The profile and potential of Incyte Corp.' s ruxolitinib (INCB18424) in myelofibrosis came into sharper focus with the release of detailed data from two major trials at the American Society of Clinical Oncology meeting and announcement of an FDA filing.

Ruxolitinib is one of several candidates in the emerging class of Janus kinase inhibitors, which are in development for a range of myeloproliferative diseases, rheumatoid arthritis and related conditions and cancer (Also see "JAK Of All Trades: Janus Kinase Inhibitors Are Ready, Willing And Orally Available For Many Diseases" - Pink Sheet, 1 February, 2011.).

An inhibitor of JAK1 and JAK2, ruxolitinib has been submitted for approval in treating the rare blood cancer myelofibrosis in the U.S., the company announced June 6, to coincide with the annual ASCO meeting in Chicago, where full data from two Phase III trials - COMFORT-1 and COMFORT-II - were released.

Incyte had been expected to file in the U.S. in the second quarter and to seek priority review, so the submission news itself was not unexpected, but the firm used the ASCO spotlight to maximize attention on the regulatory event.

Writing in a June 6 note after the data from COMFORT-I and COMFORT-II studies were aired at the ASCO meeting, Collins Stewart analyst Salveen Richter observed that an EU filing should be announced soon: "We expect a 4Q11 FDA advisory panel and continue to believe approval of ruxolitinib in MF in the U.S. and E.U. is likely by YE11," she wrote.

Symptom Relief

Patients who have myelofibrosis suffer from very enlarged spleens and reduction of this effect is an important aim of treatment. In COMFORT-1, which tested the drug against placebo over 24 weeks of treatment at sites in the U.S., Australia and Canada, the drug met the primary efficacy endpoint - reducing spleen size by 35% or more in 41.9% of patients after 24 weeks of treatment, compared to only 0.7% in the placebo arm. The median decrease in spleen volume at the 24-week mark was 33% compared to an 8% increase for those in the placebo arm.

COMFORT-1 also met the secondary endpoint of improvement in the total symptom score, which measures a range of symptoms including abdominal pain. After 24 weeks of treatment, in the ruxolitinib treatment group, 45.9% had a 50% or greater reduction in the TSS versus only 5.3% for placebo. Mean improvement was 46.1% for ruxolitinib versus 41.8% worsening of TSS for placebo.

The secondary endpoint results are "equally impressive," as the primary endpoint data, said Serge Verstovsek, principal investigator and associate professor in department of leukemia at M.D. Anderson Cancer Center, during a June 6 meeting for investors after the presentation at ASCO.

Symptoms were improved across the board, he said.

And effects of the drug were rapid. "Even after a few weeks patients reported feeling better," he said.

In cases where treatment needed to be temporarily stopped and dose adjusted, symptoms returned within a week, but then disappeared again when treatment resumed, Verstovsek said.

Collins Stewart's Richter noted: "Ruxolitinib had dramatic and statistically significant effects on individual symptom scores vs. placebo. The mean change from baseline in abdominal discomfort was an improvement of 29.4% in the ruxolitinib arm vs. a worsening of 55.7% in the placebo arm."

Waning Anemia Provides Safety Reassurance

Myelosuppression, or bone marrow suppression, has been the main safety concern for JAK inhibitors.

In COMFORT-1, adverse events of any grade occurring in more than 20% of patients on the study drug included thrombocytopenia (34.2% compared to 9.3% for placebo) and anemia (31% vs. 13.9%). Almost 13% of those on ruxolitinib had grade 3 or grade 4 low platelet counts compared to 1.3% on placebo. Grade 3 or grade 4 low hemoglobin levels were 45.2% compared to 19.2% for placebo.

However, the dropout rates for ruxolitinib and placebo due to thrombocytopenia or anemia were on par, with one in each arm. And Verstovsek noted that anemia waned during the treatment period, returning to baseline levels at the 24-week mark. The overall dropout rate related to side effects was 11% in each arm.

Verstovsek commented that the equal discontinuation rates provided reassurance when it comes to the possibility of a toxic reaction to the drug.

Although there has been much enthusiasm for the development of ruxolitinib, there have been competitive concerns when it comes to side effects. The earlier-stage JAK1/JAK2 inhibitor CYT387 from YM BioSciences has been shown to increase hemoglobin and it has been thought that the drug could become a preferred treatment for the roughly 30% of MF patients who have anemia.

Absolute anemia rates were higher than expected, writing in a June 6 note, Jefferies analyst Thomas Wei noted. In COMFORT-I, grade III rates were 45.2% compared to 19.2% and in COMFORT-II they were 42% vs. 32%.

But the rates "may be misleading," Wei suggested, because of the symptom improvements/quality of life measures which were experienced in patients with anemia as well as without this effect.

The fact that the grade 3 and grade 4 anemia rates declined over time in COMFORT-1 and did not translate to dropouts gives reason to be positive on the drug's safety profile, in Wei's view.

Comparing COMFORT-II and COMFORT-I

The European open label COMFORT-II study tested the drug against best available treatment, which typically involved antineoplastic agents, hydroxyurea in particular. Glucocorticoids and immunomodulators, represented other options for patients in the control group.

COMFORT-II was "arguably a more robust study," in that it tested ruxolitinib against best available care instead of placebo, noted JP Morgan analyst Cory Kasimov in a June 5 note, but it also was smaller with 219 vs. 309 patients.

In COMFORT-II, after 48 weeks of treatment, the drug was shown to reduce spleen volume by 35% or more in 28.5% of patients, compared to 0 for best alternative treatment after 48 weeks of treatment. A secondary endpoint measured efficacy at 24 weeks and at this stage, 31.9% taking ruxolitinib had a 35% of greater reduction in spleen volume vs. 0 for the best available treatment patients. Investigators also reported improvement in quality of life and symptoms, based on patient questionnaires, the company reported.

As for safety, the percent of patients with grade 3 or 4 low platelet counts during the study was 8.3% for ruxolitinib compared to 7.2% for best available treatment.

One patient in each arm dropped out due to thrombocytopenia and none dropped out due to anemia, Incyte reported. When it came to dropouts generally, 8.2% discontinued treatment due to adverse events in the ruxolitinib treatment group, compared to 5.5% on best available treatment.

The percentage of patients with 35% or more reduced spleen volume in COMFORT-II was 28.5%, which is lower than the 41% demonstrated in COMFORT-I.

However, Wei noted that the median spleen size reduction in COMFORT-II was 29%, which is close to the 33% reported in COMFORT-I.

The Marketing And Research Roads Ahead

With the potential of FDA approval late this year, the company has previously announced it had a marketing team in place and was hiring a sales force.

The company holds U.S. rights to the molecule but sold ex-U.S. rights for hematology and oncology indications to Novartis Pharma AG along with another drug for $200 million upfront in 2009 (Also see "Two-Compound Partnership With Novartis Brings Incyte $210 Million Immediately" - Pink Sheet, 25 November, 2009.).

Incyte developed a separate but similar molecule known as INCB28050 in rheumatoid arthritis and sold rights to that candidate to Eli Lilly for $90 million upfront, also in 2009 (Also see "With Lilly JAK Tie-up, Incyte Aims To Chase Pfizer In Rheumatoid Arthritis" - Pink Sheet, 21 December, 2009.).

-Emily Hayes (e.hayes@elsevier.com)

Incyte's Grip On Myelofibrosis Tightens With Release Of Positive JAK Data, FDA Filing

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