Intracellular Receptor-associated Tyrosine Kinases Inhibited Per Agent and the Corresponding Associated Adverse Effects

Tyrosine Kinase Inhibited (reported inhibition/deficiency-associated adverse effects)

Tofacitnib [1]

X

X [1-2]

Upadacitinib [1]

Baricitinib [2]

Brepositinib [1]

PF-06826647 [1]

Filgotinib [1]

Deucravacitinib [1]

X

Note:

Filgotinib: reduced platelets have been observed, and may occur via anti-inflammatory mechanisms. [2]

Deucravacitinib: no changes in hemoglobin or platelet counts were observed [2].

Design

Randomized, double-blinded, double-dummy, placebo-controlled, and active comparator-controlled trial, multi-center study 

N = 666

Objective

To compare the efficacy and safety of deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, versus placebo and apremilast in adults with moderate to severe plaque psoriasis

Study Groups

Placebo (n = 166)

Deucravacitinib 6 mg every day (n = 332)

Apremilast 30 mg twice a day (n = 168)

Inclusion Criteria

Individuals ≥ 18 years of age with moderate to severe psoriasis for ≥6 months before screening

Exclusion Criteria

Individuals with nonplaque psoriasis, history or evidence of outpatient active infection and/or febrile illness within 7 days before day 1, history of serious infection within 60 days before day 1, history of active tuberculosis (TB), or any current signs and symptoms of TB

Methods

Patients were randomized 2:1:1 to receive deucravacitinib 6 mg every day, placebo, or apremilast twice a day on day 1. Patient on deucravacitinib maintained their initial treatment through week 52. Individuals who were treated with a placebo maintained the therapy for 16 weeks and then crossed over to receive deucravacitinib. Patients who were treated with apremilast continued the treatment through week 52 if they reached the goal of ≥ 50% from baseline in Psoriasis Area and Severity Index (PASI) by week 24. If the goal was not achieved patient crossed over to deucravacitinib at week 16. 

Duration

52 weeks 

Outcome Measures

Coprimary endpoints: response rates for ≥75% reduction from baseline in PASI (PASI 75) and static Physician's Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib versus placebo at week 16

Secondary outcomes: sPGA 0 (clear), ≥90% and 100% reductions from baseline in PASI (PASI 90 and PASI 100)

Baseline Characteristics

Placebo

(n = 166)

Deucravacitinib

(n = 332)

Apremilast

(n=168)

Age, years

Female

White

Psoriatic-related history

Scalp

Nail

Psoriatic arthritis

93.4%

45.8%

15.7%

89.8%

41.6%

19.3%

92.9%

38.1%

18.5%

Results

Endpoint

Placebo

(n = 166)

Deucravacitinib

(n = 332)

Apremilast

(n= 168)

Difference vs. placebo (95% confidence interval [CI])

P value vs. placebo

Difference vs apremilast (95% CI)

P value vs apremilast

PASI 75 at week 16

Adverse Events

Common Adverse Events (placebo vs. deucravacitinib vs. apremilast): nasopharyngitis (4.2% vs. 6.3% vs. 8.3%) and upper respiratory tract infection (3.6% vs. 6.3% vs. 1.8%)

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events (placebo vs. deucravacitinib vs. apremilast): 4.2% vs. 5.8% vs. 7.1%

Study Author Conclusions

In POETYK PSO-1, deucravacitinib was well tolerated and demonstrated efficacy that was superior to placebo and apremilast. As expected based on its TYK2 selectivity, deucravacitinib did not elicit any laboratory changes characteristic of JAK 1/2/3 inhibitors. These data highlight the potential for deucravacitinib, a once-daily oral drug, to reduce disease activity and improve symptoms and QoL among patients who require systemic therapy for psoriasis.

InpharmD Researcher Critique

This study was limited by its duration of one year, which given the chronic nature of psoriasis, can be considered short. Further long-term analyses are warranted to validate the long-term safety profile of deucravacitinib. The result of this study is further limited by its lack of racial diversity, with >98% of patients self-reporting as White or Asian. Therefore, applicability to other racial types or ethnicities needs to be confirmed in future studies.

Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis

Design

Randomized, double-blind, placebo-controlled, phase 2 trial

N= 268

Objective

To assess the efficacy and safety of BMS-986165 (deucravacitinib) at various doses in patients with moderate-to-severe plaque psoriasis

Study Groups

Placebo (n= 45)

Deucravacitinib

3 mg every other day (n= 44)

3 mg daily (n= 44)

3 mg twice daily (n= 45)

6 mg twice daily (n= 45)

12 mg daily (n= 44)

Inclusion Criteria

Adults with plaque psoriasis for 6 months or longer and a body-mass index of 18 to 40, eligible for phototherapy or systemic therapy, moderate-to-severe disease as defined by an affected body-surface area of 10% or more, Psoriasis Area and Severity Index (PASI) score of 12 or higher, and static Physician Global Assessment (sPGA) score of 3 or higher

Exclusion Criteria

Diagnosis of nonplaque psoriasis, other immune-mediated conditions requiring current systemic immunosuppressant treatment, history or evidence of specific infections (e.g., human immunodeficiency virus infection or hepatitis B or C infection), risk of tuberculosis, previous lack of response to any therapeutic agent targeting the same pathway (e.g., antibodies to interleukin-17 or interleukin-23)

Methods

Patients were randomized (1:1:1:1:1:1) to receive one of five oral doses of deucravicitinib (3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily) or a matching placebo for 12 weeks. 

Duration

Trial duration: November 15, 2016 to November 16, 2017

Intervention: 12 weeks

Follow-up: 30 days following treatment

Outcome Measures

Primary: 75% or greater reduction from baseline in PASI score at week 12 (PASI 75)

Secondary: PASI score reductions from baseline of 50% or more (PASI 50), 90% or more (PASI 90), and 100% (PASI 100); sPGA score of 0 (clear) or 1 (minimal disease): score of 0 or 1 on the Dermatology Life Quality Index (DLQI; range 0 to 3, with higher scores indicating worse quality of life)

Baseline Characteristics

Placebo (n= 45)

3 mg every other day (n= 44)

3 mg daily (n= 44)

3 mg twice daily (n= 45)

6 mg twice daily (n= 45)

12 mg daily (n= 44)

Age, years

Male

White

Body weight, kg

Body-mass index, kg/m²

Median duration of disease, years

Previous use of biologic agent

Scores

PASI

DLQI

19

13

17

12

18

12

19

13

18

11

18

13

Body-surface area affected by psoriasis, %

24

20

23

24

25

21

Results

Endpoint

Placebo (n= 45)

3 mg every other day (n= 44)

3 mg daily (n= 44)

3 mg twice daily (n= 45)

6 mg twice daily (n= 45)

PASI 75

p-value vs. placebo

3 (7%)

-

4 (9%)

0.49

17 (39%)

< 0.001

31 (69%)

< 0.001

30 (67%)

< 0.001

33 (75%)

< 0.001

PASI 75 and no previous use of biologic agent

Difference vs. placebo (95% CI), %

1/25 (4%)

-

3/25 (12%)

8 (-21 to 36)

12/25 (48%)

44 (15 to 68)

17/26 (65%)

61 (38 to 80)

20/25 (80%)

76 (51 to 91)

21/26 (81%)

77 (55 to 91)

PASI 75 and previous use of biologic agent

Difference vs. placebo (95% CI), %

2/20 (10%)

-

1/19 (5%)

-5 (-35 to 26)

5/19 (26%)

16 (-16 to 45)

14/19 (74%)

64 (33 to 84)

10/20 (50%)

40 (7 to 67)

12/18 (67%)

57 (25 to 79)

PASI 50

Difference vs. placebo (95% CI), %

14 (31%)

-

19 (43%)

12 (-8 to 32)

30 (68%)

37 (18 to 56)

41 (91%)

60 (41 to 75)

35 (78%)

47 (29 to 65)

39 (89%)

58 (41 to 74)

PASI 90

Difference vs. placebo (95% CI), %

1 (2%)

-

3 (7%)

5 (-16 to 25)

7 (16%)

14 (-7 to 33)

20 (44%)

41 (21 to 60)

20 (44%)

42 (21 to 60)

19 (43%)

41 (20 to 58)

PASI 100

Difference vs. placebo (95% CI), %

0

-

1 (2%)

2 (-18 to 23)

0

-

4 (9%)

9 (-13 to 30)

8 (18%)

18 (-4 to 38)

11 (25%)

25 (4 to 44)

sPGA score of 0 or 1

Difference vs. placebo (95% CI), %

3 (7%)

-

9 (20%)

14 (-7 to 33)

17 (39%)

32 (11 to 50)

34 (76%)

69 (51 to 83)

29 (64%)

58 (38 to 74)

33 (75%)

68 (50 to 82)

DLQI score of 0 or 1

Difference vs. placebo (95% CI), %

2 (4%)

-

7 (16%)

12 (-2 to 26)

7 (16%)

12 (-2 to 26)

19 (42%)

38 (20 to 54)

27 (60%)

56 (38 to 71)

28 (64%)

59 (41 to 74)

Treatment effects were apparent as early as day 15 and persisted with reduced effect in the 30-day follow-up period after the last dose of the trial regimen.

Adverse Events

Common Adverse Events: nasopharyngitis (4% vs. 2% vs. 9% vs. 11% vs. 16% vs. 5%), headache (4% vs. 9% vs. 9% vs. 7% vs. 7% vs. 5%), diarrhea (4% vs. 2% vs. 2% vs. 4% vs. 4% vs. 9%), nausea (4% vs. 9% vs. 0 vs. 2% vs. 2% vs. 5%)

Treatment resulted in no significant changes from baseline in mean values of blood counts; serum levels of liver enzymes, lipids, creatinine, or immunoglobulins; vital signs; or electrocardiogram findings. However, 12 of 44 patients (27%) who received placebo and 57 of 221 patients (26%) who received deucravacitinib had cases of asymptomatic increases from baseline in creatine kinase levels (most of which had a Common Terminology Criteria for Adverse Events grade of 1 or 2) with no dose dependence and no events resulting in discontinuation of the trial regime.

Serious Adverse Events: Five serious adverse events were reported in four patients. Two events occurred in one patient in the placebo group (hemorrhagic anemia and hemorrhoidal hemorrhage), and one occurred in one patient each in the groups receiving 3 mg every other day (gastroenteritis due to rotavirus), 3 mg daily (accidental eye injury), and 3 mg twice daily (dizziness due to vestibular dysfunction with a history of the same). There was also one cause of in situ malignant melanoma (stage 0) that was diagnosed on skin biopsy of an atypical nevus at day 96 after the first dose of 3 mg daily. 

Percentage that Discontinued due to Adverse Events: 4% in placebo group and 2 to 7% of patients across active treatment groups

Study Author Conclusions

Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis.

InpharmD Researcher Critique

This study had a relatively small sample size considering the commonality of plaque psoriasis. Additionally, the trial was of relatively short duration, limiting conclusions regarding the long-term efficacy or safety of deucravacitinib. Therefore; these results require further confirmation in a larger trial of a longer duration.

Efficacy and Safety of Selective TYK2 inhibitor, Deucravacitinib, in a Phase II trial in Psoriatic Arthritis 

Design

Randomized, multicentre, double-blind, phase II trial

N= 203

Objective

To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis

Study Groups

Placebo (n= 66)

Deucravacitinib 6 mg (n= 70)

Deucravacitinib 12 mg (n= 67)

Inclusion Criteria

Diagnosis of psoriatic arthritis (PsA) for ≥6 months; active joint disease (at least three tender and at least three swollen joints); a high-sensitivity C-reactive protein (hs-CRP) level ≥ 3 mg/L and ≥ 1 plaque psoriasis lesion (≥ 2 cm); failure to respond/intolerant to ≥ 1 prior therapy, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or tumor necrosis factor inhibitors (TNFis)

Exclusion Criteria

Received any JAK inhibitors in the past; treated with systemic non-biologics and/or systemic immunosuppressives within 4 weeks prior to start of study; use of topical treatments that could affect psoriasis evaluation; nonplaque psoriasis or another autoimmune condition; tuberculosis; a history of active infections within 7 days prior to start of study 

Methods

Patients were randomized (1:1:1) to receive either a placebo once daily, deucravacitinib 6 mg once daily, or deucravacitinib 12 mg once daily. Randomization was divided depending if the patient was TNFi experienced or naive and each patient's body weight (≥ 90 kg and < 90 kg). 

Duration

Trial duration: March 28, 2019 - April 27, 2020

Treatment duration: 16 weeks

Outcome Measures

Primary: American College of Rheumatology (ACR) 20 response at Week 16, defined as ≥ 20% improvement from baseline in the number of tender joints and swollen joints, and ≥ 20% improvement from baseline in at least three of the following five areas: a patient global assessment of pain, patient global assessment of disease activity, physician global assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and hs-CRP

Secondary: Improvement from baseline function as determined by HAQ-DI; improvement in psoriatic skin lesions as determined by ≥ 75% reduction from baseline in Psoriasis Area and Severity Index (PASI) scores in patients with ≥ 3% body surface area involvement at baseline; change from baseline in the quality of life measure, Short Form-36 (SF-36) Physical Component Summary (PCS) score

Baseline Characteristics

Placebo (n= 66)

Deucravacitinib 6 mg  (n= 70)

Age, years

Female

White

65 (98.5%)

Body weight, kg

< 90kg

≥ 90kg

33 (50%)

33 (50%)

36 (51.4%)

34 (48.6%)

35 (52.2%)

32 (47.8%)

Prior/concomitant medication use

csDMARDs

Methotrexate

TNFis (once)

Oral steroids

44 (66.7%)

39 (59.1%)

11 (16.7%)

12 (18.2%)

45 (64.3%)

35 (50%)

12 (17.1%)

7 (10%)

43 (64.2%)

37 (55.2%)

8 (11.9%)

6 (9%)

Psoriatic arthritis disease duration from diagnosis, years, median (range)

10.5 ± 7.7

20.4 ± 39.1

*VAS scale ranges from 0–100 mm, with higher values indicating worse pain.

Results

Endpoint

Deucravacitinib 6 mg (n= 70)

Deucravacitinib 12 mg (n= 67)

ACR-20

Response rate (95% CI)

Adjusted OR vs. placebo (95% CI)

p-value 

31.8% (20.6 to 43.1%)

- 

- 

52.9% (41.2 to 64.6%)

2.4 (1.2 to 4.8)

0.0134

62.7% (51.1 to 74.3%)

3.6 (1.8 to 7.4)

0.0004

HAQ-DI score

Adjusted change from baseline (95% CI)

Difference from placebo (95% CI)

p-Value

-0.1 (-0.2 to 0.0)

-

-

-0.4 (-0.5 to -0.2)

−0.3 (−0.4 to −0.1)

0.0020

-0.4 (-0.5 to -0.3)

−0.3 (−0.5 to −0.1)

0.0008

PASI 75

Response rate (95% CI)

Adjusted OR vs. placebo (95% CI)

p-Value

20.4% (9.6 to 31.1%) 

- 

- 

42.4% (29.8 to 55.0)

2.9 (1.3 to 6.7)

0.0136

59.6% (46.3 to 73.0%)

5.8 (2.4 to 13.8)

< 0.0001

SF-36 PCS 

Adjusted mean change from baseline (95% CI)

Difference from placebo (95% CI)

p-Value

2.3 (0.4 to 4.2)

- 

- 

5.6 (3.8 to 7.5)

3.3 (0.9 to 5.7)

0.0062

5.8 (3.9 to 7.7)

3.5 (1.1 to 5.9)

0.0042

CI: confidence interval; OR: odds ratio

Adverse Events

Common Adverse Events: nasopharyngitis (7.6% vs. 5.7% vs. 17.9%), upper respiratory tract infection (0% vs. 5.7% vs. 1.5%), sinusitis (0% vs. 0% vs. 7.5%), bronchitis (1.5% vs. 5.7% vs. 0%), rash (0% vs. 4.3% vs. 6%), diarrhea (0% vs. 5.7% vs. 0%), and headache (4.5% vs. 7.1% vs. 1.5%)

Serious Adverse Events: placebo (thrombophilia, 1.5%)

Percentage that Discontinued due to Adverse Events: placebo (1.5%); deucravacitinib 6 mg (4.3%); deucravacitinib 12 mg (6%)

Study Author Conclusions

Selective inhibition of TYK2 with deucravacitinib is a promising therapeutic option for psoriatic arthritis. Deucravacitinib showed efficacy across multiple disease domains and patient-reported outcomes and has a safety profile that is consistent with its mechanism of action and with that observed in previous phase II and phase III trials in psoriasis.

InpharmD Researcher Critique

A relatively small sample size,  a short treatment duration, and a predominantly White population limit the generalizability of study findings. 

Deucravacitinib Versus Placebo and Apremilast in Moderate to Severe Plaque Psoriasis: Efficacy and Safety Results from the 52-week, Randomized, Double-blinded, Phase 3 Program for Evaluation of TYK2 Inhibitor Psoriasis Second Trial

Design

Multicenter, randomized, double-blinded, double-dummy, placebo- and active comparator-controlled, phase 3 trial

N= 1,020

Objective

To demonstrate deucravacitinib superiority versus placebo and apremilast in moderate to severe plaque psoriasis based on ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI) and a static Physician’s Global Assessment (sPGA) score of 0 (clear) or 1 (almost clear) with a ≥2-point improvement from baseline (sPGA 0/1) at week 16

Study Groups

Deucravacitinib (n= 511)

Placebo (n= 255)

Apremilast (n= 254)

Inclusion Criteria

≥ 18 years old with moderate to severe plaque psoriasis (PASI ≥ 12, sPGA ≥ 3, and body surface area (BSA) ≥ 10%) for 6 months before screening 

Exclusion Criteria

Received deucravacitinib or apremilast, positive tuberculosis, history/current of infectious/immune-related diseases 

Methods

The study was conducted at 191 sites in 16 countries. All participants were randomized in 2:1:1 to either receive deucravacitinib 6 mg daily, placebo, or apremilast 30 mg twice daily. Apremilast was titrated from 10 mg daily to 30 mg twice daily over the first 5 days. At week 16, the placebo group crossed over to receive deucravacitinib 6 mg daily. At week 24, deucravacitinib patients who achieved ≥ 75% PASI reduction from baseline (PASI 75) were re-randomized in 1:1 to either continue deucravacitinib or receive placebo (treatment withdrawal), and patients who did not achieve PASI 75 continued to receive deucravacitinib. Apremilast patients who did not achieve PASI 75 switched to deucravacitinib, and patients who achieved PASI 75 switched to placebo (treatment withdrawal). Those experiencing relapse (≥ 50% loss of week 24 PASI percent improvement from baseline) after switching from apremilast to placebo switched to deucravacitinib 6 mg daily. Outcomes were assessed at baseline and weeks 1, 2, 4, 8, 12, and 16, then every 4 weeks from weeks 16 to 52. After 52 weeks, eligible patients entered the open-label extension trial (POETYK PSO-LTE [NCT04036435]) to further assess long-term safety and efficacy. 

Duration

52 weeks

Placebo-controlled and apremilast-controlled period: 16 weeks (weeks 0-16)

Apremilast-controlled period: 8 weeks (weeks 16-24)

Maintenance and randomized treatment withdrawal period: 28 weeks

Follow-up: week 56 (if not enrolling in PSO-LTE) 

Outcome Measures

Coprimary outcome: PASI 75 and sPGA 0/1 for deucravacitinib vs. placebo at week 16

Secondary outcomes: ≥ 90% PASI reduction from baseline (PASI 90) at week 16 for deucravacitinib vs. placebo; PASI 75, PASI 90, and sPGA 0/1 at week 24 for deucravacitinib vs. apremilast

Safety outcome: incidences of adverse effects (AEs), serious AEs, and AEs leading to discontinuation

Baseline Characteristics

Deucravacitinib (n= 511) 

Placebo (n= 255) 

Apremilast (n= 254)

Age, years 

Female

White

Weight, kg

PASI (0-72)

sPGA (0-4)

3= moderate

4= severe

408 (79.8%)

103 (20.2%)

217 (85.1%)

38 (14.9%)

196 (77.2%)

38 (14.9%)

Results

Endpoint

Deucravacitinib (n= 511)

Placebo (n= 255)

Apremilast (n= 254)

Coprimary endpoints

PASI 75 (week 16)

vs. placebo < 0.0001

vs. apremilast 0.0004

sPGA 0/1 (week 16)

< 0.0001 for both

Secondary endpoints

PASI 90 (week 16)

< 0.0001

0.0046

PASI 75 (week 24)

PASI 90 (week 24)

sPGA 0/1 (week 24)

Adverse Events

Common Adverse Events: nasopharyngitis and upper respiratory tract infection with deucravacitinib (deucravacitinib 26.7/100 patient-years [PY] and 14.1/100 PY, respectively); headache, diarrhea, and nausea with apremilast (30.7, 36.5, and 26.1/100 PY, respectively). 

Serious Adverse Events: low and similar from weeks 0-52 (4.3/100 PY vs. 2.5/100 PY vs. 2.8 PY); Three deaths occurred, but none were considered treatment-related.

Percentage that Discontinued due to Adverse Events: 5.2/100 PY vs. 8/100 PY vs. 13.1/100 PY

Study Author Conclusions

In POETYK PSO-2, deucravacitinib was superior to placebo and apremilast and provided clinically meaningful improvements over 52 weeks in multiple efficacy measures. The overall safety profile of deucravacitinib, including a slight increase in the risk of nonserious viral infections, appears to be consistent with the mechanism of selective TYK2 inhibition. These findings suggest that deucravacitinib has the potential to be an efficacious and well-tolerated, once-daily, oral treatment option for plaque psoriasis. 

InpharmD Researcher Critique

The study has a large sample size and is a continuing study of the POETYK PSO-1 trial. However, the study has a short duration of 52 weeks for plaque psoriasis, and the majority of patients were White, limiting the applicability of study findings to other populations. There is an ongoing open-label extension trial to further observe the long-term efficacy, safety, and tolerability of deucravacitinib in patients with plaque psoriasis.