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PHILADELPHIA (FRONTLINE MEDICAL NEWS)An investigational 5-HT6 inhibitor in combination with donepezil significantly boosted cognition in patients with moderate Alzheimer’s disease and has advanced into three placebo-controlled phase III trials.

The investigational drug, idalopirdine, is a potent antagonist of the 5-HT6 receptor, which plays a key part in neurotransmission in the cerebral cortex and hippocampus. When activated, it inhibits glutamatergic, noradrenergic, and dopaminergic transmission, and it inhibits cholinergic function when blocked. The drug seems to enhance acetylcholine and glutamate signaling by blocking this system, Dr. Alireza Atri said at the Clinical Trials Conference on Alzheimer’s Disease.

Rat studies showed that combining idalopirdine with the acetylcholinesterase inhibitor improved cognition. The effect seen only when the two drugs were combined, said Dr. Atri of Massachusetts General Hospital, Boston. “Vehicle/vehicle and vehicle/ idalopirdine effected no change at all. But the combination gave us a nice augmentation of potentiation that lasted quite a long time.”

However, idalopirdine’s lack of an effect when not used in combination with donepezil may signal that it’s inhibitory effect on CYP206 just serves to increase the bioavailability of donepezil, which is metabolized by CYP206, according to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center, Los Angeles.

The preclinical experiments with idalopirdine were sufficient to launch the phase II trial , Dr. Atri said. It comprised 278 patients with moderate Alzheimer’s; all were already taking donepezil 10 mg. They were randomized to placebo plus their donepezil or to idalopirdine 90 mg/day plus donepezil. Treatment lasted 24 weeks, which included a 2-week donepezil run-in and a 2-week washout. The trial was published in the November issue of Lancet Neurology ( 2014;13:1092-9 ).

The primary endpoints were cognitive change as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and safety and tolerability. Secondary endpoints were the clinical outcomes on the Alzheimer’s Disease Cooperative Study measures, including clinical global impression (ADCS-CGI), activities of daily living (ADCS-ADL), and behavioral symptoms.

Mean age of the patients was 74.5 years, and about 70% were women. They had been diagnosed about 2 years prior to the start of the study and had used donepezil for about 1.5 years. Their mean Mini Mental State Exam score was 17, and their mean ADAS-Cog score was 28.

At week 24, scores in the placebo group worsened by about 1.4 points from baseline (indicating cognitive decline) while those in the idalopirdine group had improved by about 1 point from baseline. The 24-week score spread was slightly more than 2 points, which is a statistically and clinically significant difference, Dr. Atri said. None of the changes on the secondary endpoints were significant.

Adverse events caused 25 patients to discontinue treatment (18 taking the study drug and 7 taking placebo). The most common were increased liver enzymes, which were transient and discovered incidentally during routine blood work (10% with idalopirdine vs. 2% with placebo); diarrhea (4% vs. 7%); urinary tract infection (2% vs. 7%); falls (2% vs. 6%); and benign prostatic hyperplasia (5% vs. 0%). One death occurred in each treatment group; neither was regarded as being related to treatment.

The analysis included 12 measures of behavior. “On eight of these, there was not even a whiff of a signal,” Dr. Atri said. “On two – depression and dysphoria/appetite – there was maybe a hint of an effect, at least enough to keep and eye on.” The other measures showed nonsignificant differences.

The codevelopers of idalopirdine, Lundbeck and Otsuka, will continue to study the drug in three phase III trials, he said.

STARSHINE will randomize an estimated 930 patients to 30 mg or 60 mg idalopirdine plus donepezil or placebo for 20 weeks followed by a 4-week donepezil washout.

STARBEAM will randomize 840 patients to donepezil plus 10 mg or 30 mg idalopirdine for 20 weeks, followed by a 4-week donepezil washout.

STARBRIGHT will randomize 720 patients to any acetylcholinesterase inhibitor plus 60 mg idalopirdine for 20 weeks, plus a 4-week acetylcholinesterase inhibitor washout.

A 24-week open-label extension of donepezil plus 60 mg idalopirdine is also planned.

While Dr. Atri suggested that the drug exerts a direct effect on neurotransmission, Dr. Schneider suggested that it could simply be potentiating the effect of donepezil.

Idalopirdine is a potent inhibitor of CYP206 and its use will probably increase the bioavailability of the many drugs that depend on CYP206 for their clearance, including donepezil. In this trial, bioavailability of donepezil increased by 10%. A pharmacokinetic action could have been the real driver of results, Dr. Schneider said in an interview.

He questioned the wisdom of pursuing a drug that may have little inherent action.

“If as a hypothetical, the drug is inactive itself, but blocks an enzyme responsible for metabolizing donepezil, and donepezil levels rise and cause improvement, then one can’t say that the drug in question is effective. One can’t even say that the ‘combination’ is effective. Would you take a drug that may have side effects such as liver toxicity and others, just so it can block an enzyme to raise the level of another drug, and especially when several marketed drugs may do the same? What would likely happen if the drug group showed advantageous effects in these STAR trials is that sensitivity analyses would be done to help assess whether the drug also had an effect or what the contribution of donepezil levels was to the effect.”

Dr. Atri is on advisory board for several pharmaceutical companies, but has no financial ties with Lundbeck or Otsuka. Dr. Schneider has financial relationships with a number of pharmaceutical companies.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

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