Regulatory Decision Summary for OTEZLA

The efficacy and safety of Otezla for treatment of psoriatic arthritis were assessed in three pivotal Phase III placebo-controlled studies in adult patients with current or prior treatment with disease modifying antirheumatic drugs (DMARDs), including small molecules and/or biologics, who had active psoriatic arthritis (≥3 tender joint counts and ≥3 swollen joint counts). Approximately 1,500 patients were treated with Otezla 20 mg or 30 mg twice daily (BID) or a placebo for up to 24 weeks, with an ongoing active treatment period planned for up to five years, in total.

The efficacy of Otezla was demonstrated in three similarly designed pivotal trials. The predetermined primary efficacy endpoint, a statistically significantly greater proportion of Otezla-treated patients achieving a 20% improvement on the modified American College of Rheumatology Criteria (ACR20) at Week 16, relative to placebo-treated patients, was met in each trial. Effect sizes were generally meaningful, but modest relative to biological DMARDs that have been assessed in a similar fashion. In addition, the efficacy of Otezla on physical function, as measured by the major secondary endpoint of improvement from baseline on the Health Assessment Questionnaire Disability Index (HAQ-DI) at week 16, was supportive of the primary endpoint across the three pivotal trials.

Overall, the placebo-adjusted proportions of patients who achieved ACR20 suggested a slightly weaker treatment effect of Otezla at Week 24 compared to Week 16. However, this was based on a conservative method of assessment and data up to 52 weeks in patients treated continuously with Otezla did not suggest an attenuation of treatment response over time.

Several issues relating to efficacy were raised during the review. First, exploratory subgroup analyses of ACR20 data pooled across the three pivotal studies suggested a weaker efficacy of Otezla in female patients relative to male patients. A table was added to the product monograph to reflect this potential difference. Second, the added benefit of the Otezla 30 mg BID dose over the Otezla 20 mg BID dose, based on ACR20 response in the pooled dataset, was not apparent beyond the primary efficacy assessment at Week 16. Finally, study design limitations of the pivotal trials compromising interpretation included the lack of an active comparator arm with which to evaluate the efficacy and risks of Otezla against the current standard of care, the lack of a randomized withdrawal phase to evaluate the potential for rebound and relapse, the lack of evaluation of Otezla on structural disease progression, and limitations in the manner in which Otezla was evaluated on axial disease.

Otezla demonstrated an acceptable risk profile. In the 16-week, placebo-controlled period of the pivotal trials, the most common adverse events in the Otezla treatment groups were diarrhea, nausea, headache, upper respiratory tract infection, vomiting, and nasopharyngitis. These adverse events were generally self-limiting and mild to moderate in intensity. The most common adverse events of diarrhea, nausea, and headache were more common in females than in males. A statement to reflect this was added to the Product Monograph.

Serious adverse events were infrequent with exposure-adjusted event rates comparable to placebo. The most common serious adverse event reported in patients exposed to Otezla was psoriatic arthropathy, of which 6 of a total of 7 cases were reported in women. A statement to reflect this was added to the Product Monograph.

Previously identified safety concerns and uncertainties raised for Otezla in a separate review (control # 169862) remained relevant in the present NDS. Significant safety concerns included the potential for tachyarrhythmia, depression and weight loss with Otezla. These were previously addressed with the additions of warnings to the Product Monograph, which were extended in the present submission to patients with psoriatic arthritis. Previously identified safety signals stemming from the non-clinical assessment were for lactation-related toxicity and vascular and perivascular inflammation in rodents and abortions in monkeys. Although the human relevance of these is uncertain, contraindications were added for pregnant and nursing mothers in the Product Monograph due to this theoretical risk. The signal for vasculitis in humans was insufficient to warrant a specific warning or precaution, but the effects observed in rodents are described in the Product Monograph. Cases of accidental pregnancy and vasculitis will be monitored in a post-market setting as part of the pharmacovigilance plan.

No modifications were made to the risk management plan previously reviewed under control #169862.

The quality review did not identify issues which affected the reliability of the clinical data review.

Overall, the safety and efficacy data acquired from the three pivotal trials and in the overall safety data pool demonstrated that Otezla had statistically significant and clinically meaningful improvements on the signs and symptoms of psoriatic arthritis and is adequately tolerable with risks that are manageable through adequate labelling. Moreover, the efficacy and safety profile of Otezla was evident irrespective of baseline DMARD use. Otezla is considered to have a favourable benefit-risk profile in the treatment of psoriatic arthritis.