Another JAK1 Inhibitor Looks Promising for Treatment of Rheumatoid Arthritis

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Research suggests the JAK 1 inhibitor Filgotinib is effective in the treatment of rheumatoid arthritis.

by Dr. C.H. Weaver M.D. 10/10/2018

Several reports have confirmed the effectiveness of JAK inhibitor effectiveness in treating RA. 1,2,3,4,5

Janus-associated kinase 1 (JAK1) inhibitors mediate the signaling of cytokines and growth factors important for blood cell production and immune function. Jakafi® (ruxolitinib) was the first JAK 1 inhibitor approved for the treatment of some Myleoproliferative Neoplasms. Blocking the JAK pathway also appears important for treating the immune response in RA and investigators have begun to report results.

Oluminant (baricitnib) was recently approved by the US Food and Drug Administration for the treatment of RA.

(Upadacitinib) ABT-494, another JAK-1 inhibitor has been reported to be effective for the management of refractory moderate-to-severe RA in two clinical studies.

Filgotinib is a selective JAK1 inhibitor and results from clinical trials have demonstrated that treatment of rheumatoid arthritis (RA) patients with filgotinib led to a significantly higher proportion of patients achieving American College of Rheumatology 20% (ACR20) response when compared with placebo.

In this study moderate-to-severely active RA and a prior inadequate response or intolerance to biologic agents were treated with once-daily filgotinib 100mg, 200mg, or placebo for 24 weeks and directly compared. Overall approximately twice as many patients treated with filgotinb responded to treatment. The proportion of patients who achieved a clinical remission was also significantly higher in the filgotinib groups. Filgotinib which is currently being investigated in 2 other trials, FINCH 1 and 3, has been reported to be well tolerated.

Upadacitinib is a once daily oral JAK inhibitor also reported to produce a 20 percent reduction in RA symptoms.5 Concerns about safety from a recently reported clinical trial evaluating upadacitinib however have emerged. A research report suggested there were more serious infections and cases of herpes zoster in RA patients treated wit 30 mg compared to 15 mg or a placebo. There were also more discontinuations of therapy related to adverse events in the 30 mg group than in the other two groups. In addition two venous thrombotic events — pulmonary embolism or deep vein thrombosis were observed during the first 12 weeks of the trial: one at the 30 mg dose and one at the 15 mg dose. And another four such events occurred from weeks 12 to 24, bringing the total to six.

Upadacitinib will clearly play a role in the management of RA and other inflammatory arthritis conditions however patients and their physicians will clearly need to keep on eye on its side effects.

Jak inhibitors appear quite effective for the treatment of rheumatoid arthritis and provide patients with another way to treat the disease. The final results of the filgoitnib trials will be presented at an upcoming medical meeting and if they remain positive the drug manufacturer will apply for US Food and Drug Administration approval for use in the management of rheumatoid arthritis.

Upadacitinib is also being evaluating for several other autoimmune conditions, including psoriatic arthritis, Crohn’s disease and ulcerative colitis.

JAK Inhibitors-Next Advance in Treatment of Rheumatoid Arthritis

A new once daily JAK inhibitor, baricitinib may become available as another treatment option for individuals with rheumatoid arthritis (RA) in the next few months.

In addition there are currently two new reports in the medical journal Arthritis & Rheumatology evaluating the effectiveness and safety of another selective JAK-1 inhibitor, ABT-494, in treating RA in individuals with an inadequate response to treatment with methotrexate (MTX) or a TNF inhibitor. 1,2

These follow an initial report in the New England Journal of Medicine demonstrating that baricitinib produced a 55% response in a cohort of 527 patients with refractory RA compared with 27% of those given a placebo.3

In the first report by Genovese et al, 300 patients refractory to MTX treatment received ABT-494 and had greater response to treatment than those receiving a placebo. The second report by Kremer et al. evaluated 276 RA patients on a stable dose of MTX, who failed an anti-TNF agent. ABT-494 again had a superior response of 53-71%, compared to placebo (34%).

Taken together these reports suggest JAK inhibitors are safe, effective and should become incorporated into the overall management of RA giving physicians a new tool for the management of this condition.

According to one study author “In patients with an inadequate response or intolerance to anti-TNF agents, ABT-494 added to MTX showed rapid, dose-dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class.”

FDA determines that Oluminant should be available for treatment of individuals with rheumatoid arthritis.

The US Food and Drug Administration approved Oluminant (baricitinib) at the lower dose of 2 mg per day for use in adults with with moderate-to-severe active rheumatoid arthritis (RA) who have had an inadequate response to commonly-used treatments known as TNF inhibitors.

This follows the Arthritis Advisory Committee meeting of April 23rd, wherein the committee only recommended the lower 2mg dose (not the proposed 4 mg dose) and expressed concerns about some safety signals, especially with regard to venous thromboembolic events (VTE).

Currently Oluminant is approved in over 40 countries at both the 2 mg and 4 mg doses.

About Oluminant (baricitnib)

Baricitinib belongs to a new class of oral medicines called Jak inhibitors. Janus kinases are enzymes that play a role in inflammation and RA. Jak inhibitors like Oluminant block the activity of these enzymes leading to a reduction in inflammation.

Researchers originally reported in the March 31 issue of the New England Journal of Medicine that baricitinib produced a 55% response in a cohort of 527 patients with refractory rheumatoid arthritis, compared with 27% of those given a placebo.1

The mean age of study participants was 56, average disease duration was 14 years, and 80% were women. They had moderate to severely active disease, with baseline swollen and tender joint counts of 17 and 29, respectively. Each participant had undergone one to several previous conventional therapies and/or biologic agents.

Participants were treated with either 2 mg or 4 mg of baricitinib each day or a placebo, plus conventional therapies including DMARDs, nonsteroidal anti-inflammatory drugs, and 10 mg prednisone or less per day and directly compared.

In addition to the improved response rate, patients receiving the 4-mg dose of baricitinib also had significantly greater improvements in the disease activity score in 28 joints at week 12 and for a Health Assessment Questionnaire Disability Index.

These results are consistent with two previous clinical studies demonstrating significant improvements of barciitinib in individuals with refractory RA.2,3. In August 2017 FDA elected to allow a revised New Drug Application (NDA) for baricitinib before the end of January 2018. The resubmission package included new safety and effectiveness information.

Another JAK inhibitor—Xeljanz® (tofacitinib)—has been approved by the US Food and Drug Administration for the treatment of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to methotrexate.

References:

  1. Genovese M, Kremer J, Samani O, et al. Barcitinib in patients with refractory rheumatoid arthritis. New England Journal of Medicine. March 31, 2016. DOI: 10.1056/NEJMoa1507247
  2. Fleischmann R, et al. Baricitinib, Methotrexate, or baricitinib plus methotrexate in patients with early rheumatoid arthritis who had received limited or no treatment with disease modifying anti-rheumatic drugs: Phase III Trial Results. American College of Rheumatology 2015. Abstract 1045.
  3. Taylor P, et al “Baricitinib versus placebo or adalimumab in patients with active rheumatoid arthritis and an inadequate response to background methotrexate therapy: results of a phase 3 study” ACR 2015; Abstract 2L.

  1. Genovese MC, Smolen JS, WEinblatt ME, et al. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016 Dec;68(12):2857-2866. doi: 10.1002/art.39808.
  2. Kremer JM, Emery P, Camp HS, et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol. 2016 Dec;68(12):2867-2877. doi: 10.1002/art.39801.
  3. Genovese M, Kremer J, Samani O, et al. Barcitinib in patients with refractory rheumatoid arthritis. New England Journal of Medicine. March 31, 2016. DOI: 10.1056/NEJMoa1507247

  1. Genovese MC, Smolen JS, WEinblatt ME, et al. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016 Dec;68(12):2857-2866. doi: 10.1002/art.39808.
  2. Kremer JM, Emery P, Camp HS, et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol. 2016 Dec;68(12):2867-2877. doi: 10.1002/art.39801.
  3. Genovese M, Kremer J, Samani O, et al. Barcitinib in patients with refractory rheumatoid arthritis. New England Journal of Medicine. March 31, 2016. DOI: 10.1056/NEJMoa1507247
  4. American College of Rheumatology (ACR) 2017 Annual Meeting: Abstract 10L. Presented November 7, 2017.
  5. Genovese MC, Smolen JS, WEinblatt ME, et al. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016 Dec;68(12):2857-2866. doi: 10.1002/art.39808.
  6. Kremer JM, Emery P, Camp HS, et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol. 2016 Dec;68(12):2867-2877. doi: 10.1002/art.39801.
  7. Genovese M, Kremer J, Samani O, et al. Barcitinib in patients with refractory rheumatoid arthritis. New England Journal of Medicine. March 31, 2016. DOI: 10.1056/NEJMoa1507247.
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