While We Wait: EnVivo Compound Slowed Cognitive Decline In Phase II Alzheimer’s Trial

EVP-6124, a partial agonist of the alpha-7 nicotinic receptor, had a statistically significant effect on both cognition and clinical function in Phase IIb data presented at the Alzheimer’s Association International Conference in Vancouver; pivotal trials are in the works.

A novel drug aimed at slowing cognitive decline in patients with mild to moderate Alzheimer’s disease produced statistically significant results on measures of both cognition and clinical function in a Phase IIb dose finding trial, Forum Pharmaceuticals Inc. reported during a late-breaker session July 18 at the Alzheimer’s Association International Conference in Vancouver, British Columbia.

While highly anticipated news regarding drugs in development that might have a disease-modifying effect on Alzheimer’s disease is expected later in the year, it is a very real possibility that those results will raise more questions than they resolve (Also see "Beyond A-Beta: New Approaches To Alzheimer’s" - Scrip, 22 Jun, 2012.). Readouts are expected for Eli Lilly & Co.’s solanezumab, and for bapineuzumab, the biologic that now belongs to Pfizer Inc. in partnership with Elan Corp. PLC and Johnson & Johnson. J&J announced during its second quarter earnings call July 17 that top-line data from Phase III U.S. trials would be released in the third quarter, with detailed data to follow at a medical meeting in September.

In the interim, if it is successful, EnVivo’s compound may slow cognitive decline, affording patients a longer period of independence during the course of their disease (Also see "Amyvid Approval Just The Start Of A Critical Year For Alzheimer’s" - Pink Sheet, 16 Apr, 2012.).

The drug, EVP-6124, is a partial agonist of the alpha-7 nicotinic receptor. It works by sensitizing acetylcholine receptors in the brain to produce a normal response to lower amounts of the neurotransmitter. “As long as there is acetylcholine, our compound allows patients to use less to have the same cognition effect,” EnVivo CEO Kees Been said in an interview. “You need less acetylcholine to open the receptor and transfer the signal from one neuron to the next.”

One big question that will have to be answered in the planned Phase III program is how long the positive effect can last. Results from the Alzheimer’s Disease Assessment Scale-Cognitive subscale-13 (ADAS-Cog-13), the primary cognition endpoint in the trial, show that the EVP-6124 and placebo arms were still diverging at 23 weeks (the last efficacy measurement time point).

“The treatment arm is still slightly going up, and the placebo arm is coming down,” Been said. “We may have to dose for a year or longer to determine whether we are looking at a truly sustainable procognitive effect, as is suggested right now.” If the curves are still diverging, it may even be “suggestive of some degree of disease modifying effect,” he said.

One thing for sure, the longer those curves stay separated, the longer patients will be able to sustain or even gain some cognitive function. “If the [EVP-6124] curve comes down, I hope that it will at least decline in parallel to the natural decline curve,” said Been. “The question then becomes how far have these curves been pushed out?”

EnVivo will have to prove EVP-6124 can push the decline curve out as far as it can in order to make the pharmacoeconomic case for an expensive new therapy. In addition, the company faces pricing pressure from existing cognitive enhancement therapies that all have gone generic. “We absolutely have to show a significant effect to get the prices we will be seeking,” Been said.

EnVivo, in Watertown, Mass., is in a unique situation in that the company has only one investor, Fidelity Biosciences. “They are very committed and very patient, which gives us a wonderful opportunity to actually execute on a long-term vision” that includes commercializing the company’s products in markets accessible with a modest sales infrastructure, Been said. He acknowledged that the company will need to partner “across the world,” but said it is looking for a partner who wants to help build an integrated company. “We don’t’ want it to be a license, we want it to be, for lack of a better word, an ‘equal’ partnership,” he said.

Effective With Or Without An Acetylcholinesterase Inhibitor

The six-month, double blind Phase IIb trial evaluated three doses of EVP-6124: 0.3 mg, 1.0 mg and 2.0 mg, against placebo in 409 patients with mild to moderate disease. The all-comers study enrolled patients who were either treatment naïve or already taking an acetylcholinesterase inhibitor: Pfizer/Eisai Inc.’s Aricept (donepezil) or J&J’s Razadine (galantamine), both available as generics. The population breaks down to about a 50/50 division between treatment naïve and patients taking Aricept or Razadine, Been said.

The drug worked in both treatment-naïve patients and those taking Aricept or Razadine, Been said. “That is very, very exciting for us that it also works on top of the current standard therapy.”

“We basically did a real-life experiment,” Been said. And, though only the consolidated results have been shown, “I can tell you that our drug worked in both populations. … That is very, very exciting for us that it also works on top of the current standard therapy.”

The 2 mg dose met both of the trial’s primary endpoints with statistically significant positive effects on cognition (p=0.0189), as measured by ADAS-Cog-13, and clinical function (p=0.0253), as measured by the clinical Dementia Rating Scale Sum of Boxes (CDR-SB). It also showed statistically significant results on secondary endpoints measured by other standard metrics, as well as on a prospectively chosen subset of scores from scales known to be more sensitive in very mild patients.

Patients on the 2.0 mg dose had statistically significant cognition improvements on the cognition composite (p=0.0037); memory composite (p=0.0088) and executive function composite (p=0.0427), as well as positive effects compared to placebo on the Mini-Mental State Examination (p=0.0955) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (p=0.092).

EVP-6124 was generally safe and well-tolerated with some mild to moderate gastrointestinal side effects reported in a minority of patients in both the 1.0 mg and 2.0 mg dose groups, according to the abstract presented at the AAIC meeting.

EnVivo released positive Phase III data in 2011 for EVP-6124 in both cognitive and functional symptoms of schizophrenia and plans to launch a global Phase III trial in the fourth quarter.