WASHINGTON -- A completer analysis of data from a previous phase II trial suggests adding a novel drug to donepezil (Aricept) offers cognitive and functional benefits, researchers reported here.
At both 24 and 48 weeks, adding the investigational serotonin 5HT6 receptor antagonist RVT-101 to the acetylcholinesterase inhibitor was associated with significantly less worsening on the ADAS-Cog and the ADCS-ADL compared with those adding placebo to their daily drug, according to , of New York City-based Axovant Sciences.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
However, the addition of the drug to donepezil didn't bring significant changes on the Clinical Dementia Rating -- Sum of Boxes (CDR-SB) scores, Friedhoff reported at the here.
Drug developer Axovant garnered much attention for its recent IPO, which raised $315 million after Wall Street took note of the company's story. Its 29-year-old CEO Vivek Ramaswamy, a former analyst who'd been covering the Alzheimer's disease space, found GlaxoSmithKline's phase II data on RVT-101 promising even though the company said it wouldn't develop the drug further. Ramaswamy formed Axovant to bring the drug to market.
Axovant started its resuscitation efforts with this completer analysis of GSK's phase II data, which were initially published in 2011. Friedhoff said the 35-mg dose of the drug held benefits in the intention-to-treat population (ITT), and a completer analysis could provide more assurance.
Friedhoff is no stranger to breathing new life into abandoned compounds. He developed Eisai's donepezil program even though the company was ready to scrap that agent, he told 番茄社区. It's now among the top drugs for managing Alzheimer's symptoms -- well worth "most of these gray hairs," Friedhoff said.
It remains to be seen whether Friedhoff and Axovant can replicate those results with RVT-101. GSK's 48-week phase IIb trial was done in two parts of 24 weeks each, in 684 patients with mild-to-moderate Alzheimer's disease. They were all given donepezil, then randomized to one of two doses of add-on RVT-101 (15 mg or 35 mg) or to add-on placebo.
Friedhoff said the results of the completer analysis are consistent with those from the ITT population, with significant benefits for the 35-mg group at all time points on both the ADAS-Cog (a measure of cognition) and the ADCS-ADL (a measure of function):
- ADAS-Cog at 24 weeks (1.63, P=0.007) and at 48 weeks (-1.82, P=0.018)
- ADCS-ADL at 24 weeks (2.11, P=0.016) and at 48 weeks (2.34, P=0.048)
There were no significant benefits in these measures for the 15-mg dose, he reported.
But the CDR-SB was only significantly different from placebo at 12 weeks (P=0.018), with no significant effects at other time points.
Friedhoff noted that the trial had a low dropout rate, at 11% in RVT-101 group and 12% in the placebo group at 24 weeks, along with 20% in the drug group and 22% in the placebo group at 12 weeks.
Given that the drug is thought to work by promoting the release of acetylcholine and other neurotransmitters important for memory and cognitive function, it may have synergistic effects when combined with acetylcholinesterase inhibitors, which prevent the breakdown of this neurotransmitter, Friedhoff said.
The company is moving into phase III trials with the 35-mg dose in a total of 1,000 patients with the co-primary endpoints of ADAS-Cog and ADCS-ADL -- although the CDR-SB will be dropped -- over 24 weeks. The trial is expected to start in the 4th quarter of 2015 and finish by late 2017. Friedhoff said he didn't think the CDR-SB was an appropriate instrument for assessing the target population and saw no place for it in future studies.
, of Washington University in St. Louis, noted that the important question is whether the addition of this new agent to an acetylcholinesterase inhibitor will be clinically meaningful, especially since there has been some debate about the value of these drugs in general.
"For donepezil and other acetylcholinesterase inhibitors, the actual clinically meaningful benefit has been extremely modest," Morris said. "Anything that can add to that benefit would be desirable."
Disclosures
Friedhoff is an employee of Axovant Sciences.
Primary Source
Alzheimer's Association International Conference
Source Reference: Friedhoff L, et al "The efficacy of RVT-101, a 5-HT6 receptor antagonist, as an adjunct to donepezil in adults with mild-to-moderate Alzheimer's disease: Completer analysis of a phase 2b study" AAIC 2015; Abstract DT-01-04.