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Melinda J. Gooderham, MSc, MD, FRCPC1,2; H. Chih-ho Hong, MD, FRCPC2,3; Ivan V. Litvinov, MD, PhD, FRCPC4

1Skin Centre for Dermatology, Peterborough, ON, Canada
2Probity Medical Research, Waterloo, ON, Canada
3Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
4Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada

Conflict of interest:
M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Arena Pharmaceuticals, Asana BioSciences, ASLAN Pharmaceuticals, Bausch Health/Valeant, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, and UCB. H. C. Hong has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli-Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Leo Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Roche, Sanofi-Genzyme, Sun Pharma, and UCB. I. Litvinov has received a grant or an honorarium from AbbVie, Actelion, Bausch Health, Bristol-Myers Squibb, Galderma, ICPDHM, Janssen, Johnson & Johnson, Merck, Novartis, Pfizer, and Sun Pharmaceuticals.

Funding for this manuscript was provided in the form of an educational grant from Bristol Myers Squibb Canada Co.

Abstract:
Moderate to severe chronic plaque psoriasis may be difficult to control using current therapies, which has led to development of a novel class of therapy, selective tyrosine kinase 2 (TYK2) inhibitors, to address this unmet need. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, which has shown efficacy in moderate to severe chronic plaque psoriasis from two phase III pivotal trials (POETYK PSO-1 and PSO-2), whereby response rates were significantly higher with deucravacitinib vs. placebo or apremilast for Psoriasis Area Severity Index (PASI) 75 and static Physician’s Global Assessment (sPGA) 0/1. Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast. Although deucravacitinib is a type of Janus kinase (JAK) inhibitor, it only blocks specific cytokine-driven responses, potentially reducing off-target effects more commonly associated with other JAK inhibitors on the market. Incidence rates of serious adverse events, such as serious infections, malignancies, thrombosis, cardiovascular events, creatinine kinase elevation, hematologic changes, and lipid profile abnormalities were absent or low.

Key Words:
plaque psoriasis, TYK2 inhibitor, deucravacitinib, apremilast, clinical trial, efficacy, safety, PASI, sPGA

Introduction

Psoriasis is a common, chronic, immune-mediated inflammatory disease, estimated to affect 1 million people in Canada.1,2 The most common type is chronic plaque psoriasis, which affects 90% of this patient population.1

Moderate chronic plaque psoriasis is typically defined as involving ≥3-10% body surface area (BSA), with severe disease involving more than 10% BSA.3 When inadequately treated, this can cause severe psychosocial impact and impair patients’ quality of life (QoL).3

Currently, various oral systemic agents, biologic agents, and phototherapy have Health Canada-approved indications for management of moderate to severe chronic plaque psoriasis. Despite numerous treatment options, unmet needs still exist. An emerging class of therapy in development are selective tyrosine kinase 2 (TYK2) inhibitors, which may meet those needs. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, recently US FDA approved and currently under review by Health Canada. Other oral selective TYK2 inhibitors for treatment of moderate to severe plaque psoriasis in various stages of development include GLPG3667 and NDI-034858.4,5

Pathogenesis of Plaque Psoriasis

The pathogenesis of chronic plaque psoriasis starts with environmental, immunologic, and/or genetic triggers that can lead to release of cytokines from innate immune cells, activating myeloid dendritic cells.6,7 Activated myeloid dendritic cells present antigens to T cells and release cytokines, including interleukin (IL)-23 and IL-12;6-8 both IL-23 and IL-12 signal through TYK2-mediated pathways. IL-12 contributes to T helper (Th)1-cell differentiation and IL-23 activates keratinocytes via pro-inflammatory Th17 cells;6 both processes lead to tumor necrosis factor (TNF)-α and interferon (IFN)-γ production. Cytokines secreted by Th17 and Th1 cells activate keratinocytes;9 this is one of the first steps in the development of psoriatic lesions. A positive feedback loop recruits other immune cells, further potentiating the inflammatory process.6

Rationale for Targeting TYK2 in Plaque Psoriasis Treatment

TYK2 is a Janus kinase (JAK) enzyme that is coded by the TYK2 gene and constitutively expressed in immune cells.10 Mutations and polymorphisms in TYK2 impact IL-23, IFN-α/β, and IL-12 immune-mediated signalling, and are associated with an altered risk for psoriasis; for example, loss of function mutations in TYK2 have been found to be protective against autoimmunity, including psoriasis.10 Selective TYK2 inhibition blocks IL-23, IL-12, and type I IFN-driven responses, but not those driven by other JAKs (Figure 1).11-13

Selective TYK2 Inhibition in the Treatment of Moderate to Severe Chronic Plaque Psoriasis - image
Figure 1. Cytokine responses in tyrosine kinase 2 (TYK2) and Janus kinase (JAK) pathways
EPO, erythropoietin; GH, growth hormone; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; JAK, Janus kinase; MHC, major histocompatibility complex; Th, T helper; TNF, tumor necrosis factor; TPO, thrombopoietin; Treg, regulatory T cell; TYK, tyrosine kinase.
Adapted from Baker and Isaacs. 2018.11

Deucravacitinib: Mechanism of Action

Deucravacitinib is a specific, oral, intracellular TYK2 inhibitor that targets immune responses driven by type 1 IFN and IL-23 that contribute to psoriasis pathogenesis, including IL-17 production and Th1/Th17 polarization.12-14 It binds with high specificity to the TYK2 regulatory domain, blocking kinase activity and conferring selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis (Figure 2).12-14

Selective TYK2 Inhibition in the Treatment of Moderate to Severe Chronic Plaque Psoriasis - image
Figure 2. Deucravacitinib mechanism of action
ATP, adenosine triphosphate; IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; Th, T helper; TYK, tyrosine kinase.

Deucravacitinib uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range while reducing off-target effects.11-13 In contrast, JAK 1–3 inhibitors bind to the active domain adenosine triphosphate (ATP) binding site common to all JAK molecules (including TYK2) to mediate both immune responses and broader systemic processes (e.g., myelopoiesis, granulopoiesis, lymphoid cell maturation and function, hematopoiesis, growth factor response, metabolic activity regulation, lipid metabolism, etc.), some of which are necessary for normal physiologic functioning, resulting in a narrower therapeutic range.13

Efficacy of Deucravacitinib: Key Evidence from Pivotal Phase III Clinical Trials

In a phase II trial of patients with psoriasis, deucravacitinib demonstrated superior efficacy vs. placebo based on ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) over 12 weeks.14 Efficacy results from two phase III pivotal trials of deucravacitinib were recently reported and confirmed results from the phase II trial.

In the 52-week, double-blinded, phase III POETYK PSO-1 trial, participants with moderate to severe chronic plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=332), placebo (n=166), or apremilast 30 mg twice daily (n=168).15 Similarly, participants in the 52-week, doubleblinded, phase III POETYK PSO-2 trial were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=511), placebo (n=255), or apremilast 30 mg twice daily (n=254).16

The coprimary endpoints of both trials were response rates for PASI 75 and static Physician’s Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib vs. placebo at week 16.15,16 Key secondary endpoints included the scalp-specific Physician’s Global Assessment (ss-PGA) and patient-reported symptoms and signs of psoriasis (evaluated using the Psoriasis Symptoms and Signs Diary [PSSD]) and QoL (evaluated using the Dermatology Life Quality Index [DLQI]).15

In both PSO-1 and PSO-2 trials, PASI 75 response rates at week 16 were significantly higher with deucravacitinib (58.4% and 53.0%) vs. placebo (12.7% and 9.4%) or apremilast (35.1% and 39.8%). Response rates for sPGA 0/1 were also significantly higher with deucravacitinib (53.6% and 50.3%) vs. placebo (7.2% and 8.6%) or apremilast (32.1% and 34.3%) (Table 1).15,16 Deucravacitinib responses improved beyond week 16 and were maintained through week 52.15 Furthermore, patients who switched from placebo to deucravacitinib at week 16 demonstrated PASI 75 and sPGA 0/1 responses at week 52 comparable to those observed in patients who received continuous deucravacitinib treatment from day 1.15

Regarding key secondary endpoints, significantly greater proportions of patients in the deucravacitinib vs. placebo and apremilast arms achieved ss-PGA 0/1 and DLQI 0/1 responses, as well as greater reduction from baseline in PSSD symptom scores at week 16 and week 24 (Table 1).15,16

Table 1. POETYK PSO-1 and PSO-2 efficacy results

Endpoint POETYK PSO-1 (n=666) POETYK PSO-2 (n=1,020) POETYK PSO-1 (n=666) POETYK PSO-2 (n=1,020)
Deucravacitinib 6 mg QD (n=332) Apremilast 30 mg BID (n=168) Placebo (n=166)

P value vs. apremilast

P value vs. placebo

Deucravacitinib 6 mg QD (n=511) Apremilast 30 mg BID (n=254) Placebo (n=255)

P value vs. apremilast

P value vs. placebo

PASI 75, %
Week 16 58.4%* 35.1% 12.7%* <0.0001 <0º.0001 53.6%* 40.2% 9.4%* 0.0003 <0.0001
Week 24 69.3% 38.1% - <0.0001 - 59.3% 37.8% - <0.0001 -
sPGA 0/1, %
Week 16 53.6%* 32.1% 7.2%* <0.0001 <0.0001 50.3%* 34.3% 8.6%* <0.0001 <0.0001
Week 24 58.7% 31.0% - <0.0001 - 50.4% 29.5% - <0.0001 -
ss-PGA 0/1, %
Week 16 70.3% 39.1% 17.4% <0.0001 <0.0001 60.3% 37.3% 17.3% <0.0001 <0.0001
Week 24 72.2% 42.7% - <0.0001 - 59.7% 41.3% - 0.0002 -
DLQI 0/1, %
Week 16 41.0% 28.6% 10.6% 0.0088 <0.0001 38.0% -28.3 9.8% <0.0001 <0.0001
Week 24 48.1% 24.2% - <0.0001 - 41.8% -29.1 - <0.0001 -
Change from baseline PSSD symptom score, adjusted mean
Week 16 -26.7 -17.8 -3.6 <0.0001 <0.0001 -28.3 -21.1 -4.7 <0.0001 <0.0001
Week 24 -31.9 -20.7 - <0.0001 - -29.1 -21.4 - <0.0001 -

Table 1. POETYK PSO-1 and PSO-2 efficacy results
*Coprimary endpoints: response rates for PASI 75 and sPGA 0/1 with deucravacitinib vs. placebo at week 16.
BID, twice daily; DLQI, Dermatology Life Quality Index; PASI 75, ≥75% reduction from baseline in Psoriasis Area and Severity Index; PSSD, Patient-reported symptoms and signs of psoriasis, evaluated using the Psoriasis Symptoms and Signs Diary; QD, once daily; SE, standard error; sPGA 0/1, static Physician’s Global Assessment score of 0 or 1; ss-PGA, scalp-specific Physician’s Global Assessment. Adapted from Armstrong AW, et al. 2022 and Armstrong A, et al. 2021.15,16

Pooled PSO-1 and PSO-2 data showed that significantly greater proportions of patients receiving deucravacitinib achieved absolute PASI ≤1, ≤2, and ≤5 vs. patients receiving placebo (week 16) or apremilast (weeks 16 and 24), and proportions of patients achieving different PASI thresholds with deucravacitinib increased from week 16 to week 24.17

In an analysis of PSO-1 and PSO-2 that compared efficacy of deucravacitinib vs. placebo and apremilast in individual scoring components (erythema, induration, desquamation) and body regions of PASI (head/neck, upper extremities, trunk, lower extremities), deucravacitinib was associated with numerically greater percent reductions from baseline in each PASI body region and component scores at week 16 than placebo and apremilast.18 Higher proportions of patients in the deucravacitinib vs. placebo and apremilast groups achieved ≥75% reduction at week 16 in each PASI body region and PASI scoring; differences in efficacy when compared to apremilast were maintained at week 24.18 For patients in the deucravacitinib group, improvements occurred as early as week 1 and increased over time on treatment.18

In a long-term extension study of PSO trials, investigators analyzed the efficacy of deucravacitinib in patients who did not respond adequately to treatment with apremilast by week 24. Patients initially randomized to apremilast who failed to achieve a PASI 50 in PSO-1 (n=54) or PASI 75 in PSO-2 (n=111) were switched to deucravacitinib through week 52. After switching from apremilast to deucravacitinib, 46.3% of PASI 50 nonresponders and 42.3% of PASI 75 non-responders achieved PASI 75 by week 52.19 Improvements were also seen for sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score.19

Two-year data from a long-term extension of both PSO trials showed that deucravacitinib had durable clinical efficacy, including mean response rates of 79.8% for PASI 75 and 60.7% for sPGA 0/1 at week 60, regardless of which treatment was initiated at week 16 (when patients in the placebo group could switch to deucravacitinib) or at week 24 (when apremilast nonresponders could switch to deucravacitinib) in the parent study.20

Deucravacitinib: Safety and Tolerability Profile

During weeks 0–16 and weeks 0–52 assessment periods in both PSO trials, overall adverse event (AE) rates were similar across all 3 treatment groups (deucravacitinib, placebo, and apremilast).15,16,21 The most frequent AEs in patients treated with deucravacitinib were nasopharyngitis (9.0%) and upper respiratory tract infection (5.5%). The most frequent AEs in apremilast-treated patients were diarrhea (11.8%), headache (10.7%), nausea (10.0%), and nasopharyngitis (8.8%); placebotreated patients most frequently experienced nasopharyngitis (8.6%) and diarrhea (6.0%).16,21 Incidence rates for AEs of interest, including skin events (e.g., acne and folliculitis), herpes zoster, serious infections, malignancies, thrombotic events, cardiovascular events, creatinine kinase elevation, changes in complete blood count, and changes in lipid profile were absent or low in the deucravacitinib group.15

The frequency of serious adverse events (SAEs) reported in weeks 0–16 were low across all groups (1.8% in deucravacitinib treated patients vs. 2.9% with placebo and 1.2% with apremilast).16,21 Discontinuation rates due to AEs were lowest in the deucravacitinib group (2.4%) vs. placebo (3.8%) and apremilast (5.2%).16,21

A pooled analysis of PSO-1 and PSO-2 trials confirmed that deucravacitinib was well tolerated for up to 52 weeks across patient subgroups based on baseline characteristics of age, sex, race, and body weight. The frequency and type of AEs and SAEs in each subgroup were consistent with the overall patient population, with similar trends for overall AEs and AE classes in the placebo and apremilast groups across subgroups.21

In the long-term extension trial, safety results were consistent with those reported in PSO-1 and PSO-2 trials. SAEs remained low, including those that led to discontinuation. There were no new safety signals or clinically meaningful changes in laboratory values.20 The most common AEs included nasopharyngitis (16.8% at 1 year; 17.8% at 2 years), upper respiratory tract infection (9.1% at 1 year; 9.9% at 2 years), headache (5.9% at 1 year; 6.5% at 2 years), diarrhea (5.1% at 1 year; 5.5% at 2 years), and arthralgia (4.0% at 1 year; 5.6% at 2 years).20 An increase in serious infections was observed, which the authors concluded was attributable to COVID-19 infections due to the ongoing pandemic (studies were conducted during the pandemic through the cut-off date of October 1, 2021, prior to widespread availability of vaccines).

These safety results have not as of yet uncovered treatmentemergent SAEs that are more commonly associated with JAK inhibitors, such as herpes zoster, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities.20-24

Discussion

Selective TYK2 inhibition is a promising novel target for the treatment of moderate to severe chronic plaque psoriasis. Molecules that confer selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis, without involvement of other JAKs, can lead to a broad therapeutic range while reducing off-target effects such as serious infections, malignancies, thrombosis, and MACE.

Key data from the pivotal phase III POETYK PSO-1 and PSO-2 clinical trials showed that patients with moderate to severe chronic plaque psoriasis treated with the first-in-class, oral, selective TYK2 inhibitor deucravacitinib achieved statistically significant PASI 75 and sPGA 0/1 outcomes that were superior to placebo and apremilast at week 16.15,16 Additionally, significantly greater proportions of patients achieved absolute PASI ≤1, ≤2, and ≤5 with deucravacitinib vs. placebo or apremilast.17 Body region-specific data showed that deucravacitinib had numerically larger percentage improvements at weeks 16 and 24 from baseline vs. apremilast and placebo, across all components of scoring and with onset of action as early as week 1.18

Deucravacitinib was efficacious at week 52 in patients who had inadequate responses to apremilast at week 24 and subsequently switched to deucravacitinib, which was demonstrated in physician-assessed endpoints (PASI 75/90, percentage change from baseline in PASI, and sPGA 0/1) and in patient-reported outcomes (DLQI 0/1 and change from baseline in PSSD symptom score).19

Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast, with overall AE rates similar across all 3 treatment groups.15,21 The most common AEs in patients treated with deucravacitinib were nasopharyngitis and upper respiratory tract infection, while incidence rates of SAEs and AEs of interest were low.15,21


Test Your Knowledge

  1. What are the off-target serious adverse effects associated with JAK inhibitors?
  2. In the PSO-1 and PSO-2 clinical trials, what were the outcomes of apremilast non-responders who were switched to deucravacitinib at week 24?

 

Answers



Test Your Knowledge – Answers



  1. Serious adverse effects that are more commonly associated with JAK inhibitors include serious infections, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities. Although deucravacitinib is a type of JAK inhibitor, it uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range, potentially reducing off-target effects.

  2. A large proportion of patients with an inadequate response to apremilast at week 24 in the PSO-1 and PSO-2 trials had clinical improvement and strong responses after switching to deucravacitinib through week 52. Improvements were seen for PASI 75, sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score. For example, after switching from apremilast to deucravacitinib, 46.3% of PASI 50 non-responders (in PSO-1) and 42.3% of PASI 75 nonresponders (in PSO-2) achieved PASI 75 by week 52.




Conclusion

Selective TYK2 inhibition is a novel target in the treatment of moderate to severe plaque psoriasis. The first-in-class oral TYK2 inhibitor deucravacitinib, already approved by the FDA in the US, has been shown to be efficacious, safe, and tolerable for up to 2 years of use. It is expected that deucravacitinib, and potentially other oral TYK2 inhibitors in development, will offer dermatologists and their patients with a convenient, effective, and safe alternative to other currently available oral systemic agents biologic agents, and phototherapy for the management of moderate to severe chronic plaque psoriasis.

Acknowledgements

The authors wish to thank Teri Morrison and Athena Kalyvas from the International Centre for Professional Development in Health and Medicine (ICPDHM) for editorial support.

References



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