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8 octobre 2011 6 08 /10 /octobre /2011 20:52
Nature Reviews Drug Discovery 10, 717-718 (October 2011) | doi:10.1038/nrd3571

Companies hope for kinase inhibitor JAKpot
Elie Dolgin

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Abstract
Drugs that block Janus kinases are showing promise in diseases ranging from myelofibrosis to rheumatoid arthritis, but with the leading agent in line for approval questions remain about their optimal selectivity.


In 2005, a series of studies reported that an activating mutation in Janus kinase 2 (JAK2) — JAK2V617F — was highly linked to three related blood diseases: polycythaemia vera, essential thrombocythaemia and myelofibrosis. For haematologists, these observations were reminiscent of the mutant BCR–ABL kinase that underlies chronic myeloid leukaemia (CML), another myeloproliferative disorder. And remembering the success of Novartis' ABL kinase inhibitor imatinib in transforming CML treatment after its approval in 2001, companies reached into their kinase inhibitor libraries in the hope of developing another blockbuster targeted oncology drug.

Six years on, the first of those agents — Incyte's ruxolitinib, which leads over a dozen JAK inhibitors in development for a range of indications (Table 1) — is up for regulatory approval. In August, the US Food and Drug Administration began reviewing the New Drug Application for ruxolitinib (also known as INCB18424 or INC424) against myelofibrosis, and a decision is expected by 3 December. Novartis, which licensed the rights to ruxolitinib for sale outside the United States, has similarly filed the drug for approval with the European Medicines Agency and other regulatory bodies around the world.

Table 1 | Janus kinase pipeline


Full table
Figures and tables index
Download high-resolution PowerPoint slide (114 KB)

If approved, analysts say the oral drug could fetch global sales approaching US$1 billion by 2015. “The market is substantial,” says Ren Benjamin of the investment bank Rodman & Renshaw. “In this indication, there really is nothing else out there that's helping to better the symptoms.” If the product gets approved for polycythaemia vera as well, for which Phase III trials are ongoing, “then I think the story of it becoming a blockbuster candidate is possible”, adds Andrew Weiss, an analyst with Vontobel.

Yet, despite the excitement — and the widespread expectation that the drug will be approved before the end of the year owing to its two positive pivotal trials — ruxolitinib does not seem to stop myelofibrosis progression in the way scientists had hoped. In fact, no investigational JAK inhibitors do. “At first there was a thought — and, in retrospect, it was a bit of an unrealistic thought — that they would lead to complete remissions like we see [with imatinib] in CML,” says Ruben Mesa, a haematologist at the Mayo Clinic in Scottsdale, Arizona, USA, who has been involved in testing several of the drugs. Yet although they do not stop cancer growth, JAK inhibitors do block the inflammatory cytokine signalling associated with various symptoms of disease, such as enlarged spleens and severe itching. “We seem to have effectively shut down the JAK2 dysregulation pathway, and also to have reined in the overactivation of the pro-inflammatory cytokine pathway,” says Paul Friedman, CEO of Incyte.

“They're not perfect drugs by any stretch of the imagination,” admits Jerry Spivak, a haematologist at Johns Hopkins School of Medicine in Baltimore, Maryland, USA, who hasn't consulted with any companies developing JAK inhibitors for more than 3 years. “But they're not bone marrow mutagens” — like the chemotherapy agent hydroxyurea that is currently used to treat people with myeloproliferative disorders — “and they do palliate better than anything we have.”

Although clinicians may be happy to see any efficacy, understanding why the drugs don't work as initially hoped may provide crucial insight for the development of future agents. A first surprising finding was that the JAK2 inhibitors seem to ease disease symptoms regardless of whether the JAK2V617F mutation is present or not. “We're finding that the response is independent of the JAK2 mutational status,” says Olatoyosi Odenike, a haematologist at the University of Chicago Medical Center in Illinois, USA, who has also tested JAK compounds.

Perhaps more critically, questions over JAK inhibitor selectivity abound. “A lot of work is still ahead of us to fully understand how these drugs work,” says Herve Hoppenot, President of Novartis Oncology. Because the JAK inhibitors all have different patterns of activity against the three members of the JAK family, drug developers have room to differentiate their products. Ruxolitinib, as well as YM Biosciences' CYT387 and AstraZeneca's AZD1480, for instance, have similar activity against both JAK1 and JAK2. “It may make a difference if you don't hit JAK1 and JAK3,” says Pamela Cohen, Associate Vice President of Oncology Clinical Research at Sanofi. Last year, the company in-licensed SAR302503, which is around 35 times more selective for JAK2 than for JAK1 (and over 300 times more selective for JAK2 than for JAK3).

Meanwhile, Lilly's JAK2 inhibitor LY2784544, unlike other players in the field, is around 40 times more active against JAK2V617F than against the wild-type kinase — an attribute that the firm hopes will make a difference in the clinic. “It's possible with a selective inhibitor to get more disease-modifying activity,” argues Richard Walgren, Lilly's Senior Medical Advisor for oncology.

JAKs of all trades

Questions about the ideal selectivity of JAK inhibitors for other indications — in particular, autoimmune diseases — also remain a hot topic of debate.

JAKs first attracted attention as possible immunomodulatory targets following the elucidation of their key downstream position in cytokine signalling pathways in the 1990s. The more limited tissue distribution and profile of cytokine receptor partners for JAK3, in particular, led some companies to focus initially on developing JAK3 inhibitors against transplant rejection, and also to treat immunoinflammatory diseases such as rheumatoid arthritis and psoriasis. Pfizer was the first to report its tofacitinib (originally known as CP-690550) as an orally active selective agent, and the company is still the leader in this space. Yet although Pfizer's chemists had set out to develop tofacitinib as a JAK3 inhibitor, it actually has considerable activity against JAK1 and JAK2 as well. “It's not as selective as we thought it was when we published,” says Paul Changelian, former Director of Inflammation Biology at Pfizer, now Vice President of Lycera.

Either in spite, or because, of this selectivity profile, the drug has progressed well through clinical trials. Earlier this year at the European League Against Rheumatism Congress in London, UK, Pfizer announced that all five Phase III trials for tofacitinib met their primary end points. Initial data from three of these trials and long-term follow-up data from the other two will be presented in November at the American College of Rheumatology Annual Scientific Meeting in Chicago, USA.

Tofacitinib has been linked to infections, lower neutrophil counts, elevated cholesterol levels and one drug-related death from respiratory failure. For Saeed Fatenejad, Head of Inflammation and Immunology at Pfizer's Specialty Care Business Unit, these “infrequent side effects are consistent with what you would expect to see in patients with rheumatoid arthritis and when taking medications that further modulate the immune system”.

Still, this side-effect profile, along with uncertainty about the ideal selectivity for efficacy, leaves wriggle room for other drug firms. Vertex's VX-509 is thought to be highly selective for JAK3, for instance, and Incyte and Lilly's LY3009104, a compound that is structurally related to ruxolitinib, preferentially targets JAK1 and JAK2. Both of these rheumatoid arthritis candidates are currently in Phase II development.

Pfizer, meanwhile, expects to file tofacitinib for approval in rheumatoid arthritis before the end of the year. It is also developing the drug for psoriasis, inflammatory bowel disease, dry eye disease and kidney transplant. “The excitement is pretty big” for tofacitinib, says Decision Resources analyst Benjamin Guikema, who forecasts sales of $1.2 billion by 2019. “This would be the first oral therapy that would have efficacy on par with the biologics such as tumour necrosis factor-targeted therapies. Patients could have the same efficacy without having to receive injections.”

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