Regulatory Decision Summary for Rexulti

This Supplement to a New Drug Submission was filed for Rexulti to get approval for a new indication for the treatment of Agitation associated with Alzheimer’s Disease.

The efficacy and safety of Rexulti for the treatment of Agitation associated with Alzheimer’s Disease (AAD) was mainly supported by three Phase 3, 12-week, double-blind, placebo-controlled, pivotal clinical trials, Study 331-12-283, Study 331-12-284, and Study 331-14-213. The clinical dataset also included a 2-month observational study, a 12-week extension study that enrolled subjects from one of the pivotal trials, as well as preliminary data from an ongoing controlled trial conducted in Japan and its extension study. The pivotal trials were completed under similar experimental conditions and design. They were all conducted for a 12-week double-blind period and included Alzheimer’s Disease (AD) subjects with a variety of dementia severity based on a Mini-Mental State Examination (MMSE) score between 5 and 22, who were required to have significant agitation. Based on the knowledge acquired in the two prior trials (Study 331-12-283 and Study 331-12-284), trial Study 331-14-213 had an additional entry criteria, where subjects had to meet the criteria for Cohen-Mansfield Agitation Inventory (CMAI) Factor 1 agitation (hitting, kicking, scratching, grabbing, pushing, hurting self or others, throwing things, cursing or verbal aggression, spitting, tearing things or destroying property, screaming and biting). In two of the three pivotal trials, a fixed dosing regimen was evaluated (Study 331-12-283: 1 milligram per day [mg/day], 2 mg/day vs. placebo; Study 331-14-213: 2-3 mg/day vs. placebo) while in the third one, a flexible dosing regimen was tested (Study 331-12-284: 0.5-2 mg/day vs. placebo). In the three pivotal trials, the primary and secondary efficacy endpoints were the change from baseline to Week 12 in the CMAI total and Clinical Global Impression-Severity of illness (CGI-S) scores, respectively.

In Study 331-12-283, a statistically significant reduction in the CMAI total score was observed for the 2 milligram (mg) dose group compared to placebo. However, this observation was not supported by either sensitivity analyses or the key secondary endpoint. Because of the partially failed primary endpoint (1 mg dose group was not different from placebo) and the hierarchical testing procedure, none of the initially planned subsequent analyses could be considered to support the efficacy. In Study 331-14-213, which included subjects exhibiting aggressive behaviors (CMAI Factor 1), the primary and key secondary efficacy endpoints were reached. One consistent observation was that Rexulti’s benefits on agitation took approximately 8 weeks to take effect. Study 331-12-284 (flexible dosing regimen) did not meet the primary endpoint and due to the hierarchical testing procedure, none of the initially planned subsequent analyses could be considered to support the efficacy. Several uncertainties remained following the assessment of the efficacy dataset however, a benefit on agitation in subjects with AAD exhibiting aggressive behaviors was observed and all uncertainties were mitigated by strengthening the labelling, notably by limiting the indication to patients with AAD that have aggressive behaviors and are unresponsive to non-pharmacological approaches.

The safety profile of Rexulti in subjects with AAD was assessed using mainly the pooled dataset of the three pivotal trials and the 12-week extension study of trial Study 331-14-213. As part of the 12-week pivotal trials in AAD, a total of 655 subjects were exposed to at least one dose of Rexulti . Study completion rates were high (86.8% in the Rexulti-exposed subjects and 88.9% in the placebo group). Overall, the use of Rexulti in subjects with AAD was safe. Incidences of treatment-emergent adverse events and serious adverse events were similar between the all- Rexulti group (51.1% and 6.4%, respectively) and the placebo group (45.9% and 4.1%, respectively). The most common treatment-emergent adverse event included nasopharyngitis, urinary tract infection, dizziness, somnolence, and insomnia. A known risk associated with antipsychotic exposure in elderly patients with dementia is the increased mortality, which is highlighted in a box warning in all antipsychotics’ Product Monographs (PM). An imbalance in the mortality rates was observed between the Rexulti-treated and placebo elderly subjects during the clinical development program of Rexulti in AAD subjects. There were 11 deaths reported with 10 of them in subjects exposed to Rexulti (mortality rates of 0.7% versus [vs.] 0.2%); therefore, an increased mortality risk in elderly patients cannot be ruled out for Rexulti. Despite this imbalance, the risk of mortality was lower in the Rexulti clinical trials in AAD subjects when compared to published mortality rates of elderly patients with dementia exposed to antipsychotics (4.5% vs. 2.6% in placebo group according to the Food and Drug Administration meta-analyses). Because of this imbalance, the existing box warning on mortality risk in elderly patients with dementia was maintained in the Rexulti PM and additional information was added to the dosing and administration section. In addition, in order to maintain a positive benefit-risk ratio, the indication was limited to patients with agitation that demonstrate aggressive behaviors.

Longer-term use of Rexulti (daily dosing with 2 or 3 mg for up to 24 weeks) was generally safe and well tolerated in subjects with AAD, with no death and no new safety signals observed in the 12-week extension trial (Study 331-201-00182). However, only 142 subjects were exposed to Rexulti for 24 weeks, which was deemed insufficient, as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety for Drugs used in Long-Term Treatment: Population exposure: The extent of population exposure to assess clinical safety Guideline, to properly characterize the long-term safety profile of Rexulti among AAD patients. Exploratory efficacy results indicated that agitation continued to decrease during the 12 weeks of Rexulti treatment extension, suggesting maintenance of the Rexulti effect on agitation up to 24 weeks.

An updated Risk Management Plan for Rexulti was reviewed by Health Canada and considered acceptable.

Overall, the benefits of Rexulti for the symptomatic management of AAD in subjects with aggressive behaviors and unresponsive to non-pharmacological treatment approaches outweigh the risks when used according to the information detailed in the PM. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Rexulti, please refer to the PM, approved by Health Canada and available through the Drug Product Database.