TICKERS: REPL

FDA Rejects Melanoma Drug Again as Analysts Slash Targets and Approval Path Comes Under Fire

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Source: Streetwise Reports (5/8/26)

Replimune Group Inc. (REPL:NASDAQ) received a second FDA rejection for RP1 in advanced melanoma, prompting analyst downgrades, price target cuts, and renewed debate over approval standards for cancer therapies.

Replimune Group Inc. (REPL:NASDAQ) announced that it received a complete response letter from the U.S. Food and Drug Administration for the company’s Biologics License Application for RP1 in combination with nivolumab for the treatment of advanced melanoma.

According to the company, the BLA was based on data from the IGNYTE trial involving patients with confirmed progression on an anti-PD-1-based regimen. Replimune stated that patients who received RP1 plus nivolumab demonstrated a 34% response rate with a median duration of 24.8 months and a favorable safety profile.

"It is deeply disappointing that the FDA has not exercised regulatory flexibility to meet patients' needs given the data supporting strong efficacy and the favorable safety profile," said Sushil Patel, Ph.D., CEO of Replimune, in a company news release. Patel added that "without timely accelerated approval, the development of RP1 will not be viable."

The company stated that the complete response letter followed a review process in which a different review team was appointed for the resubmission. According to the release, the new review team replaced the prior team that had interacted with the company during earlier stages of the application process.

Replimune said a senior member of the prior review team publicly stated that the "BLA clinical team thought the applicant had provided adequate evidence to support contribution of effect of RP1 plus nivolumab, but leadership did not agree."

The company also stated that the FDA appeared to contradict positions expressed during a September 2025 Type A meeting. Replimune said that after testimony from melanoma experts, the agency had not raised additional concerns regarding the heterogeneity of the patient population in the IGNYTE study and had acknowledged that randomizing patients to an anti-PD-1-only arm in the confirmatory study was not feasible.

According to the release, the company submitted a descriptive analysis proposal from IGNYTE-3 supporting the contribution of components and included data from IGNYTE showing median progression-free survival on RP1 plus nivolumab of 30.6 months compared to 4.4 months on the patients' prior PD-1-based regimen.

Replimune also stated that the FDA raised points related to tumor assessment methodology. The company said responses in IGNYTE were assessed using RECIST 1.1 without modifications and that analyses showed no material difference in response rates between injected and non-injected lesions. The company further stated that biopsies and surgical interventions did not impact tumor response.

Prior to the original BLA submission, Replimune stated that regulatory meetings were conducted to discuss trial design, patient population, and BLA package requirements. According to the release, FDA meeting minutes from March 2021 indicated that a single-arm trial could be acceptable for accelerated approval consideration if the data were sufficiently compelling. The company later submitted the BLA, which was accepted with a breakthrough therapy designation and granted priority review.

Replimune stated that melanoma is the fifth most common cancer, with approximately 112,000 new cases estimated in the United States in 2026 and nearly 8,500 deaths annually.

The company also referenced updated biomarker and clinical data presented at the 22nd European Association of Dermato-Oncology Congress in Prague, Czech Republic. According to the poster presentation, RP1 combined with nivolumab demonstrated an objective response rate of 33.6% and a median duration of response of 24.8 months in patients with advanced melanoma following anti-PD-1 treatment failure.

Advanced Melanoma Treatments Faced Ongoing Questions Around Approval Standards and Post-PD-1 Care

According to a May 2 report from Scientific American, approximately 110,000 new melanoma cases are diagnosed each year in the United States, while advanced disease remains significantly more difficult to treat once the cancer spreads beyond the original tumor site. The publication stated that "adding even one new option" for patients whose melanoma had not responded to first-line therapies "could make a big difference for patients' prognoses."

Scientific American wrote that some patients with advanced melanoma had "been left behind" after failing standard therapies. Yana Najjar, director of the Clinical and Translational Research Center at the University of Pittsburgh Medical Center Hillman Cancer Center, stated, "There's really no second-line treatments" for some patients. She added, "This is where I had hoped RP1 would come in."

The report described RP1 as an "oncolytic immunotherapy drug" created from "a modified version of a herpesvirus" designed to be injected directly into melanoma tumors. According to Scientific American, the treatment approach aimed to trigger the body's immune system to attack cancer cells "without damaging healthy tissue."

Scientific American also reported that the FDA had previously granted RP1 "breakthrough therapy" designation after early clinical trial results. The publication stated that a phase 1/2 clinical trial showed that "nearly 33 percent of patients with treatment-resistant advanced melanoma saw their condition improve with a combination of RP1 and a widely used immunotherapy drug called nivolumab." The article contrasted that outcome with "the 6 to 7 percent of similar patients who responded to nivolumab alone."

The publication reported that FDA review concerns centered on "the study population was too heterogeneous" and uncertainty regarding whether positive results were linked to RP1 rather than nivolumab. Scientific American noted that researchers and clinicians argued that the patient population "will be, by necessity, heterogeneous."

Michael Postow, chief of the melanoma service at Memorial Sloan Kettering Cancer Center, stated, "This is a space where patients need new advances the most.... It's always nice to have another option for them." Postow later added, "I really just want to make sure we all know what to do next here because we need some guidance."

Scientific American also discussed broader regulatory changes at the FDA, reporting that agency leadership announced a shift toward requiring one "pivotal" trial rather than two phase 3 studies for some approvals. The publication stated that randomized controlled trials in advanced cancer settings could be difficult because patients in control groups "would have to continue to use medications that previously had not worked for them."

In a separate May 6 sector report discussing melanoma development programs, Kaitlyn Bader wrote that unresectable or metastatic melanoma remained "one of the most clinically challenging presentations in dermatologic oncology." The article noted that before 2011, median overall survival for metastatic melanoma patients was "approximately six to nine months, with fewer than 10% surviving to five years."

According to the report, checkpoint inhibitors targeting CTLA-4, PD-1, and LAG-3 had "substantially altered the prognosis for a subset of patients," though "a meaningful proportion of patients experience primary or acquired resistance to checkpoint inhibition, limiting durable disease control."

The report stated that "patients who progress on PD-1-based therapy face a narrower range of subsequent options, making the development of mechanistically distinct approaches a continued clinical priority."

The article also discussed FDA Fast Track designation processes, stating that the designation was intended to "facilitate development and expedite FDA review of drugs targeting serious conditions with demonstrated potential to address unmet medical need." However, the report added that Fast Track status "should not be interpreted as evidence of clinical efficacy or safety."

A May 5 report from Stocktwits stated that the FDA rejected RP1 for a second time in April, citing "insufficient data to provide 'substantial evidence of effectiveness' in the treatment of unresectable advanced cutaneous melanoma."

According to the report, FDA Commissioner Marty Makary stated, "I don't work for Replimune, I work for the American people, and I stand by the scientists at the FDA." The report also quoted Makary as stating, "If your drug works, it's going to get approved."

The Stocktwits article reported that doctors writing in The Wall Street Journal criticized the FDA's decision and noted that the second FDA review team "did not say that the drug was ineffective, instead saying that it is 'unclear whether the drug was effective.'"

Analysts Cut Ratings and Targets Following FDA Setback

In an April 13 report, Robert Driscoll of Wedbush downgraded Replimune to "NEUTRAL (from OUTPERFORM)" and reduced its 12-month price target to US$2.00 from US$19.00.

Wedbush wrote that "the FDA issued a second complete response letter for REPL's BLA for RP1 (vusolimogene oderparepvec) in combination with nivolumab in PD-1 refractory melanoma." The report stated that the FDA identified "three deficiencies related to the IGYNTE study," including "an inability to isolate the contribution of RP1 when administered in combination with nivolumab, heterogeneity of the study population, and uncertainty of response assessments, including surgical interventions with potential for confounding response results."

According to the Wedbush report, the FDA also stated that the BLA resubmission included "exploratory analyses from IGNYTE and an early analysis of data from the ongoing confirmatory Ph 3 that it did not believe alleviated concerns previously communicated regarding the inconsistency of response criteria used in IGNYTE with RECIST v1.1."

Wedbush noted that Replimune's response "highlights inconsistencies with FDA regulatory process and communications." The report stated that Replimune indicated data from the Phase 3 study "showed a PFS of 30.6 months for RP1 plus nivo. compared to 4.4 months on prior PD-1-based regimen, indicating a significant treatment effect for the addition of RP1."

The report also stated that Replimune indicated "detailed analyses provided to the FDA showed no material difference in response rates between injected and non-injected lesions," and that "a comprehensive analysis showed that biopsies and surgical interventions did not impact tumor response."

Wedbush wrote, "Overall, we view the additional CRL as disappointing given what we viewed as convincing treatment effect in a patient population with significant unmet need." The firm added, "We see no path forward for RP1 with IGNYTE, and significant risk with regards to the ongoing Ph 3 study." Wedbush stated that it was "downgrading to NEUTRAL and reducing our PT to US$2 (from US$19)."

In a separate April 13 H.C. Wainwright research note, analyst Robert Burns downgraded Replimune to "Sell" from "Buy" and removed its price target.

H.C. Wainwright wrote, "RP1's path to market just became painfully longer, in our view—downgrading to Sell without a price target." The report stated that the FDA's second complete response letter cited "three principal areas: (1) inability to isolate the contribution of RP-1 when administered in combination with nivolumab; (2) heterogeneity of the patient population, preventing adequate interpretation of the results; and (3) lack of a well-established historical control, which limits comparisons of response rate."

According to the H.C. Wainwright report, "we believe that the ongoing Phase 3 IGNYTE-3 trial evaluating RP-1 + Opdivo vs. the physician's treatment choice will also inevitably encounter the same issues with the FDA."

The report further stated, "We see a significantly longer path for RP-1 to reach the market, if at all." H.C. Wainwright added, "The company is facing a significant crisis and may not be able to pivot successfully."

H.C. Wainwright stated that it was "downgrading our rating to Sell from Buy, while removing our price target," and added that it awaited "clarity on the regulatory path forward and the revised timeline to potential submission of the RP1 dossier with additional clinical data ahead of revising our assumptions."

IGNYTE Trial and Regulatory Developments

According to Replimune, the company initiated the global Phase 3 IGNYTE-3 trial following FDA feedback in order to satisfy the regulatory requirement that a confirmatory study be underway for accelerated approval.

The company stated that the IGNYTE trial enrolled 140 patients with anti-PD-1-failed cutaneous melanoma. The poster presentation reported that updated objective response rates showed "clinically meaningful benefits across biological subgroups.

Streetwise Ownership Overview*

Replimune Group Inc. (REPL:NASDAQ)

Restructures

Date	Old Symbol	Old Shares	New Symbol	New Shares
07/07/11	REPLD	1	REPL	1
12/01/10	REPL	1	REPLD	15

^*Share Structure as of 5/8/2026

The presentation also reported a 26.2% objective response rate in patients previously treated with anti-PD-1 and anti-CTLA-4 therapy and a 34.8% response rate in patients with primary resistance to anti-PD-1 therapy.

According to the data, treatment with RP1 plus nivolumab resulted in increases in intratumoral PD-L1 expression and CD8+ T cells post-treatment. The presentation stated that PD-L1 expression increased in 56% of paired lesions, and CD8+ T cells increased in 37% of paired lesions.

The presentation further stated that RP1 plus nivolumab increased expression of the interferon-gamma signature and expanded existing T-cell clones while generating new T-cell clones associated with melanoma and HSV-1 responses.

As per the conclusions section of the presentation, the safety profile remained consistent with the primary analysis, with "generally transient grade 1/2 side effects."

Ownership & Share Structure¹

Replimune Group Inc. has a market cap of US$140.37 million, with 82.57 million shares outstanding. The company's 52-week range is US$1.50-US$13.24.

Institutions hold 97.32% of shares, and Management & Insiders own 2.68% of shares.

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Important Disclosures:

James Guttman wrote this article for Streetwise Reports LLC and provides services to Streetwise Reports as an employee.
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1. Ownership and Share Structure Information

The information listed above was updated on the date this article was published and was compiled from information from the company and various other data providers.

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