RARE Daily

FDA Tells Soligenix It Will Not Accepts Its Application to Approve Treatment for CTCL

February 14, 2023

Rare Daily Staff

The U.S. Food and Drug Administration notified Soligenix that it would not review its application seeking approval to market HyBryte for the treatment of early-stage cutaneous T-cell lymphoma, a rare cancer.

The FDA determined that the New Drug application was not sufficiently complete to permit substantive review. Soligenix first learned of the decision through a letter from the agency and is reviewing it to determine the appropriate next steps.

The company could request 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 application so it would be deemed acceptable.

“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,” said Christopher Schaber, president and CEO of Soligenix. “We remain focused on advancing HyBryte as a potential new first-in-class treatment option for the CTCL community of patients, families and healthcare professionals.”

CTCL is a class of non-Hodgkin’s lymphoma (NHL), a type of cancer of the white blood cells that are an integral part of the immune system. Unlike most NHLs, which generally involve B-cell lymphocytes (involved in producing antibodies), CTCL is caused by an expansion of malignant T-cell lymphocytes (involved in cell-mediated immunity) normally programmed to migrate to the skin.  These malignant cells migrate to the skin where they form various lesions, typically beginning as patches that may progress to raised plaques and tumors.  Mortality is related to the stage of CTCL, with median survival generally ranging from about 12 years in the early stages to only 2.5 years when the disease has advanced. There is currently no cure for CTCL. Typically, CTCL lesions are treated and regress but usually return either in the same part of the body or in new areas.

HyBryte is a novel, first-in-class, photodynamic therapy utilizing safe, visible light for activation. The active ingredient in HyBryte is synthetic hypericin, a potent photosensitizer topically applied to skin lesions that is taken up by the malignant T-cells, and then activated by visible light approximately 24 hours later.  The use of visible light in the red-yellow spectrum has the advantage of penetrating more deeply into the skin (much more so than ultraviolet light) and therefore potentially treating deeper skin disease and thicker plaques and lesions. This treatment approach avoids the risk of secondary malignancies (including melanoma) inherent with the frequently employed DNA-damaging drugs and other phototherapy that are dependent on ultraviolet exposure.

Combined with photoactivation, the company said hypericin has demonstrated significant anti-proliferative effects on activated normal human lymphoid cells and inhibited growth of malignant T-cells isolated from CTCL patients. In a published phase 2 clinical study in CTCL, patients experienced a statistically significant improvement with topical hypericin treatment whereas the placebo was ineffective.  HyBryte has received orphan drug and fast track designations from the FDA, as well as orphan designation from the European Medicines Agency.

The recently published phase 3 FLASH trial enrolled a total of 169 patients with Stage IA, IB or IIA CTCL. The trial consisted of three treatment cycles. Treatments were administered twice weekly for the first six weeks and treatment response was determined at the end of the 8th week of each cycle. In the first double-blind treatment cycle, 116 patients received HyBryte treatment (0.25 percent synthetic hypericin) and 50 received placebo treatment of their index lesions. A total of 16 percent of the patients receiving HyBryte achieved at least a 50 percent reduction in their lesions compared to only 4 percent of patients in the placebo group at 8 weeks during the first treatment cycle. HyBryte treatment in the first cycle was safe and well tolerated.

In the second open-label treatment cycle, all patients received HyBryte treatment of their index lesions. Evaluation of 155 patients in this cycle demonstrated that the response rate among the 12-week treatment group was 40 percent. Comparison of the 12-week and 6-week treatment groups also revealed a statistically significant improvement between the two groups, indicating that continued treatment results in better outcomes. HyBryte continued to be safe and well tolerated. Additional analyses also indicated that HyBryte is equally effective in treating both plaque (response 42 percent relative to placebo treatment in Cycle 1) and patch (response 37 percent, relative to placebo treatment in Cycle 1) lesions of CTCL, a relevant finding given the historical difficulty in treating plaque lesions in particular.

The third treatment cycle, which was optional, was focused on safety and all patients could elect to receive HyBryte treatment of all their lesions. Of note, 66 percent of patients elected to continue with this optional compassionate use / safety cycle of the study. Of the subset of patients that received HyBryte throughout all three cycles of treatment, 49 percent of them demonstrated a positive treatment response. Moreover, in a subset of patients evaluated in this cycle, it was demonstrated that HyBryte is not systemically available, consistent with the general safety of this topical product observed to date. At the end of Cycle 3, HyBryte continued to be well tolerated despite extended and increased use of the product to treat multiple lesions.

Photo: Christopher Schaber, president and CEO of Soligenix

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