Summary Basis of Decision for Mounjaro

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Health Canada’s clinical review of the New Drug Submission for Mounjaro was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .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 (C_max) 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 (t_max) 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 t_max of approximately 12 hours following injection into the thigh; however, there was no clinical significance as a result of this difference.

The median t_max 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 t_max 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 t_max and C_max 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 C_max 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 (AUC_0-tlast) (16% and 20%, respectively) and delays in t_max (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

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.