New AD Drug May Improve Memory and Function

By Jamie Santa Cruz

Encenicline, now in phase 3 clinical trials, has shown promise in improving memory and function in Alzheimer’s patients.

For patients suffering from Alzheimer’s disease (AD), there are few pharmacologic treatments currently available, but a new drug option may be on the horizon. FORUM Pharmaceuticals, formerly known as EnVivo, announced in January the opening of a phase 3 clinical trial of its AD drug encenicline (EVP-6124), which in earlier trials had shown promise in terms of improving AD patients’ memory and function.

Encenicline is targeted toward patients who have impairments related to both function and memory but who still are in the mild to moderate stages of the disease. Reaching patients in these phases of AD can significantly impact their long-term well-being, according to Deborah Dunsire, MD, president and CEO of FORUM. “We really believe that improving cognition and memory [in these earlier stages] is going to make a difference to their ability to live with their disease and be cared for in a family setting as opposed to outside of that,” she says.

If the phase 3 trial is successful and the drug receives FDA approval, encenicline will provide an important alternative to cholinesterase inhibitors, the main class of drugs currently available for treating AD. Though it’s difficult to establish with certainty how cholinesterase inhibitors operate, they appear to work primarily by impeding the enzyme acetylcholinesterase that breaks down acetylcholine, a neurotransmitter that’s critical to higher-order brain functioning. Acetylcholine is dramatically reduced in the brains of patients with AD. By preserving the amount of acetylcholine in the brain, cholinesterase inhibitors, which include donepezil (Aricept), rivastigmine (Exelon), and galantamine (Nivalin, Razadyne), help enhance function and cognition.

By contrast, encenicline doesn’t prevent the breakdown of acetylcholine; instead it’s thought to mimic the action of acetylcholine and modulate an important nicotinic receptor at which acetylcholine binds, namely the alpha-7 receptor. “This drug is brain penetrant, so it gets where we need it to get,” Dunsire says. “It’s very selective for these alpha-7 receptors.”

By stimulating and increasing the receptors’ sensitivity in the same way that acetylcholine does naturally, the drug primes brain networks for better neural processing and improved cognition. And because it operates by a different mechanism, encenicline may be able to avoid some of the disadvantages of cholinesterase inhibitors, which must be given in limited doses because of their significant systemic toxic side effects.

Encenicline already has successfully completed a phase 2 trial. The six-month, double-blind trial enrolled 409 patients with mild to moderate AD, some of whom also were taking cholinesterase inhibitors. Patients were randomized to three different daily doses of the drug, 0.3 mg, 1 mg, and 2 mg, or a placebo. While patients on the lower doses showed positive trends, the results were not statistically significant. However, those taking the highest dose showed statistically significant effects compared with those in the placebo group both for cognition and function, as assessed by the Alzheimer’s Disease Assessment Scale-cognitive subscale 13 (ADAS-Cog), a commonly used measure of cognition (p = 0.0189) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), a clinical rating scale that assesses function (p = 0.0253).

“It’s a pretty substantial effect,” Dunsire says. “The difference on the rating scales translates into what might be equivalent to maybe a 10 point change […] on an IQ scale.”

Potential Game Changer
Though the size of encenicline’s effect on cognition was relatively large in the phase 2 trial, Lon Schneider, MD, a professor of psychiatry and behavioral sciences, neurology, and gerontology at the University of Southern California (USC) and a consultant for FORUM, cautions that it’s difficult to draw specific conclusions from those early results because the sample size was quite small, as in most phase 2 trials. But he says the promising results in the early trials are noteworthy. “The main thing here is that … phase 2 was positive,” he says. “It’s rather uncommon that we’ve seen positive results [with potential AD drugs] in phase 2.”

According to Dunsire, the major difference between encenicline and other currently available AD drugs is that it has a dual effect on memory, including visual and long-term memory, as well as executive function. “Not many previous drugs really impacted both memory and executive function, certainly not at these levels,” she says.

In the earliest stages of testing, the drug also proved to have beneficial effects even in subjects without AD. “These are ostensibly normal people and cognition improves, and that’s not been seen with other medicines,” Schneider adds.

In addition to being developed as an AD treatment, encenicline is simultaneously being developed as a schizophrenia treatment. Like AD patients, schizophrenic patients struggle with the inability to organize themselves, and encenicline has proven effective in improving function in these patients as well. “We see changes in EEG-evoked potentials, which actually shows the organization of thought in the brain,” Dunsire says. “That hasn’t ever been shown with any other schizophrenic medication.”

None of the currently available AD drugs has been shown to inhibit disease progression, and at present, encenicline isn’t known to do so either. However, according to Schneider, who also is director of the USC California Alzheimer’s Disease Center and clinical core of the USC NIH Alzheimer’s Disease Research Center, the studies currently being conducted with encenicline are too short term to assess whether it modifies the long-term course of the disease, so definite answers on the question will have to wait. “We’re not going to know [whether encenicline is a disease modifier] for a long time,” he says.

But even if the drug ultimately doesn’t modify the disease course, Schneider believes it will be of significant value to AD patients if its effects are confirmed in phase 3 trials. “Right now, we’ve got essentially the cholinesterase inhibitors and another particular drug ... called mementine,” he says. “Those drugs have limited effects, like all drugs in medicine, and this would provide an additional option. So it may help other patients who were not helped by the previous ones or provide an additive effect.”

Currently, patient dosing is underway in the phase 3 clinical trial, which consist of two separate randomized, double-blind trials to evaluate both the safety and efficacy of encenicline. The trials, involving approximately 1,600 patients at sites across the United States and worldwide, are testing two different daily doses of encenicline against placebo. Each patient in the trial will be followed for six months. As in the phase 2 trials, efficacy will be evaluated at the end of the six-month period by the ADAS-Cog and the CDR-SB. Secondary measures of efficacy will include the Disability Assessment for Dementia, the Neuropsychiatric Inventory, the Mini-Mental State Examination scale, and the Controlled Oral Word Association Test.

After the initial six-month study period is completed, patients will be followed for another six months. Those on placebo will be randomized to one of the two doses, and those already receiving encenicline will continue receiving their dose as long as it’s well tolerated. This design will result in a six-month efficacy readout and a 12-month safety readout.

According to Dunsire, the extended time frames mean that final data from the trials won’t be available for two to three years, and FDA approval can be expected to take another 12 months or so beyond that. Hence, even if the trials are successful, encenicline likely won’t be available on the market for several more years.

If the drug is approved, however, Dunsire believes it will offer significant value to AD patients and their families, specifically by reducing the amount of time AD patients must spend in nursing homes or similar care settings. “Alzheimer’s patients often have to go into care outside of their family because the disease takes their memory away and they become unable to remember to do the most basic things [such as] bathing and dressing,” she says. “If we can prolong the period of time that they can do some of those things and remain with their family, the incredibly important thing to me is that those connections and familiar bonds can be maintained for longer.”

— Jamie Santa Cruz is a freelance writer based in New York City.