Desperate times call for desperate measures, so the unlucky US biotech company Curis probably had little to lose in taking a stab at a deal focused at something it could call immuno-oncology.
But even in the current bull market the tie-up it announced yesterday with Aurigene, a unit of Dr Reddy’s Laboratories, failed to excite, with the stock virtually unmoved and still 64% off where it stood before a crippling US clinical hold. The idea that the groups can develop a small molecule to target PD-L1 – a large protein structure – is surely too good to be true.
Yet this is a target of one of the compounds in the alliance. The deal will see Curis hand across around $24m of equity – equivalent to 19.9% of its issued capital – to Aurigene for an exclusive two-year development period during which the US firm will have the option to license individual projects.
Aurigene’s second lead molecule targets IRAK4 (IL-2 receptor-associated kinase 4), which is claimed to interact with the MYD88 protein to drive cell survival. The companies say IRAK4 targeting could have potential in diseases associated with MYD88 mutations, such as large B-cell lymphomas and Waldenstrom’s macroglobulinaemia, and postulate that inhibiting IRAK4 could promote cell killing.
Preclinical work has been undertaken with this target by companies including Ligand Pharmaceuticals, Nimbus Discovery and TG Therapeutics. However, this concerned inhibition of the IRAK4 kinase complex to damp down immune response, with possible application in rheumatoid arthritis and as immunosuppressant therapy.
Oral small molecules
Both molecules have only been tested in cell-based assays and in vivo, so much remains to be proved, though Curis is set on filing INDs and starting clinical trials this year – presumably after taking up full licences.
An oral small molecule against an immune checkpoint like PD-L1 could represent the holy grail of cancer therapy, though there are obvious reasons why this would have long odds. Protein-protein interactions, such as between PD-1 and PD-L1, involve complex molecules whose large surface area typically means that disruption with a small molecule is a non-starter.
Indeed, all the players here, including Merck & Co, Bristol-Myers Squibb and Roche, are using antibodies to achieve this. But Curis said it had been encouraged by the potency of the Aurigene compound in vivo, saying this was on a par with antibodies.
It acknwoledged that attempting to hit PD-L1 with a small molecule was unconventional, but pointed to proteins like Bcl-2, which has successfully been targeted by AbbVie’s venetoclax. Curis’s own early-stage small molecule CUDC-427 aims to antagonise IAP proteins that promote cancer cell survival.
CUDC-427, of course, is the project whose US study was halted after a patient death, though this has since been lifted (Curis hit badly by cancer drug clinical hold, November 7, 2013). But the company’s stock was hit badly, and as of the end of last September it had only $54.6m in the bank.
Curis has committed to funding development of the Aurigene assets, and says a formal exclusive licence to the first two projects would include up to $10m in pre-commercial milestones for the initial indications.
If moving quickly to exercise a licence and starting clinical trials this year are realistic goals then the group surely needs to raise cash. Given the lukewarm market reaction this appears to be a long shot.