Summary Basis of Decision for Eperzan

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Eperzan is located below.

Recent Activity for Eperzan

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.

Post-Authorization Activity Table (PAAT) for Eperzan

Updated:

2018-05-22

The following table describes post-authorization activity for Eperzan, a product which contains the medicinal ingredient albiglutide. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

Drug Identification Numbers (DINs):

  • DIN 02443635 – 30 mg/0.5 mL albiglutide, powder for solution, subcutaneous
  • DIN 02443643 – 50 mg/0.5 mL albiglutide, powder for solution, subcutaneous

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
DINs (02443635, 02443643) cancelled (Pre-market)Not applicableDiscontinuation date:
2017-10-24

The manufacturer notified Health Canada that sale of the drug has been discontinued pre-market. Health Canada cancelled the DINs pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.

NC # 1891942015-11-02Issued No Objection Letter
2016-02-05
Submission filed as a Level II (90 day) Notifiable Change Moderate Quality Changes) to fulfill several quality-related post-authorization commitments. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 1870162015-08-18Issued No Objection Letter
2015-11-17
Submission filed as a Level II (90 day) Notifiable Change Moderate Quality Changes) to fulfill several quality-related post-authorization commitments. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NDS # 1651452015-05-24Issued NOC
2015-07-15
Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Eperzan

Date SBD issued: 2015-10-08

The following information relates to the new drug submission for Eperzan.

Albiglutide, 30 mg/0.5 mL and 50 mg/0.5 mL, powder for solution, subcutaneous

Drug Identification Number (DIN):

  • DIN 02443635 - 30 mg/0.5 mL, powder for solution
  • DIN 02443643 - 50 mg/0.5 mL, powder for solution

GlaxoSmithKline Inc.

New Drug Submission Control Number: 165145

On July 15, 2015, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product, Eperzan.

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/risk profile of Eperzan is favourable for once-weekly administration for the treatment of adults with type 2 diabetes mellitus, as an adjunct to diet and exercise to improve glycemic control.

  • as monotherapy in patients inadequately controlled by diet, exercise and when metformin is inappropriate due to contraindication or intolerance.
  • in combination with one of the following therapeutic options in patients who have not achieved adequate glycemic control:
    • metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control;
    • metformin and sulfonylurea, when diet and exercise plus dual therapy with metformin and sulfonylurea do not achieve adequate glycemic control; and
    • basal insulin with oral antidiabetic therapies, when diet and exercise plus basal insulin (with oral antidiabetic therapies) do not achieve adequate glycemic control.

The combination of Eperzan with prandial insulin (short acting) has not been studied.

1 What was approved?

Eperzan, an antihyperglycemic agent, was authorized for once-weekly administration for the treatment of adults with type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise to improve glycemic control.

  • as monotherapy in patients inadequately controlled by diet, exercise and when metformin is inappropriate due to contraindication or intolerance.
  • in combination with one of the following therapeutic options in patients who have not achieved adequate glycemic control:
    • metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control
    • metformin and sulfonylurea, when diet and exercise plus dual therapy with metformin and sulfonylurea do not achieve adequate glycemic control; and
    • basal insulin with oral antidiabetic therapies, when diet and exercise plus basal insulin (with oral antidiabetic therapies) do not achieve adequate glycemic control.

The combination of Eperzan with prandial insulin (short acting) has not been studied.

Eperzan should not be used in type 1 diabetes (formerly known as insulin-dependent diabetes mellitus or IDDM) or for the treatment of patients with diabetic ketoacidosis.

No dosage adjustment is required in geriatric patients. Of the total number of patients receiving Eperzan in Phase III clinical studies, 444 (19%) were 65 years of age or older, and less than 2% were 75 years of age and older. No overall differences in efficacy or safety were observed between older and younger patients, however greater sensitivity in older individuals cannot be ruled out.

The safety and efficacy of Eperzan in children under 18 years of age have not been studied. Eperzan is not indicated for use in pediatric patients.

Eperzan is contraindicated for patients with known hypersensitivity to this product or to any ingredient in the formulation or component of the container. Eperzan is also contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN2). Additionally, Eperzan is contraindicated during pregnancy or in breast-feeding women.

Eperzan was approved for use under the conditions stated in the Eperzan Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Eperzan (30 mg/0.5 mL and 50 mg/0.5 mL, albiglutide) is supplied as a pre-filled, single-use pen for self injection once weekly. Each pen contains lyophilized albiglutide powder and clear diluent solution which are stored in separate chambers. The 30 mg pen contains 40.3 mg lyophilized albiglutide and 0.65 mL diluent designed to deliver a dose of 30 mg in a volume of 0.5 mL after reconstitution. The 50 mg pen contains 67.0 mg lyophilized albiglutide and 0.65 mL diluent designed to deliver a dose of 50 mg in a volume of 0.5 mL after reconstitution. In addition to the medicinal ingredient albiglutide, Eperzan also contains the following non medicinal ingredients: sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous; trehalose dehydrate; mannitol; polysorbate 80; and water for injection. Eperzan does not contain a preservative.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Eperzan Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Eperzan approved?

Health Canada considers that the benefit/risk profile of Eperzan is favourable for once-weekly administration for the treatment of adults with type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise to improve glycemic control.

  • as monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindication or intolerance.
  • in combination with one of the following therapeutic options in patients who have not achieved adequate glycemic control:
    • metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control;
    • metformin and sulfonylurea, when diet and exercise plus dual therapy with metformin and sulfonylurea do not achieve adequate glycemic control; and
    • basal insulin with oral antidiabetic therapies, when diet and exercise plus basal insulin (with oral antidiabetic therapies) do not achieve adequate glycemic control.

The increasing burden of T2DM in terms of patient numbers and costs to treat complications are well-established. Glycemic control remains one of the cornerstones in the management of patients with diabetes along with blood pressure, lipids, and weight control. Despite the expanding portfolio of agents available to lower plasma glucose, many patients do not achieve appropriate glycemic control and there has been a shift toward individual patient focus in tailoring diabetic therapy.

Glucagon-like peptide-1 receptor (GLP-1R) agonists have demonstrated substantial effectiveness in improving glycemic control in patients with T2DM while mitigating the risk of hypoglycemia and weight gain commonly associated with some other treatments for T2DM. However, within this class of compounds there remain opportunities to improve the management of T2DM while minimizing the established and emerging risks associated with GLP-1R agonists.

Eperzan has been shown to be efficacious in the treatment of patients with T2DM. The market authorization was based primarily on six controlled Phase III clinical studies, namely GLP112753 (or Harmony 3), GLP112757 (or Harmony 5), GLP108486 (or Harmony 6), GLP112754 (or Harmony 4), GLP114179 (or Harmony 7), and GLP114130 (or Harmony 8). These six Phase III studies evaluated the use of Eperzan as a monotherapy in patients with renal impairment, and as an add-on therapy to other commonly prescribed antidiabetic agents including metformin, glimepiride, pioglitazone, liraglutide, sitagliptin, and basal insulin. The primary efficacy endpoint for all six studies was the change in glycated hemoglobin (HbA1c) from baseline. The timing of the primary endpoint assessment ranged from 26 weeks to 104 weeks, depending on the study. Results from these studies demonstrated a statistically superior reduction in HbA1c from baseline with Eperzan compared to, sitagliptin, or glimepiride, and also met the pre-specified non-inferiority margin (0.3%) when compared to insulin glargine and when compared to insulin lispro. However, Eperzan did not meet the pre-specified non-inferiority margin when compared to pioglitazone and liraglutide.

The safety profile of Eperzan was found to be similar to other marketed GLP-1R agonists in Canada. The most common adverse reactions occurring in ≥10% of patients at 104 weeks for Eperzan and more frequently than comparators (including placebo) were: diarrhea; nausea; and injection site reaction including rash; erythema; or itching at the injection; and upper respiratory tract infection.

One major concern identified during the safety review of the Eperzan submission was the potential risk of developing thyroid cancer with the use of Eperzan as with other GLP-1R agonists. Thyroid C-cell tumors have been observed in animal studies conducted with other similar GLP-1R agonists at clinically relevant doses. While it cannot be confirmed whether Eperzan does cause thyroid C-cell tumors, a Serious Warnings and Precautions Box has been inserted in the Eperzan Product Monograph indicating Eperzan is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC).

Other relevant safety issues identified include: cardiovascular events (increase in heart rate, PR interval prolongation and atrial fibrillation/flutter), cases of pancreatitis and gastrointestinal events. In addition, the uncertainty around the cardiovascular safety profile of Eperzan remains to be addressed from the ongoing Cardiovascular Outcomes Trial (CVOT).

A Risk Management Plan (RMP) for Eperzan was submitted by GlaxoSmithKline Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. 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.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Eperzan has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal Phase III studies with Eperzan, in combination with other T2DM drugs, demonstrated a statistically significant, and clinically meaningful improvements on glycemic control in patients with T2DM when compared to sitagliptin, or glimepiride, and also met the pre-specified non-inferiority margin (0.3%) when compared to insulin glargine and when compared to insulin lispro. However, Eperzan did not meet the pre-specified non-inferiority margin when compared to pioglitazone and liraglutide. In T2DM patients at different stages of renal impairment, Eperzan was shown to be statistically significant superior to sitagliptin in reducing HbA1c. In addition, Eperzan demonstrated an acceptable safety profile based on the non-clinical data and clinical studies provided. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Eperzan Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted 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 Eperzan?

A New Drug Submission (NDS) for Eperzan was filed with Health Canada on May 24, 2013. During the review of the Eperzan submission, a concern was raised in regards to the cardiovascular safety profile of Eperzan where an adequate benefit risk assessment could not be conducted with the information provided. As a result, on May 7, 2014 the sponsor was issued a Notice of Deficiency (NOD) requesting additional data from all completed and ongoing clinical studies since the original NDS was filed in order to provide more recent data which could assist in establishing a more comprehensive benefit risk assessment. A revised summary of major adverse cardiovascular events (MACE) analysis incorporating the new data requested above was also requested as part of the NOD. In response to the NOD, additional information and data were provided by the sponsor. As a result, all issues outlined in the NOD were satisfactorily addressed and a Notice of Compliance (NOC) was issued on July 15, 2015.

Submission Milestones: Eperzan

Submission MilestoneDate
Pre-submission meeting:2011-07-14
Submission filed:2013-05-24
Screening 1
Screening Acceptance Letter issued:2013-07-19
Review 1
On-Site Evaluation:2014-03-17 - 2014-03-21
Quality Evaluation complete:2014-05-07
Clinical Evaluation complete:2014-05-07
Labelling Review complete:2014-05-07
Notice of Deficiency (NOD) issued by Director General (safety issues):2014-05-07
Response filed:2014-08-21
Screening 2
Screening Acceptance Letter issued:2014-09-18
Review 2
Quality Evaluation complete:2015-03-13
Clinical Evaluation complete:2015-05-15
Labelling Review complete:2015-07-09
Notice of Compliance issued by Director General:2015-07-15

The Canadian regulatory decision on the non-clinical and clinical review of Eperzan was based on a critical assessment of the Canadian data package.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Eperzan is a glucagon-like peptide-1 (GLP-1) receptor agonist. Like endogenous GLP-1, Eperzan helps regulate postprandial blood glucose concentrations by stimulating glucose-dependent insulin secretion resulting in increased glucose utilization by tissues. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia, therefore Eperzan has a low intrinsic potential for hypoglycemia. Eperzan also suppresses glucagon secretion in a glucose-dependent manner, leading to reduced hepatic glucose output. In addition, Eperzan also slows gastric emptying thereby reducing the rate at which postprandial glucose appears in the circulation.

The clinical pharmacology program included reports on human pharmacodynamics and pharmacokinetics. Results from these studies support the proposed dosing regimen of 30 mg or 50 mg administered once weekly. Population pharmacokinetic data from the Phase III program which included Caucasian, African American/African, Asian and Hispanic/Non-Hispanic also suggest that there is no need for dose modification according to age, gender, race/ethnicity, weight or renal function. Eperzan was not studied in people with hepatic impairment, but the metabolic pathways for proteins of this size are unlikely to have any effect on the elimination of albiglutide (the medicinal ingredient of Eperzan).

Eperzan was associated with concentration-related increases in heart rate. After repeat dose treatment with the 50 mg dose, the increase in heart rate ranged from 6.0 to 7.8 beats per minute (bpm) over the 24-hour time period studied. Eperzan also resulted in PR interval prolongation. On Day 4, after a single dose of Eperzan 30 mg, the maximum mean difference from placebo was 3.9 ms [90% Confidence Interval (CI) 1.3, 6.5] at 6 hours. On Day 39, during repeat dose treatment with albiglutide 50 mg, the maximum mean difference from placebo was 4.5 ms (90% CI 1.2, 7.8) at 3 hours. In addition, repeat dose treatment with Eperzan 50 mg was associated with shortening of the QTc interval, with a maximal reduction of -3.7 ms (90% CI -5.9, -1.5) at 12 hours. The clinical significance of an acquired, drug-induced QTc shortening of this magnitude is not known.

Drug-drug interaction studies showed no clinically relevant pharmacokinetic or pharmacodynamic interactions identified with a range of commonly co-administered medications.

Eperzan can also be administered at any time of day without regard to meals.

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

Clinical Efficacy

The efficacy of Eperzan was evaluated primarily in six controlled Phase III clinical studies, namely GLP112753 (or Harmony 3), GLP112757 (or Harmony 5), GLP108486 (or Harmony 6), GLP112754 (or Harmony 4), GLP114179 (or Harmony 7), and GLP114130 (or Harmony 8). Note, when referring to these studies here onward, the latter title provided in parentheses shall be used.

The six Phase III clinical studies were designed to evaluate the efficacy and safety of once-weekly subcutaneous (SC) injections of Eperzan in a broad spectrum of type 2 diabetes mellitus (T2DM) patients when administered as a monotherapy, and as an add-on therapy to other commonly prescribed antidiabetic agents including metformin, glimepiride, pioglitazone, liraglutide, sitagliptin, and basal insulin. The primary efficacy endpoint for all six studies was the change in glycated hemoglobin (HbA1c) from baseline. The timing of the primary endpoint assessment ranged from 26 weeks to 104 weeks.

All six Phase III studies assessed the use of Eperzan 30 mg and 50 mg administered once-weekly, with five of the six studies allowing for optional titration of Eperzan from 30 mg to 50 mg once-weekly. For studies which allowed for optional dose up-titration, the glucose levels that triggered up-titration were the same for Eperzan and oral comparators (for those comparators which permitted up-titration). All studies consisted of four study periods: a Pre-screening and Screening period of 2 weeks; a Run-in/Stabilization period of 4 weeks (4-8 weeks in Harmony 6 and 6-8 weeks in Harmony 5); a Treatment Period evaluating efficacy and safety; and Post-treatment Follow-up period of 8 weeks (16 weeks in Harmony 5).

For all studies, the inclusion/exclusion criteria were reflective of a general population of adults with T2DM. Patients' age ranged from 18 to 86 years old (mean 56 years), 51% were male, with a mean body mass index (BMI) of 32 kg/m2 and included patients who were Caucasian (46%), Black (14%), and Asian (13%); and patients of Hispanic/Latino ethnicity (26%). The majority of patients had been previously treated with one or more oral antidiabetic medications or insulin. Studies included a broad spectrum of T2DM patients with respect to duration of disease with equal representation across each of the following categories: <5 years; ≥5 to <10 years; and ≥10 years.

With regard to renal function status, the inclusion criteria in the individual studies required randomized patients to have creatinine clearance [estimated glomerular filtration rate (eGFR)] >60 mL/min, as calculated using the Cockroft-Gault (CG) formula. In addition, one pivotal study (Harmony 8) was conducted specifically in T2DM patients with either mild, moderate, or severe renal impairment.

Key secondary efficacy endpoints included the percentage of patients achieving HbA1c treatment goal of <7.0% and <6.5%, change from baseline in fasting plasma glucose (FPG), change from baseline in body weight, and time to hyperglycemia rescue.

Combination Therapy
Study Harmony 3: Add On to Metformin

In the Harmony 3 study, the efficacy of Eperzan was evaluated in a 3-year, randomized, double-blind, multicentre study [Number of patients (n) = 999]. On background therapy of metformin ≥1,500 mg daily, Eperzan 30 mg subcutaneous (SC) weekly (with optional up-titration to 50 mg weekly after a minimum of 4 weeks) was compared to sitagliptin 100 mg daily, glimepiride 2 mg daily (with optional titration to 4 mg daily), or placebo.  The primary endpoint was the change in HbA1c from baseline to 104 weeks compared to placebo.

At 104 weeks, study results demonstrated that Eperzan was statistically superior for the reduction in HbA1c from baseline compared to placebo, sitagliptin, or glimepiride. Superiority testing against active control was only performed after demonstration of non-inferiority. By Week 104, 52.6% in the Eperzan group and 53.8% in the glimepiride had up-titrated.

At Week 104, Eperzan-, placebo- and sitagliptin-treated patients had an adjusted mean weight loss from baseline of 1.2 kg, 1.0 kg and 0.9 kg, respectively. Glimepiride patients had an adjusted mean weight gain from baseline of 1.2 kg.

As this analysis was based on the last value prior to hyperglycemia rescue, these results should be interpreted with caution given the potential for bias against treatment groups with higher proportions of patients with hyperglycemia rescue and with shorter time to hyperglycemia rescue. The incidence of hyperglycemia rescue at Week 104 was 21.2%, 45.0%, 30.0%, and 26.5% in the Eperzan, placebo, sitagliptin, and glimepiride groups, respectively. Over the total duration of treatment of 156 weeks, the median time to hyperglycemia rescue was 67.7 weeks for placebo. As the probability of hyperglycemia rescue did not reach 50% for Eperzan, sitagliptin and glimepiride groups over the total duration of treatment of 156 weeks, the median times to hyperglycemia rescue could not be estimated.

Study Harmony 5: Add-On to Metformin plus Sulfonylurea

In the Harmony 5 study, the efficacy of Eperzan was evaluated in a 3-year, randomized, double-blind, multicenter study (N = 657). On background therapy of metformin ≥1,500 mg daily plus glimepiride 4 mg daily, Eperzan 30 mg SC weekly (with optional up-titration to 50 mg weekly after a minimum of 4 weeks) was compared to placebo or pioglitazone 30 mg daily (with optional titration to 45 mg daily). The primary endpoint was change in HbA1c from baseline at 52 weeks compared to placebo.

At 52 weeks, study results showed that treatment with Eperzan resulted in statistically significant reductions from baseline in HbA1c [-0.6% for Eperzan versus (vs.) +0.3% for placebo, p<0.05]. Treatment with Eperzan did not meet the pre-specified non-inferiority margin (0.3%) against pioglitazone for HbA1c (-0.6% for Eperzan vs. -0.8% for pioglitazone). In this study, Eperzan provided less HbA1c reduction than pioglitazone, and the treatment difference was statistically significant in favour of pioglitazone. 

At Week 52, Eperzan- and placebo-treated patients had an adjusted mean weight loss from baseline of 0.4 kg and 0.4 kg, respectively. Pioglitazone patients had an adjusted mean weight gain from baseline of 4.4 kg.

As this analysis was based on the last value prior to hyperglycemia rescue, these results should be interpreted with caution given the potential for bias against treatment groups with higher proportions of patients with hyperglycemia rescue and with shorter time to hyperglycemia rescue. The incidence of hyperglycemia rescue at Week 52 was 19.0%, 16.8% and 45.2% in the Eperzan, pioglitazone, and placebo groups, respectively. Over the total duration of treatment of 156 weeks, the median time to hyperglycemia rescue was 49.6 weeks and 137.7 weeks for placebo and Eperzan, respectively. As the probability of hyperglycemia rescue did not reach 50% for pioglitzone over the total duration of treatment of 156 weeks, the median time to hyperglycemia rescue could not be estimated.

Study Harmony 6: Add-On to Insulin Glargine

In the Harmony 6 study, the efficacy of Eperzan was evaluated in a 52 week, randomized, open-label, multicentre study (N = 563). On background therapy of insulin glargine (started at 10 units and titrated to ≥ 20 units per day) and with or without metformin, Eperzan 30 mg SC weekly (with optional up-titration to 50 mg weekly after Week 8) was compared to prandial insulin lispro (administered daily at mealtimes, started according to standard of care and titrated to effect). The primary endpoint was the change in HbA1c from baseline at 26 weeks. At Week 26, the mean daily dose of insulin glargine was 53 international units (IU) for the Eperzan treatment group and 51 IU for the insulin lispro treatment group. The mean daily dose of insulin lispro at Week 26 was 31 IU.

At 26 weeks, study results showed the between-treatment difference in HbA1c of 0.2% (-0.32, 0.00) for Eperzan and insulin lispro met the pre-specified non-inferiority margin (0.3%). Superiority testing against insulin lispro was only performed after demonstration of non-inferiority. By Week 26, the percentage of patients treated with Eperzan who up-titrated was 50.8%.

At Week 26, Eperzan-treated patients had an adjusted mean weight decrease from baseline of 0.7 kg, and insulin lispo patients had an adjusted mean weight increase from baseline of 0.8 kg.

As this analysis was based on the last value prior to hyperglycemia rescue, these results should be interpreted with caution given the potential for bias against treatment groups with higher proportions of patients with hyperglycemia rescue and with shorter time to hyperglycemia rescue. The incidence of hyperglycemia rescue at 26 weeks was 21.6% and 23.5% in the Eperzan and insulin lispro treatment groups, respectively. As the probability of hyperglycemia rescue did not reach 50% for Eperzan and insulin lispro over the total duration of treatment of 52 weeks, the median time to hyperglycemia rescue could not be estimated. 

Study Harmony 4: Active-Controlled Study versus Insulin Glargine in Combination with Metformin ± Sulfonylurea

In the Harmony 4 study, the efficacy of Eperzan was evaluated in a 3-year, randomized, open-label, insulin glargine-controlled study (N = 735). On background therapy of metformin ≥1,500 mg daily (with or without sulfonylurea), Eperzan 30 mg SC weekly (with optional up-titration to 50 mg weekly as early as Week 4) was compared to insulin glargine (started at 10 units and titrated weekly per prescribing information). The primary endpoint was the change in HbA1c from baseline at 52 weeks. The starting total daily dose of insulin glargine ranged between 2 and 40 units (median daily dose of 10 units) and ranged between 3 and 230 units (median daily dose of 30 units) at Week 52.

Results at 52 weeks showed that the between-treatment difference in HbA1c of 0.1% (-0.04, 0.27) for Eperzan and insulin glargine met the pre-specified non-inferiority margin (0.3%). Superiority testing against insulin glargine was only performed after demonstration of non-inferiority. By Week 48, the percentage of patients treated with Eperzan who up-titrated was 67.1%.

At Week 52, Eperzan-treated patients had an adjusted mean weight decrease from baseline of 1.1 kg, and insulin glargine patients had an adjusted mean weight increase from baseline of 1.6 kg.

As this analysis was based on the last value prior to hyperglycemia rescue, these results should be interpreted with caution given the potential for bias against treatment groups with higher proportions of patients with hyperglycemia rescue and with shorter time to hyperglycemia rescue. The incidence of hyperglycemia rescue at Week 52 was 22.0% and 21.3% in the Eperzan and insulin glargine groups, respectively. Over the total duration of treatment of 156 weeks, the median time to hyperglycemia rescue was 107.6 weeks for albiglutide. As the probability of hyperglycemia rescue did not reach 50% for insulin glargine over the total duration of treatment of 156 weeks, the median time to hyperglycemia rescue could not be estimated.

Study Harmony 7: Active-Controlled Study versus Liraglutide in Combination with Metformin, Thiazolidinedione, or Sulfonylurea (as Monotherapy or Dual Therapy)

In the Harmony 7 study, the efficacy of Eperzan was evaluated in a 32 week, randomized, open-label, liraglutide-controlled study (N = 805). Eperzan 30 mg SC weekly (with up-titration to 50 mg weekly at Week 6) was compared to liraglutide 1.8 mg daily (titrated up from 0.6 mg at Week 1 and 1.2 mg at Week 1 to Week 2)in patients inadequately controlled on monotherapy or combination oral antidiabetic therapy (metformin, thiazolidinedione, or sulfonylurea, or a combination of these) compared to liraglutide. The primary endpoint was change in HbA1c from baseline at 32 weeks compared to liraglutide.

At 32 weeks, study results showed that the between-treatment difference of 0.2% (0.08, 0.34) for Eperzan and liraglutide did not meet the pre-specified non-inferiority margin (0.3%).

At Week 32, Eperzan- and liraglutide-treated patients had an adjusted mean weight loss from baseline of 0.6 kg, and 2.2 kg, respectively.

As this analysis was based on the last value prior to hyperglycemia rescue, these results should be interpreted with caution given the potential for bias against treatment groups with higher proportions of patients with hyperglycemia rescue and with shorter time to hyperglycemia rescue. The incidence of hyperglycemia rescue at 32 weeks was 15.2% and 8.4% in the Eperzan and liraglutide groups, respectively. As the probability of hyperglycemia rescue did not reach 50%, the median time to hyperglycemia rescue over the total duration of treatment of 32 weeks could not be estimated.

Study Harmony 8: Renal Impairment

In the Harmony 8 study, the efficacy of Eperzan was evaluated in a randomized, double-blind, active-controlled 52-week study vs. sitagliptin in patients (N = 486) with mild, moderate, and severe renal impairment inadequately controlled on a current regimen of diet and exercise or other antidiabetic therapy (metformin, thiazolidinedione and sulfonylurea, either alone or in combination). Eperzan 30 mg SC weekly (with optional up-titration to 50 mg weekly if needed as early as Week 4) was compared to sitagliptin. Sitagliptin was dosed according to renal function [100 mg daily in mild renal impairment (eGFR ≥50 to 89 mL/min), 50 mg in moderate renal impairment (eGFR ≥30 to <50 mL/min), and 25 mg daily in severe renal impairment (eGFR <30 mL/min)]. The primary endpoint was change in HbA1c from baseline at 26 weeks.

At 26 weeks, study results showed the mean decrease in HbA1c from baseline with Eperzan was -0.80 (N = 125), -0.83 (N = 98), and -1.08 (N = 19) in patients with mild, moderate, and severe renal impairment, respectively. Superiority testing against active control was only performed after demonstration of non-inferiority. By Week 26, the percentage of patients treated with Eperzan who up-titrated was 34.5%.

At Week 26, Eperzan- and sitagliptin-treated patients had an adjusted mean weight decrease from baseline of 0.8 kg, and 0.2 kg, respectively.

As this analysis was based on the last value prior to hyperglycemia rescue, these results should be interpreted with caution given the potential for bias against treatment groups with higher proportions of patients with hyperglycemia rescue and with shorter time to hyperglycemia rescue. The incidence of hyperglycemia rescue at 26 weeks was 6.1% and 12.1% in the Eperzan and sitagliptin groups, respectively. As the probability of hyperglycemia rescue did not reach 50%, the median time to hyperglycemia rescue over the total duration of treatment of 52 weeks could not be estimated.

Across different demographic subgroups, the efficacy of Eperzan was consistently confirmed. Eperzan was equally effective in males and females and was also effective in African Americans, Hispanics, Asian and other ethnic groups.

Other Studies

The Phase II bioavailability and clinical comparability study (GLP114856) confirmed that the commercial formulation of albiglutide (medicinal ingredient in Eperzan) met the criteria of bioequivalence and has a similar efficacy and safety profile to the formulation used in clinical Phase III studies.

Conclusion for Efficacy

The efficacy of Eperzan as a monotherapy and as add-on to other commonly prescribed antidiabetic agents including metformin, glimepiride, sitagliptin, and basal insulin was supported as demonstrated in the six Phase III studies. A reduction in HbA1c from baseline was noted when to sitagliptin, or glimepiride, and also met the pre-specified non-inferiority margin (0.3%) when compared to insulin glargine and when compared to insulin lispro. However, Eperzan did not meet the pre-specified non-inferiority margin when compared to pioglitazone and liraglutide. In T2DM patients at different stages of renal impairment, Eperzan was shown to be statistically significant superior to sitagliptin in reducing HbA1c.

Overall, the therapeutic benefits observed in the six Phase III studies support the use of Eperzan as an efficacious therapy for the management of hyperglycemia in patients with T2DM. As a monotherapy in T2DM patients with renal impairment or in combination with other antidiabetic therapies, a once-weekly SC injection of Eperzan 30 mg, up-titrated (if necessary) to 50 mg, resulted in appropriate glycemic control. Therefore, the efficacy data provided support the approval of Eperzan for its use in accordance with the approved indication.

For more information, refer to the Eperzan Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Eperzan in patients with T2DM was evaluated primarily based on the six active and placebo-controlled Phase III clinical studies previously described in the Clinical Efficacy section. The duration of the studies ranged from 32 weeks up to three years.

The majority of the safety data analyzed consisted of pooled safety data from seven Phase III clinical studies which included approximately 7,500 patient-years of overall program exposure at the time of this application.

In this pooled safety population, the most common adverse reactions occurring in ≥10% of Eperzan-treated patients at 104 weeks and more frequently than all comparators (including placebo) were diarrhea (12.9% vs. 9.2%), nausea (11.5% vs. 10.6%), and injection site reaction including rash, erythema, or itching at the injection site (13.1% vs. 2.9%) and upper respiratory tract infection (12.9% vs. 11.2%). The proportion of patients with adverse events leading to withdrawals was 7.5% for Eperzan and 5.8% for all comparators. The most common adverse event leading to withdrawal for Eperzan was injection site reaction (1.5% for Eperzan vs. 0% for all comparators).

Based on the pooled safety analysis, incidences of gastrointestinal adverse events (in particular nausea and diarrhea) were more frequently reported in the Eperzan-treated patients compared to all comparators or placebo. Therefore, Eperzan is not recommended for patients with pre-existing severe gastrointestinal disease, including severe gastroparesis. A cautionary note to this effect has therefore been inserted in the Eperzan Product Monograph.

The incidence of serious adverse events was similar for Eperzan vs. all comparators (11.2% vs. 10.9%), placebo (11.1% vs. 13.7%), and active comparators groups (11.3% vs. 10.2%). Cardiac disorders and infections and infestations were the most commonly reported serious adverse events in both the Eperzan and all comparators groups. Most severe serious adverse events were reported as cardiac disorders, infections and infestations, and neoplasms [benign, malignant, and unspecified (including cysts and polyps)].

Cardiovascular morbidity and mortality is a significant complication for patients with T2DM. In Phase III clinical studies, administration of Eperzan therapy caused an increase in the patient heart rate with mean increases of 1 to 2 bpm in Eperzan-treated patients compared to placebo.

In a thorough QT study conducted in healthy volunteers, a mean increase in heart rate (6 to 8 bpm) was observed after repeat dosing with Eperzan 50 mg compared to baseline values. In studies in T2DM patients, adverse reactions of atrial fibrillation (1.1%) and atrial flutter (0.2%) were reported more frequently in Eperzan-treated patients than for all comparators (0.6% and 0%, respectively). The observed increases in heart rate could potentially lead to worsening of cardiac conditions in patients with a history of ischemic heart disease or tachyarrhythmias. Therefore, caution should be taken when treating this patient population with Eperzan.

Clinical studies in healthy volunteers also showed that Eperzan caused a prolongation of the PR interval of 4 to 5 ms as observed on electrocardiograms. As such, caution should be used when administering Eperzan in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease, or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. In studies conducted with T2DM patients, a mean PR interval prolongation of approximately 2 ms was observed with Eperzan compared to placebo. Prolongation of the PR interval has also been associated with an increased risk of atrial fibrillation; therefore, caution is warranted in patients with a history of atrial fibrillation.

The impact on the PR interval of co-administration of Eperzan with other drugs that prolong the PR interval [including, but not limited to, antiarrhythmics, non-dihydropyridine calcium channel blockers, beta adrenoceptor blockers, digitalis glycosides, human immunodeficiency virus (HIV) protease inhibitors, and somatostatin analogues] have not been evaluated. As a result, co-administration of Eperzan with these drugs should be undertaken with caution.

Medullary thyroid cancer (MTC) was identified as an area of special interest based on non-clinical studies conducted in animal studies using similar GLP-1R agonists which suggests GLP-1R agonists may be associated with an increased risk of thyroid C-cell focal hyperplasia and C-cell tumors. However, the relevance of these animal findings to humans is unknown. Carcinogenicity studies were not conducted with Eperzan due to anti-drug antibodies which develop in rodents. In addition, there were no drug-related thyroid histological findings in a 52-week monkey study with Eperzan. Given this, it cannot be confirmed whether or not Eperzan causes thyroid C-cell tumors, including MTC in humans. Therefore, as a cautionary measure, a Serious Warnings and Precautions box has been included in the Product Monograph for Eperzan to highlight this uncertainty. Additionally, the use of Eperzan is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN2). Given MTC cancer is rare; it shall be monitored post approval as part of the Eperzan risk management plan.

Another issue which emerged from post-marketing reports with the use other similar GLP-1R agonists, and also observed with Eperzan, is that of acute pancreatitis. In the Eperzan Phase III clinical development program there were six cases of probable or definite pancreatitis possibly related to the use of Eperzan (rate 1.6/1,000 person-years). Two adjudicated cases of probable pancreatitis considered related to investigational product occurred with liraglutide (rate 7.1/1,000 person-years), no cases of adjudicated pancreatitis occurred with any other comparator. Given it remains uncertain whether patients with a family history of pancreatitis are at an increased risk to develop pancreatitis, appropriate warnings and precautions regarding these concerns have been included the Eperzan Product Monograph.

Based on the pooled safety data, injection site reactions (typically including rash, erythema, or itching at the injection site) occurred in 15.4% of Eperzan treated-patients vs. 6.7% with all comparators including placebo. In general, injection site reactions were mild in intensity and few patients required treatment.

Administration of therapeutic proteins, including recombinant homologues of human proteins, can elicit an immune response and lead to the production of anti-drug antibodies. Anti-drug antibodies can impact the efficacy and safety of a biotherapeutic by altering pharmacokinetics, neutralizing the activity of the protein, or causing immune-mediated adverse events such as hypersensitivity reactions. In the pooled safety analysis (32 weeks to at least 104 weeks duration) for Eperzan, 116 out of 2,098 patients (6%) tested positive for anti-albiglutide antibodies at any time during the studies. None of these antibodies were shown to neutralize activity in an in vitro assay and antibody formation was not associated with reduced efficacy (as measured by HbA1c and FPG or alterations in the pharmacokinetics of albiglutide). In general, the antibody response was transient and did not persist. Antibody titres were generally low and not different from those observed in a small number of patients (~0.6%) who tested positive for albiglutide cross-reactive antibodies prior to treatment. Consistent with the high homology of albiglutide with human GLP-1, the majority of patients with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. Although most patients with injection site reactions were antibody negative (~85%), injection site reactions were reported more frequently for antibody positive patients (41%, N = 116) than antibody negative patients (14%, N = 1,927).  These events were predominantly mild and generally resolved without interruption of treatment and did not lead to discontinuation.  Patients with antibodies did not have injection site reactions of greater severity or longer duration compared to patients without antibodies. Otherwise, the pattern of adverse events was generally similar for antibody positive and negative patients. No serious adverse events relating to hypersensitivity were noted in antibody positive patients. Therefore, based on available clinical data, anti-albiglutide antibody formation is not expected to impact the overall clinical benefit of Eperzan treatment.

Patients with diabetes are known to be at increased risk for a number of common infections, including pneumonias. In the pooled safety analysis the incidence of pneumonia was higher with Eperzan vs. all comparators (1.8% Eperzan-treated patients vs. 0.8% for all comparators). Given the consistently higher incidence of events noted in the Eperzan treatment group, a note to this effect has been inserted in the Eperzan Product Monograph.

The risk of hypoglycemia is increased when Eperzan is used in combination with insulin secretagogues [that is (i.e.) sulfonylureas] or insulin. This risk of hypoglycemia can be lowered by reducing the dose of sulfonylurea or insulin.

There are no adequate data to support the use of Eperzan during pregnancy. Animal studies have shown reproductive toxicity. Eperzan is therefore not recommended for use in humans during pregnancy.

There are no adequate data to support the use of Eperzan for nursing women. It is not known if Eperzan is excreted into human milk during lactation. Given that Eperzan is an albumin-based protein therapeutic, it is likely to be present in human milk.

During review of the New Drug Submission (NDS) for Eperzan, a Notice of Deficiency (NOD) was issued to the sponsor on May 7, 2014 given an adequate benefit-risk analysis could not be conducted with the current information provided. To address this deficiency, Health Canada requested to be sent additional data from all completed and ongoing clinical studies since the original application was filed to establish a more comprehensive benefit-risk analysis. A revised summary of major adverse cardiovascular events (MACE) analysis incorporating the new data requested above was also requested as part of the NOD. In response to the NOD, the sponsor provided all additional information requested by Health Canada. Health Canada assessed the additional information submitted and determined it to be satisfactory. As a result, a Notice of Compliance (NOC) was issued to the sponsor on July 15, 2015.

Conclusion on Safety

The safety of Eperzan as a monotherapy

and as add-on to other commonly prescribed antidiabetic agents was supported primarily based on a pooled safety analysis derived from the Phase III clinical studies. All safety issues, including uncertainties, identified during the safety review have been clearly labeled with appropriate warnings and precautions in the approved Eperzan Product Monograph. The possibility of the increased incidence of thyroid C-cell focal hyperplasia and C-cell tumors has been identified with a Black Box warning in addition to contraindicating the use of Eperzan in patients with a personal or family history of MTC or in patients with MEN2. In addition, Eperzan is contraindicated during pregnancy or in breast-feeding women. Eperzan should also not be used in patients with type 1 diabetes mellitus or for the treatment of patient with diabetic ketoacidosis.

For more information, refer to the Eperzan Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical pharmacology, pharmacokinetic, and toxicology studies have characterized the non-clinical profile of albiglutide (the medicinal ingredient in Eperzan), in sufficient detail to support the intended clinical indication. In view of the intended use of Eperzan, no pharmacological/toxicological issues within this submission were identified which could preclude authorization of the product. However, it is important to note that due to anti-drug antibodies which develop in rodents, no carcinogenicity studies were conducted in preclinical studies. As a result, the safety issue of thyroid malignancies identified in animal studies with other GLP-1R agonists will be closely monitored through the risk management plan as part of the ongoing benefit-risk assessment.

Pregnancy and Lactation

In pre and postnatal development studies in mice administered albiglutide during pregnancy or while nursing, reduced pre-weaning body weight of F1 offspring was observed at ≥1 mg/kg/day [0.63 times clinical exposure based on the area under the concentration time curve (AUC)]. Reduced F1 body weight reversed post-weaning with the exception of F1 females from dams treated perinatally (end of gestation to 10 days postpartum) at ≥5 mg/kg/day (2.2 times clinical exposure based on AUC) with no other effects on development. Albiglutide was detected at trace levels in the plasma of offspring. It is unknown whether the reduced offspring body weight was caused by a direct albiglutide effect on the offspring or secondary to effects on the dam.

For more information, refer to the Eperzan Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Albiglutide, the medicinal ingredient of Eperzan, is a recombinant fusion protein consisting of two copies of a 30-amino acid sequence of modified GLP-1 (fragment 7-36) genetically linked in series to human albumin (hA).

Detailed characterization studies were performed to provide assurance that albiglutide consistently exhibits the desired characteristic structure. Results from process validation studies indicate that the processing steps adequately control the levels of product and process related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Albiglutide is produced in Saccharomyces cerevisiae using recombinant deoxyribonucleic acid (DNA) technology. The albiglutide drug substance manufacturing process consists of a series of steps which include cell culture, harvest, and purification stages.

The manufacturing of the Eperzan drug product consists of formulating the albiglutide drug substance, filling, and lyophilization to produce a sterile lyophilized cake which is then stored in a clear glass dual chamber cartridge (DCC). The front chamber contains albiglutide. The rear chamber is filled with the diluent water for injection. The contents of the two chambers of the DCC are separated by a bromobutyl rubber stopper. Prior to administration, the contents of the two chambers are combined.

Process consistency as well as adherence to product quality and safety requirements is monitored during manufacturing with in-process controls.

Process validation data demonstrate that the Eperzan manufacturing process operates in a consistent manner, yielding product of acceptable quality.

The Eperzan manufacturing process underwent several process changes during development. Data from product quality assessments demonstrate that Eperzan produced by different manufacturing process versions is comparable and that there has been no significant impact on quality observed due to the associated process changes.

Control of the Drug Substance and Drug Product

The identity, quality and purity of drug product are assured by employing a similar battery of release tests used for testing of drug substance.

Copies of the analytical method protocols and, where appropriate, validation reports were provided for all analytical procedures used for release and stability of Eperzan drug substance and drug product, and are considered satisfactory.

Batch analysis results were also reviewed and were found to comply with specifications demonstrating consistent quality of the batches produced.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24 months shelf-life for Eperzan is considered acceptable when stored at 2 to 8°C and protected from sun light.

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.

Facilities and Equipment

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The facility was assigned a compliant rating with observations resolved on site.

An OSE of the facility involved in the manufacture and testing of the drug product was waived.

Adventitious Agents Safety Evaluation

Raw materials of recombinant DNA 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 of animal or human origin.