Summary Basis of Decision for Otezla

Clinical Pharmacology

Apremilast, the medicinal ingredient of Otezla, is a small-molecule inhibitor of phosphodiesterase 4 (PDE4), and works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. In clinical studies in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes.

Apremilast pharmacokinetics were significantly altered in patients with severe renal impairment and dosage reductions to a maximum of 30 mg once a day (QD) is indicated in these patients. No dosage adjustment is necessary for patients with hepatic impairment.

Exposure and maximal concentrations of apremilast decreased to 72% and 42%, respectively, and may result in loss of efficacy, when co-administered with rifampin a cytochrome P450 (CYP) 3A4 inducer. Co-administration with CYP3A4 inducers (phenobarbital, rifampin, carbamazepine, and phenytoin) is therefore not recommended. Apremilast has not been evaluated and is not indicated in combination with potent immunosuppressive drugs (e.g.: cyclosporine, tacrolimus) or biological therapeutics for psoriasis such as TNF antagonistsm and anti-IL-12/23 p40 antibodies.

In a double-blind, placebo- and positive-controlled, randomized, multiple-dose, four period crossover study performed to investigate the effects of apremilast on electrocardiogram (ECG) interval parameters in healthy volunteers [number (n) = 60], a modest elevation in heart rate was observed. Apremilast was tested at a therapeutic dose of 30 mg twice a day (BID) on Days 1-4 and 30 mg QD on Day 5, and at a supratherapeutic dose of 50 mg BID on Days 1-4 and 50 mg QD on Day 5. On Day 5 of treatment, the maximum mean difference from placebo in heart rate was 3.4 beats per minute (bpm) [90% confidence interval (CI) 1.1, 5.6] for the 30 mg dose and 4.9 bpm (90% CI 3.3, 6.6) for the 50 mg dose. Apremilast did not have noteworthy effects on the QTc, QRS, or PR intervals on Day 5 of treatment at the doses tested.

Overall, the clinical pharmacological data support the use of Otezla for the specified indication.

For further details, please refer to the Otezla Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Otezla was based on two pivotal, multicentre, randomized, double-blind, placebo-controlled Phase III studies (Studies ESTEEM 1 and ESTEEM 2) which enrolled a total of 1,257 patients 18 years of age and older, with a diagnosis of plaque psoriasis for at least 12 months, moderate to severe plaque psoriasis at screening [that is (i.e.) had a body surface area (BSA) involvement of ≥10%, static Physician Global Assessment (sPGA) of ≥3 (moderate or severe disease), and a Psoriasis Area and Severity Index (PASI) score ≥12], and who were candidates for phototherapy or systemic therapy. Concomitant anti-psoriatic medications were prohibited during the study up to Week 32, with the exception of low potency topical corticosteroids on the face, axillae and groin, coal tar shampoo and/or salicylic acid scalp preparations. Efficacy on a background of other medications or phototherapy has not been adequately studied with Otezla.

Study ESTEEM 1 and Study ESTEEM 2 had a similar design through Week 32. In both studies, patients were randomized 2:1 to Otezla 30 mg BID or placebo for 16 weeks (Placebo-Controlled Phase). All patients were initiated on study drug with dose-titration over 5 days. From Weeks 16-32, all patients received Otezla 30 mg BID (Maintenance Phase). From Weeks 32-52, a selected subgroup of patients underwent a Randomized Treatment Withdrawal Phase.

Baseline demographics were generally similar across the treatment groups in each study and comparable between the studies. Across both studies, patients ranged in age from 18 to 83 years, with an overall median age of 46 years. A total of 108 patients (8.6%) were aged ≥65 years old, including 9 patients (0.7%) aged ≥75 years old. Most of the patients (68%) were male. Race was predominantly White (90%).

Baseline disease characteristics were generally similar across the treatment groups in each study and comparable between the studies. The mean baseline BSA involvement was 25.2% (median 21.0%), the mean baseline PASI score was 19.1 (median 16.8), and the proportions of patients with sPGA scores of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. The mean duration since diagnosis of plaque psoriasis was 19.0 (median 16.6) years. A total of 18% of patients had a history of psoriatic arthritis.

Approximately 35% of patients had not received prior phototherapy, conventional systemic or biologic therapy for the treatment of psoriasis. Approximately 30% of all patients had received prior phototherapy, 38% had received prior conventional systemic therapy, and 30% had received prior biologic therapy for the treatment of psoriasis.

In both studies, the primary efficacy endpoint was the difference in the proportions of patients in the Otezla 30 mg BID and placebo treatment groups who achieved at least a 75% improvement on the Psoriasis Area and Severity Index (PASI-75) at Week 16 in reference to the baseline visit. The primary analysis was based on the Full Analysis Set (FAS), using a last observation carried forward (LOCF) approach to impute missing values at Week 16. In Study ESTEEM 1, the placebo-adjusted response rate (95% CI) in the proportion of patients achieving PASI-75 at Week 16, was 27.8% (23.1, 32.5; p<0.0001) for Otezla 30 BID patients. The percentage of responders was 5.3% (15/282) in the placebo group, and 33.1% (186/562) in the Otezla group. In Study ESTEEM 2, the placebo-adjusted response rate (95% CI) in the proportion of patients achieving PASI-75 at Week 16, was 23.0% (16.3, 29.6; p<0.0001) for Otezla. The percentage of responders was 5.8% (8/137) in the placebo arm, and 28.8% (79/274) in the Otezla group.

The major secondary endpoint was the difference in proportions of patients in the Otezla 30 mg BID and placebo groups who achieved a static sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at Week 16. In Study ESTEEM 1, the placebo-adjusted response rate (95% CI) in the proportion of Otezla-treated patients achieving a sPGA score of 0 or 1 at Week 16, was 17.8% (13.7, 21.9; p<0.0001). In Study ESTEEM 2, the placebo-adjusted response rate (95% CI) in the proportion of Otezla-treated patients achieving a sPGA score of 0 or 1 at Week 16, was 16.1% (10.2, 21.9; p<0.0001). These data, as well as certain other secondary endpoints, including the proportion of patients who achieved PASI-50 (50% improvement, regarded as a minimally meaningful difference), supported the primary endpoint.

Despite trends in the data to suggest that some early (Week 32) responders could continue to benefit from Otezla for up to 52 weeks, any meaningful conclusion on the durability of efficacy beyond Week 32 cannot be supported due to the study design. In patients exposed to Otezla for up to one year, the most common reason for discontinuation was lack of efficacy, reported by 21% of patients.

Overall, Otezla was demonstrated to have clinically meaningful efficacy on a modest, but reasonable, proportion of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

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

Clinical Safety

The primary safety data pool (PSOR Phase III Data Pool) consisted of data from the two pivotal, Phase III, multicentre, randomized, double-blind, placebo-controlled studies (Studies ESTEEM 1 and ESTEEM 2) described in the Clinical Efficacy section. In this data pool, a total of 1,184 patients with moderate to severe plaque psoriasis were exposed to Otezla (apremilast), 968 patients were treated for at least 24 weeks and 564 patients were treated for at least 52 weeks. The more comprehensive Apremilast Data Pool included data from 2,357 Phase II/III patients exposed to Otezla 30 mg BID, 1,308 of which were from the psoriasis clinical program, and the remainder from the psoriatic arthritis or rheumatoid arthritis clinical programs. While this data pool included patients with different disease profiles, it was considered useful for detecting uncommon adverse event signals.

During the 16-week placebo-controlled period of the two pivotal studies, the primary reason for discontinuation of Otezla was due to adverse events (4.3%) whereas in the full Otezla Exposure Period, which included patients treated for more than 52 weeks, 644/1184 (54.4%) of patients discontinued, primarily due to of lack of efficacy (25.4%), voluntary withdrawal (10.8%) and adverse events (8.4%).

In the PSOR Phase III Data Pool, 57.2% of patients randomized to the placebo group experienced an adverse event during the placebo-controlled period (Weeks 0-16) compared to 68.9% of patients randomized to Otezla. The most common adverse events in the Otezla group which were greater than in the placebo group were diarrhea (17.8%), nausea (16.6%), upper respiratory tract infection (8.4%), nasopharyngitis (7.3%), tension headache (7.3%), and headache (5.8%). The incidences of these events were higher in females than males. In particular, nausea was experienced by 29.7% of women (9.9% of males), diarrhea by 24.0% of women (14.6% of men), vomiting by 7.9% of women (1.6% of men), and tension headache by 11.5% of women (5.2% of men). The majority of the adverse events of diarrhea, nausea, headache, and tension headache occurred at the highest incidence during the first 2 weeks of dosing with Otezla. These events were generally mild in intensity, with the incidence of severe episodes being uncommon.

In general, the safety profile of Otezla did not change between the earlier and later exposure periods within the pivotal studies.

In the full period of exposure to Otezla (including patients with >52 week total exposure), the most common severe events reported by treated patients were psoriasis (0.5%), headache (0.4%), migraine (0.4%), diarrhea (0.3%), nausea (0.3%) and vomiting (0.3%). The most common adverse events leading to discontinuation were nausea (1.4%), diarrhea (0.9%), psoriasis (0.9%), headache (0.4%) and vomiting (0.4%); and the most common serious adverse events were nephrolithiasis (0.3%), osteoarthritis (0.3%), and coronary heart disease (0.3%). In the psoriasis clinical program, a total of 6 deaths were reported; 2 in patients with no previous exposure to Otezla. A death of acute cardiac failure in a 30-year old female was reported with no plausible etiology or significant risk factors. No death in these studies could be causally associated with Otezla.

In the more comprehensive Apremilast Data Pool, exposure to Otezla was associated with an increased incidence of tachyarrhythmias, including atrial fibrillation. During the placebo-controlled period, the incidence of adverse events subsumed by the preferred term, tachyarrhythmia, was 0.2% for placebo and 0.6% for Otezla. The most frequent tachyarrhythmic adverse event was atrial fibrillation with an incidence of 0.1% (0.2 events per 100 subject years) for placebo-treated patients and 0.3% (0.8 events per 100 subject years) for patients treated with Otezla.

In the PSOR Phase III Data Pool, during the placebo-controlled period, the incidence of depression (excluding suicide and self-injury) was 1.2% for patients treated with Otezla (0.5% for placebo). In the broader Apremilast Data Pool, the incidence of depression as a serious adverse event was 0.85% for Otezla (0% for placebo), with the incidence of adverse events of suicidal ideation and behavior of 0.12% for Otezla (0.07% for placebo).

Weight loss of >5% of baseline body weight was reported during the placebo-controlled period in 13.3% of patients treated with Otezla (5.0% of patients on placebo), and in 19.6% of patients following 52 weeks of treatment, with 5.7% of patients with weight decreases of ≥10% of baseline body weight.

Despite a lack of clinical evidence, there are potential safety concerns for the use of Otezla in pregnant and breastfeeding women. Although not substantiated by mechanistic or non-clinical evidence for teratogenicity, Otezla does share a portion of its molecule with a class of teratogens (thalidomide, lenalidomide and pomalidomide). However, the key pharmacophore believed to be responsible for the teratogenicity of thalidomide, lenalidomide and pomalidomide (the amino-glutarimide ring, which binds to the cereblon protein) is different in Otezla. In studies with mice, developmental malformations were not observed up to the highest dosage of 80 mg/kg/day (4.0-fold the clinical exposure), and no treatment-related fetal developmental effects or malformations were observed in monkeys up to the highest dosage of 1000 mg/kg/day (3.5-fold the clinical exposure). In mice and monkeys, Otezla was not teratogenic.

Non-clinical data demonstrated that treatment with apremilast is associated with embryofetal risk (increased resorptions in mice and increased abortions in monkeys) and nursing mouse pup mortality at dose levels that are equivalent to 2-4 times human exposure. In humans, significant weight loss observed with Otezla, particularly in women, can pose a theoretical risk for use in pregnancy. Given its potential for exposure in women of child-bearing potential and intended use for a non-life-threatening condition, Otezla is contraindicated in women who are pregnant, or who are breastfeeding.

An increased risk of serious infection was not observed, but based on its mechanism of action, there is a theoretical increased risk of infection in susceptible populations, which were limited in the studies. Based on a signals observed in the non-clinical studies, events of vasculitis were examined across all the clinical studies conducted with Otezla, including nonpsoriasis studies. In total, the sponsor confirmed 3 cases of vasculitis in patients exposed to Otezla, one which was serious and led to discontinuation, the others resolved while on the study drug.

Overall, the safety profile of Otezla is acceptable and manageable for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Appropriate warnings and precautions are in place in the approved Otezla Product Monograph to address the identified safety concerns.

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