Regulatory Decision Summary for Soliqua

The current NDS for Soliqua was filed to obtain marketing authorization for a drug/device combination product in a disposable SoloSTAR pen injector device which contains two approved drugs: a biologic (insulin glargine, active substance in Lantus) and a pharmaceutical (lixisenatide, active substance in Adlyxine) in a fixed-ratio combination (FRC) for subcutaneous injection. As such, a joint review between the Biologics and Genetic Therapies Directorate (BGTD) and the Therapeutic Products Directorate (TPD) at Health Canada was performed.

The safety and efficacy of Soliqua was assessed in two randomized clinical studies in patients with type 2 diabetes mellitus (T2DM). During the review cycle, Health Canada requested to revise the proposed indication and limit the use of Soliqua in patients not adequately controlled by basal insulin alone or in combination with metformin. As such, only Study EFC12405 was considered as pivotal to grant the revised indication.

Study EFC12405 was a randomized, 30-week, active-controlled, open-label, 2-treatment arm, multicenter study comparing the efficacy and safety of the FRC to insulin glargine in T2DM patients (n = 730) who were not adequately controlled at baseline with basal insulin therapy (alone or in combination with metformin).

Data derived from the pivotal trial (EFC12405) demonstrated that FRC is more effective than insulin glargine in the treatment of patients with T2DM inadequately controlled by basal insulin therapy (alone or in combination with metformin). The primary objective of the study was met, as statistical superiority of the FRC over insulin glargine was demonstrated by a change in glycated haemoglobin A1C (HbA1c) from baseline to Week 30. At Week 30, the HbA1c decreased by -1.13% for the FRC group and by -0.62% for the insulin glargine group with a statistically significant difference between the 2 treatment groups of -0.52% (p<0.0001). These results were robust across various sensitivity analyses. Subgroup analyses were also consistent with the primary analysis.

The pre-specified secondary endpoints also supported the primary efficacy outcome. Specifically, the improvement in HbA1c was reflected by the markedly higher proportion of FRC-treated patients reaching the pre-specified HbA1c target (<7%) than that of insulin glargine-treated patients. Treatment with FRC significantly improved prandial glycemic control after a standardized meal test compared to insulin glargine. Mean body weight decreased from baseline to Week 30 in the FRC group (-0.67 kg) and increased in the insulin glargine group (+0.70 kg), leading to a statistically significant difference of -1.37 kg (p<0.0001). The FRC allowed substantially more patients to reach the HbA1c target while minimizing the weight gain typically observed at initiation or intensification of insulin-based therapy and without increasing the hypoglycemia rate.

Similar improvements in fasting plasma glucose (FPG) levels were noted in both treatment groups with a steady increase in the mean daily insulin dose, reaching similar values of 46.7 units (for FRC: 46.7 units insulin glargine/15.6 mcg lixisenatide) at Week 30. The majority of patients in both treatment groups had a final daily insulin dose >40 and ≤60 U. The contribution of the lixisenatide component of the combination to glycemic and body weight control is evident. In addition, data from supportive studies showed that the FRC of insulin glargine and lixisenatide provided better glycemic control with comparable safety profile versus either drug alone. Those results are in line with those presented in the pivotal trial.

The results from the pivotal study revealed that FRC carries drug-specific safety risks attributable to insulin glargine and lixisenatide. Treatment with FRC and insulin glargine was associated with a greater risk of hypoglycemia and weight gain than lixisenatide alone. Treatment with FRC and lixisenatide was associated with a greater risk of gastrointestinal (GI) adverse reactions and allergic reactions than insulin glargine alone. Overall, 992, 992 and 233 patients received at least one dose of FRC, insulin glargine and lixisenatide, respectively, in the clinical development program. The two clinical studies included 834 patients treated with FRC for about 30 weeks. Long-term safety of FRC is also supported by long-term safety data from the individual drugs (Adlyxine and Lantus).

Overall, the FRC therapy provides a tolerable safety profile with clinically and statistically significant benefits over the individual components while minimizing undesirable effects of these components. The FRC reduces treatment complexity and provides a benefit to patients with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) alone or in combination with metformin as an adjunct to diet and exercise to improve glycemic control. The once-daily injection of a dual anti-hyperglycemic therapy potentially improves treatment compliance. This, in turn, may allow more patients to reach glycemic goals. Major safety concerns and uncertainties are updated in the Canadian Product Monograph and the Risk Management Plan.

Based on the totality of the data, Soliqua has a positive benefits-risk-uncertainty profile for adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) alone or in combination with metformin as an adjunct to diet and exercise to improve glycemic control.