Summary Basis of Decision for Mounjaro
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Mounjaro is located below.
Recent Activity for Mounjaro
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Mounjaro
Date SBD issued: 2023-03-17
The following information relates to the new drug submission for Mounjaro.
Tirzepatide
Drug Identification Number (DIN):
- DIN 02532891 - 2.5 mg/0.5 mL tirzepatide, solution, subcutaneous injection
- DIN 02532905 - 5 mg/0.5 mL tirzepatide, solution, subcutaneous injection
- DIN 02532913 - 7.5 mg/0.5 mL tirzepatide, solution, subcutaneous injection
- DIN 02532921 - 10 mg/0.5 mL tirzepatide, solution, subcutaneous injection
- DIN 02532948 - 12.5 mg/0.5 mL tirzepatide, solution, subcutaneous injection
- DIN 02532956 - 15 mg/0.5 mL tirzepatide, solution, subcutaneous injection
Eli Lilly Canada Inc.
New Drug Submission Control Number: 259103
On November 24, 2022, Health Canada issued a Notice of Compliance to Eli Lilly Canada Inc. for the drug product Mounjaro.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit‑harm-uncertainty profile of Mounjaro is favourable when indicated once-weekly as an adjunct to diet and exercise to improve glycemic control for the treatment of adult patients with type 2 diabetes mellitus.
- As monotherapy when metformin is inappropriate due to contraindication or intolerance.
- In combination with:
- metformin, or
- metformin and a sulfonylurea, or
- metformin and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or
- basal insulin with or without metformin.
1 What was approved?
Mounjaro, an antihyperglycemic agent, is indicated for once-weekly administration as an adjunct to diet and exercise to improve glycemic control for the treatment of adult patients with type 2 diabetes mellitus.
- As monotherapy when metformin is inappropriate due to contraindication or intolerance.
- In combination with:
- metformin, or
- metformin and a sulfonylurea, or
- metformin and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or
- basal insulin with or without metformin.
Limitations of Use:
- Mounjaro has not been studied in combination with short-acting, medium-acting, or dual formulation insulins.
- Mounjaro is not a substitute for insulin.
- Mounjaro should not be used in patients with type 1 diabetes mellitus (formerly known as insulin-dependent diabetes mellitus or IDDM).
- Mounjaro should not be used for the treatment of diabetic ketoacidosis.
The safety and efficacy of Mounjaro have not been studied in pediatric patients (less than 18 years of age). Mounjaro is not indicated for use in pediatric patients.
No overall differences in safety or efficacy were observed in clinical trial patients 65 years of age or older compared to younger patients.
Mounjaro (2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5 mL, 12.5 mg/0.5 mL, and 15 mg/0.5 mL tirzepatide) is presented as a solution in a single-dose prefilled pen for subcutaneous administration. In addition to the medicinal ingredient, the solution contains hydrochloric acid solution, sodium chloride, sodium hydroxide solution, sodium phosphate dibasic heptahydrate, and water for injection.
The use of Mounjaro is contraindicated:
- in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
- in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).
- during pregnancy or breastfeeding.
The drug product was approved for use under the conditions stated in its Product Monograph, taking into consideration the potential risks associated with its administration. The Mounjaro Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Mounjaro approved?
Health Canada considers that the benefit-harm-uncertainty profile of Mounjaro is favourable for once-weekly administration as an adjunct to diet and exercise to improve glycemic control for the treatment of adult patients with type 2 diabetes mellitus (T2DM).
- As monotherapy when metformin is inappropriate due to contraindication or intolerance.
- In combination with:
- metformin, or
- metformin and a sulfonylurea, or
- metformin and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or
- basal insulin with or without metformin.
Limitations of Use:
- Mounjaro has not been studied in combination with short-acting, medium-acting, or dual formulation insulins.
- Mounjaro is not a substitute for insulin.
- Mounjaro should not be used in patients with type 1 diabetes mellitus (formerly known as insulin-dependent diabetes mellitus or IDDM).
- Mounjaro should not be used for the treatment of diabetic ketoacidosis.
Diabetes mellitus is a global health issue that affects approximately 463 million adults aged 20 to 79 years worldwide. Type 2 diabetes mellitus (T2DM) accounts for approximately 90% of all types of diabetes and is a leading cause of kidney failure, blindness, amputation, and cardiovascular disease. These complications are major causes of death in Canada.
Type 2 diabetes mellitus is usually initially managed with lifestyle changes, specifically, diet and exercise. It is a progressive disease; therefore, treatment intensification and good adherence to medication are key for maintaining glycemic control over time. Despite the availability of several classes of antihyperglycemic agents that are prescribed as monotherapy or as combination therapies to target the pathophysiological deficiencies and comorbidities associated with T2DM, studies continue to show that substantial numbers of patients with T2DM do not reach their goals for glycemic control, weight loss, blood pressure control, or lipid control.
There are currently several classes of medications approved for the treatment of T2DM in Canada. Metformin is the initial therapy recommended for T2DM. The SGLT2i class of medications has recently been added to the list of antihyperglycemic agents recommended for T2DM. Dipeptidyl peptidase‑4 inhibitors and glucagon-like peptide‑1 (GLP‑1) receptor agonists are incretin-based therapies. Older antihyperglycemic agents such as alpha-glucosidase inhibitors, thiazolidinediones, and various secretagogues (e.g., meglitinides and sulfonylureas) are used less frequently due to higher rates of adverse events. Insulin is an effective third- or fourth-line treatment option for T2DM that is not adequately controlled by oral agents along with diet and exercise. It is also used extensively in the acute management of diabetic coma and hyperosmolar syndromes.
The Canadian Diabetes Association recommends, along with diet and exercise, pharmacological therapies designed to achieve an initial hemoglobin A1C (HbA1c) level of 7.0%, with a goal of an HbA1c level of 6.5% or lower in certain populations.
Mounjaro is a 39‑amino acid synthetic peptide that has agonist activity at glucose-dependent insulinotropic polypeptide (GIP) and GLP‑1 receptors. As a GIP and GLP‑1 receptor agonist, it exerts its function by binding to either the GIP or GLP‑1 receptor with high affinity, increasing insulin secretion and sensitivity, and reducing glucagon secretion.
Five pivotal Phase III studies, four supportive Phase III studies, and two Phase II studies were submitted to support the safety and efficacy of the 5 mg, 10 mg, and 15 mg doses of Mounjaro in patients with T2DM.
The two Phase II studies (Study GPGF and Study GPGB) demonstrated the preliminary efficacy of Mounjaro in lowering HbA1c in patients with T2DM. Additionally, these studies established a dose range of 5 mg, 10 mg, and 15 mg with dose increases, if needed, after no less than four weeks.
Study GPGK (SURPASS-1) was a 40‑week, randomized, multicentre, double-blind, parallel‑group, placebo-controlled Phase III study comparing the efficacy and safety of all three doses of Mounjaro versus placebo in 478 adult patients with T2DM that was inadequately controlled with diet and exercise alone.
Study GPGL (SURPASS-2) was a 40‑week, randomized, open-label, multicentre, active-controlled Phase III study that compared the glycemic-lowering effects of all three doses of Mounjaro once weekly to semaglutide 1 mg once weekly in 1,879 patients with T2DM that was inadequately controlled with concomitant metformin.
Study GPGH (SURPASS-3) was a 52‑week, open-label, active-controlled Phase III study comparing the glycemic-lowering effects of all three doses of Mounjaro to titrated insulin degludec in 1,444 patients with T2DM that was inadequately controlled with concomitant metformin, with or without an SGLT2i.
Study GPGM (SURPASS-4) was a long-term 104‑week, open-label, multicentre, parallel-group, active-controlled Phase III study that compared the glycemic-lowering effects of all three doses of Mounjaro to titrated insulin glargine in 2,002 patients with T2DM, along with increased cardiovascular risk, that was inadequately controlled with either metformin, an SGLT2i, sulfonylurea, or a combination of these agents.
Study GPGI (SURPASS-5) was a 40‑week, randomized, multicentre, double-blind, parallel-group, placebo-controlled Phase III study assessing the efficacy and safety of all three doses of Mounjaro as add-on therapy in 475 patients with T2DM, along with HbA1c levels 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), with or without metformin (≥1,500 mg). Study patients had a long-standing history of diabetes (mean duration of more than 13 years).
The primary endpoints of HbA1c reduction from baseline in all five pivotal Phase III studies described above were statistically significant and clinically relevant. Key secondary endpoints were supportive of the primary endpoint and included: responder rates of patients achieving HbA1c levels of 7% and 5.7%; fasting serum glucose reduction from baseline; and weight loss.
The pooled safety assessment was based on a total of 7,769 patients from the completed Phase II studies and all of the pivotal and supportive Phase III studies. Of these, 5,415 patients received Mounjaro with a combined exposure of 4,833 patient years. A total of 2,375 patients received Mounjaro for 52 weeks or longer in the Phase II/III studies; of these, 535 received treatment for 78 weeks or longer.
The safety of Mounjaro was found to be acceptable when compared to placebo and active comparators. The main adverse events observed in the studies were gastrointestinal in nature, including nausea and diarrhea. Severe gastrointestinal events may lead to some cases of dehydration. Hypoglycemic events were rare and mostly associated with the use of insulin and sulfonylureas. Mild increases in heart rate of 2 to 4 beats per minute were observed; however, the clinical relevance of this is unknown. A decrease in blood pressure was observed without any reports of hypotension. An increase in pancreatitis, in laboratory values of amylase and lipase, and in cholecystitis events were observed in some studies. Hypersensitivity reactions occurred during some studies in patients who were positive and negative for treatment-emergent antidrug antibodies (TE ADAs). All cases resolved independently of their TE ADA status. Local injection site reactions were also reported in 1.9% to 4.5% of patients. A rapid decrease in HbA1c may lead to worsening or the development of diabetic retinopathies; however, no cases were observed in the Phase III studies.
Appropriate warnings and precautions are included in the approved Mounjaro Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box describing the following:
- Tirzepatide causes dose-dependent and treatment duration-dependent thyroid C‑cell tumours (adenomas and carcinomas) at clinically relevant exposures in male and female rats. It is unknown whether Mounjaro causes thyroid C‑cell tumours, including medullary thyroid carcinoma (MTC) in humans. The human relevance of tirzepatide-induced rodent thyroid C‑cell tumours has not been determined.
- Mounjaro is contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C‑cell tumours. Patients should be counseled regarding the risk and symptoms of thyroid tumours.
A Risk Management Plan (RMP) for Mounjaro was submitted by Eli Lilly Canada Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product. As part of the RMP, Eli Lilly Canada Inc. will conduct studies to further characterize the safety concerns of thyroid C‑cell tumours, pancreatic malignancy, and diabetic retinopathy complications.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Mounjaro Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Mounjaro was accepted.
Overall, Mounjaro has been shown to have a favourable benefit-harm-uncertainty profile for its intended use as per the Mounjaro Product Monograph.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Mounjaro?
The New Drug Submission (NDS) for Mounjaro was reviewed as part of the New Active Substance Work-Sharing Initiative, a work-sharing initiative of the national health regulatory agencies of Canada, Australia, Singapore, Switzerland, and the United Kingdom (the Access Consortium). This partnership aims to promote collaboration, optimize the use of resources, reduce duplication, and enhance the ability of each agency to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.
Health Canada, the Therapeutic Goods Administration (Australia), the Health Sciences Authority (Singapore), and the Swiss Agency for Therapeutic Products (Swissmedic) collaborated on the review of the submitted data package for Mounjaro. Health Canada completed the review of the quality component of the NDS for Mounjaro, while Swissmedic completed the review of the clinical and non-clinical/quality components. The review of the submission was collaborative, with each regulatory agency sharing the outcome of its review with the others. However, each agency made its regulatory decision independently. Health Canada’s review of the clinical and non-clinical components of the New Drug Submission for Mounjaro was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Mounjaro
Submission Milestone | Date |
---|---|
Pre-submission meeting | 2021-08-24 |
New Drug Submission filed | 2021-11-29 |
Screening | |
Screening Deficiency Notice issued | 2022-01-12 |
Response to Screening Deficiency Notice filed | 2022-02-22 |
Screening Acceptance Letter issued | 2022-02-24 |
Review | |
Quality evaluation completed | 2022-10-07 |
Non-clinical evaluation completed | 2022-11-02 |
Review of Risk Management Plan completed | 2022-11-04 |
Labelling review completed | 2022-11-21 |
Clinical/medical evaluation completed | 2022-11-23 |
Notice of Compliance issued by Director General, Pharmaceutical Products Directorate | 2022-11-24 |
4 What follow-up measures will the company take?
As part of the marketing authorization for Mounjaro, Health Canada requested, and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) conducting studies to further characterize the safety concerns of thyroid C-cell tumours, pancreatic malignancy, and diabetic retinopathy complications.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
As described above, the New Drug Submission for Mounjaro was reviewed as part of the New Active Substance Work Sharing Initiative. The Swiss Agency for Therapeutic Products (Swissmedic) completed the review of the clinical component of the NDS for Mounjaro. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently. Health Canada’s clinical review of the New Drug Submission for Mounjaro was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .
Clinical Pharmacology
Tirzepatide, the medicinal ingredient in Mounjaro, is an agonist of the selective glucose-dependent insulinotropic peptide (GIP) receptor and the glucagon-like peptide‑1 (GLP‑1) receptor. It is a 39‑amino acid peptide with a C20-fatty diacid moiety that enables albumin binding and results in a prolonged half-life of approximately five days. The activity of tirzepatide on the GIP receptor is similar to that of the native GIP hormone and is lower on the GLP‑1 receptor compared to that of the native GLP‑1 hormone. Tirzepatide enhances first- and second-phase insulin secretion and reduces plasma glucagon levels, both in a glucose-dependent manner.
The clinical pharmacology of tirzepatide was based on data from ten Phase I studies that were performed in healthy participants and patients with type 2 diabetes mellitus (T2DM). Additionally, data collected from two Phase II and seven Phase III studies contributed to the pharmacokinetic analyses. Throughout the studies, the sampling schedule around the maximum observed concentration (Cmax) was sparse. However, the schedule was adequate for a long-acting molecule and was supported by the comparability of the time to maximum plasma concentration (tmax) observed for tirzepatide to that of other acylated incretin peptide molecules.
Two formulations of tirzepatide were used throughout the clinical program: lyophilized (administered by syringe) and solution (administered by pre-filled syringe or pen/autoinjector). Three biopharmaceutic studies were conducted to assess the effect of formulation, drug delivery device, and injection site on bioavailability. Following the subcutaneous administration of a single 5 mg dose of tirzepatide, bioequivalence was demonstrated between delivery devices and between formulations (the solution formulation was used in all Phase III studies). Generally, comparable pharmacokinetic parameters were observed following the subcutaneous injection of 5 mg tirzepatide into the abdomen, thigh, or upper arm. One exception was a delayed median tmax of approximately 12 hours following injection into the thigh; however, there was no clinical significance as a result of this difference.
The median tmax of tirzepatide was found to be 24 hours (range: 8 to 72 hours). With an assumption of linear pharmacokinetics across the investigated dose range, the bioavailability of subcutaneously administered tirzepatide was determined to be 80%. Steady state was predicted to be reached after approximately four once-weekly doses. Based on population pharmacokinetic post hoc parameters, tirzepatide had an accumulation ratio of 1.7. Overall, tirzepatide exposures increased with dose. Additionally, higher exposures were observed in healthy subjects compared with patients with T2DM. This was presumed to be due to the higher baseline body weight of patients with T2DM, and so, disease status was not identified as a significant covariate in the population pharmacokinetic analysis. Based on simulations with the population pharmacokinetic model, it was recommended that a missed dose should be administered as soon as possible within four days. If more than four days have passed, the missed dose should be skipped.
Circulating tirzepatide was 99.06% protein bound, primarily to albumin. Metabolism of tirzepatide occurred primarily by proteolytic cleavage of the peptide backbone, β‑oxidation of the C20-fatty acid moiety, and amide hydrolysis. Metabolites were excreted primarily in the urine and also in the feces.
Based on population pharmacokinetic post hoc parameters, the apparent clearance in patients with T2DM following multiple tirzepatide doses was estimated at 0.0606 L/hour, resulting in a mean terminal half-life of 5.4 days.
Due to tolerability issues (gastrointestinal in nature), the maximum tolerated single dose of tirzepatide was 8 mg. However, of the proposed tirzepatide strengths, the maximum tolerated dose is 5 mg. Consequently, many single-dose studies were limited to 5 mg tirzepatide, and as such, the impacts of the highest proposed dose (i.e., 15 mg tirzepatide) were extrapolated from the totality of data. Based on 5 mg tirzepatide, pharmacokinetic parameters were generally comparable for all populations tested, including healthy participants, patients with T2DM, and participants with hepatic impairment. There was an observed increase in tirzepatide exposure in subjects with renal impairment wherein severe impairment was associated with a comparable half-life and a shorter tmax compared to healthy counterparts. However, the effects were not considered to be clinically significant. Utilizing data from 5,802 Phase I/II/III study participants, population pharmacokinetic analysis determined no dose adjustments to be necessary based on any of the investigated covariates, including sex, age, body weight, and race.
In vitro studies demonstrated that there was low risk of drug interactions between tirzepatide and cytochrome P450 enzymes or hepatic or renal transporters. When using acetaminophen as a marker in healthy participants, a delay of acetaminophen tmax and Cmax was associated with delayed gastric emptying at doses of 4.5 mg or higher. The delayed gastric emptying was most evident with the first dose of a multiple-dose regime. Similar findings were observed in healthy female participants after a single 5 mg dose of tirzepatide in combination with steady-state oral contraceptive treatment, wherein a significant decrease in Cmax of ethinyl estradiol (55%) and norgestimate (66%) was observed along with a reduced area under the concentration-time curve from dosing to the time of the last measured concentration (AUC0-tlast) (16% and 20%, respectively) and delays in tmax (2.5 to 4.5 hours). Though this was not determined to be of clinical significance, cautionary statements are included in the Mounjaro Product Monograph regarding the use of additional barrier methods or alternate non-oral methods of contraception.
A physiologically based pharmacokinetic (PBPK) modelling approach was performed to assess the impact of tirzepatide on ten drugs with differing solubility and permeability properties and/or narrow therapeutic indices. Since PBPK models alone are not sufficient to determine the presence/absence of drug-drug interactions, a statement regarding the potential impact of tirzepatide on concomitant oral drugs was included in the Mounjaro Product Monograph.
The administration of tirzepatide once weekly demonstrated an improvement in blood glucose regulation and reduced fasting and postprandial glucose. After 28 weeks of dose-escalation treatment with tirzepatide, patients with T2DM exhibited enhanced first- and second-phase insulin secretion, increased insulin sensitivity, and reduced glucose-stimulated glucagon concentrations, compared with placebo and active comparator. Furthermore, greater hemoglobin A1C (HbA1c)-lowering efficacy was observed for tirzepatide compared with placebo and active comparator. The administration of tirzepatide was associated with reduced food intake in an ad libitum meal test.
A thorough corrected QT interval (QTc) study investigating the effect of supratherapeutic tirzepatide doses on cardiac repolarization was not conducted. However, an exposure-response analysis was conducted using date-matched relationships of QTc corrected according to Fridericia (QTcF) and PR intervals with observed tirzepatide concentrations from Phase III studies. Additionally, a concentration-effect analysis based on data from Phase I/II studies was conducted. These analyses showed the absence of an unacceptable prolongation in cardiac repolarization or any impact on PR interval compared to placebo across the therapeutic dose range, with intervals within clinically acceptable limits.
Overall, the clinical pharmacology data support the use of Mounjaro for the recommended indication.
For further details, please refer to the Mounjaro Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Five pivotal Phase III studies, four supportive Phase III studies, and two Phase II studies were submitted to support the safety and efficacy Mounjaro in patients with T2DM.
Phase II Studies
Two major Phase II studies demonstrated the efficacy of Mounjaro in lowering hemoglobin A1C (HbA1c) and body weight in patients with T2DM.
Study GPGB was a 26‑week multicentre, randomized, double-blind, parallel-group, placebo- and active comparator-controlled Phase II study designed to examine the safety, efficacy, and pharmacokinetics/pharmacodynamics of four dose levels of Mounjaro in patients with T2DM who had inadequate glycemic control with diet and exercise. Mounjaro was compared with dulaglutide 1.5 mg once weekly and placebo. Patients were either already treated with metformin (stable dose ≥1,000 mg/day for at least three months) or treatment naïve for T2DM. Mounjaro was superior to dulaglutide at doses greater than 5 mg. The 1 mg dose of Mounjaro was non-inferior, but not superior, to dulaglutide. Based on this study, the 1 mg dose of Mounjaro was abandoned.
Study GPGF was a 12‑week, multicentre, randomized, double-blind, placebo-controlled Phase II study designed to examine the efficacy of three algorithms for dose titration of up to 12 mg and 15 mg of Mounjaro in patients with T2DM who had inadequate glycemic control with diet and exercise. Prior antidiabetic treatment of these patients could have included metformin (stable dose ≥1,000 mg/day for at least three months). All groups showed a superior antiglycemic effect (1.7% to 2.0% HbA1c reduction) compared with placebo (0.2% HbA1c reduction). The reduction in HbA1c was greatest in the 15 mg group. Notably, weight loss of 5 kg was noted in the treatment arms at 12 weeks, compared with 0.5 kg in the placebo arm.
Based on these two phase II studies, the 5 mg, 10 mg, and 15 mg doses were established, with a minimum titration of no less than four weeks. Additionally, the preliminary efficacy of Mounjaro was demonstrated in these relatively small and short studies.
Phase III Pivotal Studies
Five pivotal Phase III studies were submitted to support the safety and efficacy of the Mounjaro 5 mg, 10 mg, and 15 mg doses in patients with T2DM, from those who are newly diagnosed to patients who have longer duration and more advanced disease, including those with increased cardiovascular risk.
The primary endpoint of HbA1c reduction from baseline in all five pivotal Phase III studies described below were statistically significant and clinically relevant. Key secondary endpoints were supportive of the primary endpoint and included the responder rates of patients achieving HbA1c levels of 7% and 5.7%, fasting serum glucose reduction from baseline, and body weight reduction.
Study GPGK (SURPASS-1) was a 40‑week, multicentre, randomized, double-blind, parallel-group, placebo-controlled study comparing the efficacy and safety of all three doses of Mounjaro versus placebo in 478 adult patients with T2DM that were inadequately controlled with diet and exercise alone. Patients had a mean age of 54 years and 52% were male.
Mounjaro 5 mg, 10 mg, and 15 mg resulted in an HbA1c reduction of 1.8%, 1.7%, and 1.7%, respectively, versus 0.1% in the placebo arm (p<0.001). Responder rates achieving HbA1c levels ≤7.0% were 82%, 85%, and 78%, respectively, in the Mounjaro arms, versus 23% in the placebo arm (p<0.001). Responder rates achieving HbA1c levels ≤5.7% were 31%, 27%, and 38%, respectively, versus 1.4% in the placebo arm (p<0.001). Fasting blood glucose levels were reduced by 2.2%, 2.2%, and 2.1%, respectively, versus a 0.2% increase in the placebo arm (p<0.001). Body weight reduction from baseline compared to placebo was also statistically significant (p<0.001). There was a dose dependency to the degree of weight reduction. At 40 weeks, body weights were reduced by 6.3 kg, 7.0 kg, and 7.8 kg, respectively, versus a 1.0 kg reduction in the placebo arm.
Study GPGL (SURPASS-2) was a 40‑week, randomized, open-label, multicentre, active-controlled study that compared the glycemic-lowering effects of all three doses of Mounjaro once weekly to semaglutide 1 mg once weekly in 1,879 patients with T2DM that was inadequately controlled with concomitant metformin. Patients had a mean age of 57 years and 47% were male.
Mounjaro 5 mg, 10 mg, and 15 mg resulted in an HbA1c reduction of 2.0%, 2.2%, and 2.3%, respectively, versus 1.9% in the semaglutide arm. There was no significant dose responsiveness. The results were statistically significant in the 5 mg arm (p = 0.018) and in the 10 mg and 15 mg arms (p<0.001). Responder rates achieving HbA1c levels of 7% were 82%, 86%, and 86%, respectively, in the Mounjaro arms, versus 79% in the semaglutide arm. Statistical superiority was achieved in the 10 mg (p = 0.007) and 15 mg (p = 0.005) arms, while the 5 mg arm did not reach statistical significance. Responder rates achieving HbA1c levels ≤5.7% were 27%, 40%, and 46%, respectively, versus 19% in the semaglutide arm (p<0.001 in the 10 and 15 mg arms). There were no statistically significant differences between Mounjaro doses for these endpoints. Mounjaro 5 mg, 10 mg, and 15 mg resulted in a body weight reduction of 7.6 kg, 9.3 kg, and 11.2 kg, respectively, versus a 5.7 kg reduction in the semaglutide arm. The differences between the individual treatment arms and the comparator were statistically significant (p<0.001). There was also a dose responsiveness to the weight reduction that achieved statistical significance between treatment arms (p<0.05).
Study GPGH (SURPASS-3) was a 52‑week, open-label, active-controlled study comparing the glycemic-lowering effects of all three doses of Mounjaro to titrated insulin degludec in 1,444 patients with T2DM that was inadequately controlled with concomitant metformin, with or without a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Patients had an average age of 57 years and 44% were female.
All three Mounjaro doses met the primary objective of non-inferiority and superiority to insulin degludec in the reduction of HbA1c. Mounjaro 5 mg, 10 mg, and 15 mg resulted in an HbA1c reduction of 1.9% (p<0.001), 2.0% (p<0.001), and 2.1% (p<0.001), respectively, versus 1.3% in the insulin degludec arm. There was not a statistically significant dose responsiveness. Responder rates in the Mounjaro 5 mg, 10 mg, and 15 mg arms achieving HbA1c levels <7.0% were 79%, 82%, and 83%, respectively, versus 58% in the insulin degludec arm (p<0.001). There was not a statistically significant dose responsiveness. Body weight was reduced by 7.0 kg, 9.6 kg, and 11.3kg, respectively, in the Mounjaro arms, versus a 1.9 kg weight increase in the insulin degludec arm. The difference between the treatment arms and the comparator arm was statistically significant (p<0.001). There was also a statistically significant dose responsiveness between treatment arms (p<0.05).
Study GPGM (SURPASS-4) was a long-term 104‑week, multicentre, open-label, parallel-group, active-controlled study that compared the glycemic-lowering effects of all three doses of Mounjaro to titrated insulin glargine in 2,002 patients with T2DM and increased cardiovascular risk who were inadequately controlled with either metformin, an SGLT2i, sulfonylurea, or a combination of these agents.
All three doses of Mounjaro were superior to insulin glargine in the reduction of HbA1c. Mounjaro 5 mg, 10mg, and 15 mg resulted in an HbA1c reduction of 2.1%, 2.3%, and 2.4%, respectively, versus 1.4% in the insulin glargine arm (p<0.001). Responder rates achieving HbA1c levels <7.0% were 75%, 83%, and 85%, respectively, in the Mounjaro arms, versus 49% in the insulin glargine arm (p<0.001). Mounjaro also achieved a significant weight reduction of 6.4 kg, 8.9 kg, and 10.6 kg, respectively, in the Mounjaro arms, versus a 1.7 kg weight increase in the insulin glargine arm (p<0.0001).
Study GPGI (SURPASS-5) was a 40‑week, multicentre, randomized, double-blind, parallel-group, placebo-controlled study assessing the efficacy and safety of Mounjaro 5 mg, 10mg, and 15 mg as add-on therapy in 475 patients with T2DM and HbA1c levels 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), with or without metformin (≥1500 mg). Study patients had a long-standing history of diabetes (mean duration >13 years). Patients had an averaged age of 61 years and 44% were female.
Mounjaro 5 mg, 10 mg, and 15 mg resulted in an HbA1c reduction of 2.1%, 2.4%, and 2.3%, respectively, versus 0.9% in the placebo arm (p<0.001). Responder rates achieving HbA1c levels <7% were 87%, 90%, and 85%, respectively, in the Mounjaro arms, versus 35% in the placebo arm (p<0.001). Responder rates achieving HbA1c levels <5.7% were 24%, 42%, and 50%, respectively, in the Mounjaro arms, versus 3% in the placebo arm (p<0.001). Mounjaro also achieved significant weight reductions of 5.4 kg, 7.5 kg, and 8.8 kg, respectively, versus a weight increase of 1.6 kg in the placebo arm (p<0.001). There was also a dose response to weight reduction that was statistically significant between the 5 mg and 15 mg doses (p<0.05).
Phase III Supportive Studies
Study GPGH-CGM (SURPASS-3 CGM) was a parallel sub-study of SURPASS-3 that used a 24‑hour continuous glucose monitor profile in patients treated with Mounjaro versus insulin degludec. The primary endpoint was percentage-time-in-target (PTIT). The results showed Mounjaro-treated patients spent more time in-target than patients receiving insulin (72.6% versus 48.04%, p<0.001).
Study GPGH-MRI (SURPASS-3 MRI) was a parallel sub-study of SURPASS-3 that used magnetic resonance imaging to assess liver fat content (LFC). The primary endpoint was the reduction in LFC. Mounjaro reduced LFC by 8.1% versus insulin at 3.4% (p<0.05). Secondary endpoints included the reduction of visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) in patients who were on stable doses of metformin, with or without an SGLT2i. Mounjaro-treated patients had lower VAT and ASAT for all doses of Mounjaro compared with patients in the placebo group.
Study GPGO (SURPASS J-mono) was a Phase III regional Japanese study. The primary endpoint was HbA1c reduction. The secondary endpoint included weight reduction. Mounjaro demonstrated an improved efficacy in HbA1c reduction, with a reduction ranging from 1.09% (5 mg) to 1.53% (15 mg) compared with placebo (p<0.05). Mounjaro demonstrated a weight reduction ranging from 5.2% (5 mg) to 10.1% (15 mg) compared with placebo (p<0.001). Further, Mounjaro demonstrated significant reductions in HbA1c, liver fat content, and insulin dosing. The study drug also demonstrated increases in continuous glucose monitoring time-in-control, rates of glycemic control, and other glycemic control metrics.
SURPASS J-combo was a 52‑week Phase III add-on regional study which assessed the safety and efficacy of Mounjaro in patients with T2DM who were taking therapeutic doses of various oral antihyperglycemic medications including metformin, an SGLT2i, an alpha-glucosidase inhibitor, thiazolidinedione, sulfonylurea, or glinides. The primary efficacy endpoint was the mean change in HbA1c. Treatment with Mounjaro reduced HbA1c by 2.3%, regardless of the pre-existing or concomitant therapy. Mounjaro also caused weight reductions across all subgroups and treatment groups.
Indication
Sponsor's proposed indication |
Health Canada-approved indication |
Mounjaro (tirzepatide) is indicated for the once-weekly treatment of adult patients with type 2 diabetes mellitus to improve glycemic control, in combination with:
Mounjaro is not a substitute for insulin. Mounjaro should not be used in patients with type 1 diabetes mellitus (formerly known as insulin-dependent diabetes mellitus or IDDM). |
Mounjaro (tirzepatide injection) is indicated for once-weekly administration as an adjunct to diet and exercise to improve glycemic control in the treatment of adult patients with type 2 diabetes mellitus.
Limitations of Use:
|
For more information, refer to the Mounjaro Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety assessment of Mounjaro was based on a total of 7,769 patients in the nine completed Phase II/III studies described in the Clinical Efficacy section. Of these, 5,415 patients received Mounjaro with a combined exposure of 4,833 patient-years. A total of 2,375 patients received Mounjaro for 52 weeks or longer; of these, 535 received treatment for 78 weeks or longer.
The percentage of patients reporting serious adverse events was similar across Mounjaro doses, all Mounjaro patients combined, and placebo/comparator groups. There was an incremental increase of discontinuation due to treatment emergent adverse events (TEAEs) with higher dose groups. The percentage of discontinuations from study drug due to an adverse event was higher in the Mounjaro group (6.7%) compared to the placebo group (2.6%). The most frequently reported TEAEs for Mounjaro-treated patients were gastrointestinal disorders (Mounjaro 5 mg, 10 mg, 15 mg groups versus placebo), including nausea (12.2%; 15.4%; 18.3% versus 4.3%), diarrhea (11.8%; 13.3%; 16.6% versus 8.9%), dyspepsia (8.0%; 7.5%; 5.4% versus 2.6%), vomiting (5.1%; 5.0%; 9.1% versus 2.6%), constipation (5.9%; 5.8%; 6.6% versus 1.3%), and abdominal pain (5.9%; 4.6%; 5.4% versus 4.3%).
The rates of gastrointestinal adverse events (GIAE) were similar to semaglutide. However, in the two regional studies, Japanese patients had a higher rate of GIAE when treated with Mounjaro (6.9%) versus dulaglutide 0.75 mg (0.6%). Clinically, the GIAEs were mitigated by a prolonged titration regimen. Severe gastrointestinal events may lead to some cases of dehydration. The incidence of dehydration in Mounjaro-treated patients ranged from 0.18% to 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.
The rate of pancreatitis was increased in the Mounjaro group (0.23%) versus the placebo group (0.16%). There was a higher rate of elevated pancreatic enzymes (amylase and lipase) in the Mounjaro group, consistent with other GLP–1 receptor agonists. The values were numerically higher in the Mounjaro 15 mg group. Further, there was an increase in cholecystitis (0.6% in the Mounjaro group versus 0% in the placebo group) in the Phase III studies.
Overall, Mounjaro was associated with a small (2 to 4 beat/minute) increase in heart rate. The clinical relevance of this finding is not clear.
The immunogenicity of Mounjaro was prominent as there was a marked increase in the percentage of patients who were positive for treatment-emergent antidrug antibodies (TE ADAs) compared with placebo. The percentage of patients positive for TE ADAs was similar across the three Mounjaro dose groups. Hypersensitivity reactions occurred with similar frequencies in patients who were positive and negative for TE ADAs.
Mounjaro-induced severe hypoglycemia was rare. The risk of hypoglycemia with Mounjaro was comparable with, but slightly exceeded, the rate of currently approved GLP–1 receptor agonists. The hypoglycemic events were observed with concomitant use of sulfonylureas and insulin.
Mounjaro has not been evaluated in pregnant or breastfeeding women. Due to the Mounjaro-induced fetotoxicity observed in rodent studies, Mounjaro is contraindicated in pregnancy and breastfeeding. A one-month drug-free period after discontinuation of Mounjaro, based on five half-lives (equalling 25 days), is considered a safe margin to attempt pregnancy.
No safety signals were observed with respect to thyroid disease and thyroid malignancy in the Phase II or Phase III studies. However, Mounjaro caused dose-dependent and treatment duration-dependent thyroid C–cell tumours in rats. It is unknown whether Mounjaro causes thyroid C–cell tumours, including medullary thyroid carcinoma (MTC) in humans. The human relevance of Mounjaro-induced rodent thyroid C–cell tumours has not been determined.
Mounjaro has not been evaluated in Type 1 diabetes and should not be used in this patient population. Mounjaro should not be used for the treatment of diabetic ketoacidosis. Mounjaro has not been evaluated in pediatric patients and therefore is not recommended in pediatric patients (less than 18 years of age).
Finally, a rapid reduction in HbA1c can be associated with the progression of diabetic retinopathy. There were no cases of Mounjaro-associated diabetic retinopathy in the Phase II or Phase III studies.
As part of the Risk Management Plan for Mounjaro, the sponsor will conduct studies to further characterize the safety concerns of thyroid C–cell tumours, pancreatic malignancy, and diabetic retinopathy complications.
Ongoing Studies
A number of ongoing studies to evaluate the safety of Mounjaro on cardiovascular and peripheral arterial symptom clusters are expected to be completed in the next 24 months. Further, an ongoing dedicated addendum study to SURPASS-CVOT will further investigate and characterise the potential safety issue of diabetic retinopathy.
Appropriate warnings and precautions are included in the approved Mounjaro Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box describing the following:
- Tirzepatide causes dose-dependent and treatment duration-dependent thyroid C–cell tumours (adenomas and carcinomas) at clinically relevant exposures in male and female rats. It is unknown whether Mounjaro causes thyroid C–cell tumours, including MTC in humans. The human relevance of tirzepatide-induced rodent thyroid C–cell tumours has not been determined.
- Mounjaro is contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C–cell tumours. Patients should be counseled regarding the risk and symptoms of thyroid tumours.
For more information, refer to the Mounjaro Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As described above, the New Drug Submission (NDS) for Mounjaro was reviewed as part of the New Active Substance Work Sharing Initiative. The Swiss Agency for Therapeutic Products (Swissmedic) completed the review of the non-clinical component of the NDS for Mounjaro. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently. The non-clinical review of the New Drug Submission for Mounjaro was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .
The non-clinical package supported the pharmacodynamics and pharmacokinetics of Mounjaro (tirzepatide), as well as the proposed indication in humans. The non-clinical pharmacology, safety pharmacology, and toxicology of tirzepatide were evaluated in a series of in vitro and in vivo non-clinical studies in multiple species (i.e., rats, mice, rabbits, and monkeys). The results of the in vitro studies supported the proposed mechanism of action of tirzepatide as an agonist of the human glucose-dependent insulinotropic polypeptide (GIP) receptor (which has the same affinity as native GIP) and the glucagon-like peptide‑1 (GLP‑1) receptor (which has a 20‑fold lesser affinity than native GLP‑1). Tirzepatide was tested in vivo in rats and/or mice for efficacy on glucose control, insulin secretion, insulin sensitization, and body weight management in obese animals. The results of these studies support the proposed use of tirzepatide in the treatment of type 2 diabetes mellitus.
Albumin, a plasma protein, influenced the pharmacodynamics and pharmacokinetics of tirzepatide, as it reduced the affinity of tirzepatide to the GIP and GLP‑1 receptors in all species and reduced the activity of tirzepatide. Albumin increased the half-life of tirzepatide since the drug was more than 99% bound to this plasma protein.
It was concluded that the observed cardiovascular effects of tirzepatide in animals (increased heart rate) are similar to those observed with other GLP‑1 receptor agonists. However, this should not exclude the implication of tirzepatide-GIP receptor interactions.
Tirzepatide was eliminated by metabolism (92% within 120 hours in rats and 97% within 672 hours in monkeys). Tirzepatide accounted for approximately 80% of circulating radioactivity. The four minor plasma metabolites identified in humans (M1, M3, M4, and M13; each ≤5.7%) were also detected in rat and monkey plasma.
Tirzepatide was not genotoxic in vivo. Although in vitro mutagenicity/clastogenicity studies were lacking from the battery of genotoxicity tests, the negative results from the in vivo genotoxicity study were considered acceptable.
In a two-year carcinogenicity study, the carcinogenic effect of tirzepatide in rat thyroids (both sexes) at clinical concentration levels is consistent with findings reported for other GLP‑1 receptor agonists (class effect). The human relevance of the GLP‑1 receptor-related carcinogenic effects in rodents is unknown. Thyroid C‑cell tumours are considered an important potential risk.
In the reproductive and developmental toxicological studies, the sponsor considered the fetal abnormalities (variations and malformations combined) observed at 0.5 mg/kg as “indirect effects secondary to severe maternal toxicity” due to the lack of a clear pattern of affected organ/tissue structures and the lack of respective findings at the 0.1 mg/kg dose. However, a direct effect of tirzepatide on embryofoetal development in rats could not be excluded. Mounjaro is contraindicated during pregnancy and in women who are breastfeeding.
In a juvenile toxicity study, tirzepatide led to a delay in sexual maturity in male and female rats, which was attributed to a reduced body weight gain during treatment. The observed effects were related to tirzepatide pharmacodynamics and were not considered specific to the juvenile groups.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Mounjaro Product Monograph. In view of the intended use of Mounjaro, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Mounjaro Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the New Drug Submission (NDS) for Mounjaro was reviewed as part of the New Active Substance Work Sharing Initiative. Health Canada completed the review of the quality component of the NDS for Mounjaro. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.
The chemistry and manufacturing information submitted for Mounjaro has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at 2 ºC to 8 ºC and protected from light. The patient in-use period is 21 days when stored at or below 30 ºC.
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).
All sites involved in production are compliant with good manufacturing practices.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
None of the excipients used in the formulation of Mounjaro is of human or animal origin.
Related Drug Products
Product name | DIN | Company name | Active ingredient(s) & strength |
---|---|---|---|
MOUNJARO | 02532948 | ELI LILLY CANADA INC | TIRZEPATIDE 12.5 MG / 0.5 ML |
MOUNJARO | 02532891 | ELI LILLY CANADA INC | TIRZEPATIDE 2.5 MG / 0.5 ML |
MOUNJARO | 02532905 | ELI LILLY CANADA INC | TIRZEPATIDE 5 MG / 0.5 ML |
MOUNJARO | 02532956 | ELI LILLY CANADA INC | TIRZEPATIDE 15 MG / 0.5 ML |
MOUNJARO | 02532921 | ELI LILLY CANADA INC | TIRZEPATIDE 10 MG / 0.5 ML |
MOUNJARO | 02532913 | ELI LILLY CANADA INC | TIRZEPATIDE 7.5 MG / 0.5 ML |