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Pivotal studies investigating encenicline (Forum Pharmaceuticals/Mitsubishi Tanabe) in Alzheimer’s disease have been placed on clinical hold based on a recommendation from the US Food and Drug Administration (FDA) following the observation of severe gastrointestinal (GI) events in some participants. Encenicline, the first of its class to enter Phase III clinical trials, is also being investigated for the treatment of cognitive impairment associated with schizophrenia (CIAS). While a Phase III extension trial for the drug for CIAS was also placed on hold, two fully enrolled Phase III efficacy trials will carry on with added caution, where patients will be closely monitored for GI-related safety events. The clinical hold seriously dampens encenicline’s prospects of reaching the Alzheimer’s disease market, providing competing pipeline drugs idalopirdine (Lundbeck/Otsuka) and RVT-101 (Axovant Sciences), which have a different mechanism of action, with a significant advantage.

Initially discovered by Bayer Healthcare, encenicline was licensed to EnVivo Pharmaceuticals, which later changed its name to Forum Pharmaceuticals in April 2014. Encenicline is designed to boost cholinergic transmission, which is otherwise severely reduced in Alzheimer’s disease. The drug is a selective, oral, alpha-7 nicotinic partial agonist developed as a long-term treatment for Alzheimer’s disease and CIAS. It acts by enhancing the sensitivity of alpha-7 nicotinic receptors to the naturally occurring neurotransmitter acetylcholine. Encenicline’s mechanism of action is related to the longstanding acetylcholinesterase inhibitor class, which also includes donepezil, rivastigmine, and galantamine, which are well established as symptomatic treatments for Alzheimer’s disease. By enhancing acetylcholinergic transmission, brain networks associated with memory and cognition are activated, resulting in the alleviation of Alzheimer’s disease symptoms. In addition, increased acetylcholinergic transmission results in an increase in the release of neurotransmitters relevant for the treatment of CIAS, such as glutamate and acetylcholine.

The FDA’s clinical hold for encenicline in Alzheimer’s disease comes as a surprise, considering the drug’s previously promising results from a Phase IIb clinical trial in mild to moderate patients. Three different encenicline doses – 0.3mg, 1mg, and 2mg – were assessed over a six-month treatment period and compared to placebo. Patients receiving the 2mg dose significantly outperformed those on placebo on the Alzheimer’s Disease Assessment Scale – Cognitive Subscale and Clinical Dementia Rating – Sum of Boxes scale, meeting both of the trial’s primary endpoints. Although mild GI symptoms were reported in approximately 10% of participants, encenicline was concluded to be generally safe and well tolerated. These findings prompted Forum to initiate COGNITIV AD, a global Phase III program designed to further evaluate the safety and efficacy of encenicline using higher dosing regimens (2mg and 3mg) over a six-month period. However, serious GI side effects were reported, forcing the trials to be placed on hold. While Forum has not provided any further detail on the specific side effects and their cause, the higher incidence rate of serious GI events generally experienced by Alzheimer’s disease patients and the use of higher doses in these trials could be precipitating factors.

Despite the emergence of serious GI events in Alzheimer’s disease patients, the FDA is allowing Forum to continue its pivotal studies of encenicline as a treatment for CIAS, as no safety signals have been discovered in these patients. As well as encenicline’s apparently cleaner side-effect profile in CIAS patients, Forum has also presented proof-of-concept efficacy data from a Phase IIb clinical trial of encenicline as an adjunct treatment with atypical antipsychotics. Over a three-month treatment period, patients receiving 0.3mg and 1.0mg encenicline experienced numerically greater improvements on the CogState Overall Cognition Index, with the lower dose achieving statistical significance. Both doses also yielded numerical improvements on the MATRICS Consensus Cognitive Battery compared to placebo. This trial led Forum to initiate COGNITIV SZ, a global Phase III registration program for encenicline in CIAS. In this program, the FDA has allowed two pivotal six-month efficacy studies, which are now fully enrolled, to continue, despite the development of encenicline-associated GI effects in Alzheimer’s disease patients. A third study, a long-term extension of the two pivotal studies measuring encenicline’s safety, was still recruiting at the time and was thus placed on hold. Datamonitor Healthcare expects that the FDA wants more information on encenicline’s safety in CIAS before allowing patients to be exposed to the drug over a long-term treatment period.

Drug development for Alzheimer’s disease has been frustrating over the last decade, as pharmaceutical companies have been unable to discover a breakthrough disease-modifying drug that may affect the underlying Alzheimer’s disease pathology. As such, there is still room for improved symptomatic drugs, and with only two drug classes currently available, identifying novel mechanisms of action with minimal side effects is necessary. Encenicline had a purported mechanistic benefit over other acetylcholinergic-targeting drugs, because by targeting a specific receptor, it avoids side effects associated with acetylcholine excess. While the clinical trials evaluating the use of encenicline for Alzheimer’s disease were placed on hold due to GI safety events, it remains to be determined if this is a dose-dependent matter that can be resolved. For as long as the FDA maintains its clinical hold on encenicline, other symptomatic drugs in the pipeline will move ahead in their development. The two most advanced symptomatic drugs in the pipeline, idalopirdine and RVT-101, are now both 5-HT6 receptor antagonists, which are either in, or entering, Phase III trials. Launching ahead of encenicline would be important for idalopirdine and RVT-101 as Phase II data on these products were mixed and suggested a less competitive clinical profile. The serious GI side effects noted with encenicline may also have ramifications for other nicotinic acetylcholine agonists in the pipeline, including candidates under development by Novartis and Bristol-Myers Squibb, necessitating stringent safety monitoring and potential restrictions.

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