Adlyxin (lixisenatide): BLA 208471

The product was approved with a Risk Evaluation and Mitigations Strategy (REMS) and several postmarketing required studies.

Both Dr. Shiu and Dr. Qian recommend approval of the device.

The Office of Clinical Pharmacology (OCP) has reviewed the clinical pharmacology data submitted on 07/27/2015 under NDA 208471 and recommend approval with the following recommendations.

On May 25, 2016, the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommended approval of lixisenatide with a 12-2 vote.

The results for change in fasting plasma glucose and for change in body weight were less consistently demonstrated (Figure 7, Figure 8).

While lixisenatide was generally statistically superior to placebo for change in fasting plasma glucose, no apparent difference was seen in two of the placebo-controlled studies (study EFC6016 and study EFC10781).

In total, 399 MACE+ were observed in placebo-treated subjects compared to 406 MACE+ in lixisenatide treated subjects (Table 15).

When including MACE+ events the absolute difference remained similar (13.7% lixisenatide vs 10.1% placebo).

Within statin non-users, the MACE+ event rate was higher in lixisenatide group (17.7%) than in placebo group (11.8%) with a wide confidence interval.

For the other sites mentioned above all subjects treated were included in the analyses, and the applicant also performed a sensitivity analysis for the primary efficacy endpoint (HbA1c change from baseline to Week 24) excluding these sites.

During review, the Office of Clinical Pharmacology noted that phase-2 data suggested the benefit-risk balance could have been possibly more favorable had a twice daily administration schedule been selected for evaluation in the phase 3 program.

In addition, required postmarketing studies will continue to inform us of the benefit-risk profile of lixisenatide.

Though the overall incidence is low, anaphylaxis is a serious and life-threatening condition.

Therefore I do not think a REMS is required for lixisenatide, and the risk for pancreatitis can be addressed by appropriate labeling.

Therefore, until the ELIXA trial is complete, there is still an element of uncertainty about exclusion of excess CV risk with lixisenatide, which will have to be included when weighing risk-benefit considerations for approval.

DRISK and the Division of Metabolism and Endocrinology Products agree that a REMS is not needed to ensure the benefits of lixisenatide outweigh its risks.

As a result, the OBP consult has recommended that the applicant perform additional assessments as a postmarketing requirement.