Rafael Holdings' Phase 3 NPC trial misses primary endpoint, subgroup hits significance

Rafael Holdings announced topline results on September 30, 2026 from its Cyclo Therapeutics, LLC subsidiary's pivotal Phase 3 TransportNPC study (CTD-TCNPC-301) of Trappsol Cyclo (intravenous hydroxypropyl-β-cyclodextrin) in 94 patients with Niemann-Pick Disease Type C.

The global, double-blind, placebo-controlled study enrolled 94 patients ages 3 to 70, randomized to receive 2000 mg/kg of Trappsol Cyclo intravenously every two weeks (n=63) or placebo (n=31) for 96 weeks, measuring change in the 4-domain NPC Clinical Severity Scale (4DNPCSS).¹

On the primary endpoint, Trappsol Cyclo showed a directionally favorable treatment effect versus placebo, indicating a 64% slowing of disease progression on 4DNPCSS change at Week 96 (LS mean change from baseline of 0.46 vs 1.28 points; difference −0.81 points [95% CI −2.04, 0.41]; p=0.19), which did not reach statistical significance.¹

A prespecified subgroup analysis fared better: among patients receiving background miglustat and/or leucine therapy (n=78), Trappsol Cyclo showed a 71% slowing of disease progression versus placebo at Week 96 (LS mean change of 0.46 vs 1.57 points; difference −1.11 points [95% CI −2.19, −0.02]; p=0.046).¹

On safety, treatment-emergent adverse events occurred in 93.8% of Trappsol Cyclo patients versus 100.0% on placebo; serious TEAEs were more frequent with Trappsol Cyclo (35.9% vs 16.7%) though treatment-related serious TEAEs were similar (3.1% vs 3.3%); hearing-related TEAEs occurred in 15.6% vs 13.3%, mostly mild or moderate, with one severe case of bilateral deafness in the treatment group; no TEAEs led to death, and one patient discontinued due to a TEAE.¹

A separate analysis comparing infantile-onset NPC patients to external registry controls found an 85% reduction in mortality risk versus matched controls from the International Niemann-Pick Disease Registry (n=93), HR=0.154, 95% CI 0.025-0.950, p=0.044.¹ An expanded analysis found a 94% reduction in mortality risk when including additional historical cohorts (n=133), HR=0.057, 95% CI 0.011-0.306, p=0.0008.¹

The company said it remains on track to submit an NDA to the FDA in the fourth quarter of 2026, based on its previously announced pre-NDA meeting.¹ The topline data remain subject to full analysis and FDA review, and the company plans to present complete results at a future medical meeting.¹