Politico is a good source for national political stories, but I don’t usually look to them for coverage of drug development. But they’ve done a good job with their recent “Pharma Issue”. One of the stories (by David Freedman) is on the difficulties of Alzheimer’s drug discovery, which are legendary. The contrast between a therapeutic area like that one and the more recent trend towards rare disease drugs is not lost on them:
But as America looks squarely at the biggest health challenges of the future, there’s reason to worry that the system we’ve built may not be adequate to what’s in front of us. When it comes to the two diseases likely to become our biggest killers— Alzheimer’s and diabetes—death rates are relentlessly ticking up, with few solutions on the horizon. Even more alarming, to many experts who look at America’s long-term health future, is that incentives appear to be leading toward more drugs like Kalydeco, pricey treatments for small groups of patients, rather than toward drugs to tackle major new chronic killers. And if they ever do succeed against these diseases, the costs could be high enough to threaten the solvency of the whole U.S. health care system.
. . .the puzzles of Alzheimer’s and diabetes begin to look as much like a policy challenge as a scientific one. With today’s incentives, the pharma industry has built an attractive business model on narrowly targeted drugs like Kalydeco. Bigger, murkier and more complex diseases like diabetes and Alzheimer’s require a much larger investment with little confidence that it will result in correspondingly lucrative products—or even any products at all.
As the article does mention, that hasn’t stopped a number of companies from trying – Lilly’s massive investment in Alzheimer’s is noted, for example, but the fact that it hasn’t paid off at all so far is perhaps an illustration of just that point made above. One possibility is that we’re kidding ourselves when we think of Alzheimer’s as just one disease, subject to one therapy. Perhaps the rare-disease model can apply there as well:
Some are already talking about Alzheimer’s as a bundle of diseases rather than a single distinct problem. “Alzheimer’s is a mix of pathologies,” says Serge Gauthier, who directs Alzheimer’s research at the Centre for Studies in Aging at McGill University in Montreal. “We need to try treating it not with a single drug, but with different drugs that target the specific disease activities in the patient’s brain.” Trials that will test Alzheimer’s drug candidates on the 10 percent of patients who have a particular pair of genes that seem linked to a particular variation of the disease are already in the planning stage, Gauthier says. If such narrower patient-population tests produce encouraging results, he adds, drug companies are likely to take a fresh look at some of the previously tested candidates who failed in bigger groups of patients, and consider a new trial on more carefully filtered groups of individuals.
The tricky part of that, as the piece also mentions (to its credit) is that the underpinnings of Alzheimer’s are currently so obscure that even getting such trials underway is difficult. Part of the whole rare-disease mindset is that you have such a clear, solid link to human pathology that your chances of success in the clinic are increased dramatically, but “clear, solid link” is a hard thing to come by in Alzheimer’s, where even the most broadly considered hypotheses are constantly under attack (and with reason). Alzheimer’s is about as far from a classic monogenic disease as you can get, and it’s worth remembering that even those are still no stroll through the peony beds, either. Rare disease drug discovery only looks appealing in contrast to the rest of the drug industry.
The article does bring up a worry that I’ve expressed myself, that the system as it exists now is set up for a company to make huge profits from (say) a new Alzheimer’s drug that shows statistically significant results, enough to get FDA approval, but not enough to make much (if any) real-world difference. No one’s even been able to get that far, but scientifically the likelihood is that if anyone does find something that it’ll be in that category, unfortunately.
There’s also the clinical readout to consider. If you’ve got that solid mechanistic hypothesis (restore function of Protein X), then you can generally expect a reasonably fast, reasonably strong clinical effect. But Alzheimer’s trials are a fearsome grind because the disease is so slow-moving and difficult to quantify, and it’s hard to see what’s going to change that part. To that end, though, the article ends up with a call for better biomarkers to speed up trials and make them less expensive, but that’s hardly controversial. Everyone’s realized for decades that we need such things, but here we are, and not for lack of trying. On the other hand, the good news is that even expensive Alzheimer’s therapies, if they really do some good, will almost surely save more health care costs overall because of the horrible burden of chronic care. But first we have to get something to work. . .