Rafael Plans FDA Filing Despite NPC Drug Missing Main Goal in Phase 3 Trial

Rare Daily Staff

Rafael Holdings said its experimental therapy Trappsol Cyclo for the rare, fatal lysosomal storage disorder Niemann-Pick disease type C (NPC) failed to reach statistical significance on its main endpoint in a phase 3 trial.

The company said the drug still slowed disease progression in a prespecified subgroup. It plans to file a marketing application with the U.S. Food and Drug Administration in the fourth quarter of 2026.

NPC is a genetic, progressively debilitating, fatal neurovisceral disease. A genetic mutation causes patients to produce a misfolded NPC protein, which prevents the body from clearing certain lipids. These lipids build up in tissues and organs, including the brain, and cause progressive damage.

Trappsol Cyclo is an experimental intravenous drug for NPC. Its active ingredient is hydroxypropyl-β-cyclodextrin. Cyclodextrins are ring-shaped sugar molecules that bind cholesterol and carry it out of cells. The company has said the drug effectively stands in for the defective NPC1 protein. In animal models of NPC, this type of molecule cleared cholesterol from several organs, including the brain. It also delayed symptoms and extended survival.

The TransportNPC study enrolled 94 people with NPC, ages 3 to 70. Participants were randomly assigned to receive either Trappsol Cyclo at 2,000 mg/kg every two weeks (63 patients) or a placebo (31 patients) for 96 weeks. The company’s subsidiary, Cyclo Therapeutics, ran the study.

Researchers measured change on the 4-domain NPC Clinical Severity Scale. By week 96, patients on the drug had worsened by an average of 0.46 points, compared with 1.28 points for those on placebo. The company described this as a 64 percent slowing of progression. The difference did not meet the threshold for statistical significance.

The company also reported a prespecified analysis of 78 patients, about 83 percent of the study population, who were taking miglustat, leucine, or both in the background. Leucine is a food supplement available in some European countries. In this group, patients on Trappsol Cyclo worsened by 0.46 points versus 1.57 points on placebo, a 71 percent slowing. That result was statistically significant, though only narrowly. Because the overall result was not significant, regulators will likely scrutinize how much weight a subgroup finding can carry.

The company called the drug well tolerated and reported no new safety signals. Nearly all patients reported at least one adverse event: 93.8 percent on the drug and 100 percent on placebo. Serious events happened more often with the drug (35.9 percent versus 16.7 percent). Serious events judged related to treatment were similar, at 3.1 percent versus 3.3 percent.

Hearing-related events, a known concern with cyclodextrins, affected 15.6 percent of patients on the drug and 13.3 percent on placebo. Most were mild or moderate. One case of bilateral deafness in the drug group was considered treatment-related and severe. No adverse event led to death, and one patient on the drug left the study early because of an adverse event.

Separately, the company compared 41 patients with infantile-onset NPC who received the drug across its clinical program with matched patients from the International Niemann-Pick Disease Registry (93 patients). It reported an 85 percent lower risk of death. A broader comparison that added published natural history data (133 controls) showed a 94 percent lower risk. Because these comparisons used outside control groups rather than randomized placebo patients, they cannot show a survival benefit as firmly. The confidence intervals are also wide.

“The phase 3 TransportNPC study is the most comprehensive trial in NPC conducted to date,” said Karen Mullen, Rafael’s chief medical officer. She said the totality of the data gives “a compelling rationale” for continued development.