Regulatory Decision Summary for Abilify Maintena / Abilify Asimtufii

The purpose of this Supplement to a New Drug Submission was to obtain market authorization of a new higher dose and longer-acting aripiprazole prolonged-release injectable suspension, Abilify Asimtufii, supplied as pre-filled syringes of 960 milligrams (mg)/3.2 milliliters (mL) and 720 mg/2.4 mL for administration by intramuscular injection, for the treatment of adult patients with schizophrenia and for maintenance monotherapy treatment of adult patients with bipolar I disorder.

With this Supplemental New Drug Submission the sponsor sought approval of Abilify Asimtufii (960 milligrams [mg] and 720 mg), a new higher dose and longer-acting prolonged-release injectable suspension of aripiprazole that was developed to provide therapeutic exposure levels of aripiprazole for 2 months, following intramuscular (IM) administration to the gluteal muscle. The sponsor currently markets aripiprazole oral tablets (Abilify) and aripiprazole for prolonged-release injectable suspension that provides therapeutic exposure levels of aripiprazole for 1 month following gluteal or deltoid administration (Abilify Maintena, 400 mg and 300 mg). An exposure-matching (pharmacokinetic [PK]-bridging) approach coupled with evaluation of safety, was used to support extending the approved indications for Abilify Maintena, for treatment of adults with schizophrenia and monotherapy maintenance treatment of adults with bipolar I disorder, to Abilify Asimtufii. The rationale for the exposure-matching approach was that the clinical trial data from oral aripiprazole and Abilify Maintena and more than 10 years of post-marketing experience with both products have established a history of efficacy, safety, and tolerability for the aripiprazole molecule, in different formulations and various patient populations.

A Phase 1b, randomized, open-label, 32-week study that compared the safety, tolerability and bioavailability of 4 doses of Abilify Asimtufii 960 mg administered once every 2 months (8 weeks) to 8 doses of Abilify Maintena 400 mg administered once monthly (4 weeks) to adults with schizophrenia or bipolar I disorder who were clinically stable at enrollment, served as the pivotal PK and safety clinical trial for Abilify Asimtufii. The study demonstrated comparable bioavailability of aripiprazole with Abilify Maintena 400 mg and the clinical trial batch of Abilify Asimtufii 960 mg. The safety data, which were based on a sufficient number of patients and relevant safety evaluations for atypical antipsychotics and IM administered products, suggested that Abilify Asimtufii 960 mg and Abilify Maintena 400 mg were tolerated similarly in both patient populations, following multiple gluteal administrations during the 32-week treatment period of the study. The study included relevant measures for evaluating the efficacy of antipsychotic treatments in patients with schizophrenia or bipolar disorder but, was not designed to rigorously assess efficacy (open-label, no placebo arm, no planned statistical comparisons between treatment arms). Therefore, it cannot be claimed that similar efficacy or effectiveness relative to Abilify Maintena 400 mg was demonstrated/established for Abilify Asimtufii 960 mg in this study. Rather, the previous clinical data that supported authorization of Abilify Maintena and similar bioavailability of aripiprazole with both formulations demonstrated in the pivotal PK study, suggested efficacy may be similar with both formulations in the indicated patient populations. There were no outstanding issues related to the clinical data, or the non-clinical data reviewed for the new formulation. A population PK model for aripiprazole that was developed previously with PK data for oral aripiprazole and Abilify Maintena was updated to include PK data from studies that used the new formulation of aripiprazole prolonged-release injectable suspension. The model was adequately developed to use for the model-based simulations that informed all proposed dosing recommendations for Abilify Asimtufii, but missing information related to the presentation and interpretation of the simulations precluded assessment of the proposed dosing recommendations for Abilify Asimtufii (Biostatistics, Epidemiology, and Pharmacometrics Unit [BEPU] consult).

The Notice of Deficiency (NOD), issued in July 2023, identified deficiencies in the quality data and data provided to support the bridging of the manufacturing site for the clinical trial batch of Abilify Asimtufii 960 mg and the site planned for manufacturing the commercial product. A change in manufacturing site for a drug product with a complex dosage form, such as Abilify Asimtufii, typically requires either a clinical study or, model-based simulations employing an in vitro – in vivo correlation (IVIVC) or, physiologically based biopharmaceutics modelling (PBBM) to demonstrate that the manufacturing site change does not affect in vivo performance of the drug product. A comparison of in vitro dissolution profiles of the drug product used in the pivotal PK clinical trial and the proposed commercial drug product that was submitted in the SNDS was not adequate to support equivalence of the proposed commercial product. In addition to the deficiencies identified from the quality and biopharmaceutics modelling reviews, a request for missing information that was required for the assessment of the population PK model-based simulations and Abilify Asimtufii dosing recommendations (BEPU consult), and a request for the inclusion of medication errors as a potential risk in the Risk Management Plan (RMP) (Marketed Health Products Directorate [MHPD]), were included in the NOD. The response to NOD sufficiently addressed the concerns raised from the quality/biopharmaceutics modelling reviews, from the MHPD review of the RMP and, from the assessment of the population PK model-based simulations used to inform all dosing recommendations for Abilfy Asimtufii.

The main risk mitigation tools for Abilify Asimtufii are the Product Monograph (PM) and the RMP. The RMP proposed by the sponsor was considered acceptable by the MHPD. A Periodic Safety Update Report (PSUR)/Periodic Benefit Risk Evaluation Report (PBRER) will be requested by the MHPD for review 2 years after market entry of Abilify Asimtufii in Canada. During the clinical assessment of the response to NOD, revisions to the proposed single, combined PM for Abilify Maintena and Abilify Asimtufii were completed. Based on the population PK modelling and simulation data, in consultation with BEPU, extensive revisions were made to the proposed dosing recommendations for Abilify Asimtufii. The required revisions included: introduction of a contraindication for CYP2D6 poor metabolizers and a recommendation to avoid concomitant use of Abilify Asimtufii with strong CYP2D6 inhibitors. This was due to simulation-predicted aripiprazole exposures from the 720 mg dose in these conditions substantially exceeding predicted exposures from the 960 mg dose in the absence of these conditions. Abilify Asimtufii was designed to deliver sustained aripiprazole exposure over a 2-month period and, based on the simulation-predicted high exposures for these conditions with the 720 mg dose, it may not be possible to effectively lower drug concentrations in a timely manner to manage tolerability problems or an adverse event (AE) that requires drug discontinuation. Other simulation-based dosing recommendations that required modification included: providing acceptable limits for repeated earlier or later administration around the scheduled 8-week dosing interval and, the management of missed doses depending on the timing of missed doses relative to achieving steady state drug concentrations. Other PM revisions that were made to the Abilify Maintena / Abilify Asimtufii PM include the addition of safety and PK information for Abilify Asimtufii from the pivotal PK study, information about the simulation-predicted aripiprazole exposure from Abilify Asimtufii 960 mg vs Abilify Maintena 400 mg, and re-organization of the DOSAGE AND ADMINISTRATION section to fully separate the information for one product from that of the other. This was implemented as an interim measure to facilitate navigation in this section of the single combined PM and to minimize the risk of dosing/administration errors, until the sponsor fulfills a commitment to file a post-Notice of Compliance submission to create a separate PM for each product.

Overall, the simulation-based dosing recommendations for Abilify Asimtufii and several other aspects of the Abilify Maintena / Abilify Asimtufii PM were revised to support an acceptable benefit-harm profile for Abilify Asimtufii under the proposed conditions of use in adult patients with schizophrenia or bipolar I disorder.

For further details about Abilify Maintena / Abilify Asimtufii, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.