Rare but Severe Side Effects Sideline Some Phase 3 Encenicline Trials

Reports of severe gastrointestinal events in some participants led the Food and Drug Administration to put four of six Phase 3 trials of encenicline on hold. FORUM Pharmaceuticals of Waltham, Massachusetts, is developing the drug—an α7 nicotinic acetylcholine receptor agonist—to improve cognition in Alzheimer’s and schizophrenia patients. The drug appeared to slow cognitive decline in AD patients in earlier trials. The company is now working with the FDA to take steps to remove the hold and continue the trials, according to a company press release. 

Encenicline, also known as EVP-6124, belongs to a class of drugs designed to enhance the cholinergic system, which wanes as AD worsens. The first drugs approved to treat AD symptoms were acetylcholinesterase (AChE) inhibitors, which prevent the degradation of the neurotransmitter acetylcholine. EVP-6124 boosts cholinergic transmission in a different way: The drug binds the α7 subunit of the nicotinic acetylcholine receptor and enhances the receptor’s sensitivity to its natural ligand, dialing up the cholinergic response (see Nov 2010 conference news). EVP-6124 has been reported to modulate dopaminergic and glutamatergic responses, as well (Huang et al., 2014). Researchers have proposed using the drug on its own or in combination with currently approved AChE inhibitors, such as donepezil.

Initially discovered by Bayer Healthcare, EVP-6124 was licensed in 2004 to EnVivo Pharmaceuticals, which changed its name to FORUM Pharmaceuticals last year. In 2012, a Phase 2b trial in people with mild to moderate AD yielded promising results (see Jul 2012 conference news and clinicaltrials.gov). Patients who took EVP-6124 alone or in combination with an AChE inhibitor held steady scores across a range of cognitive tests over two years, while those on placebo or AChE inhibitors alone declined. The effects were dose-dependent, with people taking the highest daily dose of 2 mg outperforming other groups. Back then, the researchers also reported gastrointestinal symptoms, including mild nausea and constipation, in about 7 percent of participants taking 2 mg EVP-6124 alone, although most instances were mild and transient. People on AChE inhibitors alone experienced comparable gastrointestinal troubles. The researchers concluded that the drug was well-tolerated, and moved forward into Phase 3 trials.

Three international Phase 3 trials are ongoing at multiple sites in the United States, Europe, Australia, Mexico, Japan and other countries, each designed to test the effectiveness of EVP-6124 against cognitive decline in mild to moderate AD patients (see clinicaltrials.gov, trial, and trial). A total of 875 patients so far have been enrolled in the trials, which were initiated in 2013. The patients were randomized to receive daily oral doses of 2 mg or 3 mg of EVP-6124, or placebo, for 26 weeks. Primary outcome measures included changes in scores on the ADAS-Cog13 and CDR-Sum of Boxes between baseline and 26 weeks, as well as safety and tolerability. The trials were slated to run until January 2017. The FDA has put all of them on hold.

Representatives at FORUM Pharmaceuticals would not elaborate on the details of the gastrointestinal symptoms, including whether the symptoms were dose-related or occurred more frequently in the treatment groups. The Phase 3 studies included a higher dose—3 mg—than did the Phase 2 study. The severe symptoms occurred in a small number of patients and were somewhat variable in their presentation, wrote Priscilla Harlan, a communications consultant at the company, in an email to Alzforum. “It is worth bearing in mind that most Alzheimer’s disease patients are elderly, many with comorbid conditions and receiving concomitant medications, many of which are themselves associated with a GI risk for this patient population,” she added. “AD patients are known to have a higher risk of GI adverse events than do elderly patients without AD.” Harlan added that the company is investigating the potential causes of the GI events, and the extent to which the drug played a role.

EVP-6124 is being tested in Phase 3 in schizophrenia patients as well. Two of these ongoing trials are fully enrolled (see clinicaltrials.gov, and trial); the third is still recruiting (see clinicaltrials.gov). The FDA has stipulated that the two enrolled trials, which are efficacy trials, can continue, while they put the newest trial, a safety extension, on hold. FORUM Pharmaceuticals declined to comment on the reason for this hold. Harlan noted that none of the more than 1,500 schizophrenia patients enrolled in the trials have experienced severe gastrointestinal symptoms. This could be due to their younger age, which averages 35 to 40 years, compared to the average age of 75 in the AD trials, Harlan said. She said that patients who remain in the ongoing trials will be monitored closely for GI events.

What comes next? According to Harlan, the company is speaking with regulators to chart a path forward. “We are working with the FDA to better understand the requirements to be able to lift the clinical hold and progress the program,” she wrote. 

At this point it is unclear if, when, and under what circumstances the hold will be lifted. “The FDA may place a clinical hold on a study if the agency assessed that the participants are being exposed to a significant risk of injury,” commented Lon Schneider of the University of Southern California, Los Angeles. “The effect of the clinical hold on the Phase 3 Alzheimer trials will depend, of course, on how long it lasts, and the extent to which the protocol may have to be modified.”

FORUM Pharmaceuticals is funded by Fidelity Investments, as is Alzforum.—Jessica Shugart

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References

Therapeutics Citations

  1. Encenicline
  2. Donepezil

News Citations

  1. Toulouse: Experimental Drug Sensitizes Receptor, Boosts Cognition
  2. Experimental α7 Agonist Meets Cognitive and Clinical Endpoints

Paper Citations

  1. Huang M, Felix AR, Flood DG, Bhuvaneswaran C, Hilt D, Koenig G, Meltzer HY. The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. Psychopharmacology (Berl). 2014 Dec;231(23):4541-51. Epub 2014 May 9 PubMed.

External Citations

  1. press release
  2. clinicaltrials.gov
  3. clinicaltrials.gov
  4. trial
  5. trial
  6. clinicaltrials.gov
  7. trial
  8. clinicaltrials.gov

Further Reading

Papers

  1. Deardorff WJ, Shobassy A, Grossberg GT. Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication. Expert Rev Neurother. 2015 Jan;15(1):7-17. Epub 2014 Dec 15 PubMed.
  2. Barbier AJ, Hilhorst M, Van Vliet A, Snyder P, Palfreyman MG, Gawryl M, Dgetluck N, Massaro M, Tiessen R, Timmerman W, Hilt DC. Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective α7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies. Clin Ther. 2015 Feb 1;37(2):311-24. Epub 2014 Oct 14 PubMed.

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