With Infinity’s failure, spotlight falls on Synta

The phase II failure of Infinity Pharmaceuticals’ Hsp90 inhibitor retaspimycin deals yet another blow not only to the troubled company but also to this pharmacological approach.

While Infinity’s already battered stock fell a further 5% yesterday, it is perhaps Synta Pharmaceuticals' 3% dip yesterday that is more significant, although it recovered those losses this morning. Synta’s ganetespib is the most advanced Hsp90 inhibitor in development. Bulls may argue that Infinity’s failure leaves the field clearer for Synta, but it must also raise further doubts about the validity of Hsp90 inhibition as an anticancer approach.

Infinity’s relatively modest share price decline attests to the fact that few analysts had expected great things of retaspimycin, which had already failed a phase III trial in gastro-intestinal stromal tumours and phase I in multiple myeloma. AstraZeneca had handed back rights to Infinity in 2008.

But its failure does cast further shadow over Infinity, whose bloated market cap had exceeded $2bn in April but is now off 50% year to date. Failure to reassure investors about the safety of its lead project, IPI-145, at Asco provided a strong sell signal.

Hsp90 is a chaperone protein that is thought to play a protective role in some cancer cells, stabilising growth factor receptors and signalling molecules including PI3K and AKT proteins, and its inhibition might thus induce apoptosis – or so the thinking goes.

Unfortunately for Infinity, the phase II trial in 226 NSCLC patients, adding retaspimycin on top of docetaxel, failed to hit its primary overall survival endpoint either in all patients or in the sub-population with squamous cell histology. Cutting the data by prespecified biomarkers, including patients with KRAS, p53 and plasma levels of Hsp90-alpha, also failed to show any benefit.

Sector read-across

This also casts a shadow over remaining Hsp90 inhibitors in development, none more so than the leader of the pack, Synta’s ganetespib.

Already Synta’s stock had been hit after various cuts of the data from an open-label phase II study, Galaxy, failed to live up to the company’s hype (Asco Event Analyzer – 2013’s winners and losers, June 6, 2013).

Galaxy tested ganetespib on top of docetaxel in NSCLC, and retaspimycin’s failure in broadly the same setting is unlikely to add confidence to the outcome of the phase III trial, Galaxy 2; this specifically excludes patients with the squamous cell histology, where ganetespib does not work.

The other prominent Hsp90 inhibitor still in development is Novartis/Vernalis’s AUY922, which is in a number of phase II trials, including in NSCLC. Astex Pharmaceuticals is also active in this area, but has recently agreed to be bought by Otsuka Holdings.

Hsp90 inhibitors in clinical development
Product Company 2018e sales Status
Ganetespib Synta Pharmaceuticals 481 Phase III
AT13387 Astex Pharmaceuticals (Otsuka) 103 Phase II
Retaspimycin  Infinity Pharmaceuticals 40 Failed phase II
AUY922 Novartis/Vernalis - Phase II
KW-2478 Kyowa Hakko Kirin 4 Phase II
Debio 0932 Curis/Debiopharm - Phase II
SNX-5422 Esanex - Phase II
Hypericin Hy Biopharma - Phase II
BIIB021 Biogen Idec - Phase II completed
DS-2248 Daiichi Sankyo 1 Phase I
XL888 Exelixis - Phase I

But more than anything, despite early promise Hsp90 inhibition seems to have been associated with failure. EvaluatePharma lists no fewer than 28 Hsp90 inhibitors that have been abandoned in development, two of the most advanced ones being Bristol-Myers Squibb’s tanespimycin and alvespimycin.

Infinity says it will not start any new retaspimycin trials. In this case at least, AstraZeneca’s decision to pull the plug five years ago looks entirely justified.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter

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