FDA Rejects NDA for Synthetic Hypericin in Early-stage Cutaneous T-cell Lymphoma


The FDA has issued a refusal to file letter for a new drug application seeking the approval of HyBryte, Soligenix’s synthetic hypericin, for use in patients with early-stage cutaneous T-cell lymphoma.

Christopher J. Schaber, PhD

Christopher J. Schaber, PhD

The FDA has issued a refusal to file letter for a new drug application (NDA) for HyBryte, Soligenix’s synthetic hypericin.1 The company submitted the NDA in December 2022 seeking approval for use in the treatment of early-stage cutaneous T-cell lymphoma (CTCL), but the agency determined that the NDA was not sufficiently complete to permit substantive review.

Hypericin is a potent photosensitizer applied to skin lesions. Malignant T cells absorb the drug, which is then activated by visible light 16 to 24 hours later.

Soligenix is considering its next steps. The company could request a Type A meeting with the FDA to clarify and respond to the issues identified in the letter and to seek additional guidance concerning information that the agency would require for a resubmitted NDA to be deemed acceptable to file, among other options.

“We are fully determined to work with the FDA staff as quickly as possible to better understand the open issues and clarify the potential path to successfully resubmitting our application," Christopher J. Schaber, PhD, Soligenix president and chief executive officer, said in a news release. “We remain focused on advancing HyBryte as a potential new first-in-class treatment option for the CTCL community of patients, families and health care professionals.”

CTCL is a rare disease with an annual overall incidence in the United States of 6.4 cases per million persons from 1973 to 2002. However, incidence increased to 7.7 per million persons from 2001 to 2005.2,3

Early-stage disease presents with scaly patches alone, or patches and plaques of different shapes and sizes, commonly located on the sun-protected areas of the body. At this point, CTCL can look like a number of skin conditions, making it one of the most challenging diseases to diagnose.

Patients with early-stage disease typically receive skin-directed therapies, such as topical steroids, UVB and PUVA phototherapy, and local radiation. Those with advanced disease or SS often require multiple lines and recurrent courses of systemic therapies.

Investigators assessed the efficacy and safety of hypericin in the phase 3 FLASH trial (NCT02448381). From December 2015 to November 2020, investigators at 39 medical centers in the United States randomly assigned adults with early-stage mycosis fungoides CTCL to hypericin (n = 116) or placebo (n = 50) to 3 index lesions twice weekly for 6 weeks in cycle 1. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In the optional cycle 3, both index and additional lesions received active drug for 6 weeks.4

The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open-label response rates were secondary end points.

investigators found that hypericin induced a response rate of 16% vs 4% with placebo (P = .04) following 6 weeks of therapy. The response rate in the hypericin arm increased to 49% through 18 weeks of treatment (P <.0001 vs cycle 1). Investigators recorded significant clinical responses in both patch- and plaque-type lesions. Furthermore, responses were similar regardless of age, sex, race, stage IA vs IB disease, time since diagnosis, and number of prior therapies.

The most common treatment-related adverse effects (AEs) were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). Investigators observed no drug-related serious AEs.

Pei-Ling Chen, MD, PhD, is a member of the Pathology and Cutaneous Oncology Departments at Moffitt Cancer Center and a member of the Moffitt Cutaneous Lymphoma Multidisciplinary Clinic specializing in the research and treatment of patients with CTCL. She spoke to OncLive® in August 2022 about CTCL and the FLASH findings.

“Given the fact that mycosis fungoides is a chronic disease, there’s a need for additional treatments with minimal short- and long-term effects,” she said. “This [study] is quite important because it’s an important new therapy for early-stage disease patients with minimal adverse effects.”


  • Soligenix receives refusal to file letter from US FDA for HyBryte new drug application in the treatment of cutaneous T-cell lymphoma. Soligenix. News release. February 14, 2023. Accessed February 14, 2023. https://ir.soligenix.com
  • Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol. 2002;46(1):95-106. doi:10.1067/mjd.2002.118538
  • Keto J, Hahtola S, Linna M, Väkevä, L. Mycosis fungoides and Sézary syndrome: a population-wide study on prevalence and health care use in Finland in 1998–2016. BMC Health Serv Res. 2021;21(1):166. doi:10.1186/s12913-021-06109-9
  • 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
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