HyBryte Continues to Improve mCAILS in Early Cutaneous T-Cell Lymphoma

Ellen Kim, MD

Extended treatment with SGX301 (HyBryte) for up to 12 months led to lesion responses in patients with early-stage cutaneous T-cell lymphoma (CTCL), according to updated data from an interim analysis of the open-label, investigator-initiated phase 2 RW-HPN-MF-01 trial (NCT05872854).¹

Of the 6 patients who have been enrolled and treated for up to 44 weeks, 4 have completed at least 12 weeks of therapy. Three of these 4 patients have achieved at least a 50% improvement in their cumulative modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline. Two of these responses were achieved within the first 12 weeks of treatment, and the third was experienced within 18 weeks.

Regarding the other 3 patients, 2 have not yet reached their first efficacy evaluation visit at week 6 after recently starting treatment. The third patient, despite having a significant improvement on mCAILS at week 18, has not reached the predefined efficacy threshold of 50%.

The company also reported that HyBryte proved safe and well tolerated in all patients, with no documented treatment-related adverse effects to date.

“In the phase 3 FLASH study [NCT02448381], HyBryte was shown to be efficacious with a promising safety profile. With limited treatment options, especially in the early stages of their disease, CTCL patients are often searching for alternative treatments. In our FDA-funded study, initial results evaluating the expanded use of HyBryte in a ‘real world’ treatment setting are promising, further supporting and extending results from the previous positive phase 2 and 3 clinical trials,” Ellen Kim, MD, director of the Penn Cutaneous Lymphoma Program and vice chair of Clinical Operations in the Dermatology Department and professor of dermatology at the Hospital of the University of Pennsylvania; and principal investigator of the IIS [investigator-initiated study], said in a news release. “We look forward to continuing to work with the FDA to complete this study and to participating in the upcoming confirmatory phase 3 placebo-controlled study.”

SGX301 is a novel, first-in-class, photodynamic therapy that uses safe, visible light to activate synthetic hypericin, a potent photosensitizing ointment that is applied to skin lesions and absorbed by malignant T cells. The use of visible light that lies in the red-yellow spectrum can penetrate more deeply into the skin than ultraviolet light, providing an opportunity to target deeper skin disease and thicker plaques and lesions, thus sparing patients the risks associated with DNA-damaging drugs and other phototherapy that are dependent on ultraviolet exposure.

When used with photoactivation, hypericin has shown substantial inhibition of activated normal human lymphoid cells and the growth of malignant T cells from patients with CTCL. In a phase 2 trial, patients with CTCL experienced a statistically significant improvement with topical hypericin vs placebo (P =.04).

RW-HPN-MF-01 was designed as a multicenter clinical trial enrolling as many as 50 patients with a clinical diagnosis of stage IA, IB, or IIA CTCL mycosis fungoides. Per the trial protocol, patients with stage IA disease need to have patches, papules, and/or plaques that cover less than 10% of the skin surface; those with stage IB disease must have patches, papules, and/or plaques that cover 10% or more of the skin surface. Patients with stage IIA disease may have patches, papules, and/or plaques that cover any amount of skin surface.2

During the study, patients are receiving visible light activation starting at 5 J/cm2 24 hours (± 6 hours) after 0.25% hypericin ointment application twice weekly for up to 12 months. The primary end point is the number of patients who experience at least 50% reduction in the cumulative mCAILS score from baseline to the end of treatment.

“We are pleased with the initial study results and with the FDA’s support of the IIS that provides [patients with] CTCL an opportunity to access [SGX301] in an open-label setting,” Christopher J. Schaber, president and chief executive officer of Soligenix, stated in a news release.¹

Previously, SGX301 received orphan drug and fast track designations from the FDA and orphan drug designation from the EMA for the first-line treatment of patients with CTCL. However, the developers of SGX301 received a refusal to file letter from the FDA in February 2023 regarding the new drug application (NDA) seeking approval of the agent.³

The NDA was based on findings from the phase 3 FLASH trial which enrolled 169 patients with stage IA, IB, or IIA CTCL and evaluated 3 individual treatment cycles in which patients received twice-weekly administrations for 6 weeks before undergoing response assessment at the end of week 8.^1,4

In the first cycle, which was double-blind, 116 patients received SGX301, and 50 received placebo for their index lesions. At the end of week 8, 16% of patients who received SGX301 had documented at least a 50% improvement in their CAILS score vs 4% of patients on placebo (P =.04).

In the second cycle, which was open label, 110 patients received 12 weeks of SGX301l and 45 received 6 weeks of placebo followed by 6 weeks of SGX301. Results showed that the response rate was 40% in the 12-week treatment group in cycle 1 (P <.0001 vs placebo). Data also showed a statistically significant improvement in the 12-week course of therapy vs the 6-week course (P <.0001). SGX301 also showed activity in treating plaque and patch lesions, with respective response rates of 42% and 37%, relative to treatment with placebo in cycle 1 (P <.0001 and P =.0009, respectively).

The third cycle, which was optional, allowed all patients to receive SGX301 for their lesions. Of the 66% of patients who continued treatment, 49% demonstrated a positive treatment response vs those who received placebo in cycle 1 (P <.0001). Additionally, SGX301 remained well tolerated despite continued use of the product to treat multiple lesions.

Following the completion of the FLASH trial, the FDA and the EMA announced that they would require a second positive phase 3 trial to support marketing approval. With agreement from the EMA on the study design, the company plans to launch the FLASH2 trial by the end of 2024. Discussions are still ongoing with the FDA regarding the appropriate path forward for the agent’s evaluation.

Similar in design to FLASH, FLASH2 will serve as a randomized, double-blind, placebo-controlled, multicenter study that will enroll approximately 80 patients with early-stage CTCL. However, in FLASH2 patients will receive 18 weeks of continuous treatment, at which point response will be evaluated, unlike in FLASH where patients received 3, 6-week cycles of treatment with the primary response measurement occurring after the first cycle.

“CTCL is an incredibly difficult to treat orphan disease and remains an area of unmet medical need with a very limited number of safe and effective treatment options. Following the initial phase 3 FLASH study which demonstrated the safety and efficacy of shorter courses of [SGX301] therapy, we are pleased to see that continuing treatment for longer time periods is resulting in the anticipated improved outcomes for patients. As the body of compelling data continues to grow in support of this novel therapy, we look forward to working with Dr Kim on this important study as well as embarking on our confirmatory phase 3 replication study later this year. We will continue to provide additional updates on the IIS as data becomes available,” Schaber added.

In addition to these phase 2 and 3 trials, SGX301 demonstrated improved activity vs mechlorethamine gel (Valchlor) in another phase 2 trial (HPN-CTCL-04; NCT06149247). Findings from the open-label study showed that in addition to improved tolerability, 60% of patients treated with SGX301 (n = 5) experienced at least a 50% improvement in their cumulative mCAILS score after 12 weeks of treatment vs 20% of those who received mechlorethamine gel (n = 5).⁵

References

1. Expanded HyBryte treatment demonstrating positive outcomes in early-stage cutaneous T-cell lymphoma. News release. Soligenix. July 9, 2024. Accessed July 10, 2024. https://ir.soligenix.com/2024-07-09-Expanded-HyBryte-TM-Treatment-Demonstrating-Positive-Outcomes-in-Early-Stage-Cutaneous-T-Cell-Lymphoma
2. Treatment of mycosis fungoides with hypericin ointment and visible light (RW-HPN-MF-01). ClinicalTrials.gov. Updated October 30, 2023. Accessed July 10, 2024. https://www.clinicaltrials.gov/study/NCT05872854
3. 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 July 10, 2024. https://ir.soligenix.com/2023-02-14-Soligenix-Receives-Refusal-to-File-Letter-from-U-S-FDA-for-HyBryte-TM-New-Drug-Application-in-the-Treatment-of-Cutaneous-T-Cell-Lymphoma
4. 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
5. Soligenix announces positive clinical results from a comparative study evaluating HyBryte against valchlor in the treatment of cutaneous T-cell lymphoma. News release. Soligenix. June 25, 2024. Accessed July 10, 2024. https://www.prnewswire.com/news-releases/soligenix-announces-positive-clinical-results-from-a-comparative-study-evaluating-hybryte-against-valchlor-in-the-treatment-of-cutaneous-t-cell-lymphoma-302181378.html