More JAK inhibitors ‘coming down the pike’ despite poor understanding of mechanism

The pipeline of Janus kinase inhibitors is robust even as researchers struggle to fully understand how they work, according to a presenter at the 2023 Biologic Therapies Summit.

“If you come away with one thing from this presentation, it is about the complexity of JAK inhibitors,” Massimo Gadina, PhD, director of the Office of Science and Technology at the NIH National Institute of Arthritis and Musculoskeletal Skin Diseases, told attendees at the hybrid meeting. “Cytokines come in different flavors. Cytokine receptors come in different flavors.”

Gadina noted that, despite the regimented categorizations applied to JAK inhibitors — JAK1, JAK2, JAK3 and TYK2 — such labels, and the drugs they describe, are far from straightforward.

“We call them this, but it is not that clear,” he said. “It is not that straightforward.”

One reason is that different receptors can bind to different JAKs, which in turn activate different signal transducer and activator of transcription (STAT) pathways downstream.

“Because of this, different immunomodulatory signals are generated,” Gadina said.

Another complicating factor is that JAK inhibitors are approved for “a whole variety” of inflammatory diseases, from rheumatoid arthritis, to inflammatory bowel disease, spondyolarthritides, psoriatic arthritis, atopic dermatitis and even COVID-19.

“The mechanism is something that we still need to understand completely,” Gadina said.

Despite this incomplete understanding, the research community is moving forward with “a lot of drugs coming down the pike” in a variety of diseases, including RA and psA, he added.

One novel approach is to use covalent binding to extend the half-life of JAK3 inhibitors, which is being tested in ritlecitinib (Pfizer).

“This could be an advantage from a clinical point of view, to stick to the JAK3 and block it for a longer time,” Gadina said.

However, researchers have discovered that JAK3 is “rapidly resynthesized,” so even if the pathway is blocked, the body finds its way around the blockade, he added. Because of this, investigation into JAK3 is “falling a bit behind,” according to Gadina.

Another approach is to block not only the JAK kinase, but also the spleen tyrosine kinase (SYK). Gusacitinib (Asana BioSciences) and cerdulatinib (Alexion Pharmaceuticals) are the key drugs for this strategy. They are currently being tested in atopic dermatitis, eczema, vitiligo and various types of lymphoma.

Yet another novel mechanism is to target individual organs rather than specific kinases, according to Gadina.

“Not selectivity in terms of kinase but in terms of organs,” he said. “This is actually a very interesting idea.”

This method is coupled with novel delivery systems, including nonabsorbable or inhaled medications.

“The nonabsorbable drugs do not get absorbed in the gut,” Gadina said, noting that this may make them attractive for IBD or Crohn’s disease. Studies are ongoing in various inhaled pan-JAK inhibitors.

Researchers are also investigating JAK inhibitors using an allosteric, rather than an orthosteric, mechanism. Orthosteric medications bind at the active site, while allosteric medications bind somewhere else on the surface of the protein.

Deucravacitinib (Sotyktu, Bristol Myers Squibb) has already been approved for plaque psoriasis using this approach. Additionally, various investigational therapies using this mechanism are in phase 1 and 2 clinical trials for PsA, Crohn’s disease, alopecia areata and other indications.

As researchers continue to explore the efficacy of novel compounds in the JAK/TYK2 class, Gadina stressed that “we still don’t know” what is causing adverse events like infections, cytopenias, acne, gastrointestinal perforations or malignancies in patients being treated with these medications.

“The mechanisms are unclear,” he said.