TYK2 inhibition: changing the treatment landscape for psoriasis?

KEYWORDS:

• TYK2 inhibitor
• deucravacitinib
• phase 3
• dermatology
• BMS-986165
• psoriasis
• plaque psoriasis
• TYK2
• deucravacitinib
• JAK inhibitor
• tyrosine kinase 2

Psoriasis is a common immune-mediated inflammatory disease affecting approximately 2% of individuals living in Western countries. Patients with psoriasis suffer from a multitude of comorbidities such as psoriatic arthritis, inflammatory bowel disease, anxiety and depression, metabolic syndrome and cardiovascular disease[1]. The inflammatory process in psoriasis is driven in part by pathogenic Th17 cells, which produce interleukin (IL)-17 in response to the regulatory cytokine, IL-23, along with other key players of inflammation including tumor necrosis factor α (TNF-α) and interferons[2]. The signaling of IL-23 is known to be transmitted through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. One important JAK involved is tyrosine kinase 2 (TYK2) which makes it a suitable target for inhibition. TYK2 pairs with JAK2 for the signaling of IL-12 and −23, and TYK2 pairs with JAK1 for signaling downstream of Type 1 interferon (IFN) receptors [3,4]. TYK2 inhibition presents itself as a promising avenue for the management of psoriasis. This editorial examines the role of a new selective TYK2 inhibitor, deucravacitinib (BMS-986165), as well as reviewing its clinical efficacy and safety.

As TYK2 inhibitors are a relatively new treatment modality, there is not yet a commercially available TYK2 inhibitor for clinical use. There are also other TYK2 inhibitors in development, such as brepocitinib (TYK2/JAK1) and PF-06826647 (TYK2/JAK2), but deucravacitinib is furthest in development and will be the focus of this editorial. The other TYK2 inhibitors for use in dermatology have recently been reviewed[5].

Deucravacitinib is a novel, oral, selective TYK2 inhibitor with a unique mechanism of action through allosteric binding of the pseudokinase (JH2) domain which is regulatory in nature and lacks catalytic activity. This contrasts with other JAK inhibitors which bind to the adenosine triphosphate (ATP) site of the catalytic domain thereby blocking ATP and the downstream phosphorylation and signal transduction [6,7]. Cell-based assays have shown deucravacitinib has demonstrated higher selectivity for TYK2 versus JAK 1–3, reducing the chance of off-target effects [6,7]. Selective targeting of TYK2 results in the inhibition of signaling of IL-12, −23 and Type 1 IFN, the key cytokines involved in psoriasis pathogenesis.

Deucravacitinib demonstrated efficacy and tolerability in two phase 2 trials investigating moderate-to-severe plaque psoriasis (NCT02931838) and active psoriatic arthritis (NCT03881059) [8,9]. Two pivotal phase 3, double-blinded, clinical trials (POETYK PSO-1, POETYK PSO-2) compared deucravacitinib 6 mg once daily (OD) to placebo and apremilast 30 mg twice daily (BID) over 52 weeks in patients with moderate-to-severe plaque psoriasis (NCT03624127, NCT03611751)[10]. POETYK PSO-1 included a total of 666 participants. The coprimary endpoints at week 16 were the proportion of participants achieving a 75% or greater reduction in the psoriasis area and severity index (PASI75) and a static physician global assessment (sPGA) 0/1. At week 16, PASI75 was reached by 58.7% receiving 6 mg OD deucravacitinib compared to 12.7% receiving placebo and 35.1% receiving apremilast (P < 0.0001). sPGA 0/1 was reached by 53.6% of participants receiving deucravacitinib compared to 7.2% receiving placebo and 32.1% receiving apremilast (P < 0.0001). The ranked secondary endpoints of PASI90 and PASI100 improvement at week 16 compared to placebo were also met[10]. By week 24, deucravacitinib was found superior to apremilast with 69% of the deucravacitinib group achieving PASI75 compared to only 38.1% of the apremilast group. Similarly, for sPGA 0/1 at week 24, 58.4% and 31.0% achieved clear or almost clear for deucravacitinib and apremilast, respectively[10]. Deucravacitinib participants who achieved PASI 75 at Week 24 and continued treatment to week 52 maintained PASI 75 response at rates of 82.5%[10]. Results for POETYK PSO-2, which enrolled 1020 participants were similar to that of POETYK PSO-1 and have also been presented but have not yet been published[10]. Eligible patients from the phase 3 program will continue to receive deucravacitinib in a long-term extension study (NCT04036435).

Deucravacitinib was well tolerated and had a similar safety profile in the phase 3 trials to previously published phase 2 results. Deucravacitinib showed a similar number of adverse events (AEs) and serious AEs (SAEs) across treatment groups. In the integrated POETYK PSO-1 and POETYKPSO-2, at least one AE was reported by 55.7% of the deucravacitinib group versus 49.6% and 57.6% of the placebo and apremilast group, respectively. AEs leading to discontinuation were numerically lower with deucravacitinib versus placebo and apremilast. Commonly reported AEs for deucravacitinib included nasopharyngitis, upper respiratory tract infections (URTIs), headache, diarrhea, and nausea; however, rates of headache, diarrhea, and nausea were similar for deucravacitinib and placebo (all <5%) but higher for apremilast (10–11%)[10]. Skin events of interest in the 52 week integrated safety of POETYKPSO-1 and POETYKPSO-2 reported rates of folliculitis in 2% and acne in 2.1% of the deucravacitinib group; all cases were mild to moderate and only one led to treatment discontinuation[10].

One SAE presented as a venous thromboembolic event occurring in the deucravacitinib group in a participant who had an aortic dissection complicated by a pulmonary embolic event; upon recovery, they restarted deucravacitinib treatment without complications[10]. With regards to laboratory parameters, there were no significant changes in total cholesterol, neutrophils, platelets, or creatine phosphokinase, which are known to be affected by other JAK inhibitors[10].

Deucravacitinib showed superior efficacy compared to placebo by 16 weeks of treatment and to placebo and apremilast at week 16 and week 24 for multiple ranked secondary endpoints. The therapeutic effects of deucravacitinib were maintained for 52 weeks[10]. Deucravacitinib was well tolerated and had a safety profile that was consistent with its mechanism of action. Overall, deucravacitinib, a once-daily oral investigational drug, has the potential to become an efficacious and well-tolerated treatment of choice for patients with moderate-to-severe plaque psoriasis.

1. Expert opinion

Deucravacitinib will be a welcomed oral therapeutic option for our psoriasis patients as there remains an unmet need for accessible, efficacious, and safe therapies in this population. Safety is always a concern and conventional systemic agents (i.e., methotrexate, cyclosporine, acitretin, dimethylfumarate) are associated with safety issues including predictable off-target effects and end-organ toxicity. JAK inhibitors, as a class, although proven to be effective in the treatment of psoriasis, are also associated with some off-target effects and include boxed warnings for increased rates of serious infections, malignancy, and thrombosis. There are also noted changes in laboratory parameters (lipids, platelets, neutrophils, creatine phosphokinase) with some JAK inhibitors which are not seen with deucravacitinib. The unique mechanism of action of deucravacitinib as an allosteric inhibitor of the regulatory domain provides a high degree of selectivity and reduces the off-target effects observed with other JAK inhibitors. We don’t see the same impact on laboratory parameters or AE rates, including infection and thromboembolism, as we do with competitive inhibitors of JAKs. This selectivity will be an attractive feature for both the patient and the prescriber when looking for an oral therapeutic option. The currently available oral therapy, apremilast, which holds a portion of the market share, is very safe and easy to use, but provides an efficacy inferior to that of other agents, including deucravacitinib. Almost twice as many patients receiving deucravacitinib achieve PASI75 and sPGA 0/1 at week 24 compared to apremilast. PASI90 and PASI100 are achievable for some patients. Tolerability is also a concern when choosing a chronic therapy and is often the cause of discontinuation for both conventional agents and apremilast. Deucravacitinib, on the other hand, is well-tolerated with rates of nausea, diarrhea, and headache similar to placebo and less than half of what is seen with apremilast in the phase 3 program. This tolerability promises to improve adherence to therapy. In the current landscape where biologic therapies offer effective, safe, and convenient options for patients, oral therapies do have some advantages over injectable therapies; there is no risk of immunogenicity or injection site reactions, they are easy to transport and store since there is no cold chain requirement, and sometimes a pill is preferred by patients. However, current treat-to-target guidelines suggest ‘clear or almost clear skin’ as a target and with just over half of patients achieving sPGA 0/1 at week 24, there will be some patients who may need to optimize therapy or switch to a biologic agent.

The overall place of deucravacitinib in the treatment of moderate-to-severe psoriasis involves multiple prescriber and patient factors, including safety, tolerability, efficacy, convenience, and impact on comorbidities. Deucravacitinib seems to check all the boxes. It has proven efficacy superior to apremilast in psoriasis, promising early phase results in psoriatic arthritis, and studies ongoing for inflammatory bowel disease. It is well tolerated with low rates of headache, nausea, and diarrhea and a favourable safety profile with low rates of AEs and no impact on laboratory parameters as seen with other JAK inhibitors. Having a convenient, once-daily, oral therapeutic option with these attributes may likely change the current landscape of psoriasis therapy by either replacing or delaying the start of biologic therapy, including biosimilars, in many individuals. It could be considered as a first-line agent, but should not be limited to this, since at least one third of the POETYKPSO-1 and POETYKPSO-2 study population had prior biologic exposure[10]. The last piece is accessibility, and this will be dependent on regional factors such as regulatory approvals, payors, and local guidelines.

What is still missing is data on long-term and maintenance of response beyond 52 weeks, head-to-head trials with biologic agents, and the impact of treatment interruptions. Data so far looks promising, with 83% of patients reaching PASI75 at week 24 being able to maintain this response to week 52. We can anticipate that lack of adherence may reduce treatment responses as one pitfall of chronic daily therapy; however, the favourable tolerability may reduce this risk. Full data publication of the phase 3 program, as well as data on psoriatic arthritis and inflammatory bowel disease is eagerly awaited. Given that TYK2 plays a central role in the pathophysiology of psoriasis, inhibition of TYK2 by deucravacitinib and all the features it has to offer has great potential to change the treatment landscape of psoriasis.

Declaration of interest

M Gooderham has been an investigator, speaker, consultant or advisory board member for AbbVie, Amgen, Akros, Arcutis, Boehringer Ingelheim, BMS, Celgene, Dermira, Dermavant, Galderma, GSK, Eli Lilly, Incyte, Janssen, Kyowa Kirin, Leo Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, UCB, and Valeant/Bausch. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.