Big pharma continues to pile in to indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, with Roche signing its second deal in what has been a flurry of activity to gain access to the immunotherapy target. Roche paid US$25 million upfront and committed up to $530 million in milestones to develop Curadev's CRD1152, a preclinical-stage small-molecule dual inhibitor of IDO1 and tryptophan 2,3-dioxygenase (TDO). Last October, Roche subsidiary Genentech also licensed preclinical-stage NLG919 (now Phase I candidate RG6078) from NewLink Genetics for an upfront payment of $150 million plus up to $1 billion in milestones. Bristol-Myers Squibb, meanwhile, acquired Flexus Biosciences in February this year for $800 million upfront plus up to $450 million in milestones for access to the biotech's preclinical-stage IDO-selective, IDO and TDO dual, and TDO-selective inhibitors. And in December last year, Pfizer paid iTeos Therapeutics €24 million upfront plus undisclosed milestones for rights to preclinical-stage IDO1 and TDO2 inhibitors.

The deals are an extension of industry's focus on cancer immunotherapies. IDO1, which is constitutively expressed in many cancers, and TDO catalyze the degradation of the essential amino acid tryptophan. T cells are sensitive to tryptophan shortage, and the tumour overexpression of IDO1 and TDO acts to prevent the local proliferation of T cells into the tumour microenvironment, effectively helping cancers to hide from the immune system. By blocking the IDO1 and TDO enzymes, drug developers hope to restore the immune response.

Proof-of-concept data could start rolling in soon. Incyte has advanced its IDO1 inhibitor epacadostat into Phase II development for cervical and ovarian cancers. NewLink is also testing its IDO inhibitor indoximod, which it is not developing with Roche, in a Phase II breast cancer trial. Many oncologists anticipate that these two drug classes might work best, however, when combined with checkpoint inhibitors such as those that block cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death protein 1 (PD1) (Nature Biotech. 33, 321–322, 2015; Nature Rev. Drug Discov. 14, 374–375, 2015).