Hypericin Cutaneous T-cell Lymphoma Study Recommended for Discontinuation

The phase 3 FLASH2 trial (NCT06470451) evaluating synthetic hypericin (Hybryte) among patients with cutaneous T-cell lymphoma (CTCL) was recommended for discontinuation by a data monitoring committee for futility, according to a news release from the developer, Soligenix, Inc.^1,2

Findings from a prior study, the phase 3 FLASH trial (NCT02448381), revealed that among 116 evaluable patients treated with synthetic hypericin, 16% experienced a reduction in lesion volume of at least 50% compared with 4% of 50 patients treated with placebo at 8 weeks of treatment (P = .04).Furthermore, by the end of cycle 2, among 110 patients who received 12 weeks of therapy, the response rate was 40% (P < .0001). Moreover, compared with 45 patients who began with placebo and switched to a 6-week regimen of hypericin, the 12-week group experienced a significant improvement in efficacy (P < .0001).

Moreover, safety data revealed that synthetic hypericin was safe and well-tolerated. A total of 69.9% of patients experienced treatment-emergent adverse effects (TEAEs), 67.1% of whom experienced TEAEs related to hypericin.³ The most common TEAEs included skin/subcutaneous tissue-related disorders (31.9%), application-site pain (10.2%), upper respiratory tract infection (URI; 9.6%), pruitus (8.4%), and headache (7.8%).

Severe treatment-related AEs were observed in 3 patients, including 1 patient experiencing application-site pain in cycle 3, another experiencing erythema in cycle 1, and another with application-site pain during cycle 1 who withdrew from the study. A total of 5 serious AEs were observed on trial, but they were all deemed unrelated to synthetic hypericin.

Following the publication of the FLASH results, the FDA and European Medicines Agency necessitated a successful confirmatory phase 3 trial, the FLASH2 trial, to support marketing approval for synthetic hypericin, of which all important study design components remained the same.

“We are…disappointed with the unanticipated outcome of the study," Christopher J. Schaber, PhD, president and chief executive officer of Soligenix, said in a news release on the data monitoring committee decision.¹ "Despite the fact that [synthetic hypericin] demonstrated statistically significant reductions in CTCL lesions after 6 weeks [of] treatment in the first FLASH study, a similar signal was not observed with 18 weeks of treatment in this study. Over the coming weeks, we will analyze the data to better determine why the study did not meet expectations. “

Patients 18 years and older with stage IA to IIA mycosis fungoides-CTCL with 3 or more evaluable patch and/or plaque lesions were enrolled on the FLASH trial and treated biweekly with hypericin for up to three 6-week cycles. For cycle 1, patients were randomly assigned 2:1 to intervention or placebo, and by cycle 2, patients treated with placebo crossed over to receive hypericin for the treatment of index lesions. Moreover, an optional third cycle was created for open-label treatment of all lesions selected by the patient and physician.

In the hypericin and placebo groups, the mean age was 57.9 years (range, 19-99) vs 59.4 years (range, 20-89). Additionally, most patients were men (59.5% vs 54.0%), White (72.4% vs 72.0%), and had stage IA disease (62.1% vs 62.0%). Moreover, the mean duration of disease in each arm was 75.8 months (range, 0.4-375.6) vs 82.3 months (0.5-396.1), the baseline modified Composite Assessment of Index Lesion Severity score was 32.6 (range, 8–73) vs 32.6 (range, 3-55), and the median number of prior CTCL therapies was 3.0 (range, 0-19) vs 2.0 (range, 0-12).

The primary end point of the trial was 6-week treatment response in the hypericin group. Secondary end points included response outcomes for the second 6-week treatment cycle.

References

1. Soligenix announces interim results from the phase 3 FLASH2 trial evaluating HyBryte™ in treatment of cutaneous T-cell lymphoma. News release. Soligenix, Inc. April 28, 2026. Accessed April 28, 2026. https://tinyurl.com/4xv9n2tn
2. Confirmatory study of topical HyBryte™ vs. placebo for the treatment of CTCL (FLASH2). ClinicalTrials.gov. Updated April 3, 2026. Accessed April 28, 2026. https://tinyurl.com/3f366zkf
3. Efficacy and safety of topical hypericin photodynamic therapy for early-stage cutaneous T-cell lymphoma (mycosis fungoides): the FLASH phase 3 randomized clinical trial. JAMA Dermatol. 2022;158(9):1031-1039. doi:10.1001/jamadermatol.2022.2749