Regulatory Decision Summary for Mounjaro

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

Tirzepatide

Therapeutic area:

Drugs used in diabetes

Type of submission:

New Drug Submission (New Active Substance)

Control number:

259103
What was the purpose of this submission?

The purpose of this New Drug Submission (NDS) was to gain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Mounjaro (tirzepatide), submitted by Eli Lilly Canada Inc. Upon review, Mounjaro was approved for the following indication: to improve glycemic control in adult patients with Type 2 Diabetes Mellitus (T2DM). Tirzepatide is both a glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors agonist.

This submission was reviewed as part of an international work-sharing (IWS) project with the Therapeutic Goods Administration (TGA-Australia), Health Sciences Authority (HSA-Singapore) and Swissmedic (Switzerland). Health Canada was responsible for reviewing Module 3 (chemistry and manufacturing), Swissmedic was responsible for reviewing Module 4 (non-clinical) and Module 5 (clinical).

Why was the decision issued?

Five pivotal Phase 3 studies and supportive studies were submitted to support the safety and efficacy of tirzepatide and evaluated the 5 mg, 10 mg, and 15 mg doses of tirzepatide in a range of patients with T2DM, from those who were newly diagnosed to patients who had longer duration and more advanced disease, including those with increased cardiovascular (CV) risk.

Study GPGK (SURPASS-1) was a 40-week, multi-center, randomized, double-blind, parallel, placebo-controlled trial to assess the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg versus placebo in 478 adults with type 2 diabetes inadequately controlled with diet and exercise alone. The primary endpoint of HbA1c reduction at 40 weeks compared to placebo was statistically significant. Tirzepatide 5 mg, 10 mg, and 15 mg reduced baseline HbA1c by 1.8, 1.7, and 1.7% compared to 0.1% in the placebo arm (p<0.001). The key secondary endpoints of responder rates (achieving a HbA1c of ≤ 7.0%) were 82, 85, and 78% for the tirzepatide arms versus 23% for the placebo arm(p<0.001).

Study GPGL (SURPASS-2) was a 40 week, randomized, open label, multicenter, active controlled trial that compared the glycemic-lowering effects of tirzepatide 5 mg, 10 mg, and 15 mg once-weekly to semaglutide 1 mg once-weekly in 1879 patients with T2DM inadequately controlled with concomitant metformin. The primary endpoint was the change from baseline (40 weeks) in HbA1c. Tirzepatide 5 mg, 10 mg, and 15 mg resulted in an HbA1c reduction of 2.0, 2.2, and 2.3% versus 1.9% in the semaglutide arm. There was no significant dose responsiveness. The results were statistically significant in the 5 mg (p = 0.018) and the 10/15 mg arms (p<0.001).

Study GPGH (SURPASS-3) was a 52 week, open label, active controlled trial comparing the glycemic-lowering effects of tirzepatide 5 mg, 10 mg, and 15 mg to titrated insulin degludec in 1444 patients with T2DM inadequately controlled with concomitant metformin, with or without an SGLT-2i. All 3 tirzepatide doses met the primary objective of both non-inferiority and superiority to insulin degludec in the reduction of HbA1c from baseline at 52 weeks. HbA1c reduction were 1.9% for tirzepatide 5 mg (p<0.001), 2.0% for 10 mg (p<0.001), and 2.1% for 15 mg (p<0.001) compared to 1.3% in the insulin degludec arm. There was not a statistically significant dose responsiveness.

Study GPGM (SURPASS-4) was a long-term 104-week, multicenter, open label, parallel group, active controlled phase 3 study that compared the glycemic-lowering effects of tirzepatide 5 mg, 10 mg, and 15 mg to titrated insulin glargine in 2002 patients with T2DM with increased CV risk, who were inadequately controlled with metformin, SGLT-2i, sulfonylurea, or a combination of these agents. The primary endpoint was the HbA1c reduction at 104 weeks. All three doses of tirzepatide were superior to insulin degludec. The HbA1c reduction in the 5, 10, and 15 mg doses were 2.1, 2.3, and 2.4% versus insulin glargine at 1.4% (p<0.001).

Study GPGI (SURPASS-5) was a 40-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 study assessing the efficacy and safety of tirzepatide (5, 10, and 15 mg) as add-on therapy in 475 patients with T2DM with an HbA1c between ≥7.0% and ≤10.5% who did not achieve adequate glycemic control while treated with basal insulin (>0.25 U/kg/day or >20 U/day insulin glargine) ± metformin (≥1500 mg). Study patients had a long standing diabetes history (mean duration >13 years). The primary endpoint was the reduction of HbA1c values from baseline. Tirzepatide 5, 10, and 15 mg resulted in a 2.1, 2.4, and 2.3% HbA1c reduction, respectively, compared to placebo at 0.9% HbA1c reduction (p<0.001).

The pooled safety assessment was based on a total of 7769 patients from the completed Phase 2 studies and all the pivotal and supportive Phase 3 studies. Of these, 5415 patients received tirzepatide in the Phase 2 and 3 studies with an exposure of 4833.1 patient-years. A total of 2375 patients received tirzepatide for ≥52 weeks in the Phase 2/3 studies; of these, 535 received treatment for ≥78 weeks.

The percentage of patients reporting serious adverse events (SAE) was similar across tirzepatide doses, all tirzepatide patients combined, and placebo/comparator groups. There was an incremental increase of discontinuation due to treatment-emergent adverse events (TEAE) with higher dose groups. The percentage of discontinuations from study drug due to an adverse event (AE) was higher in the tirzepatide (6.7%) group compared to placebo (2.6%). TEAEs most frequently reported for tirzepatide-treated patients were Gastrointestinal (GI) Disorders (tirzepatide 5, 10, 15 mg arms vs placebo) including nausea (12.2%; 15.4%; 18.3% vs 4.3%), diarrhea (11.8%; 13.3%; 16.6% vs 8.9%), dyspepsia (8.0; 7.5%; 5.4% vs 2.6%), vomiting (5.1%; 5.0%; 9.1% vs 2.6%), constipation (5.9%; 5.8%; 6.6% vs 1.3%), and abdominal pain (5.9%; 4.6%; 5.4% vs 4.3%).

It was observed in study GPGL (SURPASS-2) that the rates of gastrointestinal adverse events (GIAE) were similar to semaglutide. Severe GI events may lead to some cases of dehydration. The incidence of dehydration in tirzepatide-treated patients was 0.18-0.47% (16 events). Three of the 16 events were serious or severe in nature. Most cases of dehydration had a multifactorial etiology including 12 with chronic kidney disease at baseline and 8 with an acute infection.

Pancreatitis rate was increased in the tirzepatide group (0.23%) versus placebo (0.16%). There was a higher rate of elevated pancreatic enzymes (amylase and lipase) in the tirzepatide group, consistent with other GLP-1-RAs. The values were numerically higher in the 15 mg tirzepatide group. Further, there was an increase in cholecystitis (0.6% tirzepatide group versus 0% in placebo) in the phase 3 studies. A statement in the product monograph (PM) was added in the Warnings and Precautions sections for both of these events.

Overall, tirzepatide was associated with a small (2-4 beat/minute) increase in heart rate. The clinical relevance of this finding is not clear. A statement in the PM was added in the Warnings and Precautions sections.

Tirzepatide-induced severe hypoglycemia was rare. The risk of hypoglycemia with tirzepatide was comparable with but slightly exceeding rate of currently approved GLP-1RAs. The hypoglycemic events were observed with concomitant use of sulfonylureas and insulin. Dosing and recommendation statements were added to the PM to mitigate this risk.

Tirzepatide has not been evaluated in pregnant or breastfeeding women. Due to the presence of tirzepatide-induced fetotoxicity in rodent studies, Mounjaro is contraindicated in pregnancy and breastfeeding.

No safety signals were observed with respect to thyroid disease and thyroid malignancy in the phase 2 or phase 3 trials. However, tirzepatide caused dose-dependent and treatment-duration dependent thyroid C-cell tumors in rats. It is unknown whether tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) in humans. The human relevance of tirzepatide induced rodent thyroid C-cell tumors has not been determined. A Black Box Warning has been added to the PM.

Tirzepatide has not been evaluated in Type 1 diabetes and should not be used in this patient population. Tirzepatide should not be used for the treatment of diabetic ketoacidosis. Tirzepatide has not been evaluated in pediatric patients and therefore is not recommended in pediatric patients.

Based on the information reviewed, the benefit-harm-uncertainty profile for use of tirzepatide for glycemic control in adult patients with T2DM is considered positive. It was determined that the safety issues identified for Mounjaro can be appropriately addressed with product labelling and with post-market surveillance as specified in a Risk Management Plan.

Decision issued

Authorized; issued a Notice of Compliance (NOC) in accordance with the Food and Drug Regulations.