JAK Inhibitors Newer Than Tofacitinib (and Better?) Wait in the Wings

Exactly a week after the FDA approved of tofacitinib (Xeljanz), speakers at the American College of Rheumatology meeting revealed results of clinical trials of two other oral JAK (Janus kinase) inhibitors that challenge it for both safety and efficacy.

Tofacitinib inhibits all 3 of the Janus kinases. Baricitinib, a Lilly/Incyte agent that blocks only JAK1 and JAK2, continues to show promising results at 24 weeks, building on 12-week outcomes announced at the 2012 EULAR congress. In a 301-patient study of patients already on stable methotrexate for active rheumatoid arthritis (RA), defined as 8 or more swollen and tender joints, those randomized to receive the new drug continued significantly more likely than those on placebo to achieve ratings of ACR 20, ACR 50, or ACR 70 by 24 weeks of treatment (Abstract 2487).

The longer-term results also confirm that success with the drug can be predicted early in the course of treatment. In a poster presented earlier at the meeting, Josef Smolen MD of the Medical University of Vienna revealed that these patients themselves reported improvements in pain and physical function beginning as early as 2 weeks after the start of treatment (Abstract 490). Patients who showed a change of at least 1.0 units in the DAS28 at week 4 of treatment all continued to have significant improvement at week 24, said Mark Genovese MD of Stanford University.

He had nothing new or surprising to report about adverse events. Very few patients showed Grade 3 abnormalities in neutrophil counts or serum alanine transaminase. Close to a third of patients showed increases in LDL levels to above 130 on repeat occasions, as found previously, but he said there was little change in these levels after week 4.

Patients were randomized to receive doses of 2 mg, 4 mg, or 8 mg. The 4 mg dose offered the “most impressive” results in remission as measured by the Simplified Disease Activity Index and the Clinical Disease Activity Index, Genovese said. Large Phase 3 trials are underway.

First MRI effects at 12 weeks

Further positive indications for baricitinib come from an MRI study of hands affected by RA, which Charles Peterfy MD of Spire Sciences portrayed as the first demonstration of a treatment effective in halting RA progression as early as 12 weeks after initiation of any treatment. The study involved 154 patients who had at least 8 swollen and 8 tender joints as well as definitive radiographic erosion, of whom 48 were randomized to receive placebo and the remainder took either 1, 2, 4, or 8 mg of baricitinib. All were on stable methotrexate and steroids before the trial.

The 1.5 T MRI images with gadolinium contrast were read by two observers (one of them Peterfy himself) blinded to the order in which images were taken. All of the results were scaled using the accepted RA-MRI (RAMRIS) score and a 9-point cartilage loss scale commonly used in clinical trials.

Baricitinib suppressed total damage progression at 12 weeks, Peterfy said, producing significant changes in synovitis as well as dose-dependent suppression of osteitis, synovitis, erosion and cartilage loss at both 12 and 24 weeks.

A closer focus on adverse events

Only a few months ago, merely targeting the Janus kinases in the first place seemed a significant advance; now a Belgian firm offers a candidate that targets only one of the 3 kinases, JAK1, with the prospect of reducing adverse effects. Unlike both tofacitinib and baracitinib, the oral agent GLPG0634 under testing at Galapagos NV has no effect on JAK2, which as well as acting through interleukins and interferon also modulates the erythropoietin and thrombopoeitin pathways. Therefore it can be presumed not to interfere with hematopoeisis.

For convenience, Galapagos conducted a three-arm 36-patient test of the new agent in a hospital in Moldova, where rheumatoid arthritis patients are treated in a single facility (Abstract 2485). The trial involved patients with an average of 6 years of severe RA who showed insufficient response to methotrexate, although that drug and NSAIDS were continued throughout the trial as needed.

After four weeks of treatment with 200 mg daily of GLPG0634, 83% of patients on the drug had achieved ACR20, compared with only  a third of those on placebo. They were also significant differences in results in secondary endpoints including the DAS28 and C-reactive protein, reported Galapagos’ medical director, Frederic Vanhoutte MD.  The latter showed a “rapid and lasting decline to near normal levels” at 7 days that lasted through 4 weeks.

There was no effect of treatment on liver function. As expected, platelet and neutrophil counts were similar to those for placebo, showing only a modest decrease. Hemoglobin levels improved slightly. “To our surprise and consternation,” Vanhoutte added, LDL levels declined (in contrast to the effects of the other JAK inhibitors). The firm had just completed a second study that confirmed this puzzling result, he said, but results arrived too late to present at the meeting.


Also from ACR2012:


Missed Lung Disease in Community-Treated Systemic JIA Often Fatal ACR2012 Highlights: Rheumatoid Arthritis Comorbidities and Adverse EventsACR2012 Highlights: Rheumatoid Arthritis Diagnosis and Prognosis ACR2012 Highlights: Rheumatoid Arthritis Treatment “Magic Bullet” Approaching for Systemic JIA: But Which One?FDA Panel on Biosimilars: Analytics Should Trump Clinical Trials