Is Vernalis’ Hsp90 Destined to Be a Blockbuster?

Vernalis shares shot up today after Novartis gave a shout out to AUY922, which blocks a molecular chaperone called Hsp90, in a discussion of its second-quarter results. The Swiss pharma major identified AUY922 in a list of potential blockbusters, a distinction that may seem ambitious to those who have been watching compound after compound targeting Hsp90, which helps stabilize stressed-out proteins, crash and burn.

So what makes the Vernalis drug so interesting? We took a look at the field back in 2007, and at the time it was clear the Vernalis compound differed from most of the other drugs in or poised to enter clinical studies. The first and second-generation Hsp90 inhibitors were all based on geldanamycin, an antibiotic found in soil microorganisms. On its own, the natural product is a poor drug candidate—a quinine moiety renders it highly reactive and highly insoluble. Much of the early discovery work was focused on engineering out those issues, leading to drug candidates from Kosan Bioscience (bought by Bristol-Myers Squibb in 2008, work on the Hsp90 drug, however, seems dead in the water), Conforma Therapeutics (bought by Biogen Idec in 2006, after which the Hsp90 compound was put on the backburner), and Infinity Pharmaceuticals.

But, as we wrote, Vernalis sidestepped geldanamycin altogether:

Vernalis deployed fragment-based drug discovery technology to find low-molecular-weight compounds with a weak binding affinity for Hsp90. Guided by X-ray crystal structures of prospective compounds bound to Hsp90, company researchers optimized the compounds into leads. The end result is a range of drugs that do not all fall under the geldanamycin umbrella.

That’s the structure piece, but another piece of the puzzle is that researchers appear to be figuring out how best to use these compounds. On their own, Hsp90 inhibitors have shown limited to no therapeutic benefit. “It is abundantly clear that with rare exceptions we did not see a lot of single agent activity” with Hsp90 inhibitors,  Julian Adams, president of R&D at Infinity, told me last month at the ASCO annual meeting. The lack of activity might have been predicted, he adds, given that it was known that blocking Hsp90 only activated another protein-folding chaperone called Hsp70.

Indeed, evidence is emerging that Hsp90 inhibitors could find use in combinations with other targeted agents and for specific patient populations. Infinity did a deep dive into the data gathered from a Phase I trial combining Infinity’s lead Hsp90 inhibitor retaspimycin and Taxotere in lung cancer patients. The result: signs of strong activity in people with the ALK mutation (the target of Pfizer’s lung cancer drug crizotinib), in heavy smokers, and in people who carried the normal KRas gene.

There is also interest in combining Hsp90 inhibitors with Jak2 inhibitors, like ruxolitinib, conveniently being developed by Novartis and Incyte to treat rare blood disorders. Last fall, Memorial Sloan Kettering scientists showed that Jak2 is a very unstable protein, and blocking Hsp90, which ostensibly helps keep Jak2 pieced together, in combination could improve therapeutic outcomes.

Novartis is recruiting for a slew of clinical trials looking at the effect of combining AUY922 with other targeted agents. It’s early days for AUY922, which is still in Phase II trials. If all goes well, Novartis expects to file for regulatory approval for the compound in 2015.

So will an Hsp90 inhibitor finally make it to market? Detractors? Supporters? Speak up in the comments!

Author: Lisa Jarvis

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2 Comments

  1. I have to take issue with a few of your conclusions. While this drug is free of some of the problems that plagued anamycin derivatives, it has its own problem in the form of high prevalence of ocular toxicities at the MTD. This has been common in most novel HSP90 inhibitors with the exception of ganetespib from Synta Pharma (more info at http://www.biotechduediligence.com/snta.html). Also, you are giving far too much weight/credit to Infinity for some subset analysis of a tiny number of pts in phase 1. Yes, the HSP90 inhibitors appear to work well in ALK pts, but any conclusions beyond that are premature. Finally, NVS has yet to start p2, placing them well behind SNTA and a bit behind INFI in the race to market.

  2. Thanks for your comments, BioDueDiligence. I had hoped the caveats that all of this is early days would temper enthusiasm generated by Novartis’ comments. That said, I do think that its been a long road for researchers to figure out how best to apply these compounds, and many have given up. So it seems that there is finally *some* progress on designing the right clinical trials. I didn’t see a trial recruiting for the Incyte compound + AUY992, but there does seem to be interest (at both an academic and company level) in looking at Jak2 in combo with Hsp90 inhibitors.