This is a good piece by Bruce Booth in Forbes, and it points out something that’s changing in the biopharma landscape. Readers will have noticed over the years here the occasional eye-rolling at companies that run underpowered clinical trials and go to the FDA hoping for the best. That’s not a good place to save money, actually, and if it’s come to that then something is not going right. Statistics rule in drug approvals – well, unless you’re Sarepta – and you generally have to get some real N behind you to get solid, believable numbers.
But we’re used to what you have to do to get such numbers with small molecules, and small-molecule mechanisms. What about cell- and gene-based therapies (CGT)? I was just asked about these the other day, after speaking to a group about drug discovery, and I answered that I was very hopeful about what could be accomplished in this area (although I also mentioned that the general public has no idea of how complex it is, and how early things are). Live-cell and gene-delivery modes of action are (or can be) a different order of things entirely, and we may well have to adjust our settings.
As Booth mentions, it was (in retrospect) around 2009-2010 that the situation really began to look up in this field. In the late 1990s/early 2000s, patient deaths and general bad news had sent things into back-burner mode, and it took a while to move out of it. As positive data began to show up, though, it was interesting to see how few patients were in these trials – ten, maybe. Single digits. Maybe just one, the first time. A lot of drug mechanisms (and a lot of drugs) would have trouble convincing anyone at those levels.
But it comes down to effect size. If someone has Rare Genetic Disease X because Cell Population Y cannot produce Crucial Protein Z, the effect of replacing Y or Z can be enormous. We’re used to fighting biochemical mechanisms with all kinds of compensatory pathways webbed around them; there’s often only so much you can move the needle without it starting to move back. Or we’re fighting some awful shape-shifting pile of tumor cells, where wiping out 90% of them in one go only means that the patient lives another month or something. But when there’s an actual piece missing and that piece drops back in, or when you have some handle that lets you select every last cell you’re trying to target, that’s something else again. A small N can be enough to show you the way under such conditions:
One of the salient takeaways from the history of the CGT field is the catalytic impact of truly compelling early clinical data. An axiom in drug R&D is that “great drugs reveal themselves early” and this is never more true than in the CGT space. One doesn’t need to “torture the data” to make it yield answers. In many instances the answer is clear within a few patients. With such profound unmet needs in most of the grievous, debilitating conditions where these CGT approaches are appropriate, when CGTs work well, one can often see it quickly and with very small numbers (n’s) of patients. And that holds true even in later stages of development: take Luxturna’s Phase 3 study, which only has 21 patients; Strimvelis was approved with 18 patients.
The tricky part, as it is so often, is tox. The effect sizes there can be annoyingly small but show-stopping (ask Merck about that with Vioxx), and it can take a while for them to emerge. A ten-patient trial of a small molecule is unlikely to tell you much about efficacy, but it’s highly unlikely to tell you anything about toxicity, unless you’ve run into a grievous effect size indeed. What can mitigate this in the CGT field, though, is that you’re often replacing something that the body has been expecting to be there all along, not adding in a new drug substance with a less-worked-out profile in vivo. In that case, the big questions are whether your method of delivery is safe, and whether the abrupt replacement is handled well.
But in things like CAR-T therapy for cancer, the long-term effects are still an open question, because there aren’t any really long-term beneficiaries yet. It’ll be years before we know for sure. The mitigating factor there, of course, is that without the CAR-T treatment these people, every single one of them, would be long dead. Conventional oncology therapies have long made some pretty brutal tradeoffs of side effects and toxicity for much lower odds and payouts, so the CAR-T case is actually pretty easy to make.
As it stands, the sorts of conditions being treated by CGT all fall into this dramatic “death or glory” zone. No one’s going to go in with engineered T-cells or viral gene-delivery vectors to treat a (hypothetical!) condition that causes, say, shorter eyelashes. With the huge medical need on one side, and the dramatic effects of therapy on the other, the CGT field is going to be able to go on for some time with smaller and shorter trials than just about any other part of the industry. If some new approach comes along and kills off all eight people in the trial, God forbid, that’ll be time to talk again. But so far, even though there have been deaths in some trials in this area, there hasn’t been a flat disaster of that kind, and let’s hope that there isn’t. Because the rewards of success in this area could be almost beyond measuring.