population
FDA · Jul 21, 2025 · p. 1 and that the trial was not designed to isolate the contribution
FDA · Jul 21, 2025 · p. 1 of RP1. On the Phase 3 trial, the first letter questioned the design (single-agent chemotherapy options
FDA · Jul 21, 2025 · p. 2 in the control arm); the second calls the early analysis submitted insufficient to support an efficacy claim
FDA · Apr 10, 2026 · p. 4.
The second letter also says the review team members for this BLA resubmission were different
FDA · Apr 10, 2026 · p. 1. The company's 8-K says the agency appears to have contradicted their positions expressed at the September 2025 Type A meeting
8-K · Apr 13, 2026.
Follow the thread
- What did the FDA's first letter object to?Letter 1: no mention of injected lesions or RECIST
- What did the FDA's second letter object to?The early Phase 3 analysis
- When did injected lesions become an FDA concern?53% of responders: no non-injected target lesion
This investigation connects to
- 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
- What did “no efficacy or safety issues” cover in these FDA letter announcements?Cross-investigation · Shared concern · with CorMedix, Verrica Pharmaceuticals
The documents, by date
The passages quoted
FDA Complete Response Letter, July 21, 2025
Letter 1 does not mention injected lesions, RECIST, surgery, biopsies or duration of response.
Open the document →FDA Complete Response Letter, July 21, 2025 · page 1
The RPL-001-16 trial was also not designed to isolate the contribution of vusolimogene oderparepvec to the observed ORR when administered in combination with nivolumab.Open at the source →
FDA Complete Response Letter, July 21, 2025 · page 1
However, the numerically higher response rate cannot be adequately interpreted due to heterogeneity of the RPL-001-16 trial patient population, including the type of prior therapy received, such as single agent anti-PD-1 or combination checkpoint inhibitor, duration and setting of prior anti-PD-1 therapy, and extent of disease at baseline, and due to the heterogeneity of the patient population reported in the literature.Open at the source →
FDA Complete Response Letter, July 21, 2025 · page 2
The study design may not isolate the contribution of vusolimogene oderparepvec due to the inclusion of single-agent chemotherapy options in the investigator’s choice control arm.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 1
To maintain objectivity and account for potential bias, the review team members for this BLA resubmission were different than those who reviewed the initial BLA.Open at the source →
FDA Complete Response Letter, April 10, 2026 · page 4
Thus, over half (53%) of patients with objective response did not have noninjected target lesions to assess systemic anti-tumor activity.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 4
In the Type A meeting dated September 16, 2025, FDA also communicated that the response criteria used in RPL-001-16 were not consistent with RECIST v1.1 and may not be comparable to response rates reported in the historical literature.Open at the source →
Replimune Form 8-K, filed April 13, 2026
In the CRL, the agency appears to have contradicted their positions expressed at the September 2025 Type A meeting, including on the following points:Open at the source →