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Drugs that target tyrosine kinase 2 (TYK2) were found to mediate inflammation in plaque psoriasis while lowering the risk of adverse events (AEs) often associated with this class of drugs, according to new findings published in the .

To date, no JAK inhibitor is approved to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis.

Three primary TKY2 inhibitors that are under investigation for potential use in psoriasis include deucravacitinib, an oral therapy that binds to the regulatory domain of TYK2, as well as brepocitinib and another drug known only as PF-06826647, which are two potent topical and oral TYK2 inhibitors, respectively.

Andrew Blauvelt, MD, MBA, is a physician-researcher with the Oregon Medical Research. He served as a coauthor of the recent review. Blauvelt recently discussed the review and its findings with the Reading Room. The exchange has been edited for length and clarity.

What key issue was this review designed to explore and why?

Blauvelt: Conventional therapies for psoriasis have limited efficacy and are associated with various adverse effects (AEs), drug interactions, and a loss of efficacy over time.

JAK inhibitors have demonstrated efficacy in people with moderate-to-severe psoriasis, but safety concerns persist. For example, tofacitinib was shown to be efficacious against psoriasis in phase-3 trials, but AEs included upper respiratory tract infection, nasopharyngitis, diarrhea, and headache, as well as more serious problems like dyslipidemia, infections (including herpes zoster reactivation), malignancies, anemia, leukopenia, and certain cardiovascular events.

With no JAK inhibitor being approved to treat psoriasis, an opportunity exists for novel oral therapies that are safe and effective. Tyrosine kinase 2 (TYK2), a member of the JAK family of kinases, regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with other JAK inhibitors.

This article reviewed the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.

How would you summarize your key findings?

Blauvelt: TYK2 is a great new target for treating psoriasis and mediates inflammation in plaque psoriasis.

Selective inhibition of TYK2 reduces the potential for AEs associated with JAK inhibitors (eg, hematologic and lipid abnormalities).

Did anything surprise you about the review or its findings?

Blauvelt: We found that natural genetic mutations in TYK2 can protect individuals from developing psoriasis without leading to an increased risk of infection.

Also, not all TYK2 inhibitors are the same. Some like deucravacitinib specifically block TYK2 without blocking other JAKs, which is ideal, while other TYK2 blockers have cross reactivity against other JAKs, which can lead to unwanted side effects.

What did you learn about the safety profile of these three drugs?

Blauvelt: The most common AEs in patients with plaque psoriasis were increased blood creatinine levels, increased alanine aminotransferase levels, and headache.

All AEs in patients treated with PF-06826647 were mild, with no serious AEs, deaths, dose reductions, or temporary discontinuations reported.

A previous phase 2 trial demonstrated that a significantly greater proportion of patients with moderate-to-severe psoriasis who received deucravacitinib achieved primary clinical endpoints after 12 weeks when taking 3 milligrams twice daily (69%), 6 milligrams twice daily (67%), and 12 milligrams once daily (75%) compared with placebo (7%; P<.001).

The most common AEs were nasopharyngitis, diarrhea, nausea, and upper respiratory tract infection.

What are your take-away messages for clinicians?

Blauvelt: TYK2 can be safely blocked in psoriasis and provides therapeutic benefit to patients.

TYK2 has not been successfully targeted as yet, but laboratory and clinical evidence suggest that allosteric inhibition of TYK2 may be a viable therapeutic approach in psoriasis.

What does the foreseeable future hold for TYK2 inhibitors?

Blauvelt: Deucravacitinib (an oral once-daily pill) is the TYK2 blocker that is farthest along in clinical development and will likely be approved by the FDA within the next year. More TYK2 blockers are in the pipeline, including topical TYK2.

IMPLICATIONS FOR PRACTICE

• TYK2 inhibitors are efficacious against psoriasis.
• Favorable safety profile for all three drugs included in recent literature review.
• Deucravacitinib, a once-daily pill, could be approved by FDA within a year.