Here’s what sounds like a good idea from VC firm Index Ventures, from the latest issue of BioCentury (same one I referenced the other day). Like many others in the biopharma venture capital world, they’re trying to run the “killer experiment” as soon as possible, to see which ideas for new companies look solid. Unlike the others, though, they’re planning a web site where they will detail the successes – and the failures. Here’s an example:
Founded in 2013, (Purple Pharmaceuticals) was started to identify small molecule inhibitors of proprotein convertase subtilisin/kexin type 9. Two mAbs against PCSK9 are already in Phase III testing to treat hypercholesterolemia with regulatory submissions expected this year: evolocumab from Amgen Inc. and alirocumab from partners Regeneron Pharmaceuticals Inc. and Sanofi.
Grainger said the antibodies have limitations, as they require high doses to suppress PCSK9 activity and once-weekly or once-monthly infusions. Thus a pill that could match the PCSK9 inhibition of the biologics could be “the holy grail” of lowering LDL cholesterol.
Purple began by trying to identify small molecules that were highly selective for PCSK9 over other proprotein convertases because, as Grainger noted, “PCSK9 is a member of a large family of enzymes that do some pretty critical things.”
The killer experiment, he said, “was to ask could we make a small molecule that was selective over these other proprotein convertases, and could we demonstrate that it would lower LDL cholesterol?”
After a year, Purple had identified some hits selective for PCSK9, but a conversation with researchers at the Genentech Inc. unit of Roche led to the realization that the virtual company would need to run a second experiment.
“We learned from that interaction with Genentech that they had also run a PCSK9 screening program the same way we had,” Grainger said. “They discovered that their hits, while preventing PCSK9 from cleaving an external substrate, did not prevent PCSK9 from cleaving itself.”
Purple learned that in vivo, PCSK9 is auto-activated by cleaving itself — meaning the only important interaction to inhibit is PCSK9 auto- activation, not interactions with external substrates.
Purple’s second experiment showed none of its small molecule hits that inhibited PCSK9 interaction with an external substrate also inhibited auto-activation.
“Therefore we were able to kill a project which had spent at that stage only about £300,000 over a year, only to discover at the critical moment that it didn’t have the profile that we wanted,” Grainger said. “We were able to terminate that without having created any infrastructure, without having spent a painful amount of money prosecuting the project.”
That story illustrates a number of points about drug discovery. First off, congratulations to those involved for being able to definitively test a hypothesis; that’s the engine at the heart of all scientific research. And as they say, it was good to be able to do that without having spent too much money and time, because both of those have a way of getting a bit out of control as complication after complication gets uncovered. Investors start getting jumpy when you keep coming back to them saying “Well, you know, it turns out that. . . “, but you know, it often turns out that way.
The next thing this story shows is that when you see an obvious gap in the landscape that there may well be a good reason for it. PCSK9 antibodies are widely thought to be potential blockbusters; a huge battle is shaping up in that area. So why no small molecules, eh? That’s the question that launched Purple, it seems, and it’s a valid one. But it turns out to have a valid answer, one that others in the field had already discovered. I suspect that the people behind this effort were, at the same time they were characterizing their lead molecules, also beating all the bushes for the sort of information that they obtained from Genentech. Somebody must have tried small-molecule PCSK9 inhibitors, you’d think, so what happened? Were those projects abandoned for good reasons, or was there still some opportunity there that a new company could claim for itself?
There may well be more to this story, though, than the Index Ventures people are saying. Update: there is – see the end of this post. The autocatalytic cleavage of PCSK9 was already well-known – pretty much everything in the that protease family works that way. (The difference is that with PCSK9, the prodomain part of the protein stays on longer – details of its cleavage were worked out in 2006). And in this 2008 paper from Journal of Lipid Research, we find this:
Several approaches for inhibiting PCSK9 function are theoretically feasible. Because autocatalytic cleavage is required for the maturation of PCSK9, a small-molecule inhibitor of autocatalysis might be useful, provided that it was specific for PCSK9 processing and did not lead to a toxic accumulation of misfolded PCSK9. Small molecules that block the PCSK9-LDL receptor interactions would likely be efficacious, although designing inhibitors of protein-protein interactions is a tall order. Antisense approaches pioneered by Isis Pharmaceuticals (Carlsbad, CA) are well suited for liver targets, and studies in mice suggest that this approach is efficacious for PCSK9. Finally, there is considerable interest in developing antibody therapeutics to inhibit PCSK9-LDL receptor interactions.
Even more to the point is the paper that that JLR piece is commenting on. That one demonstrates, through studies of mutated PCSK9 proteins, that its catalytic activity does not seem to be necessary at all for its effects on LDL receptors (a result that had already been suggested in cell assays). Taken together, you’d come away with the strong impression that inhibiting PCSK9’s catalytic activity, other than stopping it from turning itself into its active form, had a low probability of doing anything to cholesterol levels. And you’d come away with that impression in 2008, at the latest.
So Purple’s idea was a longer shot than it appeared on the surface, not that the real information was exactly buried deep in the literature. They shouldn’t have needed someone at Genentech to tell them that PCSK9’s autocatalysis was the real target – I’ve never worked in the area at all, and I found this out in fifteen minutes on PubMed while riding in to work. They must have had more reason to think that an assay for PCSK9’s exogenous activity would be worth running – either that, or this story has gotten garbled along the way.
But this example aside, I applaud the idea of making these early-stage calls public. And I agree with the Index Ventures folks that this should actually help academics and others unused to drug discovery to see what needs to be done to actually launch an idea out into the world. I look forward to seeing the web site – and perhaps to hearing a bit more about what really happened at Purple.
Update: David Grainger of Index Ventures has more in the comments, and says that there is indeed more to the story. He points out that mutations of PCSK9 were found that inhibited its autocatalytic activity (such as this one), and that work had appeared that suggested that molecules that inhibited only the autocatalytic activity could be useful. This is what Purple was seeking – the BioCentury piece makes things sound a bit different (see above), but the problem seems to have been that molecules that inhibited PCSK9’s activity against other substrates turned out not to inhibit its activity against itself. If I’m interpreting this right, then, Genentech’s contribution was to point out that the autocatalytic activity couldn’t be modeled by looking at another substrate.