Phase 3 Trial of Synthetic Hypericin in CTCL Advised to Stop for Futility
Following a prespecified interim efficacy analysis of the confirmatory phase 3 FLASH2 trial (NCT06470451) evaluating synthetic hypericin (SGX301; HyBryte) in cutaneous T-cell lymphoma (CTCL), the data monitoring committee has recommended halting the trial due to futility, according to developer Soligenix. The data monitoring committee completed the interim efficacy review of the FLASH2 trial and recommended the study be discontinued.
The multicenter trial was designed as a randomized, double-blind, placebo-controlled study extending continuous double-blind treatment to 18 weeks, with the primary end point assessed at that 18-week timepoint. The committee had previously confirmed an acceptable safety profile in prespecified safety evaluations prior to the efficacy analysis. Synthetic hypericin is a novel ointment photodynamic therapy that employs visible light for activation. The agent is topically applied to skin lesions and is taken up by malignant T-cells; it is then activated by visible light in the red-yellow spectrum approximately 24 hours later. Unlike ultraviolet light-based phototherapy approaches, visible light penetrates more deeply into the skin and is not associated with the risk of secondary malignancies including melanoma.
FLASH2 Trial: Context and Prior Data
In December 2022, a new drug application (NDA) for synthetic hypericin in early-stage CTCL was filed to the FDA based on positive findings from the multicenter, randomized, phase 3 FLASH trial (NCT02448381). The FDA determined the NDA was incomplete and subsequently denied acceptance of the application in February 2023, issuing a refusal to file letter. In response, the developer requested a type A meeting for further clarity on the decision. The FLASH2 trial was initiated in response to a request from the FDA during the meeting in April 2023. The FDA indicated that a second successful phase 3 trial would be required to support marketing authorization.
A key design distinction between the 2 studies was the primary efficacy assessment timepoint. In the original FLASH trial, efficacy was evaluated at week 8 after the initial 6-week double-blind treatment cycle. In FLASH2, the double-blind, placebo-controlled assessment was extended to 18 weeks of continuous treatment with no between-cycle treatment breaks, and the primary end point was set at the end of that 18-week period. Preliminary FLASH2 data from the first 9 enrolled patients, announced in April 2025, revealed that 6 (75%) of 8 evaluable patients achieved “treatment success” per the predefined criterion of at least 50% improvement in the cumulative modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline by week 18, indicating a rapid rate of response. The therapy was also well tolerated by this group, with a safety profile consistent with prior reports.
Results From the Original FLASH Trial
The original FLASH trial enrolled 169 patients, of which 166 were evaluable, with stage IA, IB, or IIA CTCL. In the first double-blind treatment cycle (cycle 1), 116 patients received synthetic hypericin (0.25%) and 50 received placebo applied to index lesions twice weekly for 6 weeks. At week 8, using the mCAILS score, 16% of patients receiving synthetic hypericin achieved at least a 50% reduction in their lesions compared with 4% in the placebo group (P =.04), meeting the primary end point. In the second, open-label treatment cycle (cycle 2), 155 patients were evaluated. Among the 110 patients who received 12 weeks of synthetic hypericin, the response rate was 40% (P <.0001 vs the placebo rate in cycle 1). Comparison of 12-week and 6-week response rates demonstrated a statistically significant improvement (P <.0001), indicating that continued treatment was associated with better outcomes.
The drug also appeared equally effective in treating both plaque (response rate, 42%; P <.0001) and patch lesions (response rate, 37%; P =.0009) relative to placebo in cycle 1. In the optional third treatment cycle (cycle 3), 66% of patients elected to continue. Among patients who received synthetic hypericin across all 3 cycles (18 weeks total), the response rate was 49% (P <.0001 vs cycle 1 placebo). The 49% response rate across all 3 treatment cycles formed the basis for the design of the FLASH2 primary end point at 18 weeks. Treatment-related adverse events were primarily mild and consisted of local skin and application site reactions, with no treatment-related serious adverse events reported.
Next Steps
Soligenix stated they will analyze the full FLASH2 dataset to better understand the discordance between the current findings and the earlier results, with a particular focus on identifying any patient subsets that may derive benefit from synthetic hypericin therapy. The company also indicated it may pursue follow-up discussions with the EMA and FDA.
