Alzheimer's Symptomatic Drug Set to Test as Donepezil Combo

      BARCELONA — RVT-101, a novel small molecule that increases acetylcholine release, is poised for what its developers say could be its pivotal trial for U.S. approval.
      The MINDSET study will examine the effect of the 5-HT6 receptor antagonist RVT-101, which will be given in conjunction with donepezil.
      As an acetylcholine booster, RVT-101 would not be a disease-modifying therapy. And like other symptomatic drugs, it would not alter the trajectory of Alzheimer's disease.
      Launched last month, MINDSET will be conducted in North America, South America, Europe, and Asia. The study investigators want to enroll least 1,000 patients with mild to moderate Alzheimer's disease who are on stable doses of donepezil, Lawrence Friedhoff, MD, PhD, said at the Clinical Trials on Alzheimer's Disease conference.
      Axovant Sciences' RVT-101, formerly developed as SB742457 by GlaxoSmithKline, has been investigated in 13 studies of both monotherapy and adjunctive therapy in more than 2,000 patients with Alzheimer's, said Dr. Friedhoff, chief development officer at Axovant Sciences. As monotherapy, it was ineffective, conferring no significant benefits on either cognition or function.

      Combination Benefit

      The earlier study upon which MINDSET is modeled was a modestly successful phase IIb dose-ranging trial that comprised 684 patients. At 48 weeks, the combination of 35 mg SB742457 (RVT-101) and donepezil conferred about a 2-point benefit on the Alzheimer's Disease Assessment Scale–Cognitive (ADAS-cog) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) over donepezil alone. Neither the 35-mg dose nor the 15-mg dose, which was also tested, conferred any benefit on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) test.
      “Regulators have told us that if our results are similar, then this study will be suitable for submission for approval,” Dr. Friedhoff said. “We have a reasonably high level of confidence that it will also be effective in this trial.”
      The 24-week MINDSET will randomize patients to their donepezil dosage plus either placebo or 35 mg RVT-101 daily. Coprimary endpoints are the ADAS-cog and the ADCS-ADL. The CDR-SB is not an endpoint in MINDSET, which Dr. Friedhoff noted was designed to maximize the chance of success. A 12-month open-label extension study focusing on long-term safety will follow the randomized trial.
      GSK ceased development of RVT-101 in 2010 without public explanation. However, a recent review of several of the GSK studies suggests that it simply didn't meet the studies' success criteria.

      Expanding Options

      Axovant was formed in 2014 to give RVT-101 a new shot as an add-on treatment. The combination makes sense, Dr. Friedhoff said.
      “It increases acetylcholine in the brain. We already know this is an effective way to treat Alzheimer's because our acetylcholinesterase inhibitors achieve this in a different way, by inhibiting the breakdown of acetylcholine,” Dr. Friedhoff explained. “It makes sense that they should work well together. It doesn't help much to increase the release if it's broken down quickly.”
      RVT-101 has an attractive safety profile, Dr. Friedhoff said. It had a low rate of gastrointestinal side effects (nausea, 2%; diarrhea, 5%) and was associated with very few falls in prior studies (about 3%). That relatively benign side effect profile is probably reflected in the study's large completer rate, Dr. Friedhoff said. The placebo and 35-mg dose had virtually identical completer rates of 88% and 89%, respectively. The dropout rates were low and similar in both groups.
      Axovant also aims to investigate RVT-101 in patients with Lewy body dementia, he added. The company expects to launch a phase IIb clinical study early next year. Dr. Friedhoff is an employee of Axovant Sciences.
      Michele G. Sullivan is with the Mid-Atlantic bureau of Frontline Medical News.