Summary Basis of Decision for Sotyktu
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Sotyktu is located below.
Recent Activity for Sotyktu
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Sotyktu
Date SBD issued: 2023-03-10
The following information relates to the new drug submission for Sotyktu.
Deucravacitinib
Drug Identification Number (DIN):
- DIN 02533030 - 6 mg deucravacitinib, tablet, oral administration
Bristol-Myers Squibb Canada
New Drug Submission Control Number: 259397
On November 24, 2022, Health Canada issued a Notice of Compliance to Bristol‑Myers Squibb Canada for the drug product Sotyktu.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit‑harm-uncertainty profile of Sotyktu is favourable for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
1 What was approved?
Sotyktu, a selective immunosuppressant, was authorized for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
No data are available to Health Canada regarding the use of Sotyktu in pediatric patients (younger than 18 years of age). Therefore, Health Canada has not authorized an indication for pediatric use.
No overall differences were observed in Sotyktu exposure, safety or effectiveness between geriatric (65 years of age and over) and younger patients. There is limited information in subjects aged 75 years and over.
Sotyktu (6 mg deucravacitinib) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains anhydrous lactose, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, Opadry II Pink (iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide), and silicon dioxide.
The use of Sotyktu is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medical ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Sotyktu Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Sotyktu approved?
Health Canada considers that the benefit-harm-uncertainty profile of Sotyktu is favourable for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Psoriasis is a chronic inflammatory skin disorder characterized primarily by erythematous scaly plaques. It affects up to 3% of the population worldwide. While psoriatic lesions can involve the skin on any part of the body, the involvement of anatomic regions such as the hands and feet (palmoplantar psoriasis), face, scalp, or nails can be disabling. Mild psoriasis is defined as ≤10% body surface area (BSA) involvement, and moderate to severe psoriasis is defined as >10% BSA involvement. Psoriasis has a profound impact on quality of life and can lead to psychological, social, and economic consequences, especially in cases of moderate to severe disease. This condition is also associated with an increased risk of depression, sleep disturbances, social stigma, and decreased work productivity. Diabetes mellitus and metabolic syndrome are among the comorbidities commonly found in patients with psoriasis. In patients with more severe forms of the disease, life expectancy is decreased due to an increased risk of cardiovascular disease.
Approved treatments for moderate to severe plaque psoriasis include phototherapy, oral systemic drugs (T‑cell inhibitors, antimetabolites, fumarates, phosphodiesterase 4 inhibitors), and biologics (tumor necrosis factor inhibitors and various interleukin [IL] inhibitors, including IL‑23 inhibitors).
Deucravacitinib, the medicinal ingredient in Sotyktu, is an oral, selective tyrosine kinase 2 (TYK2) inhibitor. Tyrosine kinase 2 is an intracellular non‑receptor kinase that mediates the signalling of the pro‑inflammatory cytokines IL‑23 and IL‑12, and type I interferons (IFNs). These are naturally occurring cytokines that are upregulated in inflammatory and immune responses. The specificity of deucravacitinib is attributed to its ability to bind to the regulatory domain of TYK2. This avoids the conserved active site in the kinase domain, resulting in inhibition of TYK2 without inhibiting the other members of the Janus kinase (JAK) family (JAK1, JAK2, or JAK3) at clinically relevant concentrations. The Janus kinases JAK1, JAK2 and JAK3 mediate a broad range of cytokines and growth factors implicated in hematopoiesis, maintenance of natural killer cell and T‑cell numbers, and lipid homeostasis. In contrast, TYK2 mediates signalling of a restricted number of cytokines, and is solely required for immune system activity. It is not required for the generation or maintenance of immune system cells, for hematopoiesis, or for lipid homeostasis.
The main evidence of the clinical safety and efficacy of Sotyktu was provided through results from two pivotal Phase III studies, PSO‑1 and PSO‑2. Additionally, a Phase IIIb open‑label extension study was designed to assess the long‑term safety of Sotyktu.
The pivotal Phase III studies, PSO‑1 and PSO‑2, enrolled patients 18 years of age and older with moderate to severe plaque psoriasis who were eligible for systemic therapy or phototherapy. In total, 1,686 patients were evaluated in the two pivotal studies, with 843 patients randomized to receive Sotyktu 6 mg once daily, 422 patients randomized to receive apremilast 30 mg twice daily, and 421 patients randomized to the placebo group. Both studies were double‑blind and placebo‑controlled through Week 16, apremilast-controlled through Week 24, and were of 52 weeks in treatment duration.
Both studies evaluated responses at Week 16 compared to placebo for the two co‑primary endpoints:
- the proportion of patients who achieved a static Physician’s Global Assessment (sPGA) score of 0 (clear) or 1 (almost clear), and
- the proportion of patients who achieved at least a 75% improvement in the Psoriasis Area and Severity Index (PASI) score (PASI 75) from baseline.
In both studies, significantly greater proportions of patients treated with Sotyktu achieved PASI 75 and sPGA 0/1 responses compared with placebo at Week 16 (p<0.0001), demonstrating the superiority of Sotyktu over placebo. A consistent and favourable treatment effect was observed for Sotyktu compared to placebo across multiple subgroups, including those based on baseline demographics, disease characteristics, and prior psoriasis treatment.
Sotyktu was well tolerated in PSO‑1 and PSO‑2. The overall incidence of adverse events with Sotyktu (55.7%) was higher than placebo (49.6%) but was comparable to apremilast (57.6%) through Week 16. The incidence of serious adverse events was similar and low across the treatment groups (1.8%, 2.9%, and 1.2% in the Sotyktu, placebo, and apremilast groups, respectively), with no specific type of serious adverse events observed more than once in any treatment group. The incidence of adverse events leading to treatment discontinuation was lower for Sotyktu (2.4%) than for placebo (3.8%) and apremilast (5.2%). Infections occurred more frequently with Sotyktu (29.1%) compared with placebo (21.5%) and apremilast (22.0%) through Week 16. Infections were predominantly mild or moderate in severity, resolved with usual care, and were rarely serious or led to treatment discontinuation.
The ongoing Phase IIIb open‑label extension study (IM011075) enrolled patients who completed either of the pivotal trials. It was designed to assess the long‑term safety of Sotyktu at a dose of 6 mg once daily, with a planned duration of approximately 5 years. Approximately 95% of patients from the PSO‑1 and PSO‑2 studies enrolled in the study. As of the data cut‑off date (June 15, 2021), the median duration of exposure to Sotyktu in PSO‑1, PSO‑2, and IM011075 was 84 weeks (588.0 days), and 90% of all patients remained enrolled in the study.
No new safety signals were identified in the open‑label extension study compared to the pivotal studies. Extended exposure of Sotyktu did not appear to correlate with increases in serious adverse events, deaths, or discontinuations. Causal attribution of long‑term safety trends was hampered by the coronavirus disease 2019 (COVID‑19) pandemic, which skewed the rates of infections and other related symptoms.
Overall, the clinical data support the safety and efficacy of Sotyktu in adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
A Risk Management Plan (RMP) for Sotyktu was submitted by Bristol‑Myers Squibb Canada to Health Canada. The RMP is designed to describe known and potential safety issues, to present safety monitoring activities and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Sotyktu Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Sotyktu was accepted.
Sotyktu has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Sotyktu Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Sotyktu?
The review of the New Drug Submission (NDS) for Sotyktu was based on a critical assessment of the data package submitted to Health Canada. In the course of reviewing the clinical and quality components of the NDS, Health Canada used the review completed by the United States Food and Drug Administration (FDA) as an added reference, in accordance with Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Additionally, for the review of the quality data package, Health Canada used the sponsor’s responses to questions by the FDA, the European Medicines Agency and Australia’s Therapeutic Goods Administration as added references, as per the aforementioned Method 3.
The Canadian regulatory decision regarding the Sotyktu NDS was made independently based on the Canadian review.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Sotyktu
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2021-10-26 |
| New Drug Submission filed | 2021-12-08 |
| Screening | |
| Screening Acceptance Letter issued | 2022-01-28 |
| Review | |
| Biostatistics evaluation completed | 2022-10-31 |
| Non-clinical evaluation completed | 2022-11-17 |
| Review of Risk Management Plan completed | 2022-11-18 |
| Quality evaluation completed | 2022-11-21 |
| Clinical/medical evaluation completed | 2022-11-22 |
| Labelling review completed | 2022-11-22 |
| Notice of Compliance issued by Director General, Pharmaceutical Products Directorate | 2022-11-24 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
As described above, the clinical review of the New Drug Submission for Sotyktu was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
Tyrosine kinase 2 (TYK2) is an enzyme which mediates the signalling of interleukin‑23, interleukin‑12, and type I interferons (IFNs), which are naturally occurring cytokines that are upregulated in inflammatory and immune responses. Deucravacitinib, the medicinal ingredient in Sotyktu, is a small molecule that selectively inhibits the TYK2 enzyme, thereby inhibiting its downstream functions in cells, including the release of pro‑inflammatory cytokines and chemokines.
The pharmacokinetics of deucravacitinib was evaluated based on data from the administration of single or repeat doses to healthy participants and repeat doses to patients with moderate to severe psoriasis. The pharmacokinetic profile of deucravacitinib is characterized by rapid and near complete absorption, dose‑related increase in exposure, and no evidence of time‑dependent pharmacokinetics. In healthy participants, deucravacitinib exhibited linear pharmacokinetics over the 3 mg to 36 mg dose range (0.5 to 6 times the approved recommended dosage) when given as a single‑dose tablet formulation. In healthy participants, the absolute oral bioavailability of deucravacitinib tablets (12 mg) was 99%, and the median time to maximum concentration (Tmax) of deucravacitinib ranged from 2 to 3 hours.
At the recommended clinical dose of 6 mg daily, the mean terminal half‑life of deucravacitinib was approximately 10 hours in healthy participants. The half‑life in healthy participants and in patients with plaque psoriasis is expected to be comparable based on a population pharmacokinetic analysis. Consistent with this half‑life, modest accumulation (less than 1.4‑fold) was observed following once‑daily dosing in healthy participants. The prediction based on population pharmacokinetic analysis in patients with plaque psoriasis taking a 6 mg daily dose was comparable (1.24‑fold).
At steady state (Day 12), deucravacitinib was the major circulating species in plasma, accounting for 49% of the measured drug‑related components and approximately 82% of the in vivo pharmacological activity. In humans, deucravacitinib is metabolized by cytochrome P450 (CYP) 1A2, carboxylesterase 2, uridine diphosphate glucuronosyltransferase (UGT), and CYP2B6/2D6. Each of the two major circulating metabolites, BMT‑153261 and BMT‑158170, accounts for approximately 20% of the measured drug‑related components and have a half‑life comparable to that of deucravacitinib. While BMT‑153261 has comparable potency to deucravacitinib, BMT‑158170 is not pharmacologically active. The metabolite BMT‑334616 represented approximately 9% of measured drug‑related components, while circulating exposures of the metabolite M11 in humans were not measurable in a study that assessed the absorption, distribution, metabolism, and excretion of 14C‑deucravacitinib. No unique human metabolites and no long‑lived circulating metabolites were identified.
Following oral administration of deucravacitinib, 99% of the dose was absorbed into the systemic circulation. It was subsequently eliminated via multiple pathways, including Phase I and II metabolism and direct renal and fecal elimination, with no predominant single pathway responsible for elimination. Direct urinary elimination and fecal elimination of the parent drug accounted for 13% and 26% of the administered dose, respectively. The metabolites BMT‑153261 and BMT‑158170 are also eliminated via the renal and fecal pathways.
In healthy participants, two TYK2‑dependent pathways were found to be inhibited by deucravacitinib based on findings from ex vivo whole blood assays, indicating robust target engagement. The maximal inhibition was observed one hour after dosing and returned to near baseline by the end of the dosing interval (12 or 24 hours). Additionally, IFN‑regulated gene expression was inhibited in vivo in a dose‑dependent manner in subjects to whom IFNα was administered, providing evidence that deucravacitinib inhibits TYK2 in vivo.
In patients with psoriasis, deucravacitinib reduced psoriasis‑associated gene expression in psoriatic skin in a dose‑dependent manner, including reduced expression of genes regulated by the IL‑23 and type I IFN pathways, and reduced levels of serum biomarkers associated with psoriasis disease activity.
Administration of the 6 mg deucravacitinib tablet with a high‑fat, high calorie meal delayed absorption by 1 hour (median Tmax of 4 hours) and decreased the Cmax and area under the concentration‑time curve to the time of the last quantifiable concentration (AUCT) by 24% and 11% respectively. Sotyktu may be administered without regard to food.
In a dedicated study, no clinically relevant effects were observed on the corrected QT (QTc) interval in patients with psoriasis at an exposure level 7 times higher than the maximum exposure achieved by the 6 mg daily dose.
Based on data from a series of drug‑drug interaction studies, the co‑administration of deucravacitinib with relevant CYP enzyme and transporter modulators is not expected to have meaningful drug‑drug interaction potential.
Mild (Child‑Pugh Class A) and moderate (Child‑Pugh Class B) hepatic impairment were not found to have clinically meaningful effects on deucravacitinib exposures. Therefore, no dose adjustment is needed for these patients. In patients with severe hepatic impairment, the maximum observed concentration of the unbound drug (unbound Cmax) increased by 62% and the total exposure as measured by the area under the concentration‑time curve to infinite time (AUC[0‑inf]) increased by 131%. The clinical data available are not sufficient to thoroughly evaluate the risk in this patient population. Deucravacitinib is therefore not recommended in patients with severe hepatic impairment.
Renal impairment was not found to have any clinically meaningful effect on deucravacitinib exposures. No dose adjustment is required for patients with mild, moderate or severe renal impairment, or in patients with end‑stage renal disease on dialysis.
Overall, the clinical pharmacology data submitted were found to be appropriate to support this submission. The clinical pharmacology data does not raise any concerns that would preclude the authorization of Sotyktu for the proposed indication.
For further details, please refer to the Sotyktu Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The main evidence of the clinical efficacy of Sotyktu (deucravacitinib) was provided by the results of two pivotal Phase III studies, PSO‑1 and PSO‑2. Data from a Phase II dose‑finding study were also submitted to support the New Drug Submission (NDS) for Sotyktu. A Phase IIIb open‑label extension study designed to assess the long‑term safety of Sotyktu is described in the Clinical Safety section.
The Phase II dose‑finding study, IM011011, was designed to assess the pharmacokinetics, safety, and efficacy of five dose regimens of Sotyktu compared to placebo in patients with moderate to severe plaque psoriasis. The results provided evidence of the biologic activity of deucravacitinib in a relevant patient population. Based on the results of this study, the dose regimen selected for Phase III studies was 6 mg once daily.
The pivotal Phase III studies, PSO‑1 and PSO‑2, enrolled patients 18 years of age and older with moderate to severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Patients had a body surface area (BSA) involvement of 10% or greater, a Psoriasis Area and Severity Index (PASI) score of 12 or greater, and a static Physician’s Global Assessment (sPGA) score of 3 or higher (moderate or severe) on a 5‑point scale of overall disease severity.
In total, 1,686 patients were evaluated in the two pivotal studies, with 843 patients randomized to receive Sotyktu 6 mg once daily, 422 patients randomized to receive apremilast 30 mg twice daily, and 421 patients randomized to the placebo group. Both studies were double‑blind and placebo‑controlled through Week 16, apremilast‑controlled through Week 24, and were of 52 weeks in treatment duration.
In PSO‑1, patients randomized to Sotyktu were treated with Sotyktu up to Week 52. Patients randomized to the placebo group received the placebo up to Week 16, and then were treated with Sotyktu up to Week 52. Patients randomized to apremilast who did not achieve a 50% improvement in PASI score from baseline (PASI 50) at Week 24 were switched to receive Sotyktu up to Week 52.
In PSO‑2, patients randomized to Sotyktu who achieved a 75% improvement in PASI score from baseline (PASI 75) at Week 24 were re‑randomized 1:1 to either continue treatment with Sotyktu (maintenance) or switch to placebo (withdrawal). Patients initially randomized to the placebo group received the placebo up to Week 16, and then were treated with Sotyktu up to Week 52. Patients randomized to apremilast who did not achieve PASI 75 at Week 24 switched to Sotyktu and continued up to Week 52.
The two co‑primary endpoints for both studies were:
- the proportion of patients who achieved a sPGA score of 0 (clear) or 1 (almost clear) at week 16 compared to placebo, and
- the proportion of patients who achieved at least PASI 75 at week 16 compared to placebo.
Statistical significance was achieved for the co‑primary endpoints. Significantly greater proportions of patients treated with Sotyktu achieved PASI 75 and sPGA 0/1 responses compared with placebo at Week 16 (p<0.0001), demonstrating the superiority of Sotyktu over placebo. In PSO‑1, 58.4% of patients treated with Sotyktu achieved PASI 75 at Week 16, compared to 12.7% of patients in the placebo group. A sPGA score of 0 or 1 was achieved by 53.6% of patients treated with Sotyktu and 7.2% of patients in the placebo group. In PSO‑2, 53% of patients treated with Sotyktu achieved PASI 75 at Week 16, compared to 9.4% of patients in the placebo group. A sPGA score of 0 or 1 was achieved by 49.5% of patients treated with Sotyktu and 8.6% of patients in the placebo group.
A consistent and favourable treatment effect was observed for Sotyktu compared to placebo across multiple subgroups, including those based on baseline demographics, disease characteristics, and prior psoriasis treatment.
Once statistical significance was demonstrated for the co‑primary endpoints, the key secondary endpoints were evaluated using a hierarchical testing order. The following secondary endpoints were achieved in both trials, with statistical significance compared to placebo at Week 16 in favour of Sotyktu: 90% improvement in PASI score from baseline (PASI 90), a scalp specific (ss)‑PGA score of 0 (clear) or 1 (almost clear), sPGA 0, 100% improvement in PASI score from baseline (PASI 100), a Psoriasis Signs and Symptoms Diary (PSSD) score of 0, and a Dermatology Life Quality Index (DLQI) score of 0 or 1 (no impact on quality of life).
The superiority of Sotyktu over apremilast was also demonstrated, as statistically significantly greater proportions of patients treated with Sotyktu achieved PASI 75 and sPGA 0/1 responses at week 16 compared with apremilast in both studies. Compared to apremilast, statistically significant benefits were also shown for Sotyktu in both studies at Week 16 in PASI 90, ss‑PGA 0/1, and sPGA 0, and at Week 24 in sPGA 0/1, PASI 75 and PASI 90.
While not controlled by a comparator treatment, the durability of the PASI 75 and sPGA 0/1 responses until Week 52 was also demonstrated for patients treated with Sotyktu.
Indication
Health Canada approved the following indication:
Sotyktu (deucravacitinib tablets) is indicated for:
- the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
For more information, refer to the Sotyktu Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Sotyktu was evaluated in study IM011011 and the pivotal studies PSO‑1 and PSO‑2 described in the Clinical Efficacy section, and in the Phase IIIb open‑label extension study IM011075, described below.
Safety findings from study IM011011 and pivotal studies PSO‑1 and PSO‑2
In the Phase II dose‑finding study IM011011, Sotyktu was generally safe and well tolerated. Treatment‑emergent adverse events (TEAEs) were generally mild or moderate, and few resulted in withdrawal of the study drug.
Based on the results from the pivotal Phase III studies, PSO‑1 and PSO‑2, Sotyktu was well tolerated. The overall incidence of adverse events with Sotyktu (55.7%) was higher than placebo (49.6%) but was comparable to apremilast (57.6%) through Week 16. The incidence of serious adverse events was similar and low across the treatment groups (1.8%, 2.9%, and 1.2% in the Sotyktu, placebo, and apremilast groups, respectively), with no specific type of serious adverse events observed. The incidence of adverse events leading to discontinuation was lower for Sotyktu (2.4%) than for placebo (3.8%) and apremilast (5.2%). Infections occurred more frequently with Sotyktu (29.1%) compared with placebo (21.5%) and apremilast (22.0%) through Week 16. Infections were predominantly mild or moderate in severity, resolved with usual care, and were rarely serious or led to treatment discontinuation. Due to the increased risk of infections, the product monograph recommends not using Sotyktu in combination with other potent immunosuppressants and to only begin treatment once clinically important active infections have been adequately treated or resolved.
The safety profile was similar in various subgroups based on sex, age, ethnicity, body weight or geographic region. The results of a population pharmacokinetic analysis demonstrated a higher exposure in females and in patients over 65 years of age. A small increase in adverse event rates was noted in females, but not in elderly participants. Instances of clinically relevant elevations in creatine kinase, liver transaminases and triglycerides were noted. Beyond Week 16, there was no apparent increase in adverse events in patients continuously treated with Sotyktu and no evidence of new, more frequent or more intense adverse events compared to the controlled safety period (Weeks 0 to 52).
Open‑label extension study IM011075
The ongoing Phase IIIb open‑label extension study, IM011075, was designed to assess the long‑term safety of Sotyktu at a dose of 6 mg once daily, with a planned duration of approximately 5 years. Patients enrolled in this study had completed one of the pivotal studies regardless of treatment assignment. Approximately 95% of patients from the PSO‑1 and PSO‑2 studies enrolled in the study. As of the data cut‑off date (June 15, 2021) the median duration of exposure to Sotyktu in PSO‑1, PSO‑2, and IM011075 was 84 weeks (588.0 days), and 90% of all patients remained enrolled in the study.
No new safety signals were identified in the open‑label extension compared to the pivotal studies. Extended exposure of Sotyktu does not appear to correlate with increases in serious adverse events, deaths, or treatment discontinuations. Causal attribution of long‑term safety trends was hampered by the coronavirus disease 2019 (COVID‑19) pandemic, which skewed the rates of infections and other related symptoms. Many patients had comorbidities which made them more susceptible to adverse outcomes of COVID‑19. The timing of the open‑label extension (compared to the pivotal studies) was especially problematic, as it overlapped with significant viral activity in the areas of the study sites.
Overall, the clinical data support the safety of Sotyktu in adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
For more information, refer to the Sotyktu Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The pharmacodynamic activity of deucravacitinib, the medicinal ingredient in Sotyktu, appears reasonably specific to the tyrosine kinase 2 (TYK2) pathway with low potential for off‑target activity. In vitro, deucravacitinib showed a high affinity for the binding target, the pseudokinase domain of TYK2 (half maximal inhibitory concentration [IC50] = 0.2 nM). Cellular assays and in vivo tests demonstrated inhibition of TYK2 pathway‑associated endpoints.
In mouse models, the administration of repeated doses of deucravacitinib ranging from 5 mg/kg/day to 100 mg/kg/day over several weeks was found to decrease inflammation.
The two major metabolites of deucravacitinib, BMT‑153261 and BMT‑158170, were tested for pharmacodynamic effects. While BMT‑153261 had a binding and activity profile similar to deucravacitinib, BMT‑158170 was found to be pharmacologically inactive.
Pharmacokinetic assessments in multiple species (mice, rats, dogs, and monkeys) found that deucravacitinib was rapidly absorbed and mostly protein bound in serum (80.9% to 86.6%). Multiple transporters are expected to contribute to the uptake and distribution of deucravacitinib and the metabolites BMT‑158170 and BMT‑153261, through both active and passive transport.
Deucravacitinib is a substrate of P‑glycoprotein (P‑gp) and breast cancer resistance protein (BCRP), which are important regulators of drug tissue permeability.
Deucravacitinib was widely distributed in tissues, with the highest levels in metabolic, endocrine, excretory, and gastrointestinal tissues. Distribution was similar between sexes.
Excretion of drug‑derived radioactivity was predominantly via the fecal route, while renal excretion was a minor route of elimination.
A core battery of safety pharmacology studies was conducted to evaluate effects on the cardiovascular, central nervous, and respiratory systems. The potential for risk to these vital organ systems was found to be low.
A 6‑month toxicity study of deucravacitinib was conducted in rats, in which the principal findings at doses of ≥5 mg/kg/day (≥9 times the maximum recommended human dose [MHRD] of 6 mg once daily) included minimally to moderately decreased lymphocyte counts, decreased spleen size and weight, decreased lymphoid cellularity in lymph nodes and spleen, and decreased T‑cell‑dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH). The decreases in lymphocytes and lymphoid cellularity in the spleen and lymph nodes were dose dependent and mostly minimal to mild in severity. They were not associated with any infections and were partially to fully reversible. The decrease in TDAR to KLH was fully reversible. Additional findings at doses of ≥15 mg/kg/day (≥42 times the MRHD) included minimally to mildly decreased platelets and red blood cell mass parameters and decreased bone marrow cellularity. These changes were not associated with any clinical signs or evidence of alterations in hemostasis. Additionally, they were typically associated with a regenerative bone marrow response and reversible and did not result in any unscheduled mortalities.
A 9‑month toxicity study of deucravacitinib was conducted in monkeys, in which skin changes were identified at doses of ≥1 mg/kg/day (≥7 times the MRHD). The skin findings were considered likely to be infectious in etiology, as they generally improved after antibiotic treatments, were present in the context of decreased TDAR to KLH, did not result in any unscheduled euthanasia or preterminal deaths, and trended towards reversibility during a 2‑month recovery period. The decreased TDAR to KLH was not accompanied by decreased blood lymphocyte counts or microscopic lymphoid depletion in the spleen, thymus or lymph nodes, or diminished serum levels of immunoglobulins G, M, or E. Minimally to moderately decreased red blood cell mass parameters were also observed at doses of ≥1 mg/kg/day and decreased platelet counts were observed at 5 mg/kg/day only (65 times the MRHD).
Deucravacitinib did not show any evidence of genotoxic activity. It was not found to be mutagenic in a bacterial mutagenicity assay or clastogenic in an in vitro chromosomal aberration assay or an in vivo peripheral blood micronucleus assay at oral doses up to 75 mg/kg/day (429 times the MRHD in male rats on Day 1). The two major metabolites, BMT‑153261 and BMT‑158170, were also examined in in vitro genotoxicity studies and did not exhibit any genotoxic potential.
The carcinogenic potential of deucravacitinib was examined in rats and in rasH2 transgenic (Tg.rasH2) mice. No evidence of tumorigenicity was observed in male or female rats at oral doses of deucravacitinib up to 15 mg/kg/day (approximately 51 times the MRHD). No evidence of tumorigenicity was observed in male or female Tg.rasH2 mice at oral doses of deucravacitinib up to 60 mg/kg/day (approximately 185 times the MRHD).
With respect to developmental and reproductive toxicity, deucravacitinib was not found to be associated with embryo‑fetal lethality or fetal malformations, or to be teratogenic at the highest doses tested in rats and rabbits. Deucravacitinib and/or its metabolites were present in the milk of lactating rats, with milk‑to‑plasma concentration ratios of 2.7 to 30.9. At 50 mg/kg/day, pup body weights decreased relative to controls during the pre‑weaning period. The observed decreases recovered during the post‑weaning period.
Studies evaluating ocular and dermal irritation and skin sensitization found that deucravacitinib was a non‑sensitizer and non‑irritant. Deucravacitinib was not phototoxic when tested in a phototoxicity assay.
The results of the non‑clinical studies as well as the potential risks to humans have been included in the Sotyktu Product Monograph. Considering the intended use of Sotyktu, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Sotyktu Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the review of the quality component of the New Drug Submission for Sotyktu was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The chemistry and manufacturing information submitted for Sotyktu demonstrated that the drug substance and drug product could be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development were considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 °C to 30 °C).
Proposed limits of drug-related impurities were considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).
All sites involved in production were compliant with good manufacturing practices.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SOTYKTU | 02533030 | BRISTOL-MYERS SQUIBB CANADA | DEUCRAVACITINIB 6 MG |