Rafael Holdings subsidiary, Cyclo Therapeutics, is forging on with regulatory submissions for its rare metabolic disease therapy despite the drug posting a late-stage primary endpoint miss in Niemann-Pick disease type C (NPC).
During the Phase III TransportNPC study (NCT04860960), Cyclo pitted a biweekly, intravenous dose of Trappsol Cyclo (intravenous hydroxypropyl-β-cyclodextrin) against placebo in 94 patients with NPC, while conducting an open-label arm that looked at the drug’s potential in infants up to three years of age over a 96-week period. In this time, researchers primarily looked at what influence Trappsol Cyclo – a cholesterol transporter – had on a patient’s fine motor skills, as well as their ability to speak, swallow and walk from baseline.
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While Trappsol Cyclo did exhibit a favourable treatment effect over placebo, prompting a mean, placebo-adjusted 0.81-point change on the four-domain NPC Clinical Severity Scale (4DNPCSS), this impact was not statistically significant, meaning the trial missed its primary endpoint.
However, the drug did trigger a significant impact on NPC severity in a subset of patients receiving background treatment with fat and sugar buildup-lowering NPC drug, Zavesca (miglustat), or neuroprotective medicine, Aqneursa (levacetylleucine / N-acetyl-L-leucine). Within this patient population, Trappsol Cyclo slowed disease progression by 71% over placebo at the 96-week mark, representing a 1.11-point change on the 4DNPCSS scale.
On top of its impact alongside other NPC therapies, Trappsol Cyclo also offered patients an overall survival (OS) benefit, with treated individuals experiencing an 85% drop in the risk of death compared with matched external controls, who Cyclo selected based on similarities in disease characteristics and progression. This risk reduction fell further to 94% when the biotech included additional matched historical cohorts from published natural history studies in a secondary analysis.
Patients also generally tolerated Trappsol Cyclo well, with serious adverse events occurring at similar rates between the treatment and placebo arms. During the trial, only one patient discontinued treatment due to a treatment-related side effect.
Next steps for Trappsol Cyclo in NPC
While Trappsol Cyclo may have failed to meet its primary endpoint in the TransportNPC study, Karen Mullen, CMO of Rafael Holdings, noted that the data collated from the trial still presents a “compelling rationale” to support the continued progression of Trappsol Cyclo in NPC. This rare, inherited metabolic disease is characterised by the body’s inability to transport lipids effectively, which leads to a toxic buildup in the cells – impacting several organs such as the brain, liver and spleen.
Rafael is continuing with its plans to submit a New Drug Application (NDA) for Trappsol Cyclo to US regulators in Q4 2026.
Other marketed drugs for NPC include Zevra Therapeutics’ Miplyffa (arimoclomol) and IntraBio’s Aqneursa (levacetylleucine).
Rafael is not the only company with a pipeline NPC asset, as Dutch biotech Azafaros is currently exploring the potential of its candidate, nizubaglustat, in the Phase III NAVIGATE (NCT07082725) and Phase II PRISMA (NCT07399704) studies.
