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Victoza® (Liraglutide) Injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

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Victoza® (Liraglutide) Injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 Victoza® (liraglutide) injection LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results NDA 22341 S-027 Briefing Document Endocrinologic and Metabolic Drug Advisory Committee June 20, 2017 Advisory Committee Briefing Materials: Available for Public Release Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 2 of 95 1 Executive summary Introduction Liraglutide is an analog with 97% homology to human glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor agonist (GLP-1 RA). Liraglutide (Victoza®) obtained marketing authorization in the United States (US) in 2010 and is currently approved in over 100 countries worldwide. In the US, Victoza® (for subcutaneous injection 1.2 mg and 1.8 mg once-daily) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) as mono- or combination therapy.1 The exposure to Victoza® in the post-marketing setting is extensive; as of 30 June 2016, the cumulative exposure was estimated to be greater than 6 million patient-years of exposure to Victoza®. The LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was a cardiovascular outcomes trial designed and conducted to determine the effect and long-term safety of liraglutide versus placebo on cardiovascular outcomes as a post- marketing requirement (PMR) for Victoza® in the US and European Union (EU). Based on the robust results from the LEADER trial demonstrating that liraglutide was superior to placebo with respect to the primary endpoint (time to first major adverse cardiovascular event [MACE]), Novo Nordisk is seeking to add an additional indication to the existing indication for Victoza® as follows (new proposed indication in bold): ‘Victoza® is indicated: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. as an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and high cardiovascular risk.’ Thus, while Victoza® is already indicated to achieve glycemic lowering in patients with T2DM, the new proposed indication based on the demonstrated benefit to reduce cardiovascular events will provide important guidance to prescribers considering their options to treat T2DM. Unmet medical need Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes.2,3 Despite improvements in T2DM care by early and multi-factorial treatment of cardiovascular risk factors such as hypertension, obesity and dyslipidemia, the risk of cardiovascular disease for patients with diabetes remains at least twice as high compared to that in adults without diabetes.4 Furthermore, patients with diabetes and established cardiovascular disease have a higher risk of additional cardiovascular events and a shorter life expectancy than patients without diabetes.5 Hence, there is a large unmet medical need for additional therapies that can further reduce the risk Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 3 of 95 of cardiovascular disease development and progression in the population with diabetes while ensuring good glycemic control. LEADER trial design and population (Sections 4 and 5) LEADER was a long-term, multicenter, multi-national, randomized, double-blind, placebo-controlled trial to determine the effect of liraglutide versus placebo on cardiovascular outcomes and long-term safety in patients with T2DM at high cardiovascular risk. Both liraglutide and placebo were used in addition to standard of care therapy. The trial was designed and conducted in accordance with the 2008 FDA guidance for evaluating cardiovascular risk in new antidiabetic therapies.6 As such, an independent external event adjudication committee (EAC) was established with appropriate subcommittees to perform ongoing blinded adjudication of cardiovascular events and deaths, as well as events of nephropathy, retinopathy, neoplasms and pancreatitis. Patients with T2DM were eligible for trial enrolment if they had an HbA1c ≥ 7.0% at screening (no upper limit) and were antidiabetic drug naïve or were treated with one or more oral antidiabetic drugs (OADs) and/or neutral protamine hagedorn (NPH) insulin, long-acting insulin, or premixed insulin. In addition, patients were to be at high risk for cardiovascular events with either established cardiovascular disease or chronic kidney disease and age ≥ 50 years, or with at least one cardiovascular risk factor and age ≥ 60 years. These cardiovascular enrichment criteria were applied to achieve the required number of MACEs as well as the number of patients with moderate (estimated Glomerular Filtration Rate [eGFR] ≥ 30 to < 60 mL/min/1.73m2 per Modification of Diet in Renal Disease [MDRD]) and severe (eGFR < 30 mL/min/1.73m2 per MDRD) renal impairment (the latter two as per FDA request). As such, this resulted in inclusion of a clinically relevant high cardiovascular risk population for ruling out cardiovascular harm associated with liraglutide, and represented patients who could benefit from either primary or secondary cardiovascular disease prevention. An overview of the key inclusion and exclusion criteria is provided in Table 1 with a complete listing provided in Appendix 2. Patients were randomly assigned, in a 1:1 ratio, to receive either liraglutide 1.8 mg (or maximum tolerated dose) or placebo once-daily, both in combination with standard of care therapy. The trial was both time and event driven. Thus, the trial ended when all patients had had a minimum treatment period of 42 months (plus a follow-up period off treatment of 30 days) and once at least 611 first events of MACE (primary endpoint defined as the composite of cardiovascular death, non- fatal myocardial infarction [MI; including silent MI] and non-fatal stroke) were recorded and confirmed by event adjudication. The minimum treatment period of 42 months was chosen to provide long-term data for liraglutide on relevant safety parameters. Because of an 18-month recruitment period, those patients first randomized into the trial could have a maximum treatment period of 60 months. A total of 9,340 patients were randomized (4,668 to liraglutide and 4,672 to placebo) including a total of 224 patients with severe renal impairment at baseline (eGFR < 30 mL/min/1.73 m2 per Novo Nordisk Victoza® (liraglutide) NDA 22341 S-027 Endocrinologic and Metabolic Drug Advisory Committee, June 20, 2017 4 of 95 MDRD). A total of 96.8% of the randomized patients (9,042 patients) were completers defined as patients who during the trial either had a primary event (MACE), died (due to non-cardiovascular causes), or completed the planned follow-up visit. Importantly, the vital status was known in 99.7% of the patients (9,311 patients). Thus, the LEADER trial had a high degree of patient retention ensuring a low amount of missing data for evaluation of the primary endpoint. For details of patient disposition, see Figure 4. The median time of observation in LEADER was 3.84 years in each treatment group (including the follow-up period off treatment) and the median time of exposure to trial product was 3.52 and 3.51 years in the liraglutide and placebo groups, respectively. In the liraglutide group, 85% of the total exposure to liraglutide was to the 1.8 mg/day dose indicating that this dose level was well-tolerated. Demographics, baseline characteristics, and use of concomitant medication were well-balanced between the two treatment groups at baseline. Cardiovascular outcomes (Section 6) The primary endpoint: time from randomization to the first occurrence of a MACE (cardiovascular death, non-fatal MI [including silent MI], or non-fatal stroke) was analyzed using a Cox proportional hazards model with treatment as factor based on the full analysis set (FAS) that included all randomized patients. The primary analysis was performed using a pre-defined hierarchy, initially testing if liraglutide was non-inferior to placebo (upper bound of the 2-sided 95% CI for the estimated hazard ratio < 1.3) to establish cardiovascular safety. If non-inferiority was confirmed, it was then tested if liraglutide was superior to placebo (upper bound of the 2-sided 95% CI for the estimated hazard ratio being < 1.0). A number of pre-specified sensitivity analyses were performed to evaluate the robustness of the result; these analyses included a per protocol (PP) analysis and two ‘on-treatment’ analyses (for definitions, refer to Table 5). In addition, a total of 13 exploratory subgroup analyses were pre-specified to evaluate the consistency of the treatment effect on the primary endpoint. A total of 1,302 first MACE events (confirmed by adjudication) were identified in the trial (608 in the liraglutide group and 694 in the placebo group). The primary analysis of time to first MACE with liraglutide versus placebo resulted in an estimated hazard ratio of 0.87 in favor of liraglutide (Figure 1). The one-sided (α-level 0.025) test for non-inferiority of liraglutide versus placebo for the primary endpoint was statistically significant (p < 0.001) with the upper 95% CI below 1.3, thus confirming non-inferiority. The one-sided (α-level 0.025) test for superiority of liraglutide versus placebo was also statistically significant (p = 0.005), thus confirming superiority of liraglutide versus placebo, with an estimated risk reduction for MACE of 13% compared to placebo. All 3 components of the primary endpoint (cardiovascular death, non-fatal MI and non-fatal stroke) contributed to the reduction in first MACE observed with liraglutide (Table 13). All pre-specified sensitivity analyses (including ‘per protocol’, ‘on treatment’ and ‘on treatment + 30 days’) supported the robustness of the primary analysis, with all hazard ratio estimates and upper bounds of the 95% CIs < 1 (Figure 1).
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