Summary Basis of Decision for Revestive

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 Revestive is located below.

Recent Activity for Revestive

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 Revestive

Updated: 2023-04-11

The following table describes post-authorization activity for Revestive, a product which contains the medicinal ingredient teduglutide. 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 and Applications Guidance.

Drug Identification Number (DIN):

  • DIN 02445727 - 5 mg teduglutide, powder for solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02445727) market notification Not applicable Date of first sale: 2021-10-13 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 255434 2021-07-29 Issued NOL 2021-10-12 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to generate a new working cell bank, change the manufacture of the drug substance, and change the cell bank qualification protocol. The submission was considered acceptable, and an NOL was issued.
NDS # 241622 2020-07-17 Issued NOC 2020-12-30 Submission filed to transfer ownership of the drug product from Shire Pharmaceuticals Ireland Limited to Takeda Canada Inc., and to migrate the PM to the 2017 format. An NOC was issued.
SNDS # 240773 2020-06-23 Cancellation Letter Received 2020-07-02 Submission filed as a Level I – Supplement to transfer ownership of the drug product. The submission was cancelled administratively by the sponsor so as to be filed as an NDS.
NC # 235719 2020-01-31 Issued NOL 2020-04-27 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 223862 2019-01-18 Issued NOC 2019-08-13 Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: for pediatric patients 1 year of age and above with short bowel syndrome (SBD) who are dependent on parenteral support. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 213633 2018-02-12 Issued NOC
2018-10-30		 Submission filed as a Level I - Supplement to update the PM to reflect revisions in the company core data sheet. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 208469 2017-08-14 Cancellation Letter Received
2017-11-06		 Submission filed as a Level II (90 day) Notifiable Change to update the PM and package inserts. The proposed revisions exceeded the scope of a Notifiable Change. The sponsor cancelled the submission so as to be filed as an SNDS.
SNDS # 207832 2017-08-04 Issued NOC
2017-10-13		 Submission filed as a Level I - Supplement to revise the carton labels. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 204342 2017-03-31 Issued NOL
2017-06-15		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes regarding the reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02445727) market notification Not applicable Date of first sale: 2017-05-23 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 200161 2016-11-10 Cancellation Letter Received
2017-01-25		 Submission filed as a Level II (90 day) Notifiable Change to update the PM. The proposed revisions exceeded the scope of a Notifiable Change. The sponsor cancelled the submission so as to be filed as an SNDS.
NDS # 199317 2016-10-13 Issued NOC
2016-12-22		 Submission filed to update the inner and outer labels and package insert, and transfer ownership of the product from NPS Pharma Holdings Limited to Shire Pharmaceutical Ireland Limited. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 200513 2016-11-23 Issued Screening Rejection Letter
2016-11-25		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The changes were not in scope of an NC but were considered to be Level III changes. A Screening Rejection Letter was issued.
Drug product (DIN 02445727) market notification Not applicable Date of first sale:
2015-10-28		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS #180223 2014-12-09 Issued NOC
2015-09-04		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Revestive

Date SBD issued: 2015-11-09

The following information relates to the New Drug Submission for Revestive.

Teduglutide, 5 mg , powder for solution, subcutaneous

Drug Identification Number (DIN):

  • 02445727

NPS Pharma Holdings Ltd.

New Drug Submission Control Number: 180223

 

On September 4, 2015, Health Canada issued a Notice of Compliance to NPS Pharma Holdings Limited for the drug product Revestive.

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 Revestive is favourable for the treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral support.

 

1 What was approved?

 

Revestive, an alimentary tract and metabolism product, was authorized for the treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral support.

Revestive is contraindicated for patients who:

  • are hypersensitive to this drug or to any ingredient in the formulation or component of the container;
  • have active gastrointestinal malignancy (gastrointestinal tract, hepatobiliary, pancreatic);
  • have a history of malignancies in the gastrointestinal tract including the hepatobiliary system within the last 5 years.

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

Revestive (5 mg teduglutide) is presented as a powder for solution. In addition to the medicinal ingredient, the powder for solution contains dibasic sodium phosphate heptahydrate, L-histidine, mannitol, monobasic sodium phosphate monohydrate. The diluent contains sterile water for injection.

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 Revestive Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Revestive approved?

 

Health Canada considers that the benefit/risk profile of Revestive is favourable for the treatment of adult patients with short bowel syndrome (SBS) who are dependent on parenteral support.

Treatment should be initiated under the supervision of a medical professional with experience in the treatment of SBS. Treatment should not be initiated until the patient is stable following a period of intestinal adaptation. Treatment effect should be evaluated on an ongoing basis.

short bowel syndrome is an intestinal malabsorption disorder caused by the removal of the majority of small intestine, or due to the complete dysfunction of a large segment of the bowel leading to insufficient functional capacity of the remaining bowel and resultant dependency on parenteral nutrition with intravenous fluids (PN/IV). Major small intestinal resections resulting in SBS often require long-term PN/IV support due to severe malabsorption of nutrients and fluids. Support with PN/IV is often associated with life-threatening complications, including infections and hepatic and biliary impairments that lead to progressive liver disease and death. A therapy that reduces the burden of parenteral support may result in clinically meaningful benefits such as an increase in the number of days off of PN/IV support per week, decreased nocturia and less interrupted sleep, reduced infusion time per day, decreased stomal output or diarrhea, and reduced costs and resources associated with managing patients dependent on PN/IV support. In Canada, it is estimated that 100-200 patients would benefit from such a therapy.

Revestive has been shown to be efficacious in SBS patients. The market authorization was based on the efficacy and safety results obtained from two pivotal 24-week Phase III controlled studies, each followed by a 2-year open-label extension study. The results obtained from these clinical studies showed that treatment with Revestive reduced parenteral support by at least 20% in patients with SBS, and by at least a one day reduction in parenteral support in some patients.

The most commonly reported (≥10%) adverse reactions in patients treated with Revestive across all clinical studies [total number (n) = 595] were: abdominal pain (31.3%), injection site reactions (21.8%), nausea (18.8%), headaches (16.3%), abdominal distension (14.8%), and upper respiratory tract infection (11.9%).

In the pivotal and extension studies, three subjects who received Revestive 0.05 mg/kg/day were diagnosed with malignancy. One of these cases (a case of metastatic adenocarcinoma in the gastrointestinal tract) was determined by the investigator to be related to Revestive. Risk minimization measures have been proposed in the Risk Management Plan.

An increase in heart rate was reported in some patients taking Revestive in a clinical trial in healthy subjects undergoing serial electrocardiogram (ECG) monitoring. Due to the limited experience in patients who have cardiac conditions that might be worsened by an increase in heart rate, such as ischemic heart disease or tachyarrhythmias, caution should be observed in these patients. As a result, a warning related to heart rate increases was included in the Warnings and Precautions section of the Revestive Product Monograph.

No clinically significant differences in safety and efficacy were observed between subjects younger than 65 years and those older than 65 years. Experience in subjects 75 years and older is limited. The safety and efficacy in pediatric patients have not been established.

There are no data from the use of Revestive in pregnant or nursing women.

All safety issues identified in this submission have been addressed through appropriate labelling in the Revestive Product Monograph.

A Risk Management Plan (RMP) for Revestive was submitted by NPS Pharma Holdings Limited 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.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Revestive therapy are considered to outweigh the potential risks. Revestive has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Revestive 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 Revestive?

 

The drug submission for Revestive was reviewed under the Priority Review Policy. Sufficient evidence was provided demonstrating Revestive provided an effective treatment for adult patients with short bowel syndrome (SBS) who are dependent on parenteral support for which no drug is presently marketed in Canada.

 

Submission Milestones: Revestive

Submission Milestone Date
Pre-submission meeting: 2014-05-13
Request for priority status  
Filed: 2014-09-24
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: 2014-10-29
Submission filed: 2014-12-09
Screening 1  
Screening Deficiency Notice issued: 2014-12-22
Response filed: 2015-02-05
Screening Acceptance Letter issued: 2015-03-10
Review  
On-Site Evaluation  
Quality Evaluation complete: 2015-09-03
Clinical Evaluation complete: 2015-09-03
Biostatistics Evaluation complete: 2015-09-03
Labelling Review complete: 2015-09-01
Notice of Compliance issued by Director General: 2015-09-04

 

The Canadian regulatory decision on the quality review of Revestive was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

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?

 

As part of the marketing authorization for Revestive, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • To provide Health Canada with Revestive medical educational materials ("Medical Deck for physicians") for review prior to the launch of the product.
  • To provide Health Canada with all outstanding reports/correspondence pertaining to post-approval commitments made to the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
  • To provide Health Canada with an update of the Product Monograph for Revestive when study reports for ongoing studies conducted as commitments to the FDA and the EMA impact the product labelling.
  • To provide Health Canada with an updated Canadian Risk Management Plan (RMP) to reflect the Canadian labelling and to capture the relevant post-approval commitments to Health Canada and other regulatory agencies.
  • To provide MHPD with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRER) for Revestive every 6 months for the first year, and annually afterwards. Include in each PSUR/ PBRER an analysis of all Adverse Drug Events as per the Pharmacovigilance Plan including safety updates from all ongoing clinical trials with Revestive.

 

5 What post-authorization activity has taken place for Revestive?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Revestive is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

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

Revestive contains the active ingredient, teduglutide which is a recombinant analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by the L cells of the distal intestine. Teduglutide differs from GLP-2 in that it has been modified at position 2 of the GLP-2 N-terminus by substituting the alanine residue with a glycine residue. This change increases its resistance to in vivo degradation caused by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in an extended half-life for teduglutide.

Teduglutide binds to GLP-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in the local increase of mediators such as insulin-like growth factor (IGF-1), vasoactive intestinal peptide (VIP), nitric oxide and keratinocyte growth factor (KGF). The main responsibility of GLP-2 is maintenance and expansion of the gastrointestinal (GI) mucosal surface area through the regulation of proliferation and apoptosis of the intestinal epithelium. In addition, GLP-2 also promotes energy absorption through a number of mechanisms including enhanced capacity for carbohydrate, amino acid, and lipid absorption, increased activity and expression of brush border digestive enzymes, and increased mucosal nutrient transport. Exogenous GLP-2 increases intestinal and portal blood flow, decreases gastrointestinal motility and inhibits gastric acid secretion. Teduglutide has been shown to preserve mucosal integrity by promoting repair and normal growth of the intestine through an increase of villus height and crypt depth. Teduglutide is intended to be used to improve intestinal absorption of fluid and nutrients in patients with short bowel syndrome (SBS).

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. Data was collected from nine clinical pharmacology studies. The cardiac safety of the drug was also studied in healthy volunteers in the Phase I clinical trial C09-001.The clinical pharmacological data support the use of Revestive for the recommended indication.

Pharmacodynamics

The ability of Revestive to improve intestinal absorption of fluids and nutrients was studied in 17 adult patients with SBS using daily doses of 0.03, 0.10, or 0.15 mg/kg [total number (n) = 2-3 per dose group] in a 21-day, open-label, multi-center, dose-ranging study. All subcutaneous (abdomen) doses studied, except the 0.03 mg/kg once-daily dose, decreased stomal output or fecal fluid and macronutrient excretion, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750-1,000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.

Cardiac Safety

Study C-09-001

Study C-09-001 was a Phase 1, single-center, randomized, double-blind, placebo- and active-controlled, four period crossover study to evaluate the electrocardiographic effects of single subcutaneous doses of Revestive, specifically with respect to cardiac repolarization (QTc interval). Seventy-two healthy males and females were randomized to receive one subcutaneous dose of Revestive (5 mg teduglutide, or 20 mg teduglutide), placebo, or 400 mg moxifloxacin (positive control for QTc prolongation).

The results of the study demonstrated that Revestive increases heart rate. The proportion of subjects with high heart rate outlier valufes >90 bpm was larger during treatment with teduglutide 5 mg (7.1%) and 20 mg (8.6%) than during placebo treatment (4.3%). Following single-dose treatment with Revestive 5 mg, statistically significant positive mean differences from placebo were observed from 1 to 16 h post-dosing, inclusive, with a maximum mean difference from placebo of 9.3 bpm [90% Confidence Interval (CI) 8.0, 10.6] at 1 h post-dosing. Following treatment with a supra-therapeutic 20 mg dose, statistically significant positive mean differences from placebo were observed from 1 to 24 h post-dosing, inclusive, with a maximum mean difference from placebo of 9.8 bpm (90% CI 8.0, 11.5) at 6 h post-dosing. As a result, a warning related to heart rate increases was included in the Warnings and Precautions section of the Revestive Product Monograph.

Single 5 mg and 20 mg doses of teduglutide were not associated with any evidence of treatment-related effects on the QTcF interval, the QRS duration, or the PRc interval. This study had limited value as a source of blood pressure data as the blood pressure assessments were performed only at 12 h and 24 h post-dosing, long after the 4-5 h time to reach maximum concentration (Tmax) of teduglutide.

Pharmacokinetics

No differences in pharmacokinetics (PK) were observed between healthy subjects younger than 65 years and those older than 65 years while taking Revestive. Experience in subjects 75 years and older is limited and there are no pharmacokinetic data available in children. No clinically relevant gender differences were observed.

Subjects with moderate hepatic impairment had lower teduglutide maximum concentrations (Cmax) and area under the curve (AUC) (10-15%) compared to healthy matched control subjects after a single subcutaneous dose of 20 mg Revestive. Teduglutide PK was not assessed in subjects with severe hepatic impairment.

In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-inf increased with the degree of renal impairment following a single subcutaneous administration of 10 mg teduglutide. Teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC0-inf) in ESRD subjects compared to healthy subjects. As a result, for patients with moderate or severe renal impairment, or end-stage renal disease the dose should be reduced by 50%.

Carcinogenicity

Given the mechanism of action of teduglutide (intestinotrophic activity or growth promoting pharmacological effect) and the findings of carcinogenicity studies in rats and mice, teduglutide has the potential to cause hyperplastic changes including neoplasia in humans.

As part of the post-market commitments, Health Canada has requested all reports/correspondence pertaining to post-approval commitments made to the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This includes the results of a prospective, multi-center, long-term, observational, registry study of short bowel syndrome (SBS) patients treated with teduglutide in a routine clinical setting. The goal of this study is to assess the long-term safety of teduglutide to rule out a clinically meaningful increase in colorectal cancer risk above an estimated background risk in a suitable comparator.

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

Clinical Efficacy

The efficacy of Revestive was evaluated primarily in two pivotal studies: CL0600-020 and CL0600-004, and their long-term open-label extensions CL0600-021 and CL0600-005, respectively. While study results from the CL0600-020 study demonstrated a benefit for patients with SBS when administered Revestive, study results from the CL0600-004 study failed to meet the primary efficacy endpoint. Nonetheless, data collected from CL0600-004 study did factor as part of the decision when evaluating Revestive's overall efficacy and safety profile.

Pivotal Studies

Study CL0600-020

Study CL0600-020 was a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-centre clinical trial in adults with SBS who were dependent on parenteral nutrition (PN)/intravenous (IV) support for at least 12 months and required PN at least three times per week.

The mean age (50.3 years) was similar across all treatment groups, with most participating patients <65 years of age. Medical and surgical histories, prior medications, and concomitant medications were consistent with SBS and were generally well balanced between treatment groups. The mean duration of PN/IV dependency prior to enrollment was 6.25 years (range 1-25.8 years)

Patients were randomized (1:1) to receive placebo (n = 43) or Revestive 0.05 mg/kg/day (n = 43). The study treatment was administered subcutaneously once daily for 24 weeks. Parenteral nutrition/IV volume adjustments (up to a 30% decrease) and clinical assessments were made at Weeks 2, 4, 8, 12, 20, and 24.

The primary efficacy endpoint was based on the number and percentage of responders, that is (i.e.) subjects with a clinically relevant response defined as a 20% to 100% reduction from baseline in weekly PN/IV volume at Week 20 and Week 24. Important secondary endpoints included the percent and absolute change in PN/IV volume between baseline and Week 24; and the number of subjects who achieved a ≥1-day reduction in PN/IV support. Duration of response for ≥3 consecutive visits was also a secondary efficacy endpoint.

The primary efficacy endpoint of the study was met. The percentages of the treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomized patients. In patients who were treated with Revestive, 63% (27/43) were considered responders compared to 30% (13/43) in the placebo group (p = 0.002). At all visits, the change from baseline in actual PN/IV volume was greater in the Revestive group compared to the placebo group. At Week 24, the mean reduction in weekly PN/IV volume was 4.4 L for Revestive (from a pre-treatment baseline of 12.9 L) versus (vs.) 2.3 L for placebo (from a pre-treatment baseline of 13.2 L/week (p <0.001). The difference in the corresponding percent change from baseline between the treatment groups was statistically significant at Week 24 [reduction of 32.1% in the Revestive group vs. 21.0% in the placebo group (p = 0.025)].

The percentage of subjects with a duration of response for ≥3 consecutive visits was higher in the Revestive group (24/43 subjects, 55.8%) than in the placebo group (12/43 subjects, 27.9%). The distribution of duration of response was statistically significant (p = 0.005).

The proportion of patients with a 20 to 100% reduction or a 2 L reduction in PN/IV volume from baseline at Weeks 20 and 24 was higher in the Revestive group (30/43 patients, 69.8%) than the placebo group (16/43 patients, 37.2%). The difference was statistically significant (p = 0.002).

Twenty-one subjects taking Revestive (53.8%) vs. 9 taking placebo (23.1%) achieved a ≥1-day reduction in PN/IV support at Week 24 (p = 0.005).

Study CL0600-004

Study CL0600-004 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study in adults with SBS who were dependent on PN/IV support for at least 12 months and required PN at least 3 times per week. The mean age was similar across all treatment groups, with most participating patients <65 years of age. Medical and surgical histories, prior medications, and concomitant medications were consistent with SBS and were generally well balanced between treatment groups and studies.

Subjects were randomized to receive 24 weeks of one of the following treatment regimens: Revestive 0.05 mg/kg/day (n = 35), Revestive 0.10 mg/kg/day dose (n = 32), or placebo (n = 16). The primary efficacy endpoint of the study was an ordered categorical response that accounted for both intensity and duration of the response at the end of the 24-week treatment period. The primary efficacy endpoint did not achieve statistical significance in this study for the high dose versus the placebo, therefore the results of the study were considered as supportive, mainly from a safety perspective.

Further evaluation of PN/IV volume reduction using the secondary endpoint of response (defined as at least 20% reduction in PN/IV fluid from baseline to Weeks 20 and 24) showed that 46% of subjects taking Revestive 0.05 mg/kg/day responded versus 6% on placebo (p = 0.010).

Supportive Studies

Study CL0600-021

Study CL0600-021 was a two-year open-label extension of study CL0600-020 in which 88 subjects received Revestive 0.05 mg/kg/day. Ninety-seven percent (76/78) of patients who completed CL0600-020 elected to enroll in CL0600-021 (37 received Revestive and 39 received placebo). An additional 12 subjects who had been optimized and stabilized also entered the study; however, they were not randomized due to closed enrolment.

Of the 39 placebo subjects from CL0600-020 entering CL0600-021, 29 completed 24 months of treatment with Revestive. The mean reduction in PN/IV was 3.11 L/week, an additional 28.3% reduction from the start of CL0600-021. Sixteen (55.2%) of the 29 completers achieved a ≥20% reduction of parenteral support. At the end of study, 14 (48.3%), 7 (24.1%), and 5 (17.2%) achieved a reduction of 1, 2, or 3 days per week in PN/IV support, respectively. Two subjects were weaned off their PN/IV support while on Revestive.

Of the 12 subjects entering CL0600-021 directly, 6 completed 24 months of treatment with Revestive. Similar effects were seen. One of the six subjects was weaned off their PN/IV support while on Revestive.

Of the Revestive-treated patients in the study, 30 completed a total duration of 30 months (CL0600-020 followed by CL0600-021 treatment). Of these patients, 28 (93%) achieved a ≥20% reduction of parenteral support. For responders in CL0600-020 who had completed two additional years of continuous treatment with Revestive, 96% (21/22) sustained their response to Revestive. The mean reduction in PN/IV (n = 30) was 7.55 L/week (a 65.6% reduction from baseline). Ten subjects were weaned off their PN/IV support while on Revestive treatment for 30 months. Subjects were maintained on Revestive even if they no longer required PN/IV support. These 10 subjects had required PN/IV support for 1.2 to 15.5 years, and prior to Revestive had required between 3.5 L/week and 13.4 L/week of PN/IV support. At the end of study, 21 (70%), 18 (60%), and 18 (60%) of the 30 completers achieved a reduction of 1, 2, or 3 days per week in PN/IV support, respectively.

Study CL0600-005

Study CL0600-005 was a blinded, uncontrolled extension of CL0600-004, in which 65 subjects from CL0600-004 received Revestive for up to an additional 28 weeks of treatment. Seventy-five percent (75%) of responder patients who enrolled from study CL0600-004 sustained their response on Revestive after one year of treatment.

In the Revestive 0.05 mg/kg/day dose group, a 20% or greater reduction of parenteral support was achieved in 68% (17/25) of patients. The mean reduction of weekly PN/IV volume was 4.9 L/week (52% reduction from baseline) after one year of continuous Revestive treatment. The subjects who had been completely weaned off PN/IV support in Study CL0600-004 (n = 2) remained off parenteral support through Study CL0600-005. During Study CL0600-005, one additional patient was weaned off parenteral support.

Overall Analysis of Efficacy

In conclusion, treatment with Revestive at a dose of 0.05 mg/kg/day in Studies CL0600-020 and CL0600-004 demonstrated a benefit for patients with SBS who are dependent on parenteral support. Revestive treatment resulted in reductions in PN/IV volume needed, and in Study CL0600-020, resulted in ≥1 day reduction in PN/IV support in some patients.

Patients who were responders in CL0600-020 who participated in Study CL0600-021 remained responders. The results of Study CL0600-021 demonstrated reproducibility as well as the durability of the beneficial effects of Revestive 0.05 mg/kg/day for up to 30 months of treatment.

The results of the long-term extension study, CL0600-005, also demonstrated the reproducibility as well as the durability of the clinical benefits of Revestive 0.05 mg/kg/day, without evidence of the development of tolerance for up to an additional 28 weeks of treatment.

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

Clinical Safety

The clinical safety of Revestive was evaluated in the studies described in the Clinical Efficacy section.

Due to the small sample sizes in the pivotal studies, an integrated safety analysis was conducted. Across all clinical studies, 595 subjects were exposed to at least one dose of Revestive (249 patient-years of exposure; mean duration of exposure was 22 weeks). Of the 595 subjects, 173 subjects were treated in Phase III SBS studies (77% at 0.05 mg/kg/day and 23% at 0.10 mg/kg/day).

The most commonly reported (≥10%) adverse reactions in patients treated with Revestive across all clinical studies (n = 595) were: abdominal pain (31.3%), injection site reactions (21.8%), nausea (18.8%), headaches (16.3%), abdominal distension (14.8%), and upper respiratory tract infection (11.9%).

The most commonly reported rates of adverse reactions (≥5%) in patients with SBS participating in the two randomized , placebo-controlled, 24-week , double blind clinical studies (CL0600-020 and CL0600-004) were: abdominal pain (38%), nausea (25%), abdominal distension (20%), vomiting (12%), flatulence (9%), appetite disorders (7%), upper respiratory tract infection (26%), sleep disturbances (5%), cough (5%), hypersensitivity (8%), skin haemorrhage (5%), fluid overload (12%), and gastrointestinal stoma complication (42%).

In the pivotal and extension studies, three subjects who received Revestive 0.05 mg/kg/day were diagnosed with malignancy. One of these cases (a case of metastatic adenocarcinoma in the gastrointestinal tract) was determined by the investigator to be related to Revestive. Risk minimization measures have been proposed in the Risk Management Plan.

Colorectal polyps were identified in 0.9% of subjects on Revestive 0.05 mg/kg/day versus (vs.) 1.7% of subjects on placebo. Twelve subjects experienced one or more episodes of intestinal obstruction/stenosis. Fluid overload was reported in 11.7% subjects on Revestive 0.05 mg/kg/day vs. 6.8% of subjects on placebo. Twelve percent of the patients in each of the Revestive 0.05 mg/kg/day and placebo treatment groups experienced an injection site reaction. The majority of these reactions were moderate in severity and no occurrences led to drug discontinuation. The most common markedly abnormal clinical laboratory finding was C-Reactive Protein (CRP) ≥21mg/L: 25% of subjects on Revestive 0.05 mg/kg/day vs. 8.6% of subjects on placebo.

Teduglutide has cross-reactivity to native GLP-2. Anti-teduglutide antibodies appear to have no impact on short term efficacy and safety; the long-term impact is unknown. Post-market safety information from other jurisdictions has demonstrated that the following adverse reactions were reported in patients receiving Revestive: cardiac arrest, cardiac failure, and cerebral hemorrhage.

Overall Analysis of Safety

Clinical data collected from close to 600 patients who received Revestive in clinical studies (249 patient-years of exposure) indicates an acceptable safety profile for this patient population for whom no currently authorized therapy exists in Canada. Appropriate warnings and precautions are in place in the approved Revestive Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The sponsor provided Health Canada with review reports from two jurisdictions, namely the United States Food and Drug Administration and the European Union's centralized procedure European Medicines Agency (EMA), which authorized teduglutide for marketing for the sought indication in 2012. The availability of the non-clinical foreign reviews, as well as the priority review status of this New Drug Submission, were the basis for Health Canada to accept and rely, for the purpose of this review, on the conclusions drawn by the two major regulatory agencies regarding the teduglutide non-clinical development program rather than conduct a formal review of the non-clinical studies in this submission.

Carcinogenicity

A 2-year carcinogenicity study conducted in Wistar Han rats at subcutaneous doses of 3, 10 and 35 mg/kg/day teduglutide (about 60, 200 and 700 times the recommended daily human dose of 0.05 mg/kg, respectively), caused statistically significant increases in the incidences of adenomas in the bile duct and jejunum of male rats. There were no drug-related tumor findings in females.

A 2-year carcinogenicity study in Crl:CD1(ICR) mice conducted at subcutaneous doses of 1, 3.5 and 12.5 mg/kg/day teduglutide (20, 70 and 250 times the recommended daily human dose of 0.05 mg/kg, respectively) caused a significant increase in papillary adenomas in the gallbladder; it also caused adenocarcinomas in the jejunum in male mice at the high dose of 12.5 mg/kg/day teduglutide (about 250 times the recommended human dose).

Given the mechanism of action of teduglutide (intestinotrophic activity or growth promoting pharmacological effect) and the findings of carcinogenicity studies in rats and mice, teduglutide has the potential to cause hyperplastic changes including neoplasia in humans.

Overall Analysis of Non-Clinical Studies

The results of the non-clinical studies as well as the potential risks to humans have been included in the Revestive Product Monograph. In view of the intended use of Revestive, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Revestive Product Monograph to address the identified safety concerns.

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

 

 

7.3 Quality Basis for Decision

 

Revestive (teduglutide) is a novel recombinant analogue of the human glucagon-like peptide-2 (GLP-2) differing from naturally occurring GLP-2 in the substitution of glycine for alanine at the second position at the N-terminus. This modification increases resistance to in vivo degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV) thus extending its half-life when compared to the native peptide.

Revestive binds to GLP-2 receptors located in the intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that teduglutide consistently exhibits the desired characteristic structure and biological activity.

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced were adequately described and comparatively addressed. Adequate data have been provided to demonstrate comparability throughout process development.

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

Drug Substance

The drug substance is manufactured from E. coli using recombinant deoxyribonucleic acid (DNA) technology. Manufacturing is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious agents in accordance with International Conference on Harmonisation (ICH) guidelines.

The manufacturing process of the drug substance consists of a series of stages which include inoculum, fermentation, harvest and centrifugation steps. Downstream operations consist of a series of filtration and chromatographic steps. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

Drug Product

Revestive (teduglutide for subcutaneous injection) is supplied as a 5 mg/vial lyophilized powder for reconstitution with 0.5 mL of sterile water for injection. Each vial of Revestive contains 5 mg of teduglutide as well as the following excipients: L-histidine, mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate heptahydrate.

The drug product manufacturing process includes the following steps: drug substance thawing, bulk compounding, pre-filtration, sterilizing filtration, filling, lyophilization and capping using conventional pharmaceutical equipment and facilities.

The manufacturing process was appropriately validated with all in-process controls and release test results for the validation batches meeting their acceptance criteria/specification limits. The manufacturing process is considered to be adequately controlled within justified limits.

Changes to the manufacturing process and formulation made throughout the pharmaceutical development were considered acceptable upon review.

The materials used in the manufacture of the drug product are considered to be suitable and/or meet standards appropriate for their intended use.

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 the teduglutide with the excipients has been demonstrated.

Diluent

The diluent manufacturing process was appropriately validated, with all in-process controls and release test results for the validation of batches meeting their acceptance criteria/specification limits.

Control of the Drug Substance and Drug Product

In-process controls and lot release tests for the drug substance and drug product were established and validated. Two specifications were tightened at the request of Health Canada during the review period.

The drug substance and drug product are routinely tested against suitable reference standards to verify that they meet the approved specifications. Analytical procedures have been validated in accordance with ICH guidelines and are considered acceptable.

Each lot of Revestive drug product is tested for appearance, content, identity, potency, purity, and impurities.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

During the submission review, the sponsor committed to making minor improvements to their quality control testing as requested by Health Canada.

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 shelf life of 48 months at 5°C ± 3°C for the drug product Revestive is considered acceptable. In addition, the stability data support storage of the lyophilized drug product by the patient for up to 3 months at 25°C.

Stability data for the diluent support the proposed shelf-life of 60-months at 2 to 30°C.

Given the lack of preservative in the formulation the reconstituted product is recommended for immediate use; however, if not used immediately, it may be stored for up to 3 hours at 25°C.

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.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

On-Site Evaluations (OSEs) of the facilities involved in the manufacture of the drug substance and drug product were not conducted as Health Canada had previously conducted satisfactory OSEs at these facilities for other products. Also, the facilities were deemed Good Manufacturing Practices (GMP)-compliant by Health Canada and there were no critical issues flagged during review.

All sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The teduglutide manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.

Raw materials of animal origin used in the manufacturing process are properly sourced. The excipients used in the drug product formulation are not of animal or human origin.

 

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