19 November 2007. Neurochem announced last week that it would halt development of tramiprosate (Alzhemed) in the wake of the failure of its large North American Phase 3 trial (see ARF news story and commentary). The Canadian company said it would immediately discontinue an ongoing European trial and put its resources into the development of a tramiprosate pro-drug that it claims achieves higher levels in the brain. The company will continue an open-label extension of the North American trial.
In a surprising twist to the story, the company said it plans to market tramiprosate, also known as 3-amino-1-propanesulfonic acid or homotaurine, as a nutritional supplement. CEO Francesco Bellini announced that Neurochem would form a separate company to sell this product. He said he expects this move to satisfy demand for the compound from patients and their caregivers, and to produce revenues to fund Neurochem’s continuing research and development activities.
The negative results of a multicenter North American trial came out earlier this year, and in August, Neurochem announced that the FDA would not accept alternative analyses of the data to compensate for problems with the trial. (Phase 2 and 3 trials between the FDA and sponsoring companies are confidential, and the FDA does not comment on them.) Barry Greenberg of Neurochem presented data from the North American trial last Friday, 9 November, at the Marian S. Ware Neurodegenerative Disease Research Retreat at the University of Pennsylvania in Philadelphia. The primary outcome measures of cognitive function showed no significant effect of treatment over placebo, but Greenberg reiterated that the ADAS-Cog and CDR-SB showed some numerical differences in favor of tramiprosate. He said that the company is getting hundreds of letters asking for the drug but cannot claim a treatment effect.
One measure did reach statistical significance in the post-hoc analysis, and that was hippocampal atrophy, Greenberg said. A subset of 312 patients out of the total 790 who completed the study had MRI assessments of hippocampal volume at the beginning and end of the study. Greenberg said that a preliminary analysis of the volume data by external statisticians found a dose-dependent reduction in hippocampal atrophy, after adjustment for confounding factors. Reportedly, a dose of 200 mg/day reduced atrophy by 65 percent, and the 300 mg/day dose halted atrophy over the 18 months.
“Neurochem is committed to analyzing and understanding the data generated in the North American trial,” Greenberg said. The company had initially hoped to use the lessons from the North American trial to improve the design of the European trial, but then decided to scrap it altogether. Instead, Neurochem will prioritize to accelerate development of NRM-8499, a pro-drug of tramiprosate. According to Bellini, that compound is in preclinical development, with results of toxicology tests in several animal species due in early 2008.
In his talk at Penn, Greenberg, as had Paul Aisen in his prior discussion of the trial’s woes (see ARF related news story), warned that problems encountered in the tramiprosate trial may stymie other researchers seeking to carry out large disease modification trials. Length, center variability, diagnostic uncertainly in mild AD, and lack of diagnostic biomarkers or surrogates for therapeutic effects all complicate the effort, Greenberg said. Added to that were limitations of psychometric measurements of cognition, most of which were validated for short-term effects. In addition, it is hard to quantify quality of life. “The clinical effect is ultimately the most important, but the tools we have are not matched to this. We need better tools with higher sensitivity,” Greenberg said. Borrowing a quote from Richard Mohs of Eli Lilly, a noted AD trials expert, Greenberg concluded by saying that trials evolve by dialog among all involved, and need to achieve both scientific rigor and clinical relevance. “It is time to reopen that dialog,” Greenberg concluded.
It should be added that, when put to leaders of AD programs in other pharmaceutical companies and academia, these scientists tended to reply that trials will succeed if the drug is effective. In addition, current trials of newer drugs are increasingly including biomarker measurements to gather the data needed for their validation. Off-the-record rumblings about a paucity of rigorous and relevant research data, either published or presented at conferences, had accompanied tramiprosate’s clinical development through the years.
Greenberg did not mention in his talk that Neurochem had announced the day before that they would pursue marketing tramiprosate as a nutritional supplement. When questioned about this, he declined comment, saying he was not involved in the decision or in any future work on those plans. In a webcast on 8 November, Bellini said the move was a reaction to the results of the trial, coupled to the “demands from physicians and family members for the drug.” Because it is a natural product, tramiprosate can be sold as a nutritional supplement without the need to establish safety or effectiveness, but it cannot carry therapeutic claims. Bellini claimed that tramiprosate could be on the market as early as 2008, but the planned subsidiary company has not been formed yet.
Could the marketing of a tramiprosate dietary supplement affect future trials of related compounds? This question will only be answered if the product hits the market and catches on with elderly people. Bellini placed the market for nutritional supplements geared toward cognition at a cool US$1 billion per year. No one knows what slice of this pie tramiprosate might eventually capture, and CEOs of struggling public companies have been known to make optimistic projections before. Neurochem’s share price tumbled from around $25 last December to about $2 following the FDA decision last August, and closed at $3.85 last Friday.—Pat McCaffrey and Gabrielle Strobel.