Regulatory Decision Summary for Lyumjev

Type 1 (T1DM) and type 2 (T2DM) diabetes mellitus are diseases of impaired glucose homeostasis that result in chronic hyperglycemia. Both types of diabetes increase the risk for microvascular and macrovascular complications and associated morbidity. Treatment with insulin (INS) is required for patients with T1DM and is often required in patients with T2DM after non-INS medications have failed to control glycemia. Fast-acting INS analogs, in combination with long-acting INS, are used to mimic the physiologic postmeal INS secretion patterns of healthy subjects. Lyumjev is a novel fast-acting formulation of insulin lispro with a faster time-action profile compared to Humalog.

The efficacy of Lyumjev administered at mealtime or postmeal in adult patients with T1DM and used in combination with basal INS was evaluated in a 26-week trial. Patients were randomized to either mealtime Lyumjev, mealtime Humalog, or open-label postmeal Lyumjev - all in combination with either insulin glargine or insulin degludec. Mealtime Lyumjev or Humalog was injected 0 to 2 minutes before the meal and postmeal Lyumjev was injected 20 minutes after the start of the meal. At Week 26, treatment with mealtime Lyumjev provided a mean change from baseline in HbA1c (-0.18%) that met the pre-specified non-inferiority margin (0.4%) compared to mealtime Humalog (-0.09%). In addition, postmeal Lyumjev provided a mean reduction from baseline in HbA1c (0.05%) that met the same pre-specified non-inferiority margin compared to mealtime Humalog. Insulin doses were similar for all treatment groups at baseline and at 26 weeks.

The efficacy of Lyumjev administered at mealtime in adult patients with T2DM and used in combination with basal insulin was evaluated in a 26-week randomized, treat-to-target, active-controlled trial. Patients at study entry were on up to three oral anti-diabetic medications (OAD), basal INS, and at least one prandial INS injection or premixed INS; they were allowed to continue on OAD. Patients were randomized to either mealtime Lyumjev or to mealtime Humalog, both in combination with insulin glargine or insulin degludec in a basal-bolus regimen. Mealtime Lyumjev or mealtime Humalog was injected 0-2 minutes before the meal. At Week 26, treatment with mealtime Lyumjev provided a mean change from baseline in HbA1c (-0.43%) that met the pre-specified non-inferiority margin (0.4%) compared to mealtime Humalog (-0.46%). Insulin doses were similar in both treatment groups at baseline and at 26 weeks.

The efficacy of Lyumjev administered by continuous subcutaneous insulin infusion (CSII) by external pump in adults with T1DM compared to Humalog was evaluated in a 16-week randomized, treat-to-target, active-controlled trial. Patients were randomized to either Lyumjev or Humalog. Mealtime Lyumjev or Humalog boluses were initiated 0 to 2 minutes before the meal. At Week 16, treatment with Lyumjev provided a mean change from baseline in HbA1c (-0.06%) that met the pre-specified non-inferiority margin (0.4%) compared to Humalog (-0.09%). Total daily insulin doses were similar for both treatment groups at baseline and at 16 weeks.

All three pivotal studies achieved their primary efficacy objectives of demonstrating non-inferiority of Lyumjev to Humalog.

The safety data for Lyumjev administered via multiple daily injections (MDI) is based on 2 pivotal studies, conducted in adult patients with T1DM and T2DM, respectively. The safety profile for Lyumjev administered via CSII is based on one pivotal conducted in adult patients with T1DM. In the MDI studies, 1116 patients were exposed to Lyumjev with a mean duration of exposure of 254.7 days. In the CSII study, 215 patients were exposed to Lyumjev with a mean duration of 107.3 days. The size of the safety database was considered acceptable.

In the MDI studies, there was a similar frequency in the incidence of treatment-emergent adverse events (TEAEs) between subjects with T1DM exposed to Lyumjev (n = 306; 67.8%) and Humalog (n = 298; 67.4%), respectively. Hypoglycemic events were the most commonly reported serious AE in T1DM subjects. There was a similar frequency in the incidence of TEAEs between subjects with T2DM exposed to Lyumjev (n = 206; 61.3%) and Humalog (n = 195; 57.9%), respectively. Hypoglycemic events were the most commonly reported serious AE in T1DM subjects.

In the pivotal studies, adverse reactions occurring in ≥1.0% of Lyumjev subjects were hypoglycemia, nasopharyngitis, upper respiratory tract infection, severe hypoglycemia, injection site reaction, infusion site reaction, and allergic reactions.

The hypoglycemia safety profile for Lyumjev was found to be consistent with Humalog. Overall incidence and rate of hypoglycemic events were similar in T1DM, and T2DM patients administered Humalog or Lyumjev as MDI regimen. The rate and incidence of postprandial hypoglycemia with mealtime Lyumjev was similar to Humalog and occurred at earlier time points (>1 to ≤2 hours) as expected due to the faster onset of action for Lyumjev. Early post-meal hypoglycemia was more frequent with Lyumjev and late post-meal hypoglycemia with Humalog. In T1DM, the analyses of time spent in hypoglycemia demonstrated that Lyumjev was associated with less time in hypoglycemia compared to Humalog. In the CSII Study, PRONTO-Pump-2, slightly lower hypoglycemia was observed with Lyumjev vs. Humalog.

The incidence of treatment emergent adverse events (TEAEs) related to injection site reactions was higher in patients receiving Lyumjev. In the pooled MDI safety data, the incidence of injection site reaction AE for Lyumjev (2.9%) was higher than Humalog (0.5%), with the most frequently reported events of injection site reaction and injection site pain. None of the injection site TEAEs in the MDI studies were reported as serious AE. All the events were mild (87.5%) or moderate (12.5%) in severity. Patients on CSII therapy had a higher incidence of TEAEs related infusion site reactions than MDI treatment, which was higher for the Lyumjev (37.7%) treatment group compared with Humalog (10.6%). The most frequently reported events were infusion site reaction and infusion site pain. None of the TEAEs of injection site in the CSII study were reported as serious.

The safety profile of Lyumjev is demonstrate to be consistent with the well-established safety profile of Humalog, with no new or unexpected safety findings.

Overall, the benefits of Lyumjev outweigh the risks in the target patient population. The benefit-risk profile is considered acceptable for the sought indication.