Trappsol Cyclo NDA Push: Primary Endpoint Miss Versus Survival Signal Creates High-Stakes Regulatory Gamble

Cyclo Therapeutics Pursues NDA for Trappsol Cyclo Despite Phase III Miss

Cyclo Therapeutics, a subsidiary of Rafael Holdings, intends to submit a New Drug Application (NDA) to US regulators for its rare metabolic disease therapy, Trappsol Cyclo, for Niemann-Pick disease type C (NPC). This decision comes despite the drug missing its primary endpoint in the Phase III TransportNPC study, where it showed a mean, placebo-adjusted 0.81-point change on the 4DNPCSS, which was not statistically significant. However, the trial demonstrated a significant impact in a subset of patients receiving background therapy, slowing disease progression by 71%, and an overall survival benefit with an 85% reduction in the risk of death compared to external controls. The company plans to proceed with the NDA submission in Q4 2026, citing compelling rationale from the collected data.

• The Phase III TransportNPC study, involving 94 NPC patients, evaluated biweekly intravenous Trappsol Cyclo against placebo over 96 weeks. The trial missed its primary endpoint, showing a mean, placebo-adjusted 0.81-point change on the four-domain NPC Clinical Severity Scale (4DNPCSS) which was not statistically significant. This endpoint assessed fine motor skills, speech, swallowing, and walking from baseline.
• Despite the primary endpoint miss, Trappsol Cyclo demonstrated a significant impact on NPC severity in a subset of patients receiving background treatment with Zavesca (miglustat) or Aqneursa (levacetylleucine). In this specific population, the drug slowed disease progression by 71% over placebo at the 96-week mark, corresponding to a 1.11-point change on the 4DNPCSS scale.
• Trappsol Cyclo also offered a notable overall survival (OS) benefit. Treated individuals experienced an 85% reduction in the risk of death compared to matched external controls. This risk reduction further improved to 94% when additional matched historical cohorts from published natural history studies were included in a secondary analysis.
• The drug was generally well-tolerated, with serious adverse events occurring at similar rates between treatment and placebo arms, and only one treatment-related discontinuation. Despite the primary endpoint miss, Cyclo Therapeutics, a Rafael Holdings subsidiary, plans to submit a New Drug Application (NDA) for Trappsol Cyclo to US regulators in Q4 2026, based on the compelling rationale from the trial data.

Addressing the Persistent Unmet Needs in Niemann-Pick Disease Type C

Despite meaningful advances in understanding Niemann-Pick disease type C (NPC), significant gaps remain in the therapeutic landscape — from the absence of FDA-approved disease-modifying therapies to unresolved questions around biomarker utility and treatment timing.

• No FDA-approved disease-modifying therapy exists. As of 2024, no disease-modifying therapy has been approved by the United States Food and Drug Administration for NPC, and treatment remains typically supportive. Miglustat (Zavesca®, Brazaves®) — a small iminosugar molecule that reversibly inhibits glycosphingolipid synthesis — is the only disease-specific drug approved for progressive neurological manifestations, but its approval is limited to stabilizing or slowing progression rather than reversing or curing the disease.

• Biomarker translation remains incomplete. The lack of robust biomarkers contributes to challenges associated with disease monitoring and quantifying treatment response. While candidates such as calbindin D, neurofilament light chain, 24(S)-hydroxycholesterol, cholestane-triol, trihydroxycholanic acid glycinate, amyloid-β, total and phosphorylated tau, and N-palmitoyl-O-phosphocholine-serine have been identified in plasma and cerebrospinal fluid, it remains unclear which biomarkers correlate with disease severity and progression, or which could reliably inform treatment response.

• Intrathecal hydroxypropyl-β-cyclodextrin shows uncertain efficacy. Although intrathecal 2-hydroxypropyl-β-cyclodextrin (VTS-270) demonstrated stable to slightly improved Neurological Severity Scale ratings over 2.5 to three years in three patients, its efficacy in the severe infantile form of NPC appears questionable — with one case report noting emergence of additional symptoms after an initial slight delay in progression, despite an absence of drug-related adverse events.

• Blood-brain barrier permeability limits systemic cyclodextrin delivery. The low permeability of hydroxypropyl-β-cyclodextrin across the blood-brain barrier restricts the positive neurological effects of systemic administration, necessitating intrathecal delivery and constraining broader therapeutic application.

• Optimal treatment initiation and discontinuation criteria remain poorly defined. Miglustat should be initiated at the onset of the first neurological symptoms, and disability scores above 20 on the modified disability scale reflect advanced neurological impairment at which miglustat therapy should be discontinued or not initiated — yet the heterogeneous clinical presentation of NPC across age groups complicates consistent application of these thresholds.

• Gastrointestinal tolerability poses a management burden. The primary tolerability issues associated with miglustat are mild to moderate gastrointestinal effects — including diarrhoea, flatulence, and abdominal pain/discomfort — along with weight loss, occurring mostly during initial therapy. These arise from inhibition of intestinal disaccharidase enzymes, leading to sub-optimal carbohydrate hydrolysis, osmotic diarrhoea, and altered colonic fermentation, requiring dietary modifications and dose titration strategies to optimize tolerability.

Trappsol Cyclo's Phase III Journey: Outcomes and Regulatory Path

Recent clinical research in Niemann-Pick disease type C (NPC) has advanced across multiple therapeutic modalities, with trials evaluating both small-molecule and biological approaches. The studies below represent key findings on efficacy and tolerability from phase 2/3 and observational settings.

• NPC-002 Phase 2/3 Trial and 48-Month Open-Label Extension (Arimoclomol): In the 12-month double-blind phase, 50 patients (aged 2–18 years) were randomised 2:1 to arimoclomol or placebo. The primary endpoint — change in 5-domain NPC Clinical Severity Scale (NPCCSS) from baseline to 12 months — showed mean progression of 0.76 with arimoclomol versus 2.15 with placebo, a statistically significant treatment difference of -1.40 (95% CI: -2.76, -0.03; P = .046), corresponding to a 65% reduction in annual disease progression. In the prespecified miglustat subgroup, arimoclomol achieved stabilisation of disease severity with a treatment difference of -2.06 (P = .006). Adverse events occurred in 30/34 patients (88.2%) on arimoclomol versus 12/16 (75.0%) on placebo; serious adverse events were less frequent with arimoclomol (5/34, 14.7%) versus placebo (5/16, 31.3%), with two treatment-related serious adverse events (urticaria and angioedema). In the subsequent 48-month open-label extension (OLE), 41 of 50 patients entered and 29 completed 48 months. Mean 5-domain NPCCSS and R4DNPCCSS scores increased by 3.2 (SD 4.8) and 2.7 (SD 4.2) over 48 months, respectively. Among patients switching from placebo to arimoclomol, mean annual change in 5-domain NPCCSS decreased from 2.0 (on placebo) to 0.1 in the first year of arimoclomol, and mean annual change in R4DNPCCSS decreased from 1.9 to 0.2. Arimoclomol was well-tolerated over 48 months with no new safety concerns identified. Arimoclomol has since been approved by the US Food and Drug Administration for treatment of NPC in combination with miglustat.

• CT-ORZY-NPC-001 Prospective Cohort Study (Miglustat as Routine Care / Biomarker Investigation): This multicentre, prospective observational study (NCT02435030) enrolled 36 individuals with genetically confirmed NPC1 or NPC2 (aged 2–18 years), of whom 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (± SD) increase in 5-domain NPCCSS scores of 1.4 (± 2.9) was observed, corresponding to an annualised progression rate of 1.5. On the 17-domain NPCCSS, mean (± SD) progression of 2.7 (± 4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p < 0.0001), HSP70 (p < 0.0001), and skin unesterified cholesterol (p = 0.0006), while cholestane-triol levels were significantly higher (p = 0.008) and correlated with 5-domain NPCCSS (Spearman's correlation coefficient = 0.265, p = 0.0411).

• G2-γ-CD versus HP-β-CD Study (Mono-6-O-α-D-maltosyl-γ-cyclodextrin): This preclinical/translational study evaluated mono-6-O-α-maltosyl-γ-CD (G2-γ-CD), a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, as an alternative cholesterol solubiliser for NPC. G2-γ-CD ameliorated NPC manifestations in model mice and demonstrated lower ototoxicity in mice than HP-β-CD. Molecular analyses — including cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modelling — indicated that G2-γ-CD maintained solely a 1:1 cholesterol inclusion complex, whereas HP-β-CD shifted to a highly soluble 2:1 complex at higher concentrations, a distinction proposed to underlie the differential ototoxicity and disease attenuation profiles of the two agents.

Trappsol Cyclo's Place in the Evolving NPC Treatment Landscape

The NPC treatment landscape has evolved from miglustat monotherapy — long the only approved disease-modifying option — toward combination regimens and novel investigational agents. Arimoclomol, recently approved in the US in combination with miglustat, has demonstrated statistically significant and clinically meaningful reductions in disease progression across both controlled and real-world settings. The data below summarize key comparative findings from published studies.

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A Bold Bet on Niemann-Pick C Survival Data

Cyclo Therapeutics' announcement to pursue a New Drug Application for Trappsol Cyclo in Niemann-Pick disease type C (NPC) marks a pivotal moment, challenging conventional regulatory pathways and highlighting the unique considerations for rare, devastating conditions. NPC is a progressive, fatal neurodegenerative disorder, and current therapeutic options, such as miglustat, primarily aim to slow disease progression. The company's decision, despite Trappsol Cyclo missing its primary endpoint in the Phase III TransportNPC study, is a bold move underpinned by compelling secondary data.

The data points to an 85% reduction in the risk of death compared to external controls and a 71% slowing of disease progression in a specific patient subset receiving background therapy. These are significant findings in a disease with such a dire prognosis, suggesting a potential for true disease modification and a survival advantage. Earlier Phase I/II studies also indicated that Trappsol Cyclo improved clinical signs and symptoms and was generally well tolerated, with the drug detected in the cerebrospinal fluid, which is crucial for a neurodegenerative condition.

However, this strategy is not without its risks. The primary endpoint miss is a substantial hurdle for regulatory bodies, who typically prioritize pre-specified outcomes. The reliance on subgroup analysis and external controls, while common in rare disease research, may invite scrutiny regarding the generalizability and robustness of the efficacy claims. Furthermore, the projected NDA submission in Q4 2026 leaves a considerable window for the competitive landscape to evolve, potentially introducing new therapies or advancements that could impact Trappsol Cyclo's future market entry. Nevertheless, this approach underscores the evolving paradigm in rare disease drug development, where profound clinical benefits, even if not captured by a single primary endpoint, can drive regulatory engagement and offer hope for patients with limited options.