NIR has been waiting for the results of two particular clinical trials to be publicly released, since these programs have achieved the kind of success that should start to catalyze a shift in sentiment about prospects for CNS drug development.
One of the two trials finally has had data presented. It is EnVivo Pharma‘s EVP-6124, a nicotinic alpha7 agonist. In this 409pt Phase IIb trial, the highest dose used (of three), 2.0mg once-daily (oral), hit both primary endpoints in this mild-moderate AD population. Some patients had also been already on a regimen including a cholinesterase inhibitor, giving the opportunity to assess how EVP-6124 might perform in a combination therapy context.
These Phase IIb results are the best Alzheimer’s data we recall from a robustly-scaled efficacy trial. At 23 weeks of treatment, cognition was improved on the ADAS-Cog-13 (p=.0189) and clinical functioning on the CDR-SB was improved as well, (p=.0253). The effect size on the ADAS-Cog-13 was .39, considerably better than the effect size for currently approved AD drugs (.15-.28)–which means that the magnitude of clinical benefit considerably exceeds that afforded by current drugs. Secondary cognitive endpoints were reached, and with room to spare. Positive trends were seen on the MMSE and ADL’s.
One finding was particularly provocative, albeit preliminary: “Patients on the 2.0 mg dose saw an improvement in cognition (not just maintenance of current cognitive function) over the 23 weeks of dosing and were still separating from the placebo group at the end of the trial, as assessed by the ADAS-Cog-13.” At six months, the mean results for high dose EVP-6124 patients demonstrated cognitive functioning that exceeded baseline; only further testing will show to what degree that improvement continues over time. The fact that, in this trial, EVP-6124’s impact on cognition outstripped the negative effect of the degenerative process begs a question: Does EVP-6124 have a disease-modifying effect? Longer-duration studies will be needed to ascertain this, but that possibility is suggested by the six-month data.
There were GI side effects in less than 10% of EVP-6124 patients, and overall the safety and tolerability of this compound appears good. This substantial Phase IIb trial shows that this once-daily drug provides robust improvement on a wide variety of cognitive and other functions, and holds out the tantalizing possibility that the disease process itself was being modified, progression slowed.
EVP-6124’s results suggest that this is an alternative mechanism that may achieve some, and perhaps all, of the primary goals of Alzheimer’s treatment. At the very least, there is compelling evidence of symptomatic improvement, and given the value of extending a patient’s capacity for independent functioning, that in itself is very important. If this drug also has some impact on the progression of the underlying disease, that would dramatically change the current calculus of Alzheimer’s therapies-in-development. Given that the current crop of putative disease-modifiers have any number of delivery, safety, efficacy, and production issues, this is big news. With so much attention currently being consumed by bapi and sola, and by the highly preliminary pilot data for Gammagard, EVP-6124 may not immediately receive the media attention it deserves , but it should not take too long for the Alzheimer’s field to take notice–we know that Big Pharma has.