Synthetic Hypericin Achieves Treatment Success in Cutaneous T-Cell Lymphoma

At the indication of the FDA and EMA, the phase 3 FLASH2 trial will further evaluate synthetic hypericin in early-stage cutaneous T-cell lymphoma.

Synthetic hypericin (HyBryte™), a first-in-class photodynamic therapy utilizing light for activation, achieved treatment success in 75% of a small cohort of patients with early-stage cutaneous T-cell lymphoma at 18 weeks, according to a press release on data from the phase 2 RW-HPN-MF-01 trial (NCT05872854) from the developer, Soligenix, Inc.1

Of the 8 patients evaluable for analysis at week 18, 6 (75%) patients had 50% or more improvement in the cumulative modified Composite Assessment of Index lesion Severity (mCAILS) score vs baseline. Additionally, 4 patients completed all 54 weeks of treatment with an average maximum improvement of 85% on the mCAILS test, 3 patients have not yet completed treatment, and 1 patient dropped out due to logistical issues.

"The complete response rates observed, including [3] patients achieving a complete response on this study to date, as well as the consistent treatment response and safety profile across multiple [synthetic hypericin] clinical studies, has been exciting to see," said Ellen Kim, MD, director of the Penn Cutaneous Lymphoma Program, vice chair of Clinical Operations in the Dermatology Department, and a professor of Dermatology at the Hospital of the University of Pennsylvania, and principal investigator of the study.1 “With limited treatment options, especially in the early stages of their disease, [patients with cutaneous T-cell lymphoma] are often searching for alternative treatments. In our study funded by the [US FDA], initial results evaluating the expanded use of [synthetic hypericin] in a ‘real-world’ treatment setting remain very promising, further supporting and extending results from the previous positive phase 2 and 3 clinical trials.”

Results came from the open-label, phase 2 RW-HPN-MF-01 trial that evaluated the continuous benefit of synthetic hypericin ointment and visible light in patients with mycosis fungoides for 54 weeks.2

Eligible patients had stage 1A, 1B, or 2A cutaneous T-cell lymphoma, were willing to follow clinical protocol, and were not pregnant. Those with a condition that was spontaneously improving, history of hypersensitivity to the sun or photosensitive dermatoses, history of systemic immunosuppression, and receipt of topical steroids or other treatments were not enrolled.

Treatment consisted of 0.25% hypericin ointment being applied to disease lesions and visible light at 24 hours plus or minus 6 hours after starting at 5 J/cm2; drug application and light sessions were done twice a week at least 2 days apart for up to 54 weeks.

The primary trial outcome was the amount of treatment successes, defined as 50% or more reduction in mCAILS score from baseline.

Additional studies include the published phase 3 FLASH trial (NCT02448381) and the upcoming FLASH2 trial (NCT06470451).

The FLASH Trial

The phase 3 FLASH trial evaluated the efficacy and safety of hypericin treatment in patients with patch or plaque phase cutaneous T-cell lymphoma. Findings from the trial were published in JAMA Network.3

In cycle 1, at the end of week 8, 16% of patients who received hypericin achieved a 50% or more reduction in their lesion via the CAILS score compared with 4% of patients who received placebo (P = .04).

In cycle 2, patients who received 12 weeks of hypericin treatment demonstrated a response rate of 40%. The treatment was also equally effective in treating plaque lesions (42%) relative to placebo treatment in cycle 1 and patch lesions (37%) relative to placebo treatment in cycle 1.

During the optional 3rd cycle, it was revealed that of all patients who received hypericin in all 3 treatment cycles, 49% achieved a positive treatment response.

Across all cycles, synthetic hypericin was considered safe and tolerable.

The FLASH2 Trial

After completion of the first phase 3 synthetic hypericin trial in cutaneous T-cell lymphoma, both the FDA and the European Medicines Agency (EMA) required an additional successful phase 3 trial to support marketing approval.

The confirmatory phase 3 FLASH2 trial is currently enrolling patients and is built to replicate the FLASH trial with an extended double-blind, placebo-controlled assessment of 18 weeks of continuous treatment.

Previously, synthetic hypericin was granted the orphan drug and fast track designations from the FDA and the orphan designation from the EMA.4

References

1. Positive outcome in 75% of CTCL patients treated with HyBryte™ for 18 weeks. News release. Soligenix. April 14, 2025. Accessed April 15, 2025. https://tinyurl.com/bddbs3dm
2. Treatment of mycosis fungoides with hypericin ointment and visible light (RW-HPN-MF-01). ClinicalTrials.gov. Updated January 22, 2025. Accessed April 15, 2025. https://tinyurl.com/48m73e2d
3. Kim EJ, Mangold AR, DeSimone JA, et al. 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
4. FDA grants Soligenix orphan drug designation for the treatment of T-cell lymphoma. News release. Soligenix. September 9, 2021. Accessed April 15, 2025. https://tinyurl.com/mrypkxm4