Investigational Drug Added to Donepezil Shows Promise in AD

Pauline Anderson

July 24, 2015

WASHINGTON, DC — Adding a potent antagonist of the 5-HT6 serotonin receptor (RVT-101, Axovant Sciences Inc) to standard dementia care with donepezil (Aricept, Eisai Inc and Pfizer Inc) improves cognitive outcomes in patients with mild to moderate Alzheimer's disease (AD), results of a new phase 2b double-blind, controlled study reveal.

On the basis of these results, company officials are keen to move forward with the investigational agent. "With these data in hand, we are one study away from being able to file this with the FDA [Food and Drug Administration]," Ilise Lombardo, MD, vice president, clinical research, Axovant Sciences Inc, told Medscape Medical News.

The company presented data on the patients who were "completers," or had data available for each time point in the study, at the Alzheimer's Association International Conference (AAIC) 2015. Positive intention-to-treat (ITT) analyses from the same trial have already been published.

The new "exceptionally robust" findings are at least as strong as — if not a bit more so — those in the ITT population, said Dr Lombardo.

5HT 6 Receptor Inhibitor

The analysis included 684 patients who had been taking donepezil for at least 6 months. These patients were assigned to also take placebo or 15 mg or 35 mg of RVT-101 daily.

This oral investigational drug inhibits the 5HT 6 receptor, which is localized entirely in the central nervous system, according to Lawrence Friedhoff, MD, PhD, chief development officer, Axovant, who is noted for leading the development of donepezil.

"Blocking that receptor leads indirectly to an increased release of acetylcholine in the brain, and increasing acetylcholine in the brain is known to improve cognition and function in AD."

The drug works hand in hand with cholinesterase inhibitors, said Dr Friedhoff. While donepezil blocks the breakdown of acetylcholine, this new drug works by increasing the release of acetylcholine.

While RVT-101 itself improves cognition to some degree, it wasn't developed to be used alone, added Dr Friedhoff. "It was always intended to be used on top of donepezil."

For the study, researchers measured cognitive function by using the AD Assessment Scale-cognitive subscale (ADAS-cog) and function by using the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL).

In the completer analysis, there were statistically significant benefits for both cognition and function for patients taking the 35-mg dose, which tended to increase with time. For example, the difference on the ADAS-cog between the drug and placebo groups was –1.29 (P = .008) at 12 weeks but –1.82 (P = .018) at 48 weeks. For ADCS-ADL, the difference was 1.72 (P = .016) at 12 weeks and 2.34 (P = .048) at 48 weeks.

"What's important and unique about this data set is that it goes out to 48 weeks, so this is a very long double-blind study," commented Dr Lombardo. "The effect that we see over treatment with donepezil alone is fully sustained and is maintained; there's no diminution or decrease in effect over the full 48 weeks."

Not only did the new analysis support the positive ITT results, but reanalysis of the data "many different ways" came up with the same findings. Results were similar with regard to different subgroups, for example, by sex, countries, and AD severity, said Dr Friedhoff.

All too often, he added, researchers present only robust analyses and "sort of forget" about the ones that didn't work out. "Here, what we are showing is that you get almost exactly the same result no matter how you analyze the data."

Adverse Events

There was no statistically significant difference in adverse events between the treatment and control groups. There were no serious drug-related adverse events. There were slightly fewer falls in the 35 mg group than in the control group.

"We think that the safety profile that we have seen is really very good," said Dr Lombardo. "There is no perceivable pattern of adverse events that we could point to in terms of the drug, so the tolerability, in particular the tolerability on top of donepezil, has been very good."

The retention rate — 89% completed the study in the treatment group and 87% in the placebo group — is "extremely high" for this type of study, noted Dr Friedhoff.

To date, the drug has been given to over 1200 patients with AD. The company plans to continue to develop the 35-mg dose and is launching a 24-week phase 3 study later this year that will compare this dose with placebo.

"We have what we think are very strong findings both in cognition and function over 48 weeks; we are now going to have a confirmatory phase 3 study to replicate that," said Dr Lombardo.

She and her colleagues also hope to eventually test the drug in other types of dementia — for example, dementia with Lewy bodies — and perhaps other doses.

Commenting on the study for Medscape Medical News, Maria Carrillo, PhD, chief science officer, medical and scientific relations, Alzheimer's Association, said the additive effect of the drug is important.

"When you think that it's on top of standard of care — it's on top of what people get today to improve their symptoms — and there is an even greater improvement, that's significant."

There hasn't been much lately in the way of new drugs that improve AD symptoms, said Dr Carrillo. "But this drug actually has a different mechanism and it showed improvement on top of what we had before, so people are excited about these results."

Better control of AD symptoms is needed "while we wait for better treatments that slow the progression of the disease or even stop it," said Dr Carrillo.

The drug, she said, should be tested in a larger trial and for a longer period.

The study was funded by Avoxant. Dr Lombardo and Dr Friedhoff are employees of Axovant. Dr Carrillo has disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2015. Oral presentation DT-01-04. Presented July 22, 2015.

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