Two years ago, I wrote about Cortexzyme and their Alzheimer’s plans. I found this approach very interesting, on several levels. The prevailing amyloid hypothesis for the disease, although plausible for decades, has been taking a severe beating as companies have tried to act on it. Beta-secretase inhibitors have failed, gamma-secretase inhibitors have failed, and antibodies to various forms of amyloid itself have failed repeatedly, thoroughly, and in exhaustive detail (the FDA’s recent approval of one notwithstanding). So other approaches to the disease are needed, and one idea that’s been floating around for a long time is that AD might have an infectious component.
There are arguments against this hypothesis, but there are some arguments for it as well (see that earlier post), and it’s a fairly straightforward thing to test. And that’s what Cortexzyme did, making a case against a particular class of bacteria and taking an inhibitor (atuzaginstat) of a key viruluence factor (gingipain) into a trial in Alzheimer’s patients. I was all for it – decent, testable ideas are not easy to come by in this area, and it was certainly better than seeing yet another disappointment targeting beta-amyloid plaques. Or soluble beta-amyloid. Or beta-amyloid oligomers. Or the tap-dancing beta-amyloid that causes Alzheimer’s on alternate Tuesdays when it doesn’t rain.
Unfortunately, this idea did not work out. It’s still Alzheimer’s disease, after all, and you have to be ready for disappointment. The drug missed its primary endpoints – the treatment group deteriorated at a rate statistically indistinguishable from the control group, and that’s not what you want to see when you think you might have a line on a real cause of the disease. I’m sorry to see it, but I’m glad that they ran the trial, because we need all the clarity we can get about the etiology of Alzheimer’s, and these results would appear to rule out anything that could have been improved by this antibiotic. In the subgroup of patients who tested positive in their saliva for the bacterium (which is also involved in gum disease), there was improvement in the highest-dose group on one Alzheimer’s rating scale (ADAS-Cog11) but no improvement on the other rating (ADCS-ADL), and that’s hard to rationalize as a real effect, to be honest.
But now we leave the (relative) clarity of clinical results and move into the Land of Rah-Rah. Cortexzyme’s management team has (in my view) disgraced themselves with the way that they’ve presented these negative results. Instead of standing up and saying “Our drug missed its endpoint. We’ll continue to look through subgroup data to see if there’s something we can learn”, they’ve chosen to come out talking as if everything worked out just fine. Yesterday’s press release already was sounding this discordant note, and the conference call was. . .well, here’s how it started off from the company’s COO/CSO:
“. . .Truly a great day for patients, a great day for Alzheimer’s research. Very pleased to be able to share positive outcomes across multiple fronts from the GAIN trial with you today. Today, our mission to alter the course of this disease has indeed taken a giant step forward. . .”
Referring to the company’s founders, he went on to say that their leadership has led the company to “this wonderful day”. Imagine if the drug had actually shown any evidence of actually working! Would the call then have consisted of nothing but incoherent shouts of ecstasy punctuated by breaking glass? Since the COO has the same last name as I do, I feel compelled to bring in yet another Lowe (Cousin Nick) for testimony on this point. Your trial failed, folks. It’s no disgrace, particularly in Alzheimer’s. To come out like a lawn sprinkler spraying happy talk and going on about how pleased you are about how great everything is – come on. And it doesn’t really do any good, either – CRTX stock is down about 75% as I write. A wonderful day indeed.
