Autoimmune and inflammatory diseases are common with a diverse array. Different organs are affected, and significant variability is seen among the individuals when talking about the severity, or the response to the treatment. Deregulated cytokine activity has a vital role in explaining autoimmune disease pathogenesis. Historically, medications that non-specifically suppress the immune system have been used in treating autoimmune and inflammatory diseases. Monoclonal antibodies (biologics) that block the action of pathogenic cytokines appeared over the last two decades and are widely used. Among all those that are available, Humira (biologic), an arthritis medication, is the most efficacious and successful drug accepted in eleven indications which include Crohn’s disease, Ulcerative Colitis, Psoriatic Arthritis, and Psoriasis. It is currently the best-selling drug in the world for the treatment of autoimmune diseases.
Prospect of Kinase Inhibitors in the Treatment Landscape
In the treatment landscape where patients generally don’t respond to biologics in an adequate manner, a diminished efficacy with second- or third-line biologics, presence of biologics-related toxicity, infusion-related adverse effects, increased risk for severe infections, and parenteral route of administration, which is usually possible in clinical settings have been observed. In such a grim scenario, JAK inhibitors offer a new efficacious treatment option to patients who previously underwent anti-TNF therapy or other biologic therapies. JAK inhibitors are administered orally, implying that patients are more inclined to take part in clinical trials and prefer selecting an oral RoA over parenteral administration, as neither they ‘require a tutorial on the way to inject themselves, nor the arrangements for transportation to the clinical site.
First-generation kinase inhibitors
In 2012, Pfizer’s Xeljanz (tofacitinib) was approved for the treatment of Rheumatoid arthritis (RA) in the United States and became the first JAK inhibitor to get launched in the major market. It is now accepted in all major markets for multiple indications, including UC, PsA, and Polyarticular Course juvenile idiopathic arthritis (pcJIA). Olumiant (baricitinib) was the second JAK inhibitor approved for RA in February 2017 by the EMA and in June 2018 by the FDA. The drug is also approved for Atopic dermatitis in the EU. Upadacitinib, along with Olumiant (baricitinib) and Xeljanz (tofacitinb), is also a part of JAK inhibitors, which is the only JAK inhibitor that has shown the kind of head-to-head supremacy against Humira. It recently got approved for the treatment of RA in the US, EU, and Japan and the treatment of active Psoriatic arthritis and adult patients with active Ankylosing spondylitis in the EU. AbbVie, with the launch of Upadacitinib, anticipates holding its position as a major player within the treatment landscape of rheumatology. The drug is also being tested in a string of other indications, including Crohn’s disease (CD), Ulcerative colitis (UC), and atopic dermatitis. Jyseleca (Filgotinib) was one of the promising JAK kinase inhibitors developed by Gilead Sciences, which gained approval in the EU and Japan for treating RA. Filgotinib has lowered expectations in comparison to other JAK inhibitors currently marketed, primarily due to safety concerns. However, presently the drug is being evaluated for UC and CD. In March 2019, Smyraf was approved in Japan for the treatment of RA. At present, CORECTIM Ointment 0.5% is the world’s first topical JAK inhibitor available in the market that improves atopic dermatitis by inhibiting the action of JAKs approved in Japan. It has the edge over other emerging options as it likely to act locally when compared with an oral JAK inhibitor that acts globally.
Next-generation kinase inhibitors
The plethora of second-generation kinase inhibitors are currently in phase II and III stage of development for indications like RA, Psoriasis, Psoriatic Arthritis, Chron’s Disease, Ulcerative Colitis, primary Sjogren’s syndrome, Atopic dermatitis, Systemic Lupus Erythematosus Vitiligo, and others. Also, besides the JAK inhibitors, compounds that target other kinase inhibitors such as SYK, SRC- family kinases, TYK2 or BTK inhibitors are expected to emerge as new therapy for autoimmune diseases, with high hopes for TYK2 inhibition. By not striking JAK2 and JAK3, it is thought that TYK2 inhibitors could sidestep the adverse events, as the toxicity issues with JAKs are assumed to be due to these drugs’ far-reaching activity across several JAK subtypes.
Major Players in the drug market
The market size of kinase inhibitors is likely to escalate as there is a plenitude of drugs in the pipeline which are being evaluated for various indications. The emerging therapies include Ritlecitinib, Ritlecitinib/PF-06650833/ Tofacitinib, Abrocitinib, PF-06826647, Brepocitinib (Pfizer), SHR0302 (Reinstone Biopharma), Ruxolitinib (Incyte Corporation), Branebrutinib, Deucravecitinib (Bristol Myers Squibb), Belumosudil (Kadmon Pharmaceuticals), ATI-450 (Aclaris Therapeutics), Remibrutinib (Novartis Pharmaceuticals) and Izencitinib (Theravance Biopharma). Their combined market share in the USA is anticipated to reach USD 9,958.5 million in 2030, owing to their high costs.
Blockade in the establishment of Kinase Inhibitors
The already established treatment regimen, including biologics for a range of autoimmune diseases, is a significant hurdle in securing a place for kinase inhibitors in the market. When talking about safety, and the improved benefit-to-risk ratio is offered by biologics instead of JAK inhibitors. Also, there is no monitoring required, as no drug-drug interaction risk is present. Despite proven efficacy in clinical trials as well as in clinics as a treatment for inflammatory and autoimmune diseases, all first-generation JAK inhibitors are facing of concerns related to safety and efficacy. Also, only limited JAK inhibitors are available in the present market with their patent expiration date approaching, compared to biologics that have already achieved a milestone; hence treating physician often is biased towards prescribing biologics. Moreover, biosimilars of some of these drugs are already in the process to enter the market, thus, likely increasing the competition with kinase inhibitors.
Despite the snags JAK inhibitors are coming across, pharma’s strong persuasion in their ability to create a standard change in patient care remains unalarmed. With the advantage of oral availability and the speedy onset of action, kinase inhibitors have shown the potential to be the game-changer in the management of autoimmune diseases. The efficacy demonstrated by first-generation agents is on par with the existing biologics, whilst emerging data with next-generation JAK inhibitors and other kinase inhibitors may suggest even greater success.