Anti-Agitation Drug Comes Up Short in Phase 3

A drug being tested for its ability to calm agitation in Alzheimer’s disease provided no benefit in the TRIAD-2 Phase 3 trial, according to topline results announced by Avanir Pharmaceuticals on September 27 (see press release). The drug, AVP-786, combines dextromethorphan hydrobromide, a weak NMDA receptor antagonist, with quinidine sulfate to enhance its calming effect. The negative finding conflicts with positive topline results from a separate Phase 3 trial of AVP-786 released earlier this year. Avanir plans to present results from these trials at a future scientific conference, but has not yet set the date or venue, spokesperson Jennifer Cabe told Alzforum.

  • AVP-786 did not work in a second Phase 3 Alzheimer’s trial.
  • The drug had met endpoints in a previous Phase 3 trial with a different design.
  • A third Phase 3 AD trial and an extension study will continue.

“I am surprised and disappointed by the outcome,” Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas wrote to Alzforum. Cummings led a Phase 2 Alzheimer’s trial of an earlier formulation of this drug, where it appeared to work. He wrote that researchers will need to see the full dataset to make sense of the conflicting findings.

Avanir, a subsidiary of Otsuka Pharmaceutical Co. Ltd., first combined dextromethorphan hydrobromide and quinidine sulfate in AVP-923, and named the mixture Nuedexta. In 2010, the Food and Drug Administration approved Nuedexta to treat pseudobulbar affect, the outbursts of laughing or crying that accompany some neurological conditions. Avanir subsequently tested Nuedexta for numerous other indications, including Alzheimer’s disease. In a 10-week Phase 2 trial, Nuedexta was reported to suppress agitation in most of the 220 AD patients who took it (Sep 2015 news; Oct 2014 conference news). Nuedexta is currently in a Phase 1/2 study for amyotrophic lateral sclerosis and a Phase 3 trial for Huntington’s disease.

AVP-786 is a deuterated form of AVP-923 that Avanir developed in 2012. This modification slows the body’s metabolism of the drug. After Phase 1 studies for safety, tolerability, and pharmacokinetics, Avanir launched three Phase 3 trials of AVP-786 for AD. Avanir lists no doses for these three trials on clinicaltrials.gov. Cabe said the company is not sharing that information at this time.

The first of these, TRIAD-1, enrolled 410 Alzheimer’s disease patients who had agitation. They took one of two doses of drug or placebo for six weeks. The placebo group was then re-randomized to either drug or placebo for the next six weeks, while the treatment groups continued on the same dose of drug. The final analysis excluded people who responded to placebo. This type of sequential parallel analysis is designed to minimize placebo effects, which often confound trials with behavioral outcomes. In March, Avanir announced topline results from this study, noting that one of the two drug doses met the primary endpoint of improvement on the Cohen-Mansfield Agitation Inventory, and the other dose trended in that direction (press release). 

The other two Phase 3 studies both used a conventional, parallel-arm design. TRIAD-2 enrolled 522 participants with AD and agitation, who took one of two drug doses or placebo for 12 weeks. Neither dose calmed patients, as determined by the Cohen-Mansfield test. A global version of TRIAD-2, which enrolled 412 participants, will keep going, according to Avanir. In addition, an extension study for Alzheimer’s patients who completed any previous study of AVP-786 or Nuedexta will continue and has enrolled around 700 participants thus far. AVP-786 is also in trials for schizophrenia and traumatic brain injury.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. AVP-786
  2. AVP-923

News Citations

  1. Paper Alert: Promising Phase 2 Results for Agitation Drug Published
  2. A New Drug to Calm Agitation, Uncontrollable Laughing and Crying, in Alzheimer’s?

External Citations

  1. TRIAD-
  2. 2
  3. press release
  4. Phase 2
  5. Phase 1/2
  6. Phase 3
  7. first
  8. press release
  9. TRIAD-2
  10. extension study
  11. schizophrenia
  12. traumatic brain injury

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