AUC[INF] area under the concentration time curve from time zero to infinity BCRP breast cancer resistance protein. PGA-F Physician's Global Assessment-Fingernail PGI -C Patient's Global Impression of Change PGI-S Patient's Global Impression of Severity. PSSD-24h Psoriasis Symptoms and Signs Diary with a 24-hour recall period PSSI Psoriasis Scalp Severity Index.
Background information on the procedure
- Submission of the dossier
- Legal basis, dossier content
- Information on paediatric requirements
- Information relating to orphan market exclusivity
- Similarity
- Applicant’s request for consideration
- New active substance status
- Scientific advice
- Steps taken for the assessment of the product
The first CHMP Rapporteur Assessment Report was distributed to all CHMP and PRAC members on The CHMP agreed on the consolidated list of questions to be sent to the applicant during the date meeting. The CHMP agreed on a list of outstanding issues in writing to be sent to the applicant.
The CHMP agreed on a second list of outstanding issues to be sent to the applicant.
Scientific discussion
Problem statement
- Disease or condition
- Epidemiology
- Biologic features, aetiology and pathogenesis
- Clinical presentation, diagnosis
- Management
Malignancies of lymphoma, lung cancer and non-melanoma skin cancer (NMSC) are also known comorbidities of psoriasis. The traditional paradigms for treating psoriasis recommend a stepwise approach to treatment, starting with topical agents, followed by phototherapy, and then systemic agents. Both professional and patient groups in the United States (US), Europe, and Canada have issued guidelines for the treatment of psoriasis and, more specifically, the use of biologics in the treatment of psoriasis.
Apremilast, an oral selective phosphodiesterase 4 inhibitor, is also approved for the second-line treatment of psoriasis.
About the product
Concerns for anti-IL-17 class agents also include Crohn's disease, neutropenia, and mucosal candida infections. Historically, approved SC biologic agents have shown maximal response rates of 70% to 80% of subjects who achieved ≥75% improvement in psoriasis area and severity index (PASI) from baseline (PASI 75), which an efficiency benchmark was considered. While conventional and systemic therapeutic modalities are available for the treatment of moderate-to-severe plaque psoriasis, most do not provide adequate efficacy for most patients when assessed using clinically meaningful endpoints such as the Investigator's Global Assessment (IGA) of cleared (0) or minimal (1), and PASI 90 and PASI 100.
While response rates for available treatments, including those for more stringent measures of efficacy, have increased over time, there is still considerable room to improve the proportion of patients achieving clear skin.
Type of application and aspects on development
Quality aspects
- Introduction
- Active Substance
- Finished Medicinal Product
- Discussion on chemical, pharmaceutical and biological aspects
- Conclusions on the chemical, pharmaceutical and biological aspects
- Recommendation(s) for future quality development
Based on the development studies, documented acceptable ranges (PARs) for the process parameters and appropriate in-process controls (IPCs) were established for the commercial manufacturing process of the finished product. Information on the development, manufacture and control of the active substance and the finished product has been presented in a satisfactory manner. The applicant has applied QbD principles in the development of the active substance and/or the finished product and their manufacturing process.
However, no design spaces were claimed for the manufacturing process of the active substance, nor for the final product.
Non-clinical aspects
- Introduction
- Pharmacology
- Pharmacokinetics
- Toxicology
- Ecotoxicity/environmental risk assessment
- Discussion on non-clinical aspects
- Conclusion on the non-clinical aspects
The organs with the highest concentrations of radioactivity obtained from BMS-986165 did not correspond to the target organs (lymphoid/immune, hematopoietic, and skin) identified in the repeated-dose toxicology studies. Similarly, in the rat carcinogenicity study at doses ≤ 15 mg/kg/day (≤ 51× RHD AUC), there was also no indication of cardiac findings associated with BMS-986165. In the 6-month rat toxicity study, BMS-986165-associated minimal to mild increases, predominantly in males, in ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin at doses ≥ 5 mg/kg /day. were observed.
No BMS-986165-related neoplastic findings were noted in the 2-year oral carcinogenicity in CD rats.
Clinical aspects
- Introduction
- Clinical pharmacology
- Discussion on clinical pharmacology
- Conclusions on clinical pharmacology
- Clinical efficacy
- Discussion on clinical efficacy
- Conclusions on the clinical efficacy
- Clinical safety
- Discussion on clinical safety
- Conclusions on the clinical safety
To assess whether BMS-986165 is superior to placebo at week 16 in the treatment of subjects with moderate to severe plaque psoriasis. To evaluate the dose-response relationship of BMS 986165 (6 or 12 mg once daily [QD]) at week 16 in the treatment of subjects with active PsA. According to the proponent, assessment of pharmacokinetics was not part of the primary and secondary objectives in the study.
Baseline PASI was not identified as a significant covariate on deucravacitinib in the final population PK model. In contrast, there was a significant decrease in exposure to the active metabolite BMT-153261; Cmax and AUC decreased approx. 94%. Race was not a statistically significant covariate in the population PK model for deucravacitinib, but on BMT-153261.
Based on the in vitro data, 13 dedicated in vivo DDI studies were conducted to assess the extent of potential interactions with deucravacitinib in the clinical setting. The primary objective was to assess whether DEUC was superior to placebo at week 16 in the treatment of subjects with moderate to severe plaque psoriasis. These results were discussed in the context of the population pharmacokinetic (PK) results and the E-R analysis.
In the overall population (N=1221), response rates for sPGA 0/1 and PASI 75 improved or were maintained over time. The efficacy of deucravacitinib (DEUC) in the treatment of moderate to severe plaque psoriasis in adults is . However, the percentage of patients with DLQI 0/1 response at week 16 was highest in all categories in the deucravacitinib group compared to the apremilast and placebo groups.
These results only reflected maintenance of the effects of deucravacitinib in the subset of patients who responded at week 24, who continued deucravacitinib through week 52. BMS-986165), placebo and Apremilast groups in the control safety group. Based on the assessment of the cases provided, the CPK of blood has been added to Article 4.8 of the CPK.
Risk Management Plan
- Safety concerns
- Pharmacovigilance plan
- Risk minimisation measures
- Conclusion
Across the entire deucravacitinib clinical program, 15 pregnancies were reported in subjects or their partners treated with deucravacitinib. The data on pregnancies reported after exposure to deucravacitinib are limited but do not indicate a specific safety concern. As there are limited data on the use of deucravacitinib in pregnant women, deucravacitinib should be avoided during pregnancy as a precautionary measure (sufficient information has been added in section 4.6 of the SPC).
In addition, use during pregnancy and lactation has been added as missing information in the RMP: a category 3 study should be conducted to further evaluate the use of deucravacitinib during pregnancy. More than 50% of patients experienced at least one adverse reaction and this increases with exposure to deucravacitinib. Although no clear relationship to deucravacitinib can currently be established, given the conclusion of the Article 20 referral on the JAK inhibitor, the risk of malignancies, NMSC, MACE and other cardiovascular side effects cannot be completely excluded.
Therefore, pending the results of the long-term extension study, the safety considerations of the RMP were further strengthened and "MACE" and "VTE (DVT/PE)" were added as "Important Potential Risks". In general, the safety profile of deucravacitinib in the intended indication is considered acceptable and adequately characterized based on the submitted safety data. To evaluate the long-term safety of deucravacitinib in patients with clinical psoriasis.
Randomized, active-controlled clinical trial to evaluate the long-term safety of deucravacitinib in patients with. Additional pharmacovigilance activities: Non-interventional cohort study (EU/UK medical records . databases/patient registries [IM011194]) Long-term safety randomized clinical trial (IM0111130).
Pharmacovigilance
- Pharmacovigilance system
- Periodic Safety Update Reports submission requirements
Product information
- User consultation
- Additional monitoring
Benefit-Risk Balance
- Therapeutic Context
- Disease or condition
- Available therapies and unmet medical need
- Main clinical studies
- Favourable effects
- Uncertainties and limitations about favourable effects
- Unfavourable effects
- Uncertainties and limitations about unfavourable effects
- Effects Table
- Benefit-risk assessment and discussion
- Importance of favourable and unfavourable effects
- Balance of benefits and risks
- Additional considerations on the benefit-risk balance
- Conclusions
A total of 1686 subjects were randomized in 2 Phase 3 studies: 843 subjects were randomized to deucravacitinib, 421 to placebo and 422 to Apremilast. In the week 0 – 52 treatment period, treatment-related TEAEs were observed in 22.3% of deucravacitinib-treated subjects, 14.4% of placebo-treated subjects, and 30.1% of apremilast-treated subjects. In the week 0 – 52 treatment period, serious TEAEs occurred in 4.0% of deucravacitinib-treated subjects compared to 2.1% in the placebo and apremilast groups.
There were a total of 10 deaths in the controlled safety and phase 3 safety groups (8 in the deucravacitinib group, 1 in the placebo group, and 1 in the apremilast group). During the treatment period from weeks 0 to 52, the incidence of TEAEs leading to treatment discontinuation was 6.2% in the deucravacitinib, placebo, and apremilast groups. Suicidality and depression: In the controlled safety arm (weeks 0–52), the incidence of depression in the deucravacitinib group was P-Y, 5 subjects) compared to 0 cases in the apremilast group.
Hematology: The incidence of treatment-related AEs in SOC blood and lymphatic system disorders was higher in the deucravacitinib (1.0%) compared to placebo (0.5%) and apremilast (0.7%) groups during 52 weeks of treatment. The most common treatment-related AEs were leukopenia and lymphopenia occurring at an incidence of 0.6% and 0.3% in the deucravacitinib group, which was higher than in the placebo and apremilast groups. No significant difference between deucravacitinib and apremilast was observed in the assessment of nail or palmoplantar psoriasis.
The efficacy of oral deucravacitinib in the treatment of moderate to severe plaque psoriasis was demonstrated in a heterogeneous population (regardless of demographic, disease or geographic characteristics, or prior psoriasis treatments). Based on the data presented, overall the beneficial effects of deucravacitinib outweigh the adverse effects observed in the clinical program.
Recommendations
During the assessment of Sotyktu, the CHMP received a third-party intervention which expressed concern about an increased risk of malignancies with TYK2 inhibition. The CHMP considered this intervention in its assessment and concluded that the comments from the third party had already been assessed by the CHMP and as such had no influence on the CHMP's assessment or its conclusions. The overall benefit/risk balance for Sotyktu is positive, subject to the conditions stated in section.
Conditions or restrictions regarding the safe and effective use of the drug. The Marketing Authorization Holder (MAH) shall carry out the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorization and any agreed subsequent updates to the RMP. Whenever the risk management system changes, particularly as a result of new information received that may lead to a significant change in the benefit/risk profile, or as a result of an important milestone (pharmacovigilance or risk minimization) being reached.
Based on the CHMP assessment of the available data, the CHMP is of the opinion that deucravacitinib should be qualified as a new active substance on its own, as it is not a component of a medicine previously authorized in the European Union.
Appendix
CHMP AR on New Active Substance (NAS) dated 26 January 2023
