TRIALISTMD ยท Drug Intelligence Platform
FDA APPROVED 2022
TYK2 Inhibitor ยท Dermatology ยท Plaque Psoriasis
Deucravacitinib
SOTYKTUโข ยท Bristol-Myers Squibb Company
The world’s first tyrosine kinase 2 (TYK2) inhibitor approved for any indication. Deucravacitinib binds selectively to the regulatory pseudokinase (JH2) domain of TYK2 โ not the catalytic domain โ producing allosteric inhibition distinct from all approved JAK inhibitors. This unique binding mechanism underpins an efficacy advantage over apremilast and a differentiated safety profile compared to JAK1/2 inhibitors, without the full JAK inhibitor Boxed Warning. Approved September 2022 for moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
Drug Overview
NDA 214958
โ NO BOXED WARNING โ TYK2 inhibitor class distinction: Deucravacitinib carries a Warnings and Precautions section noting potential risks related to JAK inhibition (Section 5.8), but does NOT carry the Boxed Warning for serious infections, mortality, MACE, thrombosis, and malignancy that applies to approved JAK1/2 inhibitors (tofacitinib, baricitinib, upadacitinib, abrocitinib). FDA concluded that the clinical safety outcomes in deucravacitinib-treated psoriasis patients differ from those described for JAK inhibitors, while noting that it is not known whether TYK2 inhibition carries the same risks. A post-marketing randomized safety trial vs an active comparator was required.
Indication
Moderate-to-Severe Plaque Psoriasis
Adults who are candidates for systemic therapy or phototherapy. First TYK2 inhibitor approved for any indication worldwide.
Mechanism
Allosteric TYK2 Inhibitor
Binds the TYK2 regulatory (JH2/pseudokinase) domain โ not the catalytic domain โ stabilising an autoinhibitory conformation; structurally and mechanistically distinct from all other approved JAK inhibitors
Co-Primary Efficacy (Wk 16) โ PSO-1
54% / 58%
sPGA 0/1: 54% vs 7% placebo; PASI 75: 58% vs 13% placebo; both p<0.001
Active Comparator (Apremilast)
Superior
sPGA 0/1: 54% vs 32% (PSO-1) and 50% vs 34% (PSO-2); PASI 75: 58% vs 35% / 53% vs 40%; both p<0.001
Mechanism of Action
Section 12.1Deucravacitinib is an inhibitor of tyrosine kinase 2 (TYK2). TYK2 is a member of the JAK kinase family. Unlike tofacitinib, baricitinib, upadacitinib, abrocitinib, and ritlecitinib โ all of which bind the ATP-binding catalytic (JH1) domain โ deucravacitinib binds the regulatory pseudokinase (JH2) domain of TYK2, stabilising an autoinhibitory interaction between the regulatory and catalytic domains. This results in allosteric inhibition of receptor-mediated TYK2 activation and downstream STAT phosphorylation in cell-based assays. TYK2 pairs with JAK1 to mediate type I IFN and IL-10, IL-6, IL-12, and IL-23 pathways, and pairs with JAK2 to transmit additional signals. In psoriasis, TYK2 mediates key pathogenic cytokine signals including IL-12, IL-23, and type I IFN โ all implicated in Th17/Th1 differentiation and the inflammatory cascade driving plaques. In patients with psoriasis, deucravacitinib reduced IL-17A, IL-19, and beta-defensin by 47โ50%, 72%, and 81โ84% respectively following 16 weeks of treatment. The precise mechanism linking TYK2 inhibition to therapeutic effectiveness in plaque psoriasis is not currently known per the label.
JH2 (pseudokinase) domain binding โ clinical significance: Because deucravacitinib occupies the JH2 regulatory domain rather than the catalytic ATP-binding JH1 pocket, it achieves higher TYK2 selectivity over other JAK family members (JAK1, JAK2, JAK3) than competitive ATP-site inhibitors. The autoinhibitory mechanism means the enzyme is locked in a low-activity conformation without blocking the ATP site โ this selectivity profile is hypothesised to account for the lack of observed thrombocytopenia, lymphocytopenia, and anemia signals that characterise JAK1/2 inhibitors, and may underlie the absence of a Boxed Warning. However, it is important to note that this mechanistic difference has not yet been demonstrated to translate to clinically meaningful long-term cardiovascular or malignancy safety advantages in a randomised head-to-head trial.
Psoriasis Disease Context
| Parameter | Detail |
|---|---|
| Disease burden | Chronic, inflammatory multi-system disorder affecting ~2โ3% of the US population; ~20% have moderate-to-severe disease; one third have concomitant psoriatic arthritis |
| Comorbidities | Cardiovascular disease, metabolic syndrome, depression/suicide, and autoimmune disease are associated with psoriasis; patients with psoriasis are at higher baseline CV risk than the general population |
| Treatment landscape at approval | Anti-metabolites (methotrexate); TNF inhibitors (adalimumab, etanercept, infliximab, certolizumab); IL-12/23 blocker (ustekinumab); IL-17A blockers (secukinumab, ixekizumab); IL-17RA antagonist (brodalumab); IL-23 inhibitors (guselkumab, tildrakizumab, risankizumab); oral small molecules (cyclosporine, acitretin, apremilast); phototherapy |
| Apremilast comparison context | Apremilast (PDE4 inhibitor) achieves sPGA 0/1 (clear/almost clear) in ~16โ18% of patients โ deucravacitinib’s 50โ54% sPGA 0/1 represents a substantially higher response rate, supporting its positioning as the first oral therapy with efficacy approaching lower-tier biologics |
| Approval significance | First approved TYK2 inhibitor for any indication globally; first new oral mechanism class for plaque psoriasis since apremilast (2014); provides an injectable-free oral option with superior efficacy to apremilast |
Source: NDA 214958 label, Ref ID 5043643 (Revised 9/2022); Medical Review Ref ID 5043097. Code name: BMS-986165. Limitations of use: not recommended in combination with other potent immunosuppressants. Not approved for psoriatic arthritis. Deucravacitinib is being evaluated in multiple other indications including lupus and other inflammatory diseases; approved only for plaque psoriasis as of label date.
Baseline & Trial Characteristics
Table 34, NDA 214958 Medical Review; Section 14 LabelTotal Randomized (Phase 3)
1,684
PSO-1 (N=664) + PSO-2 (N=1,020); deucravacitinib 6 mg QD (N=841), placebo (N=421), apremilast 30 mg BID (N=422)
Mean Age
~46โ47 yrs
PSO-1 deucravacitinib arm: 45.8 years (range 18โ80); PSO-2: 46.9 years; majority (>85%) aged <65 years; 10% aged โฅ65
Median Baseline PASI
~19โ20
PSO-1 deucravacitinib: median PASI 20 (range 12โ59); PSO-2: median 19; mean PASI 20.7โ21.8; entry criterion PASI โฅ12
Prior Biologic Use
~35%
35% had received prior biologic therapy across both trials; 40% systemic therapy-naive; 41% prior non-biologic systemic; 40% prior phototherapy
Trial Design โ PSO-1 and PSO-2
Trials IM011046 and IM011047| Parameter | PSO-1 (IM011046) | PSO-2 (IM011047) |
|---|---|---|
| ClinicalTrials.gov | NCT03624127 | NCT03611751 |
| Design | Multicenter, randomized, double-blind, placebo- and active-controlled (apremilast); 52-week trial with 16-week primary endpoint assessment period | |
| Sample size | Deucravacitinib N=330; Placebo N=166; Apremilast N=168 | Deucravacitinib N=511; Placebo N=255; Apremilast N=254 |
| Co-primary endpoints (vs placebo at Wk 16) | 1. sPGA 0/1 (clear/almost clear) with โฅ2-grade improvement from baseline; 2. PASI 75 (โฅ75% reduction in PASI from baseline) | |
| Secondary endpoints vs placebo (Wk 16) | PASI 90, PASI 100, sPGA 0, ss-PGA 0/1 (scalp), PSSD Symptom Score 0 | |
| Secondary endpoints vs apremilast (Wk 16 & 24) | PASI 75, PASI 90, sPGA 0/1, sPGA 0, ss-PGA 0/1 (scalp) | |
| Inclusion criteria | Adults โฅ18 years; moderate-to-severe plaque psoriasis; BSA โฅ10%; PASI โฅ12; sPGA โฅ3 (moderate); candidates for systemic therapy or phototherapy | |
| Placebo switch | All placebo subjects switched to deucravacitinib at Week 16; other subjects could continue or switch at Week 24 | |
| Randomized withdrawal (PSO-2) | Not applicable | PASI 75 responders at Week 24 re-randomized to continue deucravacitinib or withdraw (placebo) to Week 52 โ durability assessment |
| Missing data handling | Non-responder imputation (NRI) as primary method; sensitivity: LOCF, LOCF+NRI, MI/FCS, worst-case scenario โ all concordant | |
| Statistical method | CMH test stratified by region, body weight, and prior biologic use; multiplicity controlled by pre-specified hierarchical testing procedure | |
| Long-term follow-up | Open-label extension trial; total 1,519 subjects received deucravacitinib; 1,141 exposed โฅ1 year | |
Demographics โ Deucravacitinib 6 mg Arms (Table 34)
| Characteristic | PSO-1 Deucravacitinib (N=330) | PSO-2 Deucravacitinib (N=511) |
|---|---|---|
| Mean age, years (SD) | 45.8 (13.7); range 18โ80 | 46.9 (13.4); range 18โ84 |
| Age โฅ65 years, n (%) | 26 (8%) | 54 (11%) |
| Male, n (%) | 230 (70%) | 336 (66%) |
| White, n (%) | 265 (80%) | 474 (93%) |
| Asian, n (%) | 59 (18%) | 24 (5%) |
| Black or African American, n (%) | 2 (1%) | 8 (2%) |
| Hispanic or Latino (pooled, both trials) | 13% across both trials | |
| Mean weight, kg (SD) | 88.0 (21.8) | 92.3 (21.9) |
| Weight โฅ90 kg, n (%) | 131 (40%) | 270 (53%) |
| US subjects, n (%) | 107 (32%) | 163 (32%) |
Baseline Disease Characteristics โ Deucravacitinib 6 mg Arms (Table 34)
| Characteristic | PSO-1 Deucravacitinib (N=330) | PSO-2 Deucravacitinib (N=511) |
|---|---|---|
| Mean PASI (SD); Median; Range | 21.8 (8.6); 20; 12โ59 | 20.7 (7.5); 19; 12โ56 |
| Mean BSA (SD); Median | 26.6% (15.9); 21% | 26.3% (15.8); 20% |
| sPGA 3 (moderate), n (%) | 255 (77%) | 408 (80%) |
| sPGA 4 (severe), n (%) | 75 (23%) | 103 (20%) |
| Scalp involvement (ss-PGA โฅ3), n (%) | 209 (63%) | 305 (60%) |
| Nail involvement (PGA-F โฅ3), n (%) | 43 (13%) | 69 (14%) |
| Mean disease duration, years (SD); Median | 17.0 (12.4); 13 years | 18.6 (13.1); 16 years |
| Prior systemic therapy (any), n (%) | 199 (60%) | 274 (54%) |
| Prior systemic therapy-naive, n (%) | 131 (40%) | 237 (46%) |
| Prior biologic therapy (pooled) | 35% across both trials | |
| Prior non-biologic systemic therapy | 41% across both trials | |
| Prior phototherapy | 40% across both trials | |
| History of psoriatic arthritis | ~18% across both trials | |
Source: NDA 214958 Medical Review Table 34, Ref ID 5043097. FAS = Full Analysis Set (all randomized subjects; Site 0092 in Trial IM011046 removed per FDA review). PSO-1 had a higher proportion of Asian subjects (18% vs 5% in PSO-2) and lower proportion of White subjects (80% vs 93%) due to inclusion of Asian sites. Demographics were balanced across treatment arms within each trial. APR = apremilast; PBO = placebo; DEUC = deucravacitinib.
Clinical Efficacy
Section 14 (Label) / Tables 35โ43, 48 (Medical Review)sPGA 0/1 at Wk 16 โ PSO-1 (vs Placebo)
54%
vs 7% placebo; ฮ +47% (95% CI 40%โ53%); p<0.001 (co-primary endpoint)
PASI 75 at Wk 16 โ PSO-1 (vs Placebo)
58%
vs 13% placebo; ฮ +46% (95% CI 39%โ53%); p<0.001 (co-primary endpoint)
sPGA 0/1 at Wk 16 โ PSO-2 (vs Placebo)
50%
vs 9% placebo; ฮ +41% (95% CI 35%โ46%); p<0.001 (co-primary endpoint)
Durability โ sPGA 0/1 at Wk 52 (PSO-1)
78%
78% (151/194) of Week 24 sPGA 0/1 responders maintained response at Week 52; 82% maintained PASI 75
Co-Primary Endpoints โ sPGA 0/1 and PASI 75 at Week 16
Label Tables 2โ3 / Medical Review Table 35; FAS; NRIPSO-1 (IM011046) โ NCT03624127 ยท N=664
Co-primary endpoints vs placebo at Week 16. Secondary endpoints vs apremilast. All p<0.001 for primary comparisons.
sPGA 0/1 RESPONSE
PASI 75 RESPONSE
PSO-2 (IM011047) โ NCT03611751 ยท N=1,020
Confirmatory trial; identical design to PSO-1. Consistent results across both co-primary endpoints. All p<0.001.
sPGA 0/1 RESPONSE
PASI 75 RESPONSE
Full Efficacy Table โ PSO-1 and PSO-2 (Label Tables 2โ3)
Week 16; NRI; FAS| Endpoint | PSO-1 DEUC (N=330) | PSO-1 PBO (N=166) | PSO-1 APR (N=168) | PSO-2 DEUC (N=511) | PSO-2 PBO (N=255) | PSO-2 APR (N=254) |
|---|---|---|---|---|---|---|
| sPGA 0/1 Wk 16 (co-primary) | 178 (54%) | 12 (7%) | 54 (32%) | 253 (50%) | 22 (9%) | 86 (34%) |
| PASI 75 Wk 16 (co-primary) | 193 (58%) | 21 (13%) | 59 (35%) | 271 (53%) | 24 (9%) | 101 (40%) |
| PASI 90 Wk 16 | 118 (36%) | 7 (4%) | 33 (20%) | 138 (27%) | 7 (3%) | 46 (18%) |
| PASI 100 Wk 16 | 47 (14%) | 1 (1%) | โ | 52 (10%) | 3 (1%) | โ |
| sPGA 0 Wk 16 | 58 (18%) | 1 (1%) | 8 (5%) | 80 (16%) | 3 (1%) | 16 (6%) |
| ss-PGA 0/1 Wk 16 (scalp) | 147/209 (70%) | 21/121 (17%) | 43/110 (39%) | 182/305 (60%) | 30/173 (17%) | 61/166 (37%) |
| sPGA 0/1 Wk 24 | 194 (59%) | โ | 52 (31%) | 251 (49%) | โ | 75 (30%) |
| PASI 75 Wk 24 | 228 (69%) | โ | 64 (38%) | 296 (58%) | โ | 96 (38%) |
| PASI 90 Wk 24 | 140 (42%) | โ | 37 (22%) | 164 (32%) | โ | 50 (20%) |
Durability & Maintenance of Response
Section 14 (Label); 52-week data| Response Measure | Week 24 Responders | Week 52 Maintained | Source / Trial |
|---|---|---|---|
| sPGA 0/1 | 194/330 (59%) | 151/194 (78%) | PSO-1 (all continued on deucravacitinib) |
| PASI 75 | 228/330 (69%) | 187/228 (82%) | PSO-1 (all continued on deucravacitinib) |
| PASI 90 | 140/330 (42%) | 103/140 (74%) | PSO-1 |
| sPGA 0/1 โ continued deucravacitinib | 118/โ re-randomized | 83/118 (70%) | PSO-2 randomized withdrawal arm |
| sPGA 0/1 โ withdrawn to placebo | 119/โ re-randomized | 28/119 (24%) | PSO-2 withdrawal arm; median time to loss ~8 weeks |
| PASI 75 โ continued deucravacitinib | 148/โ re-randomized | 119/148 (80%) | PSO-2 randomized withdrawal arm |
| PASI 75 โ withdrawn to placebo | 150/โ re-randomized | 47/150 (31%) | PSO-2 withdrawal; median time to loss ~12 weeks |
Sensitivity analysis robustness: All co-primary efficacy endpoints in both PSO-1 and PSO-2 remained statistically significant (p<0.001) across all pre-specified missing data handling approaches: NRI (primary), LOCF, LOCF+NRI, MI/FCS, and even a worst-case scenario (deucravacitinib missing = non-responders; placebo missing = responders). This confirms the treatment effect was not attributable to missing data patterns.
Patient-Reported Outcomes (PSSD): A greater proportion of deucravacitinib-treated subjects achieved PSSD Symptom Score of 0 (complete absence of itch, pain, burning, stinging, and skin tightness) at Week 16 compared to placebo (8% vs 1%, both trials). Deucravacitinib was statistically superior to placebo (p<0.002) but not to apremilast (p>0.09) on this endpoint โ the only efficacy endpoint on which deucravacitinib did not demonstrate superiority over apremilast. Per medical review, the PSSD Symptom domain adequately supports labeling claims for complete resolution of symptoms.
Source: NDA 214958 label Tables 2โ3 and Section 14, Ref ID 5043643. Medical Review Tables 35, 39โ41, 48, Ref ID 5043097. FAS = Full Analysis Set. NRI = Non-Responder Imputation. DEUC = deucravacitinib; PBO = placebo; APR = apremilast. ss-PGA analysis includes only subjects with baseline ss-PGA โฅ3. Examination of age, gender, race, body weight, baseline disease severity, and prior systemic therapy did not identify differences in response to deucravacitinib at Week 16 among these subgroups.
Safety Profile
Section 6.1 (Label); 0โ52 week data
โ No Boxed Warning โ Potential JAK inhibition risks (Section 5.8): It is not known whether TYK2 inhibition may be associated with the observed or potential adverse reactions of JAK inhibition. Higher rates of all-cause mortality, MACE, overall thrombosis, DVT, PE, and malignancies were observed with another JAK inhibitor vs TNF blockers in RA patients โฅ50 years with โฅ1 CV risk factor. Deucravacitinib is NOT approved for RA and does NOT carry the Boxed Warning applicable to JAK inhibitors approved for chronic inflammatory conditions. A post-approval randomised long-term safety trial vs an active comparator in psoriasis patients was required by FDA.
Safety database: Two placebo- and active-controlled trials (PSO-1, PSO-2) + open-label extension. Total 1,519 subjects received deucravacitinib 6 mg QD; 1,141 exposed โฅ1 year; 986 patient-years exposure in the 0โ52 week period of PSO-1 and PSO-2. 16-week placebo-controlled pool: 840 deucravacitinib vs 419 placebo. Discontinuation due to ADRs: 2.4% (deucravacitinib) vs 3.8% (placebo) through Week 16.
Adverse Reactions โฅ1% (Label Table 1) โ 16-Week Placebo-Controlled Period
Deucravacitinib 6 mg QD N=840 vs Placebo N=419| Adverse Reaction | Deucravacitinib 6 mg QD (N=840) | Placebo (N=419) | Exposure-Adjusted Rate (DEUC vs PBO, /100 pt-yrs, Wk 0โ16) | Notes |
|---|---|---|---|---|
| Upper respiratory infections (incl. URTI, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis, tonsillitis) | 161 (19.2%) | 62 (14.8%) | 116 vs 83.7 per 100 pt-yrs (all infections) | Most common ADR; majority non-serious, mild-moderate; did not lead to discontinuation |
| Blood creatine phosphokinase (CPK) increased | 23 (2.7%) | 5 (1.2%) | 9.3 vs 4.1 /100 pt-yrs (incl. Grade 4) | Rhabdomyolysis cases reported โ see Warnings. Discontinue if markedly elevated or myopathy suspected. |
| Herpes simplex (oral, genital, herpes simplex, herpes virus) | 17 (2.0%) | 1 (0.2%) | 6.8 vs 0.8 /100 pt-yrs | Notable excess vs placebo. Multi-dermatomal HZ reported in one immunocompetent subject. |
| Mouth ulcers (aphthous ulcer, stomatitis, tongue ulceration) | 16 (1.9%) | 0 (0.0%) | โ | No cases in placebo group; mechanism not established |
| Folliculitis | 14 (1.7%) | 0 (0.0%) | โ | No cases in placebo group |
| Acne (acne, acne cystic, dermatitis acneiform) | 12 (1.4%) | 1 (0.2%) | โ | Modest excess vs placebo |
| Herpes zoster | <1% | <1% | โ | Occurred in <1% in SOTYKTU group (not listed in Table 1); majority of zoster events across trials in subjects <50 years of age |
Specific Adverse Reactions โ Exposure-Adjusted Incidence (Key Safety Events)
All Infections (0โ16 wks)
29% of deucravacitinib group (116 events/100 pt-yrs) vs 22% of placebo (83.7/100 pt-yrs). Majority non-serious, mild-moderate. Did not lead to discontinuation. Most common serious infections (0โ52 weeks): pneumonia and COVID-19.
Serious Infections
0โ16 weeks: 5 subjects (2.0/100 pt-yrs) deucravacitinib vs 2 subjects (1.6/100 pt-yrs) placebo. Most common serious infections at 0โ52 weeks: pneumonia and COVID-19.
Rhabdomyolysis (Section 5.5)
Cases of rhabdomyolysis resulting in treatment interruption or discontinuation were reported. Increased incidence of asymptomatic CPK elevation (including Grade 4: 9.3 vs 4.1/100 pt-yrs) vs placebo. Discontinue if markedly elevated CPK or myopathy suspected. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness especially with malaise or fever.
Malignancies (incl. Lymphoma)
0โ52 weeks in PSO-1 + PSO-2 (986 pt-yrs): 3 subjects (0.3/100 pt-yrs) โ breast cancer (Wk 24), hepatocellular carcinoma (Wk 32), lymphoma (Wk 25). Across PSO-1, PSO-2 + open-label extension: 3 subjects (0.1/100 pt-yrs) developed lymphoma at Wks 25, 77, and 98. EAIR of lymphoma (~0.1/100 pt-yrs) higher than background psoriasis rate (~0.04โ0.06/100 pt-yrs); comparable to tofacitinib 10 mg BID in RA.
CPK Elevations (Section 5.5)
0โ16 weeks: increased CPK (incl. Grade 4) in 23 subjects (9.3/100 pt-yrs) deucravacitinib vs 5 subjects (4.1/100 pt-yrs) placebo. Cases of rhabdomyolysis specifically reported.
Liver Enzyme Elevations (Section 5.6)
0โ16 weeks: ALT โฅ3รULN: 9 subjects (3.6/100 pt-yrs) vs 2 placebo (1.6/100 pt-yrs). AST โฅ3รULN: 13 subjects (5.2/100 pt-yrs) vs 2 placebo (1.6/100 pt-yrs). Evaluate LFTs at baseline in patients with known/suspected liver disease.
Triglyceride Elevations (Section 5.6)
Mean triglycerides increased by 10.3 mg/dL at 16 weeks and 9.1 mg/dL at 52 weeks. Periodically evaluate per hyperlipidemia clinical guidelines. CV significance not determined.
Decreased GFR
0โ16 weeks in subjects with moderate renal impairment (eGFR 30โ59) at baseline: decreased GFR in 4 subjects (1.6/100 pt-yrs) deucravacitinib vs 1 placebo (0.8/100 pt-yrs). Two deucravacitinib-treated subjects had worsening proteinuria. Monitor renal function in patients with pre-existing renal impairment.
Warnings & Precautions
Section 5- Hypersensitivity (5.1): Angioedema reported. Discontinue if clinically significant hypersensitivity reaction occurs and institute appropriate therapy.
- Infections (5.2): Increased risk of infections. Most common serious infections: pneumonia and COVID-19. Avoid in active/serious infection. Consider risks/benefits in chronic/recurrent infection, TB exposure, history of serious or opportunistic infection, or underlying predisposing conditions. Interrupt if serious infection develops; resume only when resolved or adequately treated. Multi-dermatomal HZ reported in an immunocompetent subject. Herpes simplex incidence significantly elevated vs placebo. Consider hepatitis B/C screening and monitoring.
- Tuberculosis (5.3): Evaluate for active and latent TB before initiating. Do not administer in active TB. Initiate latent TB treatment before SOTYKTU. One subject without latent TB developed active TB after 54 weeks of deucravacitinib. Monitor during treatment.
- Malignancy including Lymphomas (5.4): Malignancies including lymphomas observed in clinical trials. Consider risks/benefits in patients with known malignancy (other than successfully treated NMSC). EAIR of lymphoma (~0.1/100 pt-yrs) exceeds psoriasis background rate.
- Rhabdomyolysis and Elevated CPK (5.5): Cases of rhabdomyolysis resulting in treatment interruption/discontinuation. Increased incidence of CPK elevation including Grade 4. Discontinue if markedly elevated CPK or myopathy diagnosed/suspected. Prompt reporting of unexplained muscle symptoms required.
- Laboratory Abnormalities (5.6): Triglyceride elevations โ periodically evaluate per hyperlipidemia guidelines. Liver enzyme elevations โ evaluate at baseline in patients with known/suspected liver disease; interrupt if DILI suspected. Decreased GFR with proteinuria worsening in patients with pre-existing renal impairment.
- Immunizations (5.7): Update immunizations including prophylactic HZ vaccination before treatment. Avoid live vaccines. Response to live or non-live vaccines not evaluated.
- Potential Risks Related to JAK Inhibition (5.8): It is not known whether TYK2 inhibition carries the same risks as JAK inhibition. Class risks described above from RA postmarketing data noted in labeling as potential risks. Post-approval long-term randomised safety trial required.
Source: NDA 214958 label Sections 5โ6, Ref ID 5043643 (Revised 9/2022). Safety through Week 52: the exposure-adjusted incidence rate of adverse reactions in subjects treated continuously from Week 0 through Week 52 did not increase compared to the first 16 weeks. Geriatric use (โฅ65 years): higher rate of overall serious adverse reactions (including serious infections) and discontinuations during Week 0โ16 in subjects โฅ65 years vs younger adults; no overall difference in effectiveness.
Pharmacology & Pharmacokinetics
Sections 12.1โ12.3 / LabelOral Bioavailability
99%
Near-complete absolute oral bioavailability. Tmax 2โ3 hours in healthy subjects. Dose-proportional Cmax and AUC over 3โ36 mg (0.5โ6ร approved dose). Accumulation <1.4-fold with QD dosing.
Half-Life (tยฝ)
10 hours
Terminal tยฝ 10 hours; supports once-daily dosing. Steady state Cmax 45 ng/mL; AUCโโ 473 ngยทhr/mL at 6 mg QD. Active metabolite BMT-153261: Cmax 5 ng/mL; AUCโโ 95 ngยทhr/mL (~20% of total exposure).
Protein Binding
82โ90%
Plasma protein binding 82โ90%. Volume of distribution at steady state 140 L. Blood-to-plasma ratio 1.26.
Primary Metabolism
CYP1A2 โ BMT-153261
CYP1A2 forms major active metabolite BMT-153261 (comparable potency to parent; ~20% of total exposure). Also: CYP2B6, CYP2D6, CES2, UGT1A9. BMT-153261 AUC lower by 20โ50% in moderate/severe hepatic impairment โ total exposure modestly increased.
Excretion
13% urine / 26% feces (unchanged)
After radiolabelled dose: 13% unchanged drug in urine, 26% in feces. BMT-153261: 6% urine, 12% feces. Renal clearance 27โ54 mL/min. Dialysis removes only 5.4% per session โ not useful for overdose management.
QTc Effect
No Prolongation
At 6ร the approved dose (36 mg), no clinically relevant QTc prolongation. Pharmacodynamics: reduced IL-17A (47โ50%), IL-19 (72%), and beta-defensin (81โ84%) at Wk 16 in psoriatic skin.
Food Effect
High-fat, high-calorie meal (951 kcal; 52% fat, 33% CHO, 15% protein): Cmax reduced ~24% and AUC reduced ~11%; Tmax prolonged ~1 hour for parent. BMT-153261 similarly reduced ~23% Cmax and ~10% AUC, Tmax prolonged ~2 hours. These changes are not clinically significant. Administer with or without food.
Special Populations โ PK
| Population | Deucravacitinib PK Effect | BMT-153261 Effect | Recommendation |
|---|---|---|---|
| Mild RI (eGFR 60โ89) | Cmax โ14%; AUCinf unchanged | Cmax โ11%; AUCinf โ2% | No dose adjustment |
| Moderate RI (eGFR 30โ59) | Cmax +6%; AUCinf +39% | Cmax โ8%; AUCinf +24% | No dose adjustment |
| Severe RI (eGFR <30) | Cmax unchanged; AUCinf +28% | Cmax +28%; AUCinf +81% | No dose adjustment |
| ESRD on dialysis | AUCinf +34%; dialysis removes 5.4% | AUCinf +27% | No dose adjustment |
| Mild HI (Child Pugh A) | Cmax +4%; AUCinf +10% | Cmax โ25%; AUCinf โ3% | No dose adjustment |
| Moderate HI (Child Pugh B) | Cmax +10%; AUCinf +40% | Cmax โ59%; AUCinf โ20% | No dose adjustment |
| Severe HI (Child Pugh C) | Cmax +1%; AUCinf +43% | Cmax โ79%; AUCinf โ50% | NOT RECOMMENDED |
| Body weight, gender, race, age | No clinically meaningful effect on deucravacitinib exposure | No dose adjustment | |
Drug Interactions (Section 12.3)
| Interacting Agent | Direction | Magnitude / Notes | Recommendation |
|---|---|---|---|
| CYP1A2 inhibitor (fluvoxamine) | No significant effect on deucravacitinib PK | Not clinically significant | No dose adjustment |
| CYP1A2 inducer (ritonavir) | No significant effect on deucravacitinib PK | Not clinically significant | No dose adjustment |
| Dual Pgp/BCRP inhibitor (cyclosporine) | No significant effect | Not clinically significant | No dose adjustment (DDI only; cyclosporine as potent immunosuppressant is addressed in Limitations of Use) |
| UGT1A9 inhibitor (diflunisal) | No significant effect | Not clinically significant | No dose adjustment |
| OCT1 inhibitor (pyrimethamine) | No significant effect | Not clinically significant | No dose adjustment |
| H2 blocker (famotidine) / PPI (rabeprazole) | No significant effect | pH-dependent solubility does not affect systemic exposure | No dose adjustment |
| Rosuvastatin, methotrexate, MMF, OCP (norethindrone + EE) | No significant effect on co-administered drug PK | Not clinically significant | No dose adjustment for any co-administered drug |
| BCRP substrate / inhibitor | In vitro: BCRP substrate and BCRP inhibitor; also OATP1B3 inhibitor | Clinical significance not established | Monitor per clinical judgement for sensitive BCRP substrates |
Clean DDI profile: Deucravacitinib is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro. It is not an inhibitor of CES2, UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7. It is not a substrate of OATP, NTCP, OAT1, OAT3, OCT2, MATE1, or MATE2K. This profile โ including co-administration with methotrexate and MMF without significant PK interactions โ is clinically relevant given the common use of concomitant agents in moderate-to-severe psoriasis patients.
Source: NDA 214958 label Section 12, Ref ID 5043643. Molecular formula: CโโHโโDโNโOโ; MW 425.47 (free base). Chemical name: 6-(cyclopropanecarbonylamido)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide. The D3 (trideuteriomethyl) substitution reduces CYP1A2-mediated N-demethylation, contributing to the longer tยฝ (10 hours) compared to the non-deuterated analogue. BMT-153261 (active metabolite) has comparable potency to parent but contributes only ~20% of total drug-related exposure at steady state.
Dosing, Administration & Contraindications
Sections 2, 4, 5 / LabelRecommended Dose
6 mg QD
6 mg orally once daily, with or without food. Do not crush, cut, or chew tablets.
Population
Adults Only
โฅ18 years; safety and effectiveness NOT established in pediatric patients
Contraindication
Hypersensitivity Only
Known hypersensitivity to deucravacitinib or any excipient. No pharmacogenomic (CYP) contraindication. No CBC threshold requirement before initiation.
Limitations of Use
Not With Potent Immunosuppressants
Not recommended in combination with other potent immunosuppressants (e.g., cyclosporine, methotrexate, biologics)
Pre-Treatment Evaluation (Section 2.1)
Required Before Initiating
- TB evaluation: Active TB โ do not initiate. Latent TB or high-risk negative โ start preventive TB therapy before deucravacitinib.
- Viral hepatitis screening: Per clinical guidelines. Consider HBV/HCV screening and monitoring for reactivation. Not recommended in active hepatitis B or C.
- Liver enzymes: Evaluate at baseline in patients with known or suspected liver disease.
- Immunizations: Update all immunizations per current guidelines, including prophylactic herpes zoster vaccination, before initiating treatment.
- Lipids (triglycerides): Baseline assessment; repeat periodically during treatment.
- No CBC thresholds: Unlike JAK inhibitors, deucravacitinib does not require pre-treatment ALC or platelet count thresholds for initiation.
Monitoring During Treatment
- Infections: Closely monitor for signs and symptoms. Interrupt if serious or opportunistic infection develops; resume when resolved/adequately treated.
- CPK / Rhabdomyolysis: Promptly evaluate unexplained muscle pain, tenderness, or weakness with malaise/fever. Discontinue if markedly elevated CPK or myopathy.
- Triglycerides: Periodically evaluate per hyperlipidemia guidelines; manage accordingly.
- Liver enzymes: Monitor in patients with known or suspected liver disease. Interrupt if DILI suspected.
- Malignancy: Consider periodic skin examinations in patients at increased risk for skin cancer.
- Live vaccines: Avoid during treatment; response to vaccines not evaluated.
Special Populations (Section 8)
| Population | Guidance |
|---|---|
| Pregnancy (8.1) | Insufficient data from case reports. No embryo-fetal toxicity in animals at doses โฅ91ร MRHD. Advisable to avoid โ 13 inadvertent exposures in trials, no reported adverse outcomes. Pregnancy registry: 1-800-721-5072. |
| Lactation (8.2) | No human data. Deucravacitinib and/or metabolites present in rat milk. Consider benefits of breastfeeding vs potential risks. |
| Pediatric Use (8.4) | Safety and effectiveness NOT established. Not approved for any pediatric indication. |
| Geriatric Use (8.5) | 152 subjects (10%) aged โฅ65; 21 (1.4%) aged โฅ75. Higher rate of serious ADRs including serious infections and discontinuations in โฅ65 years during Wk 0โ16. No overall difference in effectiveness vs younger adults. |
| Renal Impairment (8.6) | No dose adjustment for mild, moderate, severe renal impairment or ESRD on dialysis. AUCinf modestly higher in moderate (+39%), severe (+28%), and ESRD (+34%); not considered clinically significant. |
| Hepatic Impairment (8.7) | No dose adjustment for mild (Child Pugh A) or moderate (Child Pugh B). NOT RECOMMENDED in severe HI (Child Pugh C). |
Storage & Supply (Section 16)
| Item | Detail |
|---|---|
| Storage | 20ยฐCโ25ยฐC (68ยฐโ77ยฐF); excursions 15ยฐโ30ยฐC; USP Controlled Room Temperature |
| Tablet description | 6 mg; pink, round, biconvex, film-coated; laser-printed “BMS 895” and “6 mg” on one side |
| NDC | 0003-0895-11 (bottles of 30, child-resistant closure) |
| Manufacturer | Bristol-Myers Squibb Company, Princeton, NJ 08543 USA |
| Patient support | SOTYKTU 360 SUPPORT: 1-888-SOTYKTU (768-9588); www.sotyktu.com |
| Adverse events | 1-800-721-5072 (BMS); FDA MedWatch 1-800-FDA-1088 |
Source: NDA 214958 label, Ref ID 5043643, Revised 9/2022. Inactive ingredients: anhydrous lactose, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, silicon dioxide. Film coating (Opadryยฎ II Pink): iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide. Solubility of deucravacitinib is pH-dependent; decreases with increasing pH.
Regulatory History
NDA 214958 โ Standard ReviewApplication Type
NDA 505(b)(1)
New Drug Application; Standard Review; New Molecular Entity (NME); first-in-class TYK2 inhibitor globally. Code name: BMS-986165.
Reviewing Division
DDD / OII
Division of Dermatology and Dentistry, Office of Immunology and Inflammation, CDER. Review completed September 9, 2022.
PDUFA Goal Date
Sep 10, 2022
Submitted September 10, 2021; review completed September 9, 2022 โ one day before PDUFA goal date
Approval Date
Sep 9, 2022
First TYK2 inhibitor approved for any indication worldwide; first new oral mechanism class for psoriasis since apremilast (2014)
Regulatory Timeline
NCT03624127 / NCT03611751
Phase 3 Trials PSO-1 and PSO-2 Conducted
Two 52-week, multicenter, randomized, double-blind, placebo- and active-controlled (apremilast) trials. Total 1,684 subjects with moderate-to-severe plaque psoriasis. Primary endpoint: sPGA 0/1 and PASI 75 at Week 16.
SEPTEMBER 10, 2021
NDA 214958 Submitted and Received
Bristol-Myers Squibb submitted NDA 214958 for deucravacitinib 6 mg QD for moderate-to-severe plaque psoriasis in adults. Standard Review designation. PDUFA goal date: September 10, 2022.
JULY 6, 2022
MPPRC Discussion โ Boxed Warning Decision
Medical Policy and Program Review Council (MPPRC) discussion regarding whether deucravacitinib labeling should carry the same Boxed Warning as JAK inhibitors. MPPRC advised that labeling communicate scientific information from the deucravacitinib programme AND inform of potential JAK inhibition risks โ without a full Boxed Warning. Post-approval long-term safety trial required.
SEPTEMBER 9, 2022
FDA Approval โ NDA 214958 (SOTYKTU)
Deucravacitinib 6 mg QD approved for treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. First TYK2 inhibitor approved for any indication globally. Label Revised 9/2022. Ref IDs 5043643 (label), 5043097 (medical review).
Regulatory Submission Summary
| Aspect | Detail |
|---|---|
| Application number | NDA 214958 (Orig1s000) |
| Code name | BMS-986165 |
| Applicant | Bristol-Myers Squibb Company, Princeton, NJ 08543 USA |
| Submission / receipt date | September 10, 2021 |
| PDUFA goal date | September 10, 2022 |
| Review completion date | September 9, 2022 |
| Approval date | September 9, 2022 (Initial U.S. Approval: 2022) |
| Pivotal trials | PSO-1 (IM011046; NCT03624127) and PSO-2 (IM011047; NCT03611751) โ two adequate and well-controlled Phase 3 trials |
| Primary endpoints met | sPGA 0/1 at Wk 16: 54% vs 7% (PSO-1) and 50% vs 9% (PSO-2) placebo; PASI 75 at Wk 16: 58% vs 13% (PSO-1) and 53% vs 9% (PSO-2); all p<0.001 |
| Active comparator superiority | Superior to apremilast for sPGA 0/1, PASI 75, PASI 90, ss-PGA 0/1 at Weeks 16 and 24 in both trials; all p<0.001 |
| Unique regulatory features | 1. First TYK2 inhibitor approved for any indication globally. 2. Novel pseudokinase (JH2) domain binding mechanism โ allosteric, not competitive ATP-site inhibition. 3. No Boxed Warning despite TYK2 being in the JAK family โ per MPPRC decision, labelling communicates scientific information and potential risks but does not impose the full JAK inhibitor Boxed Warning. 4. Post-approval long-term randomised clinical trial with active comparator in psoriasis required as PMR. |
| Reference IDs | 5043643 (label, Revised 9/2022) / 5043097 (multi-disciplinary review) |
| Safety database at approval | 1,519 subjects; 1,141 exposed โฅ1 year; two 52-week controlled trials + open-label extension |
Source: NDA 214958 label, Ref ID 5043643, Revised 9/2022; NDA 214958 Multi-disciplinary Review, Ref ID 5043097, completed September 9, 2022. Reviewed under Division of Dermatology and Dentistry (DDD), Office of Immunology and Inflammation (OII), CDER. Deucravacitinib is a new molecular entity with no prior approval in any indication globally at the time of FDA approval. The approval positioned deucravacitinib as the first oral therapy for psoriasis with demonstrated superiority over apremilast in Phase 3 RCTs.
