Trappsol Cyclo Misses Primary End Point in Phase 3 Trial for Niemann-Pick Disease Type C

Rafael Holdings has recently announced that topline results of the pivotal phase 3 TransportNPC trial (NCT04860960) of intravenous Trappsol Cyclo did not meet the primary end point, the change in 4-domain NPC Clinical Severity Scale (4DNPCSS) score compared with placebo, among patients with Niemann-Pick disease type C (NPC). Despite missing this, the company observed positive findings from a prespecified subgroup analysis and is planning an NDA submission in the fourth quarter of 2026.¹

“NPC is a devastating, heterogeneous disease, and preserving function and stabilizing symptoms are critical,” Caroline Hastings, MD, professor of pediatric hematology and neurology at UCSF Benioff Children's Hospital Oakland, said in a statement.¹ “As a clinician who has cared for these patients for many years, I am encouraged by the clinically meaningful TransportNPC results. The study was rigorously conducted, and its findings align with the two prior trials for Trappsol Cyclo across a decade of development. I am hopeful that these data can move us closer to delivering a much-needed therapeutic option for families facing profound unmet need.”

Trappsol Cyclo efficacy in the phase 3 TransportNPC trial

The global, double-blind, placebo-controlled TransportNPC trial randomized 94 patients aged 3 to 70 years to Trappsol Cyclo or placebo for 96 weeks.² Patients in the treatment arm (n = 63) received 2000 mg/kg intravenously every 2 weeks, and 31 patients received placebo.

In the full study population, the least squares mean change in 4DNPCSS score at week 96 was 0.46 points with Trappsol Cyclo and 1.28 points with placebo. The difference was –0.81 points (95% CI, –2.04 to 0.41; P = .19), which corresponds to a 64% slowing of disease progression.

A prespecified subgroup of 78 patients receiving background miglustat, leucine, or both, about 83% of the study population, showed a larger separation. The mean change was 0.46 points with Trappsol Cyclo vs 1.57 points with placebo, a difference of –1.11 points (95% CI, –2.19 to –0.02; P = .046). This corresponded to a 71% slowing of progression.

Trappsol Cyclo safety and survival analysis in NPC

Treatment-emergent adverse events (AEs) occurred in 93.8% of patients receiving Trappsol Cyclo and 100.0% of those receiving placebo. Serious AEs were more frequent with Trappsol Cyclo (35.9% vs 16.7%), while treatment-related serious events were similar (3.1% vs 3.3%). No events led to death, and 1 patient in the Trappsol Cyclo arm discontinued because of an AE.

Hearing-related AEs occurred in 15.6% of the Trappsol Cyclo group and 13.3% of the placebo group, and most were mild to moderate. One treatment-related severe bilateral deafness event occurred with Trappsol Cyclo. The company described the safety profile as consistent with earlier studies, with no new signals.

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A separate overall survival analysis evaluated patients with infantile-onset NPC treated with Trappsol Cyclo (n = 41). Compared with matched controls from the INPDR registry (n = 93), the hazard ratio for mortality was 0.154 (95% CI, 0.025-0.950; P = .044), an 85% risk reduction. Against an expanded historical control cohort (n = 133), the hazard ratio was 0.057 (95% CI, 0.011-0.306; P = .0008), a 94% reduction.

“The Phase 3 TransportNPC study is the most comprehensive trial in NPC conducted to date,” Karen Mullen, MBBS, chief medical officer at Rafael Holdings, said in a statement.¹ “We believe the totality of the data shared today provide a compelling rationale for the continued advancement of Trappsol Cyclo and its potential to offer clinically meaningful treatment benefit for those living with this devastating disease. We remain steadfast in our efforts to advance Trappsol Cyclo and are deeply grateful to the clinical investigators, patients, and caregivers whose courage and commitment were vital to completing this study.”

Frequently Asked Questions

What did the TransportNPC trial show?

Trappsol Cyclo slowed disease progression by 64% vs placebo on the 4DNPCSS at week 96, but the difference was not statistically significant (P = .19). A prespecified subgroup receiving background miglustat, leucine, or both showed a 71% slowing (P = .046).

How was Trappsol Cyclo dosed in TransportNPC?

Patients received 2000 mg/kg intravenously every 2 weeks for 96 weeks. The trial enrolled 94 patients aged 3 to 70 years.

What are the next steps for Trappsol Cyclo in NPC?

Rafael Holdings plans an NDA submission in the fourth quarter of 2026, following a pre-NDA meeting with the FDA. Full results are planned for presentation at an upcoming medical meeting.

REFERENCES
1. Rafael Holdings announces topline results from the pivotal phase 3 TransportNPC study of Trappsol Cyclo in Niemann-Pick disease type C (NPC). News release. Rafael Holdings. Published September 30, 2026. Accessed October 1, 2026. https://www.globenewswire.com/news-release/2026/09/30/3371740/0/en/rafael-holdings-announces-topline-results-from-the-pivotal-phase-3-transportnpc-study-of-trappsol-cyclo-in-niemann-pick-disease-type-c-npc.html
2. Rafael Holdings Announces Completion of Last Patient Last Visit for Pivotal Phase 3 TransportNPC™ Study Evaluating Trappsol® Cyclo™ for the Treatment of Niemann-Pick Disease Type C. News release. Rafael Holdings. Published June 10, 2026. Accessed October 1, 2026. https://nnpdf.org/wp-content/uploads/2026/06/Cyclo-Completes-96-Week-Phase-3-TransportNPC-06.10.2026.pdf