JAK Inhibitor: A Treatment Option for Rheumatoid Arthritis

Are JAK Inhibitors Classified as Biologic Drugs?

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JAK (Janus kinase) inhibitors are a category of drugs used to treat rheumatoid arthritis. The first JAK inhibitor, Xeljanz (tofacitinib citrate), was approved by the FDA on November 6, 2012. Others are in development. The evolution of the JAK inhibitor as a treatment for rheumatoid arthritis came on the heels of advancements in immunology and molecular biology which led to the development of biologic drugs.

Let's explore the role of JAK inhibitors in the immune system and in managing rheumatoid arthritis.  

Cytokines Explained

Most people with rheumatoid arthritis (and other inflammatory diseases) probably were unfamiliar with the medical term, cytokines, before the first biologic drug, Enbrel (etanercept), was approved in 1998. In order to understand how biologic drugs work, patients got a crash course in immunology.

Patients learned that cytokines are proteins which are produced by cells and that they are involved in regulating inflammatory responses. Cytokines interact with immune system cells to regulate the body's response to disease and infection—and to mediate normal cellular processes in the body. Cytokines are also involved in abnormal autoimmune responses. There are several different types of cytokines.

Biologic drugs have been created to interfere with cytokine function (e.g., to inhibit or block TNF (tumor necrosis factor) and several of the interleukins (IL-1, IL-6, IL-17, IL-12/23), to inhibit the second signal needed for T-cell activation, and to deplete B-cells.

While different biologic drugs have different targets within the immune system, the goal is the same—to damp down proinflammatory molecules, thereby controlling rheumatic disease.

Small Molecule Medications for Rheumatoid Arthritis

A JAK inhibitor is not classified as a biologic drug. Instead, it is classified as a small molecule DMARD (disease-modifying anti-rheumatic drug).

The target of a JAK inhibitor is the JAK pathway which is a signaling pathway located inside cells that have a prominent role in the inflammatory process associated with rheumatoid arthritis. Specifically, JAKs (Janus kinases) are intracellular enzymes (i.e., cytoplasmic protein tyrosine kinases) that transmit signals from multiple cytokine receptors to the nucleus of cells.

There are reportedly more than 500 kinases in the human "kinome" and they are divided into eight families. The JAKs are in the tyrosine protein kinase family—a family which has 90 members. The Janus kinase (JAK) family includes TYK2, JAK1, JAK2, and JAK3.

Once researchers realized the significant role JAKs play in cytokine signaling, they became more of a focus of clinical studies. Tofacitinib was the first JAK inhibitor to be clinically tested and approved for rheumatoid arthritis. Tofacitinib, which is manufactured by Pfizer, Inc., inhibits JAK3 and JAK1, and JAK2 to a lesser degree. Tofacitinib does not significantly affect TYK2.

Tofacitinib—The First JAK Inhibitor Approved for Rheumatoid Arthritis

Tofacitinib (brand name Xeljanz) was approved as a treatment for adults with moderately- to severely-active rheumatoid arthritis who had an inadequate response or intolerance to methotrexate.

Xeljanz is an oral medication, available as a 5 mg pill to be taken twice daily. It may be taken with or without food. There is also an 11 mg once-daily dose available, called Xeljanz-XR (extended release). Xeljanz can be taken alone (i.e., used as monotherapy), or it can be combined with methotrexate or some of the other non-biologic DMARDs. Xeljanz should not be used with biologic drugs.

Safety of JAK Inhibitor Drugs

As safety was assessed with regard to Xeljanz (tofacitinib), researchers concluded it was comparable to biologic drugs. There is an increased risk of infections, potential abnormalities with liver function tests, and the potential for neutropenia (low level of neutrophils, a type of white blood cell), hyperlipidemia (elevated lipids or fats in the blood), and elevated serum creatinine with tofacitinib use.

A Black Box warning was required as part of the approval and labeling of tofacitinib to warn of these serious adverse effects.

Baricitinib

Baricitinib was the second JAK inhibitor to submit a NDA (New Drug Application) to the FDA in January 2016. The FDA has extended the review period for Baricitinib to allow time for review of additional data provided by the drugmaker, Lily and Incyte. The additional data was provided in response to an FDA Information Request. The additional information is seen as a major amendment to the original NDA and adds 3 months to the review period.

In December 2016, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended granting a marketing authorization in the European Union (EU) for Olumiant (baricitinib). Baricitinib was recommended for the treatment of adults with moderate to severe active rheumatoid arthritis who have not responded adequately to, or who are unable to tolerate one or more disease‑modifying anti-rheumatic drugs (DMARDs).

Baricitinib is a once-daily oral JAK1/2 inhibitor indicated for the treatment of moderate to severe rheumatoid arthritis. Clinical trial data have demonstrated significant improvement in pain, fatigue, physical function, and physical health-related quality of life in previously untreated patients and in those who failed other drugs.

A Word From Verywell

To reiterate, JAK inhibitors are classified as small molecule DMARDs, not biologic drugs. The primary difference is that JAK inhibitors work intracellularly (inside cells) and biologic drugs have extracellular targets (e.g., receptors on the surface of cells). Also, JAK inhibitors are oral drugs, while the biologics are injectable or administered by infusion.

Since people with rheumatoid arthritis do not all have the same response to treatment, it is important to develop and make available new treatment options. In addition to tofacitinib and baricitinib which were discussed above, clinical phase III trials are in progress using filgotinib and ABT-494—both JAK1 inhibitors.

Sources:

Furst, Daniel E., MD. Overview of Biologic Agents and Kinase Inhibitors in the Rheumatic Diseases. UpToDate. Updated February 2, 2017.

McInnes, Iain B., PhD. Cytokine Networks in Rheumatic Diseases: Implications for Therapy. UpToDate. Updated November 5, 2015.

Nakayamada, S. et al. Recent Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis. BioDrugs. October 2016.

O'Shea, John J. et al. Janus Kinase Inhibitors in Autoimmune Diseases. Annals of the Rheumatic Diseases. April 2013.

Elvidge, Suzanne. FDA Delays Decision on Lilly and Incyte's Arthritis Drug. BiopharmaDIVE. January 17, 2017.

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