Regulatory Decision Summary for Longavo

This New Drug Submission was submitted in support of market authorization of Longavo (risperidone extended-release injectable suspension) for the treatment of schizophrenia in adults. Longavo was developed as a long-acting formulation of risperidone for subcutaneous injection once monthly (q1m) or once every 2 months (q2m).

The New Drug Submission for Longavo was filed as an abbreviated submission relying in part on the safety and efficacy characterized for oral risperidone.

Longavo was developed as a new long-acting injection (LAI) formulation of risperidone for subcutaneous (sc) injection monthly (q1m) or once every two months (q2m) in the upper arm or abdomen. Longavo contains risperidone and two biocompatible block copolymers that, upon injection, form an insoluble depot under the skin. As the copolymers in the depot degrade by hydrolysis, risperidone is released. The formulation for q1m and q2m administration is the same but the volume of injection is doubled for q2m administration for claimed comparable doses. The proposed doses were 50 milligrams (mg), 75 mg, 100 mg, and 125 mg for q1m and 100 mg, 150 mg, 200 mg, and 250 mg for q2m, and these doses were claimed to be comparable to oral risperidone doses of 2 mg, 3 mg, 4 mg and 5 mg, respectively. The switch to Longavo was recommended without oral supplementation or loading dose.

The clinical program included three Phase 1 studies and two Phase 3 studies. Pharmacokinetic (PK) studies included one single ascending dose in healthy subjects (Study RISPE1ZG15EU), one single and multiple (q1m) ascending doses in patients with schizophrenia (Study TV46000-SAD-10055), and one relative bioavailability (Study TV46000-BA-10148) of single-dose administration of the formulation from vials (used in the pivotal safety and efficacy study) versus from pre-filled syringes (the final commercial product, used in the safety study). The Phase 3 studies consisted of one safety and efficacy, placebo-controlled, randomized-withdrawal study (Study TV46000-CNS-30072), and one longer-term, uncontrolled safety study (Study TV-46000-CNS-30078). Both Phase 3 studies had sparse PK sampling (pre-dose monthly sampling). Additional Population PK (PopPK) (TEV-PKER-TV46000-646) and exposure-response (E-R) analyses based on PK data from the Phase 1 and Phase 3 studies were submitted.

The first review cycle resulted in a Notice of Deficiency (NOD). The major objection of the NOD pertained to data quality issues, related to a number of dosing-related protocol deviations in the two Phase 3 studies (Study 30072 and Study 30078).

In the Response to NOD (R-NOD), the sponsor provided the results of an independent audit of dosing information retrieved directly from the clinical sites. The sponsor’s sensitivity analyses on the audited dataset confirmed that the dose-related deviations and multiple enrolment did not have an impact on the efficacy, safety or PK analyses. Therefore, the original conclusions were considered reliable for this review.

The efficacy of Longavo in the maintenance treatment of schizophrenia in adult patients first stabilized in daily oral risperidone was demonstrated in the pivotal randomized-withdrawal Study 30072. The study showed that Longavo q1m and q2m regimens significantly delayed relapse in patients stabilized on daily oral risperidone, who switched to the recommended corresponding doses, as compared to a switch to placebo. However, the study was not considered adequate to support a claim of similar efficacy of Longavo compared to oral risperidone at the recommended corresponding doses, because there was no treatment arm for continuing on the same oral risperidone dose. The evidence in support of corresponding oral risperidone and Longavo doses was mainly based on PK exposure results.

PK analyses were based on the risperidone total active moiety (TAM), that is, risperidone plus the active metabolite paliperidone. PK studies provided the bridge between Longavo q1m and the reference product, oral risperidone, with further support from the PopPK analyses using data from the Phase 1 PK studies and from sparse PK sampling in the Phase 3 studies. Longavo q1m 50, 75, 100, or 125 mg provided comparable exposure to the corresponding daily oral risperidone at 2, 3, 4 and 5 mg daily doses, respectively, at steady state.

There were concerns whether the q2m regimen could maintain the efficacy in stabilized patients based on lower exposure towards the end of the 56-day dosing interval as characterized in the PopPK study. An increased risk of relapse compared to the oral stabilization treatment was considered to outweigh the benefit of patient/caregiver/health care professional preference for less frequent injections. It was concluded that the q2m regimen and associated Longavo doses could not be recommended for approval.

Since there was a 2- to 2.5-fold accumulation with multiple q1m dosing compared to single exposure, and steady-state was achieved at 6 months (following the 7th injection), initially after the switch to Longavo, exposure was lower compared to the corresponding oral risperidone doses, and this was the major objection for a Notice of Non-Compliance. For example, the average concentration following the first q1m injection was 60% of that for the corresponding daily oral dose, and more similar to the end-of-dose concentration with the corresponding oral risperidone dose, for the duration of the 28-day dosing interval. However, since there was no lag in absorption following Longavo injection, risperidone concentrations achieved levels in the therapeutic range (greater than or equal to 10 nanograms per milliliter [ng/mL]) within 6 to 24 hours, depending on the dose. Thus, initiation of Longavo was recommended without oral supplementation or loading dose. Although TAM concentrations of 10 ng/mL may be therapeutic for some patients, it is unknown if it would be sufficient to maintain efficacy in patients stabilized in oral risperidone doses that result in higher average TAM concentrations. The sponsor provided new PopPK analyses with slightly different comparative exposure results, but still lower exposure following the first Longavo q1m injection, and also presented discussions regarding therapeutic range and exposure-response for risperidone. Considering the differences in PK profile between the formulations (for example, dosing interval, fluctuation) and the complex exposure-response for risperidone, it was not established which exposure parameters better reflect the exposure required to maintain efficacy when switching from daily oral to LAI antipsychotic, or what exact variation in exposure would be acceptable for a stabilized patient after the switch.

Given the observed differences in initial exposure, but no established threshold to determine impact for efficacy, and limitation of Study 30072 to compare efficacy of corresponding oral/LAI doses, it was concluded that more information regarding the characterised PK profile for Longavo q1m should be available for prescribers. The Longavo Product Monograph was revised to indicate that corresponding Longavo and oral risperidone doses were based on model-based PK parameters at steady-state, and more PK information relevant to the switch from daily oral risperidone was added. This information was anticipated to aid prescribers in making informed decisions for their patients.

The safety of Longavo in patients with schizophrenia was characterized in two Phase 3 studies: Study 30072 discussed above, and one longer-term (up to 56 weeks), double-blind, uncontrolled study (Study 30078). Study 30078 included patients rolled over from Study 30072 and de novo patients. In the Phase 3 studies, a total of 525 patients with schizophrenia were exposed to Longavo: 264 patients in the q1m arm and 261 patients in q2m arm. Only 4 adolescent patients were treated with Longavo in the studies. Overall, 352 patients were exposed for at least 6 months and 221 patients were exposed for at least 12 months. The most common treatment-emergent adverse events were injection site reactions, extrapyramidal syndrome (EPS), somnolence/sedation, and weight increase. Injection site reactions were mostly mild to moderate in severity and most resolved before the next injection. Longavo was also associated with increases in blood prolactin, glucose and triglycerides. Dose-dependency analyses were limited by the lack of randomization to fixed dose groups; nevertheless, dose-dependency was observed for EPS. The safety characterized for Longavo was consistent with the safety characterized for other risperidone products, including oral risperidone. No new safety issues were identified. The final Longavo Product Monograph contains the risk management appropriate for risperidone as well as class labelling for the antipsychotic class in general.

The assessment of benefit-harm-uncertainty for the Longavo q1m regimen in the conditions of use and risk management described in the final acceptable Longavo Product Monograph was considered supportive of authorization, therefore a Notice of Compliance was recommended.

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