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A look into JAK Inhibitor development: Has the interest diminished post-fedratinib?

03 March 2014 Tania Rodrigues

As Sanofi's discontinuation of fedratinib for myelofibrosis (MF) in Phase III trials grabbed the headlines at the American Haematology Society annual conference in December 2013, I was curious to know what all the fuss was about with Janus Kinase (JAK) inhibitors. Despite being tipped as the next JAK inhibitor with huge potential to hit the market, fedratinib was dropped in November 2013 due to reported cases of Wernicke's encephalopathy.

Why is the pharmaceutical industry so interested in developing drugs for MF, an orphan disease? The answer lies in the molecular biology behind the JAK family of intra-cellular proteins (JAK1, JAK2, JAK3 and Tyk2). Many cytokines and growth factors (like interleukins and interferons) complete their physiological tasks via the intracellular signalling cascade involving JAKs and Signal Transducers and Activators of Transcription (STATs). The JAK-STAT pathway has been found to play a crucial part in the patho-physiology of many diseases, including cancer and auto-immune.

Trying to move away from MF
In fact, the discovery of JAK2 V617F mutation in patients with myelofibrosis (MF) resulted in the development of several small molecule inhibitors. This included Jakafi/ Jakavi (ruxolutinib), a first-in-class drug that secured US regulatory approval in November 2011 and EMA approval in August 2012 for MF. Jakafi is a JAK1 and JAK2 inhibitor, manufactured by Incyte and Novartis.

Not just resting on their first-to-market advantage, Incyte and Novartis are trying to improve Jakafi's treatment of MF, which results in impaired haematopoiesis. They are conducting Phase II trials on patients with low-platelet counts as well as exploring a sustained formulation of the twice-daily drug. They are also looking at its potential in Phase II trials to treat more common and profitable cancers (like multiple myeloma and pancreatic) as well as in plaque psoriasis and thalassemia major.

These pack leaders clearly have to stay ahead of the game since the industry-wide oncology JAK inhibitor pipeline is buzzing with activity. Excluding fedratinib, the most advanced compounds in Phase III trials for MF are once-daily formulations of momelotinib, a JAK1/JAK2 inhibitor from Gilead Sciences and Cell Therapeutics's JAK2/FLT3 inhibitor pacritinib. Both drugs appear to so far result in an improved management of anaemia, which is one of the most challenging aspects of MF.

Amongst the promising candidates in Phase II is INCB039110, a JAK 1 inhibitor from Incyte, alongside Cephalon's lestaurtinib (a JAK 2/ FLT 3 inhibitor) and Eli Lilly's LY2784544 (a JAK 2 inhibitor). Most of them are targeting MF, including those patients that have shown intolerance or failed treatment with ruxolitinib.

Looking beyond RA
The other approved drug in this class is Xeljanz/Jakvinus (tofacitinib), a JAK3 inhibitor from Pfizer. It received FDA approval for rheumatoid arthritis (RA) in November 2012. But this included a Risk Evaluation Mitigation Strategy (REMS) and Pfizer agreeing to conduct a post-marketing trial to evaluate the drug's long term safety. Concerns over safety, including serious infections, were once again raised by the EMA's CHMP after it issued a second negative opinion on Xeljanz in July 2013. This followed a re-examination request by Pfizer, which has an uphill battle to demonstrate the benefit-risk profile of the drug.

That aside, Pfizer is also seeking to expand the approved indications of Xeljanz beyond RA to include other key auto-immune diseases. The drug is currently in Phase III trials for active ulcerative colitis and psoriatic arthritis whilst there are ongoing Phase II/III trials for chronic plaque psoriasis and juvenile idiopathic arthritis. Indications being tested in Phase II trials include Crohn's disease as well as kidney transplantation, amongst others.

Hot in the pursuit of Pfizer's Xeljanz is Incyte and Eli Lilly's JAK1 and JAK2 inhibitor baricitinib, currently in Phase III trials for RA. Baricitinib stood out after demonstrating an acceptable safety profile. Another promising prospect in the auto-immune pipeline is VX-509, a JAK3 inhibitor from Vertex Pharmaceuticals, currently in Phase II/III trials for RA.

Besides Cephalon's lestaurtinib and Incyte's INCB039110, the autoimmune Phase II pipeline includes two JAK 1 inhibitors derived from biotech Galapagos in a research alliance with GSK (GSK2586184) and AbbVie (GLPG0634). Both GSK and AbbVie now have the sole responsibility for further development and commercialisation of these investigational drugs.

Take home message
Despite the shockwaves caused by the discontinuation of fedratinib, interest in JAK inhibitor development continues to be strong. Within the oncology arena, success is likely to rest in combining JAK inhibitors with traditional and/or experimental treatment (including other components in the JAK/STAT pathway) to safely improve patient outcomes. This represents another opportunity for strategic licensing deals. In the autoimmune field, in particular, manufacturers have to demonstrate a favourable risk-benefit profile of JAK inhibitors whilst touting the benefits of their oral formulation in a field largely dominated by injectable biologics.

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