Orally available, flexible and novel, Janus kinase inhibitors are poised to trigger major treatment shakeups in at least two disease spaces. Two drugs at the head of the JAK pack are close to coming of age – Pfizer Inc.’s tofacitinib and Incyte Corp.’s ‘18424 – and hopes are high, though questions remain about selectivity, long-term side effects and just how far the class can go.

Discovered in the 1990s, Janus kinases (JAKs) form one of 30 families of tyrosine kinases, a set of targets that gave birth to Gleevec (imatinib) – which proved the value of the TKI approach – and have proven valuable for many cancers. Within the JAK branch are four types: JAK1, JAK2, JAK3 and TYK2.

JAKs mediate signaling of cytokines that cause inflammation. Out of some 200 cytokines in the human genome, about 60 signal via the JAK-Stat pathway, typically using pairs of JAKs. What that means is that a wide range of diseases could be targeted with JAK inhibitors, explained John O’Shea, scientific director of the molecular immunology and inflammation branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“We are rapidly learning what it means to inhibit JAKs in humans” said O’Shea, during a presentation at the 2010 annual meeting of American College of Rheumatology in November.

Inhibitors of Janus kinases are being tested in some 50 ongoing or completed trials, with the most activity in myeloproliferative disorders, rheumatoid arthritis and cancers (see pipeline chart).

Incyte has a strong chance at hitting the market first with its JAK1/JAK2 blocker INCB18424 (ruxolitinib), partnered outside the U.S. with Novartis, initially in an indication for myelofibrosis, a rare disease of the bone marrow. In the U.S., nothing is approved and the standard of care is non-existent. Consequently, some analysts have described '18424 as a “major milestone in hematology” and a “pioneering treatment.”

Pfizer’s oral JAK inhibitor tofacitinib (recently renamed from tasocitinib) is expected to be the first or second to market for a rheumatoid arthritis indication. Developed in-house, the drug is the most advanced oral compound to show efficacy comparable to anti-TNF injectables. Tofacitinib is also in Phase II for other immune-related conditions like psoriasis, inflammatory bowel disease and organ transplantation.

In a Dec. 7 note, Bernstein Research analyst Tim Anderson referred to the molecule as “one of the most exciting compounds in the pharmaceutical industry's collective pipeline.”

The value proposition for tofacitinib is easy to understand, considering that it will be competing as an oral therapy in a category dominated by injectable products, which sell about $12 billion a year in rheumatoid arthritis alone and $20 billion when other indications are included, Anderson noted.

Incyte’s INCB18424 and Pfizer's tofacitinib could conceivably both be on the market in 2012 and each is expected to have a good lead over rivals.

On average, analysts are forecasting that tofacitinib and INCB18424 will hit about $1 billion in sales in 2016, according to EvaluatePharma, a U.K. market research firm that aggregates analyst projections (see market forecast chart). However, some individual analyst estimates project a much higher potential by that date.

Money Talks

Deal figures illustrate the perceived value of JAK inhibitors. Novartis obtained ex-U.S. rights to Incyte’s INCB18424 for hematology and oncology indications alone, along with another cancer candidate, for about $200 million upfront in a deal described at the time by analysts as “far more validating than most partnerships” (Also see "Two-Compound Partnership With Novartis Brings Incyte $210 Million Immediately" - Pink Sheet, 25 November, 2009.).

Even without much data available, Eli Lilly & Co. paid over $90 million upfront for Incyte's Phase II oral JAK1/JAK 2 inhibitor INCB28050 (LY3009104), plus up to $665 million in milestones. This drug is being positioned as a rival to tofacitinib in rheumatoid arthritis (Also see "With Lilly JAK Tie-up, Incyte Aims To Chase Pfizer In Rheumatoid Arthritis" - Pink Sheet, 21 December, 2009.).

Incyte says that while the two molecules partnered to separate Big Pharmas are very similar, they are being developed separately to simplify commercialization in different therapeutic areas.

Aside from INCB28050, tofacitinib could face competition from another oral rival by 2016. In partnership with AstraZeneca PLC, Rigel Pharmaceuticals Inc. is developing the oral fostamatinib, which it says is highly selective for a different mechanism of action – syk kinase inhibition – but also affects multiple JAKs to a lesser extent.

Few drugs in the space are currently unpartnered. Onyx Pharmaceuticals Inc. has options on U.S. and European rights to two JAK2 inhibitors developed by S*BIO Pte Ltd. One of these – SB1518 – is now Phase III-ready, and a decision from Onyx is needed soon. Vertex Pharmaceuticals Inc. has the JAK3 candidate VX509 in development for rheumatoid arthritis and would like to partner it after the Phase II results are released this year. YM Biosciences Inc. and Galapagos NV have JAK inhibitors in earlier stages in myelofibrosis and rheumatoid arthritis, respectively.

Rigel was developing R348, which it describes as an inhibitor highly selective for JAK3, in rheumatoid arthritis but discontinued development a few years ago. The firm has at least two other very early-stage JAK3 inhibitors in its pipeline, but it plans to develop them in other indications: organ transplantation and eye disease.

How They Work

Just how JAK inhibitors work in various diseases is still being discovered.

In rheumatoid arthritis and other auto-immune diseases, JAK3 was initially thought to be particularly important, as this is the pathway used by the cytokine interleukin-2, an important driver of inflammation. JAK3 associates with the IL-2 receptor γc-chain shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

“Which of these cytokines is most beneficial to blockade is not yet known,” according to Eric Mortensen, Pfizer VP and global development lead for tofacitinib.

However, other cytokines important to inflammatory disease signal through different JAK pathways. IL-6, for example, signals through JAK2.

Tofacitinib has been shown to inhibit JAK1 and JAK3 with functional selectivity over JAK2, Pfizer explained. The exact mechanism of action has not been fully characterized, but it is thought that the simultaneous control of signaling pathways blocks multiple cytokines and “breaks the cycle of inflammation.”

The mechanism of action for JAK inhibitors is a bit more straightforward in myelofibrosis and related diseases.

In the 1990s, pharma companies mostly steered clear JAK2, fearing the side effect of myelosuppression, or bone marrow suppression. That can cause changes in blood cells, including anemia (reduced red blood cells) and thrombocytopenia (low platelet counts).

But JAKs have been a hot topic in hematology since 2005, with the discovery that a particular genetic aberration – the V617F mutation – is associated with over-activity of JAK2 and causes myeloproliferative disorders like myelofibrosis and polycythemia vera.

About half of patients with MF have the V617F mutation and most patients with polycythemia vera are carriers.

It was initially thought that if you could treat MF patients with the mutation you could cure the disease, but as it turns out, patients benefit regardless of their mutation status, explained Jan-Anders Karlsson, CEO of S*BIO. “We are rewriting the textbooks as we go along,” he said.

“We are rewriting the textbooks as we go along.”

– S*BIO CEO Jans-Anders Karlsson

In myelofibrosis, the bone marrow may already be brittle, making patients more vulnerable to myelosuppression side effects. But with careful dose titration, companies have been able to find a therapeutically effective and tolerable dose for most patients to avoid side effects such as anemia. MF patients with low platelet counts may be excluded from treatment.

Bone marrow is healthier in patients with rheumatoid arthritis, so there is less risk of side effects associated with targeting JAK2, Karlsson explained.

Delivering On Phase III Results

So far the deal values and hype around a new class of drugs seem justified. In December, Incyte reported that ‘424 met its primary endpoint of reduction of size of enlarged spleens and improvement in symptoms in the Phase III Comfort-1 study, which had been carried out under a special protocol assessment with FDA.

Incyte is now expected to file in the U.S. in the second quarter of 2011. Considering the unmet need, the drug may receive priority six-month review and conceivably even launch late this year. Incyte said that it already has a marketing team in place and is hiring a sales team in expectation of a fourth-quarter 2011 commercial launch. Price per patient per year is likely to fall somewhere between $40,000 and $60,000.

The company estimates there are about 20,000 patients with MF in the U.S. and another 30,000 in Europe. JAK1/JAK2 inhibitors are also being targeted at related myeloproliferative diseases, so there is potential to broaden the total patient population size.

Pfizer Leads Way To Oral RA

In rheumatoid arthritis, patient demand is said to be high for a tablet as efficacious as the standard injectables. But the disease is chronic and effective medications are available, so the safety bar is high.

Decision Resources analyst Irene Koulinska notes that oral RA drugs are expected to fetch prices that are much higher than for small molecules and closer to the lower end of the anti-TNF injectables. However, oral RA drugs will also have to contend with competition from biosimilar anti-TNF therapies, she pointed out. So while demand is high for an oral drug, it’s unclear how much room there will be in RA for multiple JAK inhibitors in the future.

Pfizer has a sweeping RA development program ongoing in rheumatoid arthritis, with six Phase III studies in 4,000 patients covering multiple settings, for example, as a monotherapy and after anti-TNF failures and head to head against an anti-TNF inhibitor.

One Phase III monotherapy study of tofacitinib was released in November and the rest are due for release at meetings throughout 2011 (Also see "Positive Phase III Data For Tasocitinib Give Pfizer A Badly Needed Pipeline Lift" - Pink Sheet, 8 November, 2010.). Pfizer confirmed it plans to submit an application for the drug as soon as possible after the data are released.

Tofacitinib trials are due for release throughout the year, and Pfizer intends to file as soon as possible after the studies report.

Selectivity Helps Differentiate Candidates

Despite the overall optimism, questions remain about the selectivity of the JAK compounds in development, as well as side effects, dosing and the most appropriate indications.

Compared to monoclonal antibodies, kinase inhibitors tend to be less selective and the range and types of kinases hit affect the safety/efficacy profile and appropriateness for various diseases. The advantage of being less selective is potential for greater efficacy and use in multiple diseases. The downside is risk of toxicity.

Some kinds of tests done early in development may be misleading when it comes to the kinases affected. Intracellular testing is more accurate in terms of showing which kinases are actually affected, commented Rigel COO/EVP Raul Rodriguez.

Technology is now commercially available to thoroughly test a molecule to determine which kinases are affected, though companies may or may not make results of such testing public, commented O’Shea.

Different Paths In Myelofibrosis

S*BIO’s Karlsson also argues that the fact that his company has seen strong activity by targeting JAK2 specifically implies that JAK2 is the most important pathway to target in MF. S*BIO notes that in research to date, it has seen no myelosuppression effects, which means it could be appropriate for all patients, including those with anemia and end-stage disease, a large subgroup of patients.

“That’s an important differentiator for our compound,” Karlsson said.

Incyte took a different approach to development. In patients with MF, there is very high signaling of cytokines through pro-inflammatory pathways that involve both JAK1 and JAK2, explained CEO Paul Friedman. So the strategy is not only to treat JAK2 overactivity but also to address the inflammation.

Leerink Swann analyst Joshua Schimmer concluded in a Nov. 18 note that MF has a significant inflammatory component and to achieve efficacy matching that of the Incyte compound, the dose for inhibitors selective for JAK2 has to be pushed to the point where toxicity may become unacceptable. Higher rates of gastrointestinal side effects, such as diarrhea, have been reported for the S*BIO drug, he noted.

S*BIO responds to this critique by noting that the GI effects were shown to be manageable in research presented at the last ASH meeting and did not result in study drop-outs.

Meanwhile, a dose-dependent drop in hemoglobin has been reported in trials of INCB18424 and a survival and disease-modifying benefit has not been proven, at least not yet. Some analysts are now questioning whether Incyte would be better off with a lower dose to minimize effects on anemia. The uncertainty has been a source of concern for investors.

Schimmer and other analysts believe the main competitor for Incyte’s INCB18424 is actually an earlier stage candidate: YM Bioscience’s JAK1/JAK2 inhibitor CYT387, which has been shown to increase hemoglobin and therefore has potential to become a preferred treatment for the roughly 30% of MF patients who have anemia.

Another drug with potential to stand out in MF is Lilly’s Phase I JAK2 inhibitor LY2784544, said to be specific for the V617F mutation.

Jury Still Out On JAK2 In Arthritis

In rheumatoid arthritis, meanwhile, the implications for targeting JAK2 are still being debated. Pfizer’s Mortensen noted that JAK3 is the logical target for interrupting the cascade of inflammation. In vitro studies suggest that tofacitinib is extremely selective for JAK3 and JAK1.

“The hope is that it will be effective in treating rheumatoid arthritis with as little possible effect on JAK2 inhibition,” he said.

Some analysts have said that based on results at the 2010 ACR meeting, tofacitinib and Incyte/Lilly’s JAK1/JAK2 inhibitor INCB28050 are on par in terms of efficacy and safety.

Pfizer’s Mortensen contends that “we haven’t seen the depth of safety data yet” for the rival drug, so it’s not necessarily appropriate to make such comparisons.

Similarly, Decision Resources’ Koulinska said more data is needed on JAK1/JAK2 inhibitors to determine the implications of targeting JAK2 in rheumatoid arthritis.

Aside from anemia, possible side effects related to targeting JAK2 include elevated cholesterol. This is presumably related to the inhibition of the IL-6 inflammatory cytokine, which uses JAK2. However, Pfizer notes that the mechanisms responsible for the changes are unknown at this time.

Elevated cholesterol has been reported for both Incyte/Lilly’s INCB28050 and tofacitinib (Also see "JAK Inhibitors Could Face Scrutiny Over Cholesterol Effects" - Pink Sheet, 1 November, 2010.). Similar effects were previously reported with Roche/Genentech's FDA-approved Actemra (tocilizumab), an anti-IL-6 monoclonal antibody.

Pfizer is preparing to face concerns about elevated lipid levels and potential cardiovascular risk, and present a comprehensive accounting to regulators.

Pfizer’s Mortensen said it’s questionable whether the increase in lipids actually translates into an increase in cardiovascular risk. Some research suggests that treatment of inflammatory conditions actually translates into reduced cardiovascular risk, despite an increase in lipids, he explained.

Pfizer has been conducting preclinical and clinical research and has been “very aggressively monitoring safety in studies to assess cardiovascular risk.” By the filing time, the company expects it will be able to present a “comprehensive statement to regulatory authorities about safety and what the changes in lipids mean clinically as opposed to chemically,” Mortensen said.

JAK3 inhibitors affect a broader range of cytokines involved in antibody production which, in theory, raises the risk for immunosuppression. Consequently, drugs targeted at cancer avoid JAK3.

Incyte’s Friedman argues that the data suggest JAK1/JAK2 inhibitors can achieve efficacy on par with TNF inhibitors and that it doesn’t make sense to add JAK3 to the mix, because that will potentially bring immunosuppression down the line.

Longer-term efficacy and safety data in larger sample sizes are still needed for both drugs, Koulinska commented.

“There are different sets of safety concerns. What we really need to see in trials is what the incidence of each of these side effects would be and how easy it is to manage them,” she said.

Commenting during his presentation at the ACR meeting, O’Shea noted that thinking has changed dramatically since the 1990s, when it was thought that kinase inhibitors had to be absolutely specific.

“The surprise to me is that selectivity is probably less important than we thought – this is not just true for inhibiting JAKs, but inhibiting kinases in general,” says John O’Shea, National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“The surprise is to me is that selectivity is probably less important than we thought – this is not just true for inhibiting JAKs, but inhibiting kinases in general,” he said. “The question is what are the implications for second- and third-generation JAK inhibitors? Should they be more selective or less selective?”

It’s possible that in the future, it may be desirable to adapt treatment based on stage of disease. For example, to use a molecule with broader activity during the induction phase and then switch to something with more narrow effects. Seeing as the field has gone through so many changes and is still evolving, O’Shea said he is agnostic about which JAKs or combinations of JAKs are best to target in RA.

“I have been watching this field and every time I have speculated I have been wrong .… We’ll just have to wait and see,” he said.

By Emily Hayes

JAK Of All Trades: Janus Kinase Inhibitors Are Ready, Willing And Orally Available For Many Diseases

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