Summary Basis of Decision for Cibinqo

As described above, the clinical review of the New Drug Submission for Cibinqo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Abrocitinib, the medicinal ingredient in Cibinqo, is a highly selective Janus kinase (JAK)1 inhibitor. Janus kinases are intracellular enzymes that transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane. These signals influence cellular processes including hematopoiesis and immune cell function. Within signaling pathways, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Abrocitinib reversibly and selectively inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. This modulates the signaling pathway at the point of JAK1, preventing the phosphorylation and activation of STATs. It is hypothesized abrocitinib's therapeutic effect in reducing inflammation is achieved by blocking the function of the JAK1 protein.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. Abrocitinib administered orally was absorbed rapidly (time to reach maximum concentration within 1 hour), had an oral bioavailability of approximately 60%, was partially bound by plasma proteins, and was eliminated primarily by the renal excretion of three mono-hydroxylated metabolites (M1, M2, M4). The M1 and M2 metabolites have similar JAK1 inhibitory activity relative to the parent compound, and were included in a determination of the active moiety. The active moiety was calculated as the combined unbound systemic exposures of abrocitinib, M1, and M2 adjusted for relative potencies. M2 represents the main metabolite with daily administration. The enzymes involved in the majority of the abrocitinib metabolism are cytochrome P450 (CYP)2C19 (53%), CYP2C9 (30%), and CYP3A4 (11%). Steady state was achieved by Day 4 with once daily dosing. Area under the plasma concentration-time curve (AUC) increases were greater than dose proportional at doses of 400 mg and 800 mg. In general, both the maximum concentration (C_max) and AUC values of abrocitinib increased dose-proportionally following single administrations of up to 400 mg of abrocitinib.

Intrinsic factors affecting abrocitinib exposure were assessed in one Phase I study that enrolled subjects with mild to moderate hepatic impairment, and in one Phase I study that enrolled subjects with moderate to severe renal impairment. While the ratios between parent drug and the metabolites were altered in subjects with hepatic impairment, no meaningful changes in exposure to the overall active moiety C_max and AUC values were observed following single-dose administration. In subjects with renal impairment, there was an increase of over two-fold in active moiety AUC for subjects with moderate (210%) and severe (291%) impairment. Additionally, over 750 atopic dermatitis patients who had mild renal impairment were enrolled in Phase III studies. While the AUC for abrocitinib was estimated to increase by up to ~70% in these patients, the safety and tolerability of the drug in patients with mild renal impairment was comparable to other patients. Dosage recommendations have been included in the Cibinqo Product Monograph to halve the dose in patients with moderate to severe renal impairment.

Extrinsic factors affecting abrocitinib exposure were assessed in eight drug-drug interaction studies. In vitro, as a perpetrator, abrocitinib increased exposure to dabigatran, a P‑glycoprotein (P-gp) substrate. No meaningful effect on the exposure to other co-administered drugs that were tested, including oral contraceptives, was demonstrated.

As victim, consistent with metabolism being primarily through modification by CYP2C19 and CYP2C9 enzymes, inhibitors of these enzymes were found to increase exposure to abrocitinib and the active moiety by approximately two fold. Fluvoxamine (a strong CYP2C19 and moderate CYP3A inhibitor) increased the active moiety C_max by 33%, and AUC by 91%. Fluconazole (a strong CYP2C19, moderate CYP2C9 and CYP3A inhibitor) increased the active moiety C_max by 23%, and AUC by 155%. Rifampin, a strong inducer of CYP enzymes, resulted in a large reduction of the abrocitinib active moiety AUC by approximately 56%. The effect of probenecid, an organic anion transporter 3 (OAT3) inhibitor, was also investigated and demonstrated to have a significant effect on abrocitinib exposure. Probenecid increased the single‑dose abrocitinib active moiety C_max by 30% and AUC by approximately 66%. Further analysis determined that this increase was not clinically significant, taking into consideration the exposure values and safety in patients with mild renal impairment. Therefore, while dosage reductions were recommended for concomitant use with CYP2C19/C29 inhibitors such as fluvoxamine and fluconazole, and concomitant use with rifampin was not recommended, no dosage reduction was recommended for concomitant use with probenecid.

Statistical analyses of the relative bioavailability of the Cibinqo formulations determined that the rate (C_max) and extent (AUC) of exposure of abrocitinib was comparable between a 200 mg dose of the commercial formulation and a 200 mg dose of the Phase III formulation under fasting conditions. In addition, a high-fat, high-calorie meal had a significant impact on the rate and extent of exposure of the commercial formulation of Cibinqo with a demonstrated increase of approximately 29% for both C_max and AUC, for a single‑dose administration of 200 mg. 

The clinical pharmacology data support the use of Cibinqo for the recommended indication. For further details, please refer to the Cibinqo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Cibinqo was supported by data from three pivotal, randomized, double-blind, multicentre, placebo-controlled studies (MONO‑1, MONO‑2, and COMPARE), a Phase IIb study, two non-pivotal Phase III studies, and a Phase III long-term extension study.

The pivotal studies evaluated the efficacy of Cibinqo as a monotherapy (studies MONO-1 and MONO-2) and in combination with background medicated topical therapies (COMPARE Study). The studies included 1,616 patients who were 12 years of age or older with moderate to severe atopic dermatitis (AD) as defined by an Investigator’s Global Assessment (IGA) score of 3 or greater, an Eczema Area and Severity Index (EASI) score of 16 or greater, body surface area (BSA) involvement of 10% or greater, and a Peak Pruritus Numerical Rating Scale (PP-NRS) of 4 or greater at the baseline visit prior to randomization.

Patients in these studies had experienced an inadequate response to previous topical medication, or were patients for whom topical treatments were medically inadvisable, or who had received systemic therapies, including dupilumab. In each of the pivotal studies, over 40% of patients had prior exposure to systemic therapy. In the MONO-1 and MONO-2 studies, 6% of the patients had received dupilumab, whereas prior use of dupilumab was not allowed in the COMPARE study.

Patients were eligible to enroll in the long-term extension study EXTEND if they completed the full treatment period of the any of the pivotal qualifying parent studies.

The co-primary endpoints of successful treatment response in the Investigator’s Global Assessment (IGA), and a 75% reduction in the Eczema Area and Severity Index (EASI-75) were used to assess changes in AD skin lesions after 12 weeks of treatment in each of the pivotal studies.

The first co-primary endpoint, IGA, is a 5‑point scoring system, with 0 reflecting clear skin, and 4 reflecting severe skin lesions. All patients started with a score of 3 (moderate AD) or 4 (severe AD). A patient achieving a score of 0 or 1, with at least a 2‑point decrease in score, was considered to be have had a successful treatment response.

The second co-primary endpoint, EASI, is a scoring system similar to the IGA system in terms of symptom assessment, however, it also takes into account the percentage of body surface area affected. This endpoint assessed the proportion of patients who achieved a 75% reduction in EASI score (EASI-75).

Key secondary endpoints included improvements in the PP-NRS, and the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD), both of which are validated symptom scoring assessments for pruritus (and other clinically meaningful AD symptoms with the PSAAD). The co-primary and key secondary endpoints were analyzed statistically using a multiple testing procedure to control the Type I error at 5%.

Treatment with Cibinqo 100 mg or 200 mg once daily as a monotherapy or in combination with background medicated topical therapy resulted in improvement in objective signs of AD and patient-reported pruritus. Both co-primary and key secondary efficacy endpoints were met in the pivotal Phase III clinical studies. Response rates for both the IGA and EASI-75 endpoints demonstrated a significant benefit in skin lesion improvement with both the 100 mg and 200 mg daily dose in comparison to placebo. Though not formally tested statistically, the 200 mg daily dosage demonstrated a consistently improved benefit relative to the 100 mg daily dosage. The IGA response rates for the 200 mg daily dosage were 38.1% to 43.8% in the pivotal monotherapy studies and 48.4% in the pivotal combination therapy study (wherein patients also remained on medicated topical treatments). For the 100 mg daily dosage, IGA response rates were 23.7% to 28.4% in the monotherapy studies and 36.6% in the combination therapy study. Similar differences were seen for the EASI-75 endpoint, though overall response rates were higher, with 70.3% achieving EASI-75 for the 200 mg daily dose in the combination therapy study.

At Week 12 of the treatment period, the placebo-adjusted IGA response rate for the two monotherapy studies was 19.0% (95% confidence interval [CI] of 13.0, 25.0) and 33.3% (95% CI of 26.9, 39.7), for the 100 mg and 200 mg Cibinqo groups, respectively. An EASI-75 response of 29.8% (95% CI of 23.1, 36.6) and 50.3% (95% of 43.5, 57.1) was observed at the same time point, for the 100 mg and 200 mg Cibinqo groups, respectively.

The results for the key secondary endpoints were in line with the co-primary endpoint results, with a dose-dependent benefit demonstrated for relief of pruritus. In the combination therapy study (COMPARE), patients treated with Cibinqo exhibited a more rapid onset of symptom relief relative to those treated with dupilumab, the only other systemic treatment approved for moderate to severe AD at the time of the study. The overall efficacy of Cibinqo was comparable at 100 mg daily or better at 200 mg daily relative to dupilumab over a 12‑week treatment period. Sensitivity analyses and multiple other secondary endpoints supported the efficacy of both 100 mg and 200 mg daily dosages of Cibinqo. In addition, patient reported outcome assessments were also consistent in indicating a significant quality of life benefit provided by Cibinqo relative to placebo. 

In a separate adolescent combination therapy study, there was a reduced difference in efficacy between the 200 mg Cibinqo and placebo, and between the 100 mg and 200 mg Cibinqo doses. This may be partly explained by the high response rate observed in the placebo group (41.5% response rate for EASI-75 in the placebo group versus 68.5% and 72.0% in the 100 mg and 200 mg abrocitinib groups, respectively). However, the 200 mg once daily dosage more consistently produced a statistically significant benefit. Pruritus relief was marginal compared to placebo, especially at the 100 mg once daily dosage. The 200 mg once daily dosage was more consistent in demonstrating a significant benefit for both co-primary endpoints and key secondary endpoints. Overall, co-primary and secondary endpoint results in the combination therapy studies supported the use of both Cibinqo dosages in both adolescents and adults. 

For all three pivotal studies, treatment effects in subgroups (e.g., based on weight, age, sex, race, and prior systemic immunosuppressant treatment) in were consistent with the results in the overall study population.

Indication

The New Drug Submission for Cibinqo was filed by the sponsor with the following indication:

Cibinqo (abrocitinib) is indicated for the treatment of patients 12 years and older with moderate to severe atopic dermatitis, including the relief of pruritus, who have had an inadequate response to prescribed topical therapy or for whom these treatments are not advisable.

Cibinqo can be used with or without medicated topical therapies for atopic dermatitis.

To support safe and effective use of the product, Health Canada approved the following indication:

Cibinqo (abrocitinib) is indicated for the treatment of patients 12 years and older with refractory moderate to severe atopic dermatitis, including the relief of pruritus, who have had an inadequate response to other systemic drugs (e.g. steroid or biologic), or for whom these treatments are not advisable.

Cibinqo can be used with or without medicated topical therapies for atopic dermatitis.

Limitations of Use: Use of Cibinqo in combination with other JAK inhibitors, biologic immunomodulators, or potent immunosuppressants such as methotrexate and cyclosporine has not been studied and is not recommended.

Health Canada's revised indication recommends using Cibinqo as a second-line systemic treatment, in recognition of the potentially life-threatening side effects associated with this drug. For patients who have had an inadequate response to prior treatments and continue to experience moderate to severe AD symptoms, the potential benefits of Cibinqo outweigh the harms when appropriate risk mitigation is used. 

For more information, refer to the Cibinqo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A summary safety assessment examined the data of 2,856 atopic dermatitis patients (representing 1,614 patient years) who were exposed to Cibinqo (all doses) in one Phase II study, four Phase III studies, and a long-term extension study. There were 606 patients with more than 1 year of exposure to Cibinqo. The median age was 31.0 years, 12.7% were adolescents, and 5.1% were 65 years of age or older. Nearly half of the patients (45.6%) were female. The majority of the patients were White (72.2%); however, a substantial proportion were Asian (19.4%) and Black or African American (6%). At baseline, 61.4% had moderate disease (IGA of 3) and the median EASI was 26.9. An adolescent combination therapy study, completed following the summary safety assessment, included additional data from 284 patients.

Four of the placebo-controlled studies were integrated to evaluate the safety of Cibinqo in comparison to placebo for up to 16 weeks. The comparison included 608 patients who received 100 mg Cibinqo once daily, 590 patients who received 200 mg Cibinqo once daily and 342 patients who received placebo. The most common adverse reactions were: nausea (reported in 14.6%, 6.1% and 2.0% of patients in the 200 mg, 100 mg, and placebo groups, respectively); vomiting (3.2%, 1.5%, and 0.9%); upper abdominal pain (1.9%, 0.7%, and 0); herpes simplex infections (4.2%, 3.3%, and 1.8%), headache (7.85%, 5.9%, and 3.5%); dizziness (2.9%, 1.8%, and 0.9%), acne (4.7%, 1.6%, and 0); and increased blood creatine kinase levels (2.9%, 2.3%, and 1.5%). The clinical significance of elevated creatine kinase levels was unclear as it was not found to correlate with rhabdomyolysis (though increased creatine kinase can correlate with muscle damage and myocardial infarction). Other adverse reactions reported in less than 2% of patients treated with Cibinqo in placebo-controlled studies for up to 12 or 16 weeks included pneumonia, and herpes zoster.

Serious drug-related adverse events were not common and Cibinqo was generally well tolerated, with mostly mild adverse events experienced by some patients. However, evidence of thrombosis in the Cibinqo clinical studies came from observations of deep vein thrombosis (2 patients) and pulmonary embolism (3 patients), which only occurred in patients treated with the 200 mg daily dosage. A dose-related risk of thrombocytopenia was also observed in placebo-controlled studies, for up to 16 weeks. Maximum effects on platelets were observed within 4 weeks, after which the platelet count returned towards baseline despite continued therapy.

The only malignancies that occurred across all studies occurred in Cibinqo-treated patients (7 cases of non-melanoma skin cancer and 3 cases of other cancers), with the exception of one case in a control group patient treated with dupilumab. The incidence of cancer was not high enough to determine any dose dependence or causality. Cibinqo is not considered a carcinogen, however, the occurrence of malignancies following treatment may be related to the drug, as the inhibition of JAKs is known to be associated with a suppression of tumor immunosurveillance. Consistent with the risk of malignancy identified for other JAK inhibitors, it is possible that Cibinqo increases the risk of cancer in susceptible patients.

In placebo-controlled studies, for up to 16 weeks, overall infections were reported in 35.2% and 34.6% of patients treated with Cibinqo 100 mg and 200 mg, respectively, versus 26.3% of patients treated with placebo. Most infections were mild or moderate. Serious infections were reported in six patients treated with Cibinqo 100 mg, two patients treated with Cibinqo 200 mg, and two patients treated with placebo. Among all patients treated with Cibinqo, including the long-term extension study, serious infections were reported in 17 patients treated with Cibinqo 100 mg and 24 patients treated with Cibinqo 200 mg. The overall rate of serious infections was not increased with Cibinqo, although an increased risk of specific infections was observed. This included a dose-related increase in the incidence of herpes zoster and herpes simplex. These infections, along with pneumonia, were the most frequent cause of serious infections, and were associated with hospitalization in some patients. Though herpes zoster was a clear side effect with a dose-dependent increase in incidence in the long-term extension study, no cases of herpes zoster were considered as severe in the 200 mg once daily group in the Primary Safety Pool. In data from the long‑term extension study, four cases of herpes zoster or ophthalmic herpes zoster were considered to be serious. To mitigate this risk, wording in the Cibinqo Product Monograph recommends that vaccinations should be brought up to date prior to the initiation of treatment with Cibinqo.

Elderly patients in particular are likely to have increased risk factors relevant to the serious side effects associated with Cibinqo, and showed dose-related increases in incidence of herpes zoster, thrombocytopenia, and lymphocytopenia. Recommendations to initiate elderly patients on the lower 100 mg daily dosage, and to step all patients down from the 200 mg daily dosage after achieving symptom control, were proposed to help to mitigate risk of serious side effects.

Adolescent safety was generally similar to that of adults, though there was a slight increase in the overall incidence of treatment‑emergent adverse events in adolescents. This was not found to be due to any particular adverse events and no unique adverse events that affected adolescents were noted. Non-clinical findings of effects on bone dystrophy warranted an assessment of growth in adolescents. Change in height assessed at 6 and 12 months amongst adolescents who entered the long‑term extension study was not found to differ meaningfully from standardized growth curves. No specific results from the Cibinqo clinical studies indicated unique safety risks in the adolescent population. 

Though safety data from over 600 subjects administered Cibinqo over at least 48 weeks has been assessed, ongoing studies are being conducted to address the significant uncertainty that remains regarding long-term safety. There are significant safety concerns related to Cibinqo and its drug class. Janus kinase inhibitors have the potential to produce serious and severe side effects including the risk of serious infections, malignancies, thrombosis, and major adverse cardiovascular events (MACE), each of which is listed in a Serious Warnings and Precautions box in the Cibinqo Product Monograph. Evidence of increased risk of MACE with Cibinqo was not apparent in the Cibinqo clinical studies, and the likelihood of occurrence for other serious risks remains uncertain due to the low frequency of occurrence in the clinical studies. The warnings listed in the Serious Warnings and Precautions box were included to reflect the uncertainty that exists regarding the long-term safety of Cibinqo, and of JAK inhibitors in general. 

A Cibinqo Education Program comprised of educational materials for both healthcare providers and patients will be implemented by Pfizer Canada ULC. The program is part of the risk mitigation strategies specific to the potential risks of infections, thrombotic events including pulmonary embolism, malignancy, MACE, and embryo‑fetal toxicity. The materials will include a Prescriber Brochure/Guide and Patient Card/Patient Safety Information Leaflet.

Despite the potential for serious side effects, Cibinqo was generally well tolerated and was associated with a lower occurrence of serious adverse events in comparison to patients treated with placebo in the Phase III studies. In patients with moderate to severe atopic whom are not adequately treated by medicated topical treatments, and for whom a different systemic therapeutic does not present as a safer and more effective option, the use of Cibinqo is warranted.

For more information, refer to the Cibinqo Product Monograph, approved by Health Canada and available through the Drug Product Database.