Incyte announced this week that its lead compound, INCB18424, had moved into phase III trials in myelofibrosis, a significant step considering that this is only the second late-stage trial of a janus kinase (JAK) inhibitor to date.  

JAK enzymes mediate signalling of several important drivers of autoimmune diseases and cancers, and are viewed as promising new targets for drug developers. Incyte follows hot on the heels of  Pfizer, which entered its JAK3 inhibitor CP-690,550 into a pivotal rheumatoid arthritis trial in February. With the majority of the JAK compounds in the form of attractive oral pills, and most still in the hands of small drug developers like  Incyte, signs of late-stage clinical success could spark partnerships deals in the area (see tables below). 

Incyte’s candidate is a JAK2 inhibitor. Under normal circumstances, activation of JAK2 stimulates blood cell production, but genetic mutations in the enzyme are implicated in myeloproliferative diseases (MPD), conditions characterised by an overproduction of blood cells in the bone marrow. Most commonly  JAK2 mutations are found in  polycythemia vera, essential thrombocytopenia and primary myelofibrosis disorders.  

Incyte received the go-ahead from the FDA this week to start a phase III trial recruiting patients with all three of these conditions, which will involved 240 patients. A similar trial in Europe, seeking to enrol 150 patients, started recruiting earlier this month.  

With nothing on the market for these blood disorders, there is clearly a strong, albeit niche, medical need for treatments and if successful the drug could potentially be on the market by 2011. This should present an attractive prospect for partners, although Incyte has said it wants to retain North American rights and sell rest of world. Still, stellar results could illicit a tempting offer.  

Source: EvaluatePharma

Incyte’s progress will be watched with interest by the owners of the two phase II JAK2 candidates which are also being developed in myelofibrosis and one of which,  ONX 0803, originally developed by  S*Bio has already been cornered by  Onyx Pharmaceuticals. The US developer of successful cancer treatment Nexavar paid $25m for an option over North America and Europe rights to the compound and an earlier stage follow-on back in January.  

Given the scarcity of research in the field, Onyx clearly felt safer hedging its bets at this stage. S*Bio is still running the development, with a phase I/II trial due to report in the first quarter of 2010, the results from which could potentially trigger a full blown licensing deal.  

TargeGen, meanwhile, announced the start of a phase I/II trial of its candidate at the very beginning of 2008, although clinicaltrials.gov indicates that final data will not be available until mid 2010. 

Autoimmune indications

While the JAK2s dominate in cancer and myelofibrosis, the JAK3s dominate in autoimmune conditions like RA. Pfizer’s CP-690,550 is clearly leading the field, entering a 750 patient trial earlier this year, which should complete in early 2012. The drug is the most advanced oral novel RA treatment across the industry, hence the excitement around the project. Sales forecasts indicate uptake would be swift if the drug makes it to market. 

However, behind CP-690,550 the phase II pipeline is empty, with a number of products at earlier stages. Still, it is probably fair to assume that a number of other JAKs are in early stage development, but not disclosed as JAKs by their owners.

It is also interesting to note that only two JAKs have been announced as abandoned, both in pre-clinical development; KRX-211 by  Keryx Biopharmaceuticals and  R107s by  Rigel Pharmaceuticals. As these compounds in the tables above move through development, however, the field is bound to see its first clinical stage failure.