Replimune · RP1 · Jul 2025
What did the FDA's first letter object to?
One clinical deficiency with two reasons, and comments on the Phase 3 design. No mention of injected lesions or of how responses were measured.
EphemerisX Research · Published · 1 source document · 1 min read
Short answer
The July 2025 letter found that the single-arm trial could not establish effectiveness, for two reasons: heterogeneity in the trial's and the published patient populations meant the response rate could not be interpreted, and the trial could not isolate RP1's contribution. It also commented on the design of the Phase 3 trial.
What the evidence shows
The letter says the FDA cannot grant final approval because of the deficiencies outlined below
FDA · Jul 21, 2025 · p. 1. The higher response rate, it says, cannot be adequately interpreted due to heterogeneity of the RPL-001-16 trial patient population
FDA · Jul 21, 2025 · p. 1, and the trial was not designed to isolate the contribution of vusolimogene oderparepvec to the observed ORR
FDA · Jul 21, 2025 · p. 1.
On the Phase 3 trial it names RP1-104, the letter says The study design may not isolate the contribution of vusolimogene oderparepvec due to the inclusion of single-agent chemotherapy options
FDA · Jul 21, 2025 · p. 2 in the control arm, and that there is inadequate data to support the statistical assumption of a 6-month improvement in the primary endpoint of overall survival
FDA · Jul 21, 2025 · p. 3.
Letter 1 does not mention injected lesions, RECIST, surgery, biopsies or duration of response. FDA · searched Those subjects take up most of the second letter: What changed between the FDA's first and second letters?
To address the deficiency, the company must conduct and provide the results from adequate and well-controlled clinical trial(s)
FDA · Jul 21, 2025 · p. 2.
Follow the thread
- How did Replimune describe the first letter?The letter's reasons, in the 8-K
- What happened to the confirmatory trial Replimune said would not be viable?Chemotherapy in the Phase 3 control arm
- What changed between the FDA's first and second letters?Letter 1: no mention of injected lesions or RECIST
This investigation connects to
- 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
After our complete review, we have concluded that we cannot grant final approval because of the deficiencies outlined below.Open at the source →
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
To address this deficiency, 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 →
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, July 21, 2025 · page 3
inadequate data to support the statistical assumption of a 6-month improvement in the primary endpoint of overall survival.Open at the source →