Deucravacitinib is a new oral small molecule that selectively inhibits TYK2 by uniquely binding to the TYK2 regulatory pseudokinase (JH2) domain (allosteric inhibition). By not binding to the conserved active domain (competitive inhibitors), like other JAK inhibitors, deucravacitinib is considerably more selective to TYK2 than to the other JAKs. Other JAK inhibitors like tofacitinib, upadacitinib and baricitinib variably inhibit JAK 1, 2 and 3, but not TYK2. The use of deucravacitinib in psoriatic patients decreases IL-23 pathway biomarkers in lesional skin towards non-lesional levels and normalizes IFN and IL-12 pathway genes, without affecting JAK 1, 2 and 3 biomarkers. Through this mechanism of action, deucravacitinib blocks IL-12, IL-23 and type I interferon downstream signalling, without interfering with JAK2-dependent hematopoietic functions [17, 36]. Preclinical studies initially showed its efficacy in mouse models with lupus erythematosus and inflammatory bowel disease [37,38,39].
Phase I Trial
Deucravacitinib’s safety and good tolerability was shown in a phase I trial involving 108 healthy participants (ClinicalTrials.gov identifier: NCT02534636) . For approximately 3 months, there were no reports of serious adverse effects and non-serious adverse events were evenly described in the active and the placebo groups (75% and 76%, respectively). Headache, nausea, rash and upper tract respiratory infections were the most frequently reported side effects .
Another phase I study was later developed to determine whether deucravacitinib had a clinically relevant effect on electrocardiographic parameters. A single oral dose of deucravacitinib 12 mg (therapeutic dose) or 36 mg (supratherapeutic dose) did not produce clinically relevant changes on the corrected QT interval or other measured parameters in healthy adults .
Phase II Trials
A phase II multicentre, double-blind, placebo-controlled trial was conducted in 267 adult patients with moderate-to-severe psoriasis (NCT02931838) . All 267 patients presented a Psoriasis Area Severity Index (PASI) score of 12 or higher, a Physician’s Global Assessment (PGA) score > 2 and a body surface area (BSA) of 10% or worse. They were randomized into six arms, one corresponding to placebo and the other five evaluating different doses of oral deucravacitinib (3 mg every other day, 3 mg each day, 3 mg twice a day, 6 mg twice a day and 12 mg each day). At the end of 12 weeks of treatment, patients treated with deucravacitinib in a dose of 3 mg daily or higher achieved significantly greater rates of PASI75 (achieving 75% improvement in PASI from baseline) than with placebo. PASI75 was achieved in 39% of patients on 3 mg of deucravacitinib daily (p < 0.001 vs placebo). Among the groups treated with doses of 3 mg twice daily or higher, over 60% of patients reached a PASI75 response (p < 0.001 vs placebo) .
Additionally, the Dermatology Life Quality Index (DLQI) questionnaire was used to assess symptom-related discomfort and impact on daily functioning. A greater percentage of patients in the groups receiving 3 mg of deucravacitinib twice daily, 6 mg twice daily, or 12 mg daily presented a DLQI score of 0 or 1 (normal or near-normal quality of life) in comparison to the placebo group (42%, 60% and 64% in the respective deucravacitinib groups vs 4% in the placebo one—95% confidence intervals of 20–54, 38–71 and 41–74, respectively) .
A post-hoc analysis of this phase II trial evaluated the impact of deucravacitinib on patient-reported quality of life. The percentage of patients achieving a DLQI 0/1 in the three highest dosage groups combined increased through weeks 4–12. Improvement in quality of life followed a similar pattern of response to treatment to that of the clinical outcomes .
Regarding safety data, the percentage of patients with reported adverse events ranged from 55% in the group treated with 3 mg each day to 80% in the group on 6 mg twice a day, whereas the placebo group presented the lowest rate of adverse effects (51%). The most common were nasopharyngitis, headache and diarrhoea. Acne was reported only in the active treatment groups (n = 8), with four cases (9%) in the highest dose arm. Only four patients reported serious adverse effects and they belonged either to the placebo group or to groups treated with the lowest doses of deucravacitinib. No cases of herpes zoster infection, tuberculosis, opportunistic infections or cardiovascular events were reported during the 12-week period of the trial .
Phase III Trials
Two large, phase III, double-blinded, 52-week trials on plaque psoriasis were recently completed: NCT03624127 (POETYK PSO-1) and NCT03611751 (POETYK PSO-2) [44, 44].
In POETYK PSO-1, 666 patients with moderate to severe plaque psoriasis (BSA ≥ 10%, PASI ≥ 12, PGA ≥ 3) were randomly assigned to deucravacitinib 6 mg once daily, placebo or an active comparator in a 2:1:1 proportion. The first group maintained the same dose of 6 mg once a day for 52 weeks, while the placebo group switched to deucravacitinib 6 mg once a day after 16 weeks. In the active comparator group, patients were treated with apremilast 30 mg twice a day, titrated from 10 mg over the first 5 days. At the end of 24 weeks, PASI response was evaluated and patients reaching PASI50 were maintained on apremilast. All patients from this arm who did not reach PASI50 at this point were switched to deucravacitinib treatment .
POETYK PSO-2 involved 1022 patients with moderate to severe plaque psoriasis who were also randomly assigned to one of three different arms. Patients assigned to receive placebo switched to deucravacitinib 6 mg once a day after 16 weeks. The other two groups started with deucravacitinib 6 mg daily or with apremilast 30 mg twice a day, titrated up from 10 mg over the first 5 days. POETYK PSO-2 included a randomized withdrawal phase in which patients originally randomized to deucravacitinib who had achieved PASI75 response at week 24 were re-randomized 1:1 to placebo or deucravacitinib, whereas those who did not achieve PASI75 response at week 24 continued being treated with deucravacitinib. Regarding patients on apremilast for the first 24 weeks, those who achieved PASI75 were maintained under the same treatment, while those who did not were started on deucravacitinib .
According to POETYK PSO-1 results at the end of 16 weeks, response rates were significantly higher with deucravacitinib versus placebo and apremilast regarding PASI75 (58.4% vs 12.7% vs 35.1%, respectively; p < 0.0001) and PGA 0/1 (53.6% vs 7.2% vs 32.1%, respectively; p < 0.0001) [45, 45] (Table 1).
At week 16, there were more deucravacitinib patients—versus placebo and apremilast patients—achieving an absolute PASI ≤ 1 (PSO-1: 24.4%, 1.8%, 10.1%, respectively) and ≤ 5 (PSO-1: 59.3%, 14.5%, 35.7%, respectively) .
Deucravacitinib-treated patients reported greater quality of life improvement in comparison with other groups, with a significantly greater DLQI 0/1 response rate at week 16 (41.0%) versus patients who received placebo (10.6%; p < 0.0001) or apremilast (28.6%; p = 0.0088) .
These responses were maintained through week 52 in the deucravacitinib group in POETYK PSO-1, with 65.1% of patients achieving PASI75 response and 52.7% a PGA of 0/1. Patients who switched from placebo to deucravacitinib at week 16 had PASI75 and PGA 0/1 responses at week 52 comparable to those observed in patients who received continuous deucravacitinib treatment from day 1  (Table 1).
POETYK PSO-2 obtained similar results: 53.6% of patients in the deucravacitinib arm achieved PASI75 at week 16 in comparison with 9.4% (p < 0.0001) of patients receiving placebo and 40.2% (p = 0.0003) of those receiving apremilast  (Table 1). Among deucravacitinib-treated patients who achieved PASI75 at week 24 and were re-randomized to continue treatment, responses were maintained at week 52 in the most patients (PASI75 of 80.4%) . Information regarding patients who switched to placebo is still unavailable.
Efficacy outcomes on scalp psoriasis were separately analysed in both POETYK studies. Significantly more patients receiving deucravacitinib achieved scalp-specific PGA 0/1 and Psoriasis Scalp Severity Index (PSSI 90), in comparison with placebo and apremilast. At the end of 16 weeks, 70.8% of deucravacitinib-treated patients in POEYK PSO-1 and 60.3% in POETYK PSO-2 reached scalp-specific-PGA 0/1 (p < 0.0001) .
Daily evolution of symptoms (burning, itch, pain, skin tightness, stinging) and signs (bleeding, cracking, dryness, redness, scaling, shedding or flaking) was also evaluated during these trials by using a patient-reported numerical scale ranging from 0 (absent) to 10 (worst imaginable) . At week 16, in both POETYK PSO-1 and POETYK PSO-2, patients treated with deucravacitinib experienced significantly greater improvements in mean change from baseline in symptom scores (− 32.0 vs − 6.3 for placebo and − 23.7 for apremilast in POETYK PSO-1 and − 31.3 vs − 3.2 for placebo and − 23.0 for apremilast in POETYK PSO-2; p < 0.0001 for each) and sign scores (− 34.3 vs − 7.7 for placebo and − 25.4 for apremilast in POETYK PSO-1 and − 35.0 vs − 6.3 for placebo and − 26.5 for apremilast in POETYK PSO-2; p < 0.0001 for each). The greatest improvements in psoriasis symptoms were observed for itch and skin tightness .
Preliminary safety results suggested a good tolerability and safety profile in both trials. The most reported adverse effects were nasopharyngitis, upper respiratory tract infections, headache and diarrhoea . According to peer-reviewed data from POETYK PSO-1, herpes zoster infections occurred at a low rate in the deucravacitinib arm (n = 5) and all cases were mild to moderate. Acne was reported in 15 out of 531 patients on deucravacitinib against 0 among placebo and apremilast groups . Serious adverse events were more frequent with placebo (5.5%) than apremilast (2.4%) or deucravacitinib (2.1%) at week 16. Discontinuation due to adverse effects over weeks 0 to 52 were lower with deucravacitinib versus placebo and apremilast . Changes from baseline levels of standard hematologic parameters (lymphocytes, neutrophils, platelets and haemoglobin) and chemistry parameters including lipid panel and creatine phosphokinase (CPK) were globally not clinically relevant from weeks 0 to 16 in both POETYK PSO-1 and 2 [44, 49].
At the end of the 52-week POETYK PSO-1 and 2, 1221 patients were switched to an open-label deucravacitinib extension trial for up to 240 weeks. Recently, data concerning long-term extension (LTE) results was presented .
From week 0 to 60 of POETYK PSO-LTE (NCT04036435), patients who were already on deucravacitinib at week 0 kept improving (PASI75 from 70.8 to 79.4% and PASI90 from 43.6% to 50.7%). Patients who switched from apremilast to deucravacitinib at week 0 also clinically improved (PASI75 from 73.8 to 87.1% and PASI90 from 40.0 to 62.9%) .
Aside from COVID-19, the safety profile was consistent across POETYK PSO-1, PSO-2 and LTE. An increase in serious infections was observed, which is attributable to COVID-19 infections due to the ongoing pandemic .
A smaller, phase III, 52-week, open-label, single-arm, clinical trial with 80 Japanese patients with moderate-to-severe psoriasis (NCT03924427) was also recently completed, with no published results to date.
There is also emerging data suggesting good efficacy and safety results of deucravacitinib in patients with active psoriatic arthritis. A total of 203 patients with psoriatic arthritis were randomized 1:1:1 to placebo, deucravacitinib 6 mg once a day and deucravacitinib 12 mg once a day in a double-blind phase II trial (NCT03881059). American College of Rheumatology-20 (ACR-20) response at week 16 was considered the primary endpoint, which refers to an improvement from baseline in the number of tender and swollen joints and patient’s pain, among other parameters. ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%; p = 0.0134) and 12 mg once a day (62.7%; p = 0.0004) against the placebo (31.8%). Higher numbers of patients treated with deucravacitinib versus placebo also achieved enthesitis and dactylitis resolution. Adverse events were more frequently reported at both deucravacitinib doses (65.7%) compared with placebo (42.4%). The most common ones in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infections, sinusitis, bronchitis, rash, diarrhoea and headache. Acne was reported in 2 of 70 (2.9%) patients in the 6-mg, once-a-day deucravacitinib group, 1 of 67 (1.5%) in the 12-mg, once-a-day group and dermatitis acneiform was reported in 2 of 70 (2.9%) and 2 of 67 (3.0%), respectively. No placebo patients developed acne or dermatitis acneiform .
Phase III studies are currently in the recruiting phase (NCT04908202 and NCT04908189) (Table 2) .