Regulatory Decision Summary for Mounjaro Kwikpen

Mounjaro (tirzepatide injection) is currently commercialized in a single-dose prefilled pen and a single-dose vial. An alternative presentation of Mounjaro for the same indication, strengths, and route of administration was proposed by Eli Lilly Canada Inc.

This Supplement to a New Drug Submission (SNDS) was submitted to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, to support an additional presentation of a preserved tirzepatide formulation in a fixed, multi-dose, single-patient-use prefilled pen, hereafter termed as multi-dose prefilled pen (PFP). The proposed presentation is based on the well-established KwikPen delivery device platform, which is used and approved for insulin products in Canada. The formulation is similar to that used for the existing single-dose presentations (single-dose prefilled pen and vial), with the exception of added preservatives (phenol, benzyl alcohol) to ensure adequate antimicrobial efficacy for the 30-day in-use period. With the exception of data from one bioequivalence study, no new clinical data were provided for this SNDS.

The availability of alternative Mounjaro presentations for Canadian patients would provide flexibility in supply and help mitigate ongoing supply chain uncertainties.

Mounjaro is a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that 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. It was initially approved in a single-dose prefilled pen and in a single-dose vial format.

This Supplemental New Drug Submission (SNDS) was submitted to support an additional presentation of a preserved tirzepatide formulation in a fixed, multi-dose, single-patient-use prefilled pen, hereafter termed as multi-dose prefilled pen (PFP), based on the well-established KwikPen delivery device platform for the same indication, strengths, and route of administration. The KwikPen has been modified to allow use with the once-weekly tirzepatide, and each pen will contain sufficient volume to deliver four doses covering four weeks of therapy. The formulation was similar to the one used for the existing single-dose presentations (single-dose prefilled pen and vial), except for the addition of preservatives (phenol, benzyl alcohol) to ensure that the multi-dose product has adequate antimicrobial efficacy for the 30-day in-use period. With the exception of data from one bioequivalence study, Study I8F-MC-GPIP (GPIP), no new clinical data were provided for this SNDS.

From the quality standpoint, the formulation and manufacturing process used for the biolot (test batch number D577651 of the 5 mg/0.6 mL strength) were found to be representative of those proposed for the commercial lots. The biolot was manufactured at full commercial scale at the proposed commercial site (Lilly Sesto). The other five proposed strengths (2.5 mg, 7.5 mg, 10 mg, and 15 mg) were considered adequately supported considering all strengths are proportionally formulated and manufactured using the same process, where each strength concentration is adjusted with water (the vehicle), and the solutions have the same physicochemical properties. Other significant quality issues were addressed, including the higher-order structure conformational change of tirzepatide in the presence of preservatives.

The review of the bioequivalence study (GPIP), which compared the pharmacokinetics of tirzepatide administered subcutaneously by a fixed-dose multi-use prefilled (PFP) versus single-dose prefilled pen (SDP) in healthy participants, indicated that the study was well conducted and no issues of concern were noted. As noted above, the 5 mg strength was chosen for the comparative bioavailability study, and as a biowaiver for the alternate strengths (2.5 mg, 7.5 mg, 10 mg, and 15 mg) of the product was acceptable, the results and conclusions from the bioequivalence study on the product strength can be extrapolated to the other strengths based on the quality evaluation.

The applicable bioequivalence standards were met by the data from this single-dose study, i.e., the 90% confidence interval of the relative mean area under the concentration-time curve (AUCT) of the test to that of the reference is within 80 to 125%, and the relative mean maximum concentration (C_max) of the test to the reference product is between 80 and 125%. Overall, tirzepatide exposure (AUC) drives clinical efficacy, and small differences in C_max observed when comparing the multi-dose PFP with the SDP in the crossover Study GPIP are not clinically meaningful for once-weekly tirzepatide. The small differences in C_max and time to maximum concentration (Tmax) for the multi-dose PFP versus the SDP are not expected to result in any discernible clinical effect. In terms of safety profile, the lower C_max (and marginally lower AUC) is not likely to result in additional concerns over safety and tolerability. Theoretically, the slightly lower AUC may lead to greater risk of hyperglycemia. However, given that the AUC values were within the bioequivalence range, it is unlikely such hyperglycemia would be clinically meaningful or require additional oral antidiabetics or Mounjaro dose increase.

No new or unexpected safety issues were raised from the bioequivalence study. The most common treatment-emergent adverse events (TEAEs) were gastrointestinal disorders and metabolism or nutrition disorders, with the most frequently reported adverse events being nausea and decreased appetite. The TEAEs were consistent with the safety profile of the glucagon-like peptide-1 receptor agonist class and the established safety profile of tirzepatide.

Based on the data reviewed in this submission, the additional preserved tirzepatide formulation in a fixed, multi-dose, single-patient-use prefilled pen (KwikPen) offers an alternative presentation for patients over the currently approved single-dose pen and vial formulation with no significant change to the overall benefit-harm-uncertainty profile of this medication when used according to its approved indications. As a risk mitigation measure, precautionary wording was included in the Canadian Product Monograph with regard to the risks associated with benzyl alcohol, along with text indicating that caution is recommended due to the presence of this excipient. The Product Monograph was revised to reflect the updated information in several sections to emphasize information specifically related to Mounjaro KwikPen. The Instructions for Use (KwikPen, single-dose vial and pens) and Part III (Patient Medication Information) section of the Product Monograph were reviewed for consistency and accuracy with Parts I and II of the Product Monograph, as well as for readability in keeping with the principles of plain language labelling and for formatting with the appropriate template. The Mounjaro KwikPen storyboard was reviewed for accuracy and consistency with the Instructions for Use. All issues were appropriately addressed by the sponsor.

For further details about Mounjaro Kwikpen, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.