29 July 2009. At the International Conference on Alzheimer’s Disease (ICAD) held 11-16 July in Vienna, Austria, news on the drug trials landscape painted a mostly bleak picture. On Sunday afternoon in particular, as a discouraging string of one negative trial presentation after another unfolded in the main lecture hall, attendees shared, at least at a gut level, a sense of “Ugh, nothing is working.” But of course, that’s not the whole story. For one thing, a much larger number of trials are recruiting, hence, aren’t ready to present data. For another, even amid the rubble of completed trials, ICAD’s truffle seekers sniffed out efficacy signals of new drug candidates at the conference. Consider, for example, a new α7 nicotinic acetylcholine receptor (nAChR) agonist called EVP-6124. A Hot Topics poster on a Phase 1b/2a study with this compound was not listed in the program addendum, but avid conference-goers found it anyway, and a crowd in front of this poster kept attracting people, including a reporter. Here’s a summary.
The poster was the first publication on safety, tolerability, and some early hints of efficacy, for this compound in people with Alzheimer disease. The candidate drug is a selective small-molecule agonist made by the biotech company EnVivo Pharmaceuticals of Watertown, Massachusetts. In recent years, the α7 nAChR has been enjoying renewed interest as a target—either for agonists or antagonists, depending on whom you ask—in AD (see ARF related news story for background). In an interview, coauthor Gerhard Koenig of EnVivo Pharmaceuticals said that their team had previously established efficacy and potency of this compound in various animal models. Led by Dana Hilt of EnVivo, four different Phase 1 studies in some 125 healthy volunteers preceded the trial presented at ICAD. According to the Phase 1 studies, those pesky pharmacokinetic and dynamic details that don’t interest basic scientists too much yet are the downfall of so many a candidate drug appear to bode well for this one. The compound is bioavailable in the brain when taken by mouth, capsules of it can be taken once a day, and it shows no gender, age, or food effects; in other words, people need not plan their capsules around their meals. In normal volunteers, the compound was safe and well tolerated, and even then gave some hints of enhancing cognition, Koenig said.
Moreover, this compound has survived a Phase 1b trial in 20 people with schizophrenia, in whom it partially normalized evoked potentials. This is not a clinically relevant test—rather, it is an electrophysiological biomarker to indicate that the drug is active in the brain. Study volunteers have fitted to their heads electrodes which record brain activity in response to certain stimuli, for example, spaced tapping noises. People with schizophrenia have a characteristic deficit in their sensory gating that can be measured with evoked potentials, and EVP-6124 appeared to ameliorate that. The company hopes that this drug might one day treat certain cognitive deficits in schizophrenia and Alzheimer disease (see biotech newsletter story).
On the ICAD poster, then, were new data on a trial of 48 people aged 50 to 80 with mild to moderate AD, who were randomized to take either placebo or one of three doses of EVP-6124 for 28 days. The scientists first observed patients for three days in an inpatient unit, then kept them under observation for the first few days on drug/placebo before letting them finish the drug course in an outpatient setting. All trial participants had been taking stable doses of the acetylcholinesterase inhibitor (AChEI) donepezil or rivastigmine for at least four months before joining the trial. The scientists emphasized this point, because a frequent criticism of α7 agonists holds that their effects are likely to be so similar to current AChEIs that they will only work in people who do not already take these drugs. “All effects seen here are on top of stable AChE inhibition,” Koenig said. For comparison, a second Phase 1b/2a trial of this compound in AD patients who do not take AChE inhibitor is being wrapped up at present, Koenig added.
In the trial presented in Vienna, primary endpoints were safety, secondary endpoints were pharmacokinetic measures of EVP-6124 and AChE drug to check for drug-drug interaction, and cognition tests made for tertiary endpoints. On safety, Hilt and colleagues report that there were no specific adverse events they interpreted as being related to treatment or dose, nor any serious adverse events. The researchers found no evidence of drug interaction. On efficacy, the trial recorded positive effects on some of the tasks contained in either the CogState or NTB batteries used in this trial. In particular, the identification and detection tasks of CogState, as well as the COWAT, CNT, and Trail Making Tasks of the NTB appeared to show a dose-dependent response, the scientists report on the poster. These tasks measure attention, verbal fluency, and executive function. The effect grew over the course of treatment. The scientists don’t know if this short trial reached the maximum drug effect, nor whether the effect would track over time like that of other symptomatic AD drugs. For that, longer trials will be necessary. CogState (which is similar to CANTAB) is a commercial, computerized cognitive test battery; the NTB is a set of paper-and-pencil tests developed largely by scientists at Elan/Wyeth Pharmaceuticals, who claim these tests are particularly sensitive for measuring cognition in mild AD (Harrison et al., 2007). AD clinicians increasingly use these measures in the belief that they pick up slight changes faster than does the ADAS-cog.
“These are first signs of a pro-cognitive response,” said Koenig. “But it’s important to be cautious. This was a small, first trial in AD patients. We do not yet know if and how these effects will translate into ADAS-cog or clinically relevant endpoints,” he added.—Gabrielle Strobel.