Merck has published new results on their latest Alzheimer’s drug candidate, the beta-secretase inhibitor verubecestat (MK-8931). The paper in Science Translational Medicine is quite interesting, both for what it says and what it doesn’t (or can’t, yet).
BACE inhibitors have had quite a time of it over the years. Coming up with a molecule with enough potency on the enzyme is merely the first step. You also have to get it into the brain, and a lot of likely structures have trouble doing that. Then your troubles really begin. Beta-secretase is known to be important in myelination of neurons and in muscle cells, neither of which you will want to mess with, and there have been reports that it’s important in memory as well, which is really unfair. Previous compounds have had problems with myelination, and have also shown liver tox (which to be fair, can happen to any compound at any time).
Merck’s compound has been in the clinic for some years now, and they started the current trial in 2012, with <s>results expected in 2019.</s> Update: turns out that the 2019 readout is for the early stage (prodromal) patient trial. The mild-to-moderate AD patient trial is getting a first readout next year. Lilly and AstraZeneca have another one reporting around that time, and yeah, that’s the timeline for Alzheimer’s in the clinic, all right. So this paper is still an early report of a work in progress. What they’re showing is that verubecestat does indeed reduce cleaved amyloid species in rats and monkeys, without evidence of the severe tox liabilities mentioned above. (There was some fur depigmentation seen in the rats, but nothing of the sort in the monkeys). And in humans, the trend continues: the compound reduces amyloid fragments in the CSF of both the control group patients and those with diagnosed Alzheimer’s disease.
That’s a significant accomplishment – this is definitely the best shot that the beta-secretase mechanism has ever had in the clinic. But what you’ll noticed is that nothing at all is said about actual efficacy of the compound against Alzheimer’s – for that, we’re going to have to wait until the end of the trial in another three years. You wouldn’t know this from the newspaper headlines, particularly the ones in the UK press. (I really don’t know what it is over there, but it’s a tradition that every tiny bit of news about Alzheimer’s gets CURE ON THE WAY coverage, every time). If the amyloid hypothesis is right, and if we’re right about targeting this part of the pathway, and if some ugly tox event doesn’t happen in the next few years, then this has a chance of being a treatment for the disease. For Alzheimer’s disease, that’s literally as good as it gets, but to write things like “Alzheimer’s Cure In Sight” is just not responsible. This field has a success rate of basically zero per cent in the clinic; people have been trying to get beta-secretase inhibitors off the ground for twenty years now.
So looking forward to victory is kind of premature. There’s an awful lot that we don’t know about amyloid and Alzheimer’s, and the only way to discover a lot of it is to take compounds like this into humans, spend hundreds of millions of dollars, and cross our fingers. It could well be that verubecestat goes on to reduce those amyloid fragment species in human patients for the next few years, with no effect on Alzheimer’s at all. We just don’t know. I certainly hope that it actually works, because the number of Alzheimer’s patients is growing every day, and the sooner they get something to slow down the progress of the disease, the better. But telling people that it’s working already is wrong.