Summary Basis of Decision for Victoza ®
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:
Victoza®
Liraglutide, 6 mg/mL, Solution, Subcutaneous
Novo Nordisk Canada Inc.
Submission control no: 119928
Date issued: 2010-10-26
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02351064
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
Victoza® is a trademark of Novo Nordisk A/S and used under license by Novo Nordisk Canada Inc.
2 Notice of decision
On May 21, 2010, Health Canada issued a Notice of Compliance to Novo Nordisk Canada Inc. for the drug product Victoza®.
Victoza® contains the medicinal ingredient liraglutide which is an analog of human glucagon-like peptide-1 (GLP-1).
Victoza® is indicated for once-daily administration for the treatment of adults with Type 2 diabetes to improve glycemic control in combination with:
- metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
- metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control.
Victoza® should not be used in Type 1 diabetes (formerly known as insulin-dependent diabetes mellitus or IDDM).
Victoza® is an analog of human GLP-1 and acts as a GLP-1 receptor agonist. Like GLP-1, Victoza® activates the GLP-1 receptor resulting in increased intracellular cyclic adenosine monophosphate (cAMP) which leads to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease to normal levels. Victoza® also decreases glucagon secretion in a glucose-dependent manner.
The market authorization was based on quality, non-clinical, and clinical information submitted. The clinical efficacy and safety of Victoza® were evaluated based on the results of five Phase III studies from the Liraglutide Effect and Action in Diabetes (LEAD) clinical development program. Two of these studies, namely LEAD 2 and LEAD 5, support the authorized indications. Both studies were randomized, double-blind, controlled, 26-week studies that included patients with Type 2 diabetes (LEAD 2, sample size [n] = 1091; LEAD 5, n = 581) who had been on treatment with oral anti-diabetic agents for at least 3 months.
In LEAD 2, patients were randomized 2:2:2:1:2 to receive:
- Victoza® 1.8 mg + metformin 1500 to 2000 mg/day
- Victoza® 1.2 mg + metformin 1500 to 2000 mg/day
- Victoza® 0.6 mg + metformin 1500 to 2000 mg/day
- Placebo + metformin 1500 to 2000 mg/day, or
- Glimepiride 4 mg/day + metformin 1500 to 2000 mg/day.
Efficacy was assessed by changes in levels of haemoglobin A1c (HbA1c), an indicator of a person's average blood glucose level over a 3-month period. Treatment with Victoza® 1.8 mg and Victoza® 1.2 mg (but not 0.6 mg) in combination with metformin resulted in mean reductions in HbA1c that were non-inferior to treatment with glimepiride in combination with metformin.
In the LEAD 5 study, patients were randomized 2:1:2 to receive:
- Victoza® 1.8 mg + metformin 2000 mg/day + glimepiride 2 to 4 mg/day
- Placebo + metformin 2000 mg/day + glimepiride 2 to 4 mg/day, or
- Insulin glargine + metformin 2000 mg/day + glimepiride 2 to 4 mg/day.
Treatment with Victoza® 1.8 mg in combination with glimepiride and metformin resulted in a statistically significantly greater mean reduction in HbA1c compared to placebo in combination with glimepiride and metformin.
Victoza® (6 mg/mL, liraglutide) is presented as a solution for injection in a pre-filled disposable pen. For all patients, Victoza® is administered subcutaneously once daily at any time, independent of meals. Victoza® should be initiated with a dose of 0.6 mg once daily for at least 1 week. The 0.6-mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration. After 1 week at 0.6 mg/day, the dose should be increased to 1.2 mg once daily. Based on clinical response and after at least 1 week, the dose can be increased to 1.8 mg once daily to achieve maximum glycemic control. Dosing guidelines are available in the Product Monograph.
Victoza® is contraindicated for patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia Syndrome Type 2 (MEN 2). As well, Victoza® is contraindicated in pregnant or breast-feeding women as well as in patients who are hypersensitive to liraglutide or to any ingredient in the formulation.
A Black Box Warning in the Product Monograph outlines the safety concerns related to the possible risk of thyroid C-cell tumours with Victoza® treatment.
Victoza® should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Victoza® are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Victoza® is favourable for the indications stated above. As a part of the market authorization, Health Canada has required a Risk Management Plan to ensure that the benefits continue to outweigh any risk.
3 Scientific and Regulatory Basis for Decision
A Notice of Deficiency (NOD) was issued by Health Canada on June 5, 2009 for the New Drug Submission (NDS) for Victoza®. The NOD was issued as the submitted data raised concern regarding a potential risk of thyroid C-cell cancer in humans. The sponsor was requested to include in their response to the NOD a revised Risk Management Plan (RMP), in addition to providing updated study reports for a select number of studies.
On June 22, 2009 a response to the NOD was submitted by the sponsor. The submission entered the review stream and a Notice of Compliance (NOC) was issued on May 21, 2010. A timeline of these events is documented in section 4 Submission Milestones.
3.1 Quality Basis for Decision
>3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Liraglutide, the medicinal ingredient of Victoza® is an acylated human GLP-1 receptor antagonist with 97% amino acid sequence similarity to endogenous human GLP-1(7-37). Liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. The cellular action of GLP-1 is mediated through the stimulatory G protein (Gs) and adenylyl cyclase, which when activated leads to the synthesis of intracellular cAMP and subsequent release of insulin into the bloodstream. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying.
Manufacturing Process and Process Controls
The drug substance is manufactured via a multi-step process consisting of fermentation, recovery of the target protein, and purification and acylation of the target to make the liraglutide drug substance. Process validation data demonstrated that the manufacturing process operates in a consistent manner, yielding product of acceptable quality.
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use.
The drug substance manufacturing process has been scaled-up and optimized during development. The process changes introduced at each generation of the process were adequately described and comparatively assessed. Lot release, stability, and characterization data have also been used to support the comparability assessment.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that liraglutide consistently exhibits the desired characteristic structure and biological activity.
Comparability of liraglutide lots produced by different processes was performed and comparable physicochemical characteristics were demonstrated.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of liraglutide.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately controlled. The level of impurities reported for the drug substance was found to be within the established limits.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life, storage, and shipping conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
The drug product is supplied as a sterile, clear, colourless solution in a 3-mL cartridge. The closure for the cartridge consists of a cap with a latex-free laminated rubber disc. The laminated rubber consists of two layers: synthetic polyisoprene and bromobutyl rubber. The layer of bromobutyl rubber is in direct contact with the product. The rubber plunger for the 3-mL cartridge is made of red bromobutyl rubber. Each 3-mL cartridge is assembled in a pen-injector.
Each 1 mL of Victoza® contains 6 mg of liraglutide and the following non-medicinal ingredients: disodium phosphate dihydrate, propylene glycol, phenol, and water for injection. Each pre-filled pen contains 3 mL of Victoza®, equivalent to 18 mg liraglutide (free-base, anhydrous).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of liraglutide with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Victoza®, rationale for choice of formulation, manufacturing process including packaging, information on batches used for in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Victoza®. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not adversely affected by the changes described.
Manufacturing Process and Process Controls
The Victoza® drug product essentially consists of dissolution of the drug substance and other ingredients, formulation, mixing, pH adjustment, sterile filtration, aseptic filling, cartridge closure, inspection, assembly into pen-injector, labelling, and packaging. The manufacturing process has been adequately validated.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Victoza® is tested to verify that its identity, appearance, pH, particulate matter, sterility, protein content, levels of degradation products and high molecular weight proteins, and bacterial endotoxins are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Victoza®.
The results for all of the batches were within the proposed specification limits.
Through Health Canada's Lot Release Program for Schedule D (Biologic) Drugs, typical final product lots were subjected to targeted in-house testing. The results and analysis supported the decision to issue a Notice of Compliance for this product.
Stability
Based on the long-term, accelerated, and severe condition stability data submitted, the proposed 30-month shelf-life at 2 to 8°C for Victoza® is considered acceptable.
Based on the in-use stability studies of the primary and the supportive batches, an in-use period of 30 days at room temperature (up to 30°C) or in a refrigerator (between 2 to 8°C) is considered acceptable.
Victoza® 6.0 mg/mL pen-injector must be protected from light when not in use [that is (i.e.) the cap from the pen-injector should be applied after use]. Victoza® 6.0 mg/mL pen-injector should therefore also be protected from excessive heat and sunlight during use.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the facilities involved in the manufacture of the drug product and drug substance was not performed due to scheduling and workload issues.
The results of the most recent OSEs performed at these facilities to support the review of other recombinant peptides were such that the risk of not performing the OSE as part of the review process was low.
The design, operations and controls of the facility and equipment that are involved in the production of Victoza® are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Victoza® 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.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Liraglutide is a potent, selective, and full agonist on cloned GLP-1 receptors from human as well as mouse, rat, rabbit, pig, and monkey. The main principle for the protracted action of liraglutide is albumin binding, resulting in a long plasma half-life and self-association, which results in slow absorption. Also, higher enzymatic stability against the dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) enzymes are seen. The apparent reduced potency in the presence of albumin indicates that only the free fraction of liraglutide is responsible for its pharmacological effect in vitro as well as in vivo.
The glucose-lowering effect of liraglutide was investigated in mice, rats and pigs, and was shown to be due to glucose-dependent insulin secretion; glucose-dependent lowering of glucagon; slowing of gastric emptying; and increased beta-cell mass (only during the diabetic stage).
3.2.2 Pharmacokinetics
At the time of review, pharmacokinetic (PK) studies in humans had been completed which were considered more relevant than the non-clinical PK studies. As a result, the non-clinical PK studies were not reviewed for this submission.
3.2.3 Toxicology
Toxicology studies with liraglutide were conducted in rats, mice, and cynomolgus monkeys, since they were shown to be pharmacologically relevant species for non-clinical safety evaluations and also exhibited comparable metabolic patterns to humans.
Single-Dose Toxicity
Acute toxicity testing was conducted in mice and rats administered the high dose of 10 mg/kg bodyweight (bw) liraglutide by subcutaneous (SC) or intravenous (IV) routes. For both species, there were no mortalities during the 14-day observation period and the only findings were a transient decrease in bodyweight gain and food intake. Transient clinical signs were only observed in rats after IV administration with complete recovery by 4 days post-dose. As a result of these findings, the median lethal dose (LD50) was determined to be >10 mg/kg bw.
Repeat-Dose Toxicity and Carcinogenicity
Sub-chronic toxicity testing was conducted in mice and rats. The primary finding in both species was decreased bodyweight gain and food intake which was noted primarily during the first week of study.
Following chronic exposure to liraglutide in mice and rats, pre-neoplastic and neoplastic changes were apparent in the thyroid gland. These changes occurred at dose levels that were within the range of the human therapeutic dose. Data from the mechanistic studies were insufficient to conclude that thyroid C-cell findings in rodents were not relevant to human risk indicating a potentially serious safety concern of thyroid C-cell toxicity and thyroid C-cell oncogenicity to humans (see section 3.3.4 Clinical Safety/Cancer). There was also an increase of the incidence of (and deaths attributable to) dorsal fibrosarcoma in the skin and subcutis of male mice at doses approximately 45-times therapeutic dose levels.
Sub-chronic toxicity testing in cynomolgus monkeys indicated that liraglutide was generally well-tolerated. Liraglutide was administered for 1 month, 13 weeks, and 52 weeks. The primary finding was a reduction in bodyweight gain or bodyweight loss and a reduction in food consumption for the first week. There was no evidence of thyroid toxicity in monkeys.
Genotoxicity
A standard battery of genotoxicity studies demonstrated that liraglutide did not exhibit mutagenic potential.
Reproductive and Developmental Toxicity
A developmental study was conducted in rabbits at dose levels of 0.01, 0.025, and 0.05 mg/kg bw/day. There were no treatment-related findings observed for the caesarean section parameters; however, there was a trend towards an increase in the incidence of major abnormalities at all dose levels tested. In the 0.025 and 0.05 mg/kg bw/day groups, single cases of microphthalmia were noted at both dose levels. There was also an increase in the foetal incidence of connected parietals in the highest dose group and single cases of split sternum. Based on these data, liraglutide is considered to be teratogenic in rabbits at all dose levels tested. In addition, minor abnormalities considered to be treatment related included an increase in the incidence of jugal(s) connected/fused to maxilla at all dose levels tested, and an increase in the incidence of bilobed/bifurcated gallbladder at 0.025 and 0.50 mg/kg bw/day.
Treatment with liraglutide resulted in embryo/foetal toxicity in rats and rabbits and was a potential teratogenic agent in rabbits at therapeutic doses. As a result, women who are trying to become pregnant should be informed that liraglutide may result in adverse effects (AEs) to the foetus. It is highly recommended that liraglutide not be used to treat pregnant women.
Local Tolerance
In sub-chronic toxicity studies in cynomolgus monkeys, irritation at the injection site was observed at all dose levels. The degree of irritation was greatest in the 5.0 mg/kg bw/day group and was considered to be related to treatment.
3.2.4 Summary and Conclusion
Liraglutide has been shown to be a highly selective GLP-1 receptor agonist with prolonged duration of action and expected pharmacologic effects in vitro and in vivo. The pharmacokinetic properties and metabolic pathways seem similar across all species. The non-clinical safety findings did show that liraglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures in both genders of rats and mice. The relevance of this finding to humans is unknown and therefore will be closely monitored.
The toxicity database for Victoza (liraglutide) is in accordance with the International Conference on Harmonisation (ICH) Guidance S6 Pre-clinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Victoza® 1.8 mg and 1.2 mg reduced the mean fasting glucose by 3.90 mmol/L and 3.33 mmol/L, respectively, when compared to placebo. Following a standard meal, the difference versus (vs.) placebo in mean 2-hour postprandial glucose concentration was 6.02 mmol/L and 5.63 mmol/L. In addition, Victoza® 1.8 mg and 1.2 mg decreased the incremental postprandial glucose (defined as the difference between blood glucose values 90 minutes post and immediately before the meal across all three meals) on average by 1.1 mmol/L and 1.08 mmol/L, respectively.
Victoza® increased insulin secretion in relation to increasing glucose concentrations. Using a stepwise graded glucose infusion, the insulin secretion rate was increased following a single dose of liraglutide in patients with Type 2 diabetes to a level comparable to that observed in healthy subjects.
Victoza® lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza® of approximately 0.7 mg did not impair glucagon response to low glucose concentrations. Furthermore, due to increased insulin and lower glucagon secretion, a lower endogenous glucose release was observed with Victoza®.
Victoza® also caused a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appeared in the circulation.
Cardiovascular Electrophysiology
The GLP-1 receptor is present in heart tissue. Activation of this receptor by GLP-1 leads to cAMP production and protein kinase A activation. The pharmacodynamic effects of cardiac GLP-1 receptor activation are still being elucidated.
A randomized, double-blind, two-period crossover, placebo-controlled study was conducted with 51 healthy volunteers (25 males and 26 females, 18 to 44 years of age). Following randomization, subjects in the Victoza® -treatment arm received daily administration of 0.6 mg SC Victoza® for the first week of treatment, 1.2 mg SC daily for the second week of treatment, and 1.8 mg SC daily for the third week of treatment according to an upward titration design. At the end of the second and third weeks, immediately following the seventh and final doses of 1.2 and 1.8 mg Victoza® , respectively, subjects had 24 hours of serial electrocardiogram (ECG) monitoring. Subjects randomized to the placebo arm had an identical schedule of treatment and assessments with an SC placebo injection.
The results of this study indicate that Victoza® at therapeutic doses of 1.2 and 1.8 mg causes a sustained increase in heart rate, prolongation of the PR interval, and shortening of the QTc interval.
Heart Rate
Victoza® was associated with statistically significant increases in heart rate at all time points during treatment with the 1.2 mg dose on Day 14 and the 1.8 mg dose on Day 21. The incidence of subjects with heart rate values greater than 90 beats per minute (bpm) was 20.0% for Victoza® 1.2 mg vs. 8.0% for placebo and 23.5% for Victoza® 1.8 mg vs. 3.9% for placebo.
PR Interval
Victoza® at a dose of 1.2 mg caused statistically significant increases in the PR interval at all time points on Day 14. The 1.8 mg dose of Victoza® resulted in statistically significant PR interval prolongation at 10 of 12 post-dose time points on Day 21. The maximum placebo- and baseline-adjusted mean PR interval prolongation was 10.0 ms for the 1.2 mg dose and 9.0 ms for the 1.8 mg dose. Treatment-emergent PR values >200 ms were reported for 4% of subjects in the Victoza® arm and 2% of subjects in the placebo arm. The incidence of subjects who had PR values >200 ms at baseline that increased in magnitude and/or frequency during treatment was 6% for the Victoza® arm vs. 2% for the placebo arm.
QT Interval
Victoza® at 1.2 mg and 1.8 mg doses was associated with statistically significant shortening of the QTc interval at most post-dose time points. The clinical significance of an acquired, drug-induced QTc shortening of this magnitude is not known.
3.3.2 Pharmacokinetics
Absorption
The absorption of Victoza® following SC administration is slow, reaching maximum concentration 8 to 12 hours post-dosing. The estimated maximum liraglutide concentration was 9.4 nmol/L for a single 0.6 mg SC dose of liraglutide. At 1.8 mg liraglutide, the average steady-state concentration of liraglutide (AUCτ/24) reached approximately 34 nmol/L. Victoza® exposure (AUC) increased approximately linearly with the dose (µg/kg) with increasing slope due to accumulation between Days 1 and 11. The intra-subject coefficient of variation for liraglutide AUC was 11% following single-dose administration. Victoza® can be administered subcutaneously in the abdomen, thigh, or upper arm. The absolute bioavailability of Victoza® following SC administration is approximately 55%.
Distribution
The apparent volume of distribution after SC administration is 11 to 17 L. The mean volume of distribution after IV administration of Victoza® is 0.07 L/kg. Victoza® is extensively bound to plasma protein (>98%).
Metabolism
During 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Two minor plasma metabolites were detected (≤9% and ≤5% of total plasma radioactivity exposure). Victoza® is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.
Excretion
Following a [1H]-liraglutide dose, intact liraglutide was not detected in urine or faeces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or faeces (6% and 5%, respectively). The urine and faeces radioactivity was mainly excreted during the first 6 to 8 days, and corresponded to three minor metabolites, respectively.
The mean clearance following SC administration of a single dose of Victoza® is approximately 1.2 L/h with an elimination half-life of approximately 13 hours.
3.3.3 Clinical Efficacy
The efficacy of Victoza® was evaluated in five pivotal Phase III studies from the Liraglutide Effect and Action in Diabetes (LEAD) clinical development program. Two of the five studies (LEAD 2 and LEAD 5) support the authorized indications both of which were 26 weeks in length and included patients with Type 2 diabetes who had been on treatment with oral anti-diabetic agents for at least 3 months.
Pivotal Studies
Liraglutide Effect and Action in Diabetes (LEAD) 2
The LEAD 2 study examined glycaemic control in subjects with Type 2 diabetes following once daily administration of Victoza® in combination with metformin; glimepiride in combination with metformin; or metformin monotherapy. This study was a 6-month multicentre, multinational, double-blind, double-dummy study with an 18-month extension period.
A total of 1091 patients with Type 2 diabetes and at least 3 months of treatment with various oral anti-diabetic (OAD) agents were randomized in a 2:2:2:1:2 manner to receive:
- Victoza® 1.8 mg + placebo (instead of glimepiride) + metformin 1500 to 2000 mg/day;
- Victoza® 1.2 mg + placebo (instead of glimepiride) + metformin 1500 to 2000 mg/day;
- Victoza® 0.6 mg + placebo (instead of glimepiride) + metformin 1500 to 2000 mg/day;
- Placebo (instead of Victoza®) + placebo (instead of glimepiride) + metformin 1500 to 2000 mg/day; or
- Placebo (instead of Victoza®) + glimepiride 4 mg/day + metformin 1500 to 2000 mg/day.
Each group received at least one placebo and one group (metformin monotherapy) received two placebos. Victoza placebo was administered subcutaneously and the glimepiride placebo was administered orally.
At the time of randomization, subjects were stratified with respect to their previous OAD therapy (monotherapy or combination therapy). Randomization took place after a 3-week forced metformin titration period, which was optional or could be modified for subjects taking metformin before the trial, followed by a metformin maintenance period of another 3 weeks. During the titration period, the dose of metformin was increased to 2000 mg/day. After randomization, a 2-week titration period commenced followed by a 24-week maintenance treatment period with fixed daily doses of Victoza® and glimepiride. The glimepiride dose used in the study (4 mg/day) was less than the maximum Canadian approved dose (8 mg/day), but equal to the maximal dose approved in some of the other participating countries and within the usual maintenance dose of 1 to 4 mg/day. The daily dose of metformin was to be maintained throughout the study if possible; but could be decreased to a minimum of 1500 mg and increased again to 2000 mg at the discretion of the investigator.
The percentage of patients who discontinued due to ineffective therapy was 5.4% in the Victoza® 1.8mg + metformin group, 3.7% in the glimepiride + metformin group, and 23.8% in the metformin monotherapy group.
The efficacy of Victoza® was assessed by changes in levels of HbA1c, an indicator of a person's average blood glucose level over a 3-month period. The primary endpoint was the change from baseline in HbA1c after 26 weeks of treatment. Treatment with Victoza® 1.8 mg and 1.2 mg (but not 0.6 mg) in combination with metformin resulted in mean reductions in HbA1c that were non-inferior to treatment with glimepiride in combination with metformin.
Liraglutide Effect and Action in Diabetes (LEAD) 5
The LEAD 5 study examined glycaemic control in subjects with Type 2 diabetes following once daily administration of Victoza® in combination with glimepiride and metformin; glimepiride and metformin combination therapy; or insulin glargine, glimepiride, and metformin combination therapy. This study was a 6-month multicentre, multi-national study that was double-blinded with regard to Victoza® for the placebo arm, but the active-control arm received open-label treatment (insulin glargine).
A total of 581 patients with Type 2 diabetes and at least 3 months of treatment with various OAD regimens were randomized 2:1:2 to receive:
- Victoza® 1.8 mg + metformin 2000 mg/day + glimepiride 2 to 4 mg/day;
- Placebo + metformin 2000 mg/day + glimepiride 2 to 4 mg/day; or
- Insulin glargine + metformin 2000 mg/day + glimepiride 2 to 4 mg/day.
Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, the daily doses of metformin and glimepiride were increased to 2000 mg and 4 mg respectively. The glimepiride dose used in the study (4 mg/day) was less than the maximum Canadian approved dose (8 mg/day) but equal to the maximal dose approved in some of the other participating countries and within the usual maintenance dose of 1 to 4 mg. After randomization, patients randomized to receive Victoza® 1.8 mg underwent a 2 week period of titration with Victoza®. During the trial, the Victoza® and metformin doses were fixed, while the dose of glimepiride could be reduced to 3 or 2 mg/day. Patients randomized to receive insulin glargine titrated the insulin glargine dose twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration. After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the insulin glargine dose was to be revised, if necessary, at Weeks 12 and 18.
Only 20% of insulin glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤5.5 mmol/L; therefore, optimal titration of the insulin glargine dose was not achieved in most patients.
The percentage of patients who discontinued due to ineffective therapy was 0.9% in the Victoza® 1.8mg + glimepiride + metformin group, 11.3% in the glimepiride + metformin group, and 0.4% in the insulin glargine + glimepiride + metformin group.
The primary endpoint of the study was the change from baseline in HbA1c after 26 weeks of treatment. Treatment with Victoza® 1.8 mg in combination with glimepiride and metformin resulted in a statistically significant mean reduction in HbA1c compared to placebo in combination with glimepiride and metformin.
Conclusion
Adequate evidence of efficacy was provided to support the indication for Victoza® in combination therapy with metformin. Efficacy in support of combination therapy with metformin and glimepiride (a sulfonylurea) was less robust, largely because of sub-optimal titration of the open-label insulin glargine control therapy.
3.3.4 Clinical Safety
The safety of Victoza® was evaluated based on data from the five pivotal Phase III studies from the LEAD clinical development program. In addition, further information was evaluated from the Integrated Safety Summary (which drew on all clinical trials in the liraglutide development program), the 120-Day Safety Update, and information provided by the sponsor at Health Canada's request during the review.
Cancer
In the clinical trials, there were four reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and one case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 subject-years, respectively). Two additional cases of thyroid C-cell hyperplasia in Victoza®-treated patients and one case of medullary thyroid cancer (MTC) in a comparator-treated patient were subsequently reported. The comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All cases were diagnosed after thyroidectomy, prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five Victoza®-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One Victoza® and one non-Victoza®-treated patient developed elevated calcitonin concentrations while on treatment.
It is not known if the dose-dependent and treatment-duration-dependent thyroid C-cell tumours that were observed at clinically relevant exposures in rats and mice translate into an increased risk of MTC in humans. Screening for MTC has incidentally revealed a higher rate of liraglutide-associated papillary thyroid cancer. It is anticipated that community surveillance in response to the perceived thyroid cancer risk may lead to an increase in thyroidectomies, with the potential to cause more morbidity than actual drug-induced disease; this should be considered a risk in itself.
Cardiovascular
Heart Rate Increase
A 24 h time-averaged increase in mean heart rate of 7 to 8 bpm was reported with Victoza® treatment in a clinical study conducted with healthy volunteers undergoing serial ECG monitoring. In patients with diabetes, a 2 to 4 bpm increase in mean pulse rate was observed in long-term clinical studies. Caution should be used when administering Victoza® to patients with cardiac conditions that might be worsened by an increase in heart rate (i.e., ischaemic heart disease and tachyarrhythmias); there are limited clinical data from this patient population. The incidence of a composite endpoint for all tachyarrhythmia in pooled clinical studies in diabetic patients was higher following treatment with Victoza® than for placebo.
PR Interval Prolongation
A prolongation of the mean PR interval of up to 10 ms was reported with Victoza® treatment in a clinical study conducted with healthy volunteers. In healthy volunteers and in patients with diabetes, the incidence of first degree atrioventricular (AV) block was higher following treatment with Victoza® than with placebo. The clinical significance of these changes is not fully known; however, because of limited clinical experience in patients with pre-existing conduction system abnormalities (for example [e.g.] marked first-degree AV block or second- or third-degree AV block) and heart rhythm disturbances (e.g. tachyarrhythmia), caution should be observed in these patients.
Pancreatitis
In clinical studies of Victoza® there were seven cases of pancreatitis among
Victoza®-treated patients and one case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 subject-years, respectively). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. All events were serious except for one case of chronic pancreatitis in a patient treated with Victoza®. One fatal case of pancreatitis with necrosis was observed, in a Victoza®-treated patient. Five additional cases of pancreatitis have subsequently been reported in clinical studies of Victoza®. One of these was a case of acute pancreatitis in a patient whose treatment remains blinded. The remaining four cases occurred in Victoza®-treated patients; two cases were acute pancreatitis, one case was chronic pancreatitis, and one case was reported as not acute.
Additional Safety Issues
Hypoglycaemia
In the clinical studies of at least 26-weeks duration, major hypoglycaemia requiring the assistance of another person for treatment occurred in seven Victoza®-treated patients and in no comparator-treated patients. Six of the seven patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea.
Gastrointestinal Adverse Events
The most frequent Victoza®-associated AEs were gastrointestinal (GI) in nature. In pooled long-term clinical studies, GI AEs were reported in 41% of Victoza®-treated patients and were dose related. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhoea, dyspepsia and constipation. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. Most episodes of nausea were mild or moderate in severity and declined over time. Withdrawals due to GI AEs occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients, mainly during the first 2 to 3 months of the trials.
Immunogenicity
Approximately 50 to 70% of Victoza®-treated patients in pooled clinical studies of 26 weeks or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Anti-liraglutide antibodies were detected in 8.6% of the Victoza®-treated patients from these studies. The antibodies cross-reacting with native GLP-1 were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of Victoza®-treated patients in a 52-week monotherapy trial and 1.0% of Victoza®-treated patients in 26-week combination therapy trials.
Based on the data submitted, the incidence of antibody development is in line with what has been observed in other biologic products. Subjects with liraglutide antibodies to liraglutide tended to report more hypersensitivity AEs, but were few in number. The formulation-to-be-marketed was associated with more injection site disorders than the original formulation, but these were non-serious and few resulted in withdrawal.
Injection-site Reactions
Overall, injection-site reactions, most frequently bruising and pain, have been reported in approximately 2% of subjects receiving Victoza® in long-term controlled trials. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. None of these patients tested positive for liraglutide antibodies. In general, injection site reactions were non-serious but increased with liraglutide dose.
Conclusion
The main safety concerns associated with Victoza® treatment include cardiovascular events, rare cases of pancreatitis, and GI events. As well, in non-clinical studies, liraglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures in both genders of rats and mice. The relevance of these findings to humans is unknown; therefore, a potential risk cannot be ruled out.
3.3.5 Additional Issues
As part of the marketing authorization for Victoza®, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to):
- To submit to the Health Canada, prior to the launch of Victoza® a Supplementary New Drug Submission (SNDS) (as agreed) which should include data from study NN2211-1860 (liraglutide + metformin vs. metformin + sitagliptin) and any new data from studies involving liraglutide which provides further support to the indications granted in the NDS (e.g. Study NN2211-1796). If a new safety update is available for Victoza®, this should be included as well.
- To submit to Health Canada, in accordance with Canadian Regulations, all serious adverse events [including malignancies, cardiovascular events, pancreatitis, et cetera (etc.)] that occurred in all clinical trials with Victoza®.
- To submit to the Health Canada, the Victoza® Medical Educational materials and Communication Plan (for healthcare providers) for comment and feedback.
- To submit a revised Canadian RMP that reflects the post-approval activities committed, the indications granted in Canada, the international status of Victoza®, etc.
- To submit the proposals for the cardiovascular outcome study and the medullary thyroid carcinoma case series registry as well as to include Canadian patients in these studies.
- To provide Health Canada concise safety reports every three months, including copies of reports provided to other regulatory agencies, once the product is launched, in addition to the Periodic Safety Update Reports (PSURs).
- To inform Health Canada in a timely manner of all suspected cases of thyroid cancer potentially related to Victoza®, and other serious adverse events on an ongoing basis.
- To submit to Health Canada the protocols and reports for the non-clinical studies (S1583-3, 1583-4 and 1583-5), clinical studies (1583-6 and 1583-9), and any reports or correspondence to be submitted to other jurisdictions (e.g., follow-up to post-approval commitments/requirements).
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures in both genders of rats and mice. The relevance of this finding to human is unknown. Other relevant safety issues identified include: cardiovascular AEs (increase in heart rate, PR interval prolongation and tachyarrythmia), rare cases of pancreatitis, and GI events.
Victoza® in combination with metformin or in combination with metformin and sulfonylurea was effective in improving HbA1c relative to comparators. Other benefits include a lower rate of hypoglycaemia when combined with metformin vs. metformin + sulfonylurea.
Given the uncertainty regarding human risk for MTC, the rejection of this product was considered; however, the clinical benefit of Victoza® as first-in-class in Canada for the treatment of Type 2 diabetes should also be considered and deemed worthwhile to balance the unknown human risk. Although, there are several classes of products currently marketed in Canada for the treatment of Type 2 diabetes, there are still many patients with Type 2 diabetes (45% in the United States) who do not achieve the HbA1c target (<7%) indicating that there is still an unmet need for new medications. Victoza® in combination with metformin or in combination with metformin and sulfonylurea was found effective in improving HbA1c relative to comparators. In addition, Victoza® in combination with metformin has a lower risk of hypoglycaemia in comparison with metformin and sulfonylurea. Considering that metformin is the recommended first-line treatment for Type 2 diabetes, Victoza® was authorized as second- or third-line therapy only.
Other elements considered for the authorization of Victoza® include the post-approval activities and the investigations to be carried out for the management and monitoring of the risk of medullary thyroid carcinoma and cardiovascular safety issues.
Balancing the uncertainty regarding the risk of thyroid cancer and to a lesser extent the other major safety issues (cardiovascular and pancreatitis) with the clinical benefit of Victoza®, the unmet medical need, the non-availability in Canada of the pharmaceutical GLP-1 (exanetide), the seriousness of Type 2 diabetes, the authorization of Victoza® in other jurisdictions (for example, United States, Europe, Australia) and taking into consideration the proper labelling agreed upon (the restriction of the indications and warning boxes in the Product Monograph for the risk of thyroid cancer), and the planned and committed post-marketing studies and activities (including a 15 years cases series registry and other studies), Health Canada considers that, to date, the benefit of Victoza® outweighs the risks for the target patient population. Thus, in order to ensure that this benefit continues to outweigh any risk after authorization, Health Canada has required a Risk Management Plan.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Victoza® is favourable in the treatment of adults with Type 2 diabetes to improve glycemic control in combination with:
- metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
- metformin and a sulfonylurea, when diet and exercise plus dual therapy with meformin and a sulfonylurea do not achieve adequate glycemic control.
The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Victoza®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-05-15 |
| Submission filed: | 2008-07-02 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-08-15 |
| Review 1 | |
| Biopharmaceutics Evaluation complete: | 2009-06-05 |
| Quality Evaluation complete: | 2009-06-05 |
| Clinical Evaluation complete: | 2009-06-05 |
| Biostatistics Evaluation complete: | 2009-06-05 |
| Notice of Deficiency (NOD) issued by Director General (safety issues): | 2009-06-05 |
| Response filed: | 2009-06-22 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2009-07-14 |
| Review 2 | |
| Biopharmaceutics Evaluation complete: | 2010-05-21 |
| Quality Evaluation complete: | 2010-05-21 |
| Clinical Evaluation complete: | 2010-05-21 |
| Biostatistics Evaluation complete: | 2010-05-21 |
| Labelling Review complete: | 2010-03-31 |
| Notice of Compliance (NOC) issued by Director General: | 2010-05-21 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VICTOZA | 02351064 | NOVO NORDISK CANADA INC | LIRAGLUTIDE 6 MG / ML |