DLB: Intepirdine a No-Go, Nelotanserin Shrouded in Controversy

Axovant, the company founded on the idea of giving pharma cast-offs new life, will terminate development of its serotonin receptor 6 (5-HT6) antagonist intepirdine, after patients with DLB showed no improvement on multiple measures of cognition or motor function in Phase 2/2b trials. Nelotanserin, a serotonin receptor 2A (5-HT2A) agonist, passed muster on safety in a separate Phase 2b study, but the company’s January 8 claim of a benefit in a subset of patients with worse psychiatric symptoms had to be walked back the following day because the p value initially reported was off by almost 50-fold. 

  • Axovant reports data from three trials on two serotonin-targeted drugs in dementia with Lewy bodies.
  • After failing in AD, intepirdine continued its losing streak, showing no efficacy in DLB.
  • Nelotanserin passed on safety, may be tested further.

HEADWAY, a multicenter, randomized, double-blind, placebo-controlled Phase 2b trial, gave 35 mg or 70 mg of intepirdine or placebo daily to 269 patients with DLB for 24 weeks. Endpoints included function, cognition, and movement measures, none of which budged compared with placebo.

In a separate Phase 2 placebo crossover study of 38 patients with AD, DLB, or Parkinson’s dementia whose gait was impaired, none improved walking speed after 24 weeks of taking 35 mg of the drug.

The results end Axovant’s development of intepirdine, according to the press release. In a previous Phase 3 trial in Alzheimer’s disease patients, the drug failed to enhance cognition when given in concert with cholinesterase inhibitors (Sep 2017 news). The company said it will wind down ongoing extension studies in both AD and DLB.

Intepirdine is not the first 5-HT6 antagonist to bite the dust. Lundbeck and Pfizer both abandoned their own compounds for lack of efficacy in AD (Jan 2018 news). Nonetheless, Jeffrey Cummings of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas told Alzforum he’s not giving up on the target yet. “There’s a possibility that we’ve not observed optimal dosing in any of our 5-HT6 agents, and that we may still have an opportunity to push that receptor in a way that would benefit cognition,” he said. Cummings is watching with interest the one remaining effort, by SUVEN Life Sciences, which continues to trial its 5-HT6 antagonist SUVN-502. 

Nelotanserin hits a different serotonin receptor subtype, 5-HT2A, and it is an agonist. Another 5-HT2A agonist, pimavanserin, won approval in 2016 to treat hallucinations and delusions in people with Parkinson’s, and recent data suggest it may ease psychosis in AD (Dec 2017 conference news). Axovant acquired nelotanserin from Arena Pharmaceuticals, after it had failed in a Phase 2 trial to treat insomnia.

Axovant tested nelotanserin in a Phase 2 safety study. Thirty patients with DLB or Parkinson’s dementia (PDD) who had frequent visual hallucinations took drug or placebo in a crossover design. Participants received 40 mg/day of drug for two weeks, followed by 80 mg daily for another two weeks, or placebo for four weeks. The primary endpoint was safety and the drug was well tolerated, according to the company press release. For exploratory measures, the original press release reported a significant improvement in hallucinations and delusions in the 19 most severely affected patients. It claimed a p value of 0.011 for a 1.21 point improvement on the Scale for the Assessment of Positive Symptoms. However, the next day the company issued a correction, saying the improvement was as reported, but the p value was in fact 0.531. The threshold of statistical significance is generally 0.05; 0.5 reflects a coin toss.

Overall, nelotanserin in this trial produced no changes in any endpoint except for a trend toward improvement in motor function in the UPDRS-III. In a subgroup analysis of just the 19 DLB patients, the improvement in UPDRS-III was statistically significant.

According to the corrected press release, Axovant will “continue to discuss a larger confirmatory study on nelotanserin with the U.S. FDA on patients with DLB with motor function deficits.” The company said it may evaluate nelotanserin for psychotic symptoms in DLB and PDD. For his part, Cummings did not consider the nelotanserin results promising. “I don’t think the study is supportive of further development in DLB,” he said.

“These were disappointing outcomes after a great deal of effort, not least by DLB patients and their families,” said Ian McKeith of Newcastle University in the U.K. “However, the studies have demonstrated that clinical trials in DLB are feasible, and we can now look forward to seeing more drugs being tested and investigator experience growing,” he wrote in an email to Alzforum. McKeith served an advisor to Axovant on some of the studies.

Cummings echoed that idea. “These were among the very first studies of DLB, and as such are pioneering. They suggest that the FDA is willing to entertain DLB as an indication and showed that recruitment of patients could be done. Even though the drugs did not work, we do need to learn from every single trial, and the investigators deserve credit for trying to find therapies for DLB,” he said.—Pat McCaffrey

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References

Therapeutics Citations

  1. Intepirdine
  2. Masupirdine
  3. Nelotanserin
  4. Nuplazid

News Citations

  1. Intepirdine Joins the Ranks of Failed Alzheimer’s Drugs
  2. RIP: Serotonin Receptor 5-HT6 Antagonist
  3. Pimavanserin Trial Raises Hope for Treating Dementia-Related Psychosis

External Citations

  1. claim of a benefit in a subset of patients with worse psychiatric symptoms
  2. the p value initially reported was off by almost 50-fold

Further Reading

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