Rafael’s Trappsol Cyclo Misses Primary Endpoint, Targets 2026 FDA Filing

Key Points

• Trappsol Cyclo missed the Phase III trial’s primary endpoint: The 96-week TransportNPC study showed a favorable trend in slowing disease progression, but the treatment difference was not statistically significant (P=0.19).
• A pre-specified subgroup receiving miglustat and/or leucine achieved a statistically significant result, while safety was generally manageable; serious adverse events were more frequent with Trappsol Cyclo than placebo.
• Rafael plans to submit a New Drug Application to the FDA in the fourth quarter of 2026, supported by additional infantile-onset data and external-control survival analyses that indicated substantially lower mortality risk.

Rafael NYSE: RFL reported top-line results from its pivotal Phase III TransportNPC study evaluating Trappsol Cyclo for Niemann-Pick Disease Type C, a rare, progressive genetic disorder. The company said it remains on track to submit a New Drug Application to the U.S. Food and Drug Administration in the fourth quarter of 2026.

The global, double-blind, placebo-controlled study enrolled 94 patients across 27 sites in 13 countries. Patients ranging in age from 3 to 70 were randomized 2:1 to receive intravenous Trappsol Cyclo at 2,000 mg/kg plus standard of care every two weeks, or placebo plus standard of care, over 96 weeks.

Primary Endpoint Misses Statistical Significance

The trial’s primary endpoint was the change from baseline at week 96 on the four-domain NPC Clinical Severity Scale, or 4D, which evaluates swallowing, ambulation, fine motor function and speech. Lower scores represent improvement, while higher scores indicate worsening.

Chief Medical Officer Dr. Karen Mullen said the modified intent-to-treat analysis showed a mean treatment difference of negative 0.811 in favor of Trappsol Cyclo, with a P value of 0.19. While the result did not reach statistical significance, Mullen said it was directionally favorable and indicated a 64% slowing of disease progression based on the 4D change over 96 weeks.

“The main one being swallowing,” Mullen said when asked which subdomains appeared most relevant. She said the company saw favorable direction across the four domains and noted that swallowing is an important measure related to morbidity and mortality.

Subgroup Result and Safety Data

A pre-specified subgroup of 78 patients, or 83% of the overall population, received background treatment with miglustat and/or leucine. In that subgroup, Trappsol Cyclo produced a mean treatment difference of negative 1.105, with a P value of 0.046. Mullen said the finding represented a 71% slowing of disease progression versus placebo at 96 weeks.

The company said Trappsol Cyclo was generally well tolerated over the 96-week study period. Treatment-emergent adverse events were reported by 93.8% of Trappsol Cyclo patients and all placebo patients. Serious adverse events occurred in 35.9% of Trappsol Cyclo patients, compared with 16.7% of placebo patients, although treatment-related adverse events were reported at similar rates: 3.1% and 3.3%, respectively.

Hearing-related treatment-emergent adverse events occurred in 15.6% of the Trappsol Cyclo group and 13.3% of the placebo group. Most were mild to moderate, according to Mullen. One treatment-related hearing event was severe and required the patient to use bilateral hearing aids. No adverse events resulted in death, while one participant receiving Trappsol Cyclo withdrew early because of an adverse event.

Infantile-Onset Data and Survival Analysis

Rafael also discussed an open-label pediatric substudy that enrolled 10 children younger than age 3 with highly progressive infantile NPC. Among patients who reached 96 weeks, 71% showed improvement or stabilization on the Clinical Global Impression of Change, while 29% showed deterioration. The company reported 27 serious adverse events in the substudy, none of which were considered related to study drug.

Separately, Rafael presented an overall survival analysis comparing 41 Trappsol Cyclo-treated patients with infantile-onset NPC against matched external controls from the International Niemann-Pick Disease Registry. The primary analysis showed an 85% reduction in mortality risk, with a hazard ratio of 0.154 and a P value of 0.044, compared with 93 matched controls.

A secondary analysis incorporating additional matched external controls from published natural-history studies included 133 controls and showed a 94% reduction in mortality risk, with a hazard ratio of 0.057 and a P value of 0.008.

FDA Submission Plans

Chief Operating Officer Joshua Fine said the company’s pre-NDA meeting with the FDA provided alignment on its submission strategy and an understanding of the anticipated data package. He said Rafael could not provide additional detail beyond noting that the primary endpoint’s P value had not been achieved.

Fine said the company plans to complete its full TransportNPC data analysis, prepare its NDA submission and then focus on commercial readiness. Rafael said it remains eligible for a priority review voucher. The company cautioned that the complete data set and survival analyses remain subject to further analysis and FDA regulatory review.

About Rafael (NYSE:RFL)

Rafael Holdings, Inc is a diversified holding company focused primarily on commercial real estate and life sciences. The company's real estate activities include ownership and management of commercial properties, with a focus on properties in the New York metropolitan area and other strategic locations.

Through its life sciences investments and subsidiaries, Rafael Holdings has supported the development of oncology treatments and other pharmaceutical technologies. Its best-known biotechnology subsidiary, Rafael Pharmaceuticals, developed investigational cancer therapies, including devimistat, a treatment designed to target cancer-cell metabolism.

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