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Issue: April 2017
April 21, 2017
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What Rheumatologists Need to Know About Janus Kinase Inhibitors

Issue: April 2017
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Janus kinase inhibitors have grown into a promising drug class for the treatment of rheumatoid arthritis, as these have an oral route of administration and are effective in patients with inadequate response to methotrexate, patients who have failed biologics and have helped patients who are methotrexate-naïve.

In 2012, the first Janus kinase (JAK) inhibitor, 5-mg twice-daily tofacitinib (Xeljanz, Pfizer), was approved in the United States as monotherapy and in combination with methotrexate for patients with rheumatoid arthritis (RA) who responded poorly to methotrexate. In January 2017, the 2-mg and 4-mg twice-daily baricitinib (Olumiant, Eli Lilly) was recommended for approval in the European Union and is being reviewed by the FDA. Filgotinib (Galapagos), peficitinib (Astellas) and upadacitinib (AbbVie) — also known as ABT-494 — are also in phase 3 development.

John J. O'Shea, MD 

John J. O'Shea

To better understand this drug class, Healio Rheumatology reviewed the latest clinical trials and spoke with experts about the mechanisms, safety and future potential of these options.

Mechanism of Action

Janus kinase (JAK) proteins — which the drugs inhibit — “are molecules inside the cell that allow cytokines to work,” John O’Shea, MD, scientific director at the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases and chief of the Molecular Immunology and Inflammation Branch and member of the team that discovered the JAK pathway, told Healio Rheumatology. “The way JAK inhibitors are like biologics is that they are targeted therapies. They were designed to target specific molecules in specific pathways, but the way they are different than biologics is they are not large molecules. They are small molecules and they are not infused.”

Vibeke Strand

Compared with tumor necrosis factor (TNF) and interleukin-6 (IL-6) — which are targets of biologic therapy — the JAK1, 2, 3 and tyrosine kinase 2 (TYK2) proteins act inside the cell – closer to the DNA-encoding genes that regulate the immune response against joint tissue, which allows JAK inhibitors to cover a potentially larger range of immune cells. According to O’Shea in a review article published in Nature Reviews Rheumatology, TNF, IL-1 and IL-17 do not signal via JAKs, whereas JAK-dependent cytokines can induce these cytokines. As JAKs involve a greater number of immune cells, these have potentially greater efficacy, according to Vibeke Strand, MD, adjunct clinical professor in the Division of Immunology/Rheumatology at Stanford University School of Medicine and a Healio Rheumatology Peer Perspective Board member.

“The JAK/STAT ‘hub’ seems to be central because there are many cytokines that signal through it,” Strand said. “There are essentially six families of cytokines that signal through these pathways, so that is why I think they have such profound effects on inflammation and early onset of benefit. Despite different JAK specificities, the clinical data with tofacitinib and baricitinib are similar.”

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Safety

In the development program leading up to the 2012 FDA approval of tofacitinib, data suggested a similar safety profile to TNF inhibitors for most outcomes, with several exceptions, including a difference in the risk of herpes zoster and likely other viral infections, according to Kevin Winthrop, MD, MPH, assistant professor in the Divisions of Infectious Diseases, Ophthalmology, Public Health and Preventive Medicine at Oregon Health and Science University and a Healio Rheumatology Peer Perspective Board member.

“It is important that rheumatologists know the safety of these drugs. So far, [it] compares to that of the biologics [with] similar infection rates [and] malignancy rates in the ballpark to what we have seen with TNF inhibitors,” Winthrop told Healio Rheumatology. “The one difference is the viral signal and high rates of certain viral infections, like herpes zoster. We are also seeing a similar zoster signal reported from the baricitinib program thus far.”

Kevin Winthrop

O’Shea and colleagues wrote in the review article that the European Medicines Agency’s initial refusal of marketing approval for tofacitinib cited the adverse event profile of the treatment. According to a 3-year analysis presented at the American College of Rheumatology Annual Meeting in 2016 that included 760 patients who initiated tofacitinib, 4,628 patients who initiated biologic disease-modifying antirheumatic drugs (bDMARDs) and 1,328 patients who initiated conventional synthetic DMARDs (csDMARDs), researchers found the rate for serious infection was 3.69 events per 100 patient-years for tofacitinib; 3.29 for bDMARDs; and 2.39 for csDMARDs. The rate for herpes zoster was 1.43 for tofacitinib, 0.94 for bDMARDs and 0.47 for csDMARDs.

Winthrop said rheumatologists need to be aware of this increased risk, so patients can receive the shingles vaccination, as well as the pneumococcal vaccination before receiving the JAK inhibitor — a recommendation that is the same for biologics.

“For these patients, it is important to use vaccination to prevent shingles, as well as other infections,” Winthrop said. “Similar to currently approved therapies in other classes, infection prevention is important for treating rheumatologists to keep in mind as these drugs start rolling out of the pipeline.”

According to O’Shea’s review, the increased shingles risk could be due to tofacitinib’s effect on interferon and IL-15 signaling. In addition, it could be driven by specific subgroups in Asia, according to Winthrop.

“A lot of the risk we have observed to date is driven by higher rates in Asia, and we do not understand why yet,” Winthrop said. “But there is no question the rates are higher with both those compounds (tofacitinib and baricitinib) in certain sub-regions of Asia, so there is something there we need to further explore in terms of understanding the reason.”

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According to O’Shea, physicians should know these drugs show safety comparable to TNF inhibitors.

“I think physicians by nature, if they have a drug that works and in their experience is reasonably safe, they want to stick with that,” O’Shea said. “But they should know about 90,000 people worldwide have been treated with tofacitinib and in the clinical trials, there are about 9,000 patients. Looking at the safety of these drugs, they are comparable in many respects to TNF inhibitors.”

Efficacy

As tofacitinib has showed safety similar to TNF inhibitors, it has demonstrated potentially improved efficacy. A study published in the New England Journal of Medicine by Peter Taylor, MD, PhD, and colleagues found 70% of patients who took baricitinib achieved ACR20 response compared with 61% of patients who took adalimumab after 12 weeks.

“We think we know there are patients who will respond better, at least groups of patients, to this pathway than to the pathways we are used to,” Roy M. Fleischmann, MD, MACR, clinical professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center, said in an interview with Healio Rheumatology. “There are patients who will respond to baricitinib better than patients who respond to adalimumab and that is exciting.”

In addition, baricitinib has showed improved efficacy to methotrexate. According to a study from Fleischmann and colleagues published in Arthritis & Rheumatology, patients assigned baricitinib had an ACR20 response rate of 77% and patients who took methotrexate had a 62% response rate after 24 weeks. In addition, the rate of serious adverse events was similar between groups.

Roy M. Fleischmann

“I definitely think JAK inhibitors have first-line potential,” Strand said. “As we have already seen, the RA-BEGIN study with baricitinib and the START study with tofacitinib have already told us that they are, in fact, more effective than methotrexate in methotrexate-naïve patients.”

As baricitinib and tofacitinib have showed efficacy, so have the other phase 3 JAK inhibitors. In its most recent trial, filgotinib — a JAK1 inhibitor — showed efficacy as 100-mg and 200-mg once-daily monotherapy compared with placebo in a phase 2b study conducted by Arthur F. Kavanaugh, MD, and colleagues and published in the Annals of the Rheumatic Disease. The study included 283 patients who had an inadequate response to methotrexate. For all doses of filgotinib, the ACR20 response rate was 65% after 12 weeks compared with 29% for placebo. In addition, the safety profile was similar between groups. Eight patients who received filgotinib and one who received placebo had a serious adverse event, and four patients who received filgotinib — compared with zero for placebo — had a serious infection.

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Peficitinib — a JAK1, 2, 3 and tyrosine kinase 2 (TYK2) inhibitor — showed efficacy as 100-mg and 150-mg once-daily combination therapy with methotrexate in a phase 2b study by Mark C. Genovese, MD, and colleagues. The study, which was published in Arthritis & Rheumatology, included 289 patients with an inadequate response to methotrexate. The group with the highest efficacy — patients who received 150 mg peficitinib — had an ACR20 response rate of 56.3% compared with 29.4% for placebo after 12 weeks. The safety profile was similar between groups. The most common adverse events were upper respiratory tract infection (5%), nausea (4%) and urinary tract infection (4%). There was one case of herpes zoster in the placebo group and one serious infection — limb abscess — in the 25-mg peficitinib group. Investigators found no incidences of at least grade 2 neutropenia or lymphopenia.

In addition, updatacitinib (ABT-494) — a JAK1 inhibitor — showed efficacy as 3-mg, 6-mg, 12-mg, 18-mg and 24-mg twice-daily combination therapy with methotrexate in a phase 2b study from Genovese and colleagues. The study, which was published in Arthritis & Rheumatology, included 300 patients with an inadequate response to methotrexate. The group with the highest efficacy — patients who received 12-mg ABT-494 — had an ACR20 response rate of 80% compared with 46% for placebo after 12 weeks. In addition, the safety profile was similar between groups; however, one serious infection — community-acquired pneumonia — occurred in the 12-mg ABT-494 group. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol and mean hemoglobin levels decreased at higher doses.

Other Autoimmune Diseases

As all the JAK inhibitors have showed efficacy against RA, some have also demonstrated efficacy against other autoimmune diseases, including ankylosing spondylitis. According to a study published by Désirée van de Heijde, MD, PhD, and colleagues in the Annals of the Rheumatic Diseases, tofacitinib reduced inflammation in patients with ankylosing spondylitis. Researchers found 5-mg tofacitinib had an ASAS20 response rate of 80.8% compared with 41.2% for placebo after 12 weeks. In addition, the safety profile was similar between groups.

“We know that the seronegative arthritides, like psoriatic arthritis and ankylosing spondylitis, are different,” Stand said. “The IL-23/IL-17/IL-22 pathway is more prominent than the TNF pathway, so that is why the IL-17 inhibitors are becoming so popular in psoriasis and psoriatic arthritis and ankylosing spondylitis.”

In addition to ankylosing spondylitis, Strand said these drugs are effective in other cutaneous diseases.

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“We already know that JAK inhibitors are effective for alopecia and other cutaneous diseases,” Strand said. “Essentially, we are probably going to find that they are effective in lupus. I think it is more because of all these different cytokine pathways using the JAKs to signal and thus probably, we are going to see that they are effective across a broad variety of diseases.”

Another use has been for dogs with allergic dermatitis. In 2013, the FDA approved Apoquel (oclacitinib, Pfizer) to help control itch and inflammation.

“This is an efficacious drug,” O’Shea said. “It is a big seller as it turns out.”

However, the FDA declined to approve tofacitinib for psoriasis, possibly because a 10-mg dose — as opposed to the currently approved 5-mg dose — is required for optimal efficacy, which created concerns about adverse events, O’Shea and colleagues wrote in their review. The FDA will soon review tofacitinib for the treatment of psoriatic arthritis.

According to O’Shea’s review, about 20 JAK inhibitors are in clinical trials for various autoimmune diseases, which include rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and lupus.

Future Potential

Fleischmann said these drugs have great potential for the future because JAK inhibitors have shown safety and efficacy in a variety of autoimmune diseases.

“I will not be surprised if — 5 years from now — several of these are approved and people are more comfortable with them,” Fleischmann said. “I would not be surprised if we start with methotrexate and if the patient does not have a perfect response, [then] we add a JAK inhibitor, any one of them, and in those patients who do have a good response who go into remission, we try to eliminate methotrexate. Over time, it will cut down in toxicity; it will improve disease control; it will be better. It will not be perfect because I do not know if every one of these drugs works perfectly well and that everybody has been safe, but it will be an advancement.”

However, Winthrop said more data need to be collected.

“Am I worried about other things long term? Sure as with any new drug. We need years of real-world studies to evaluate whether there is increased risk for a variety of things, particularly rarer events: gastrointestinal perforations, malignancy, other types of infection,” he said. “There are a lot of things to learn. The experience with all of these products is young, with the exception of tofacitinib. But even with tofacitinib, there is not a ton of real-world data yet. It is just starting to emerge. We just need to be vigilant but for right now, these compounds look promising.” – Will A. Offit

Editor’s note: On April 14, 2017, Eli Lilly and Company and Incyte Corporation announced the FDA was unable to approve baricitinib's new drug application. In its complete response letter, the FDA said additional data are needed to determine appropriate dosage and to characterize safety concerns across treatment arms. 

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  • For more information:
  • Roy M. Fleischmann, MD, MACR, can be reached at Rheumatology Associates 8144 Walnut Hill Ln., Suite 800, Dallas, TX 75231; email: rfleischmann@arthdocs.com.
  • John O’Shea, MD, can be reached at Building 10, Room 6N204 10 Center Dr., Bethesda, MD 20814; email: osheajo@mail.nih.gov.
  • Vibeke Strand, MD, can be reached at 306 Ramona Rd., Portola Valley, CA 94028; email: vstrand@stanford.edu.
  • Kevin Winthrop, MD, MPH, can be reached at 3181 SW Sam Jackson Park Rd., Portland, OR 97239; email: winthrop@ohsu.edu.

Disclosures: Fleischmann reports he is a consultant for Eli Lilly, Pfizer and AbbVie. O’Shea reports he received the Collaborative Research Agreement and Development Award from Pfizer and receives royalties for JAK inhibitors. Strand and Winthrop report they are consultants for Eli Lilly, Pfizer, AbbVie, Galapagos and Astellas.

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