Summary Basis of Decision for Increlex

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 Increlex is located below.

Recent Activity for Increlex

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.

The following table describes post-authorization activity for Increlex, a product which contains the medicinal ingredient mecasermin. 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 AnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-10-31

Drug Identification Number (DIN):

DIN 02509733 – 40 mg/4 mL, mecasermin, solution, subcutaneous administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 275140

2023-05-09

Issued NOC 2023-10-04

Submission filed as a Level II – Supplement (Safety) to update the PM with information regarding the safe and appropriate use of Increlex. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Dosage and Administration sections of the PM. An NOC was issued.

SNDS # 272795

2023-02-27

Issued NOC 2023-07-28

Submission filed as a Level I – Supplement to modify the vial label. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 269154

2022-10-28

Issued NOL 2022-12-16

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add an alternative drug substance quality control testing site and to update the drug substance and drug product stability protocol. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 259822

2021-12-20

Issued NOC 2022-08-10

Submission filed as a Level I – Supplement for the addition of a drug product manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 252184

2021-04-29

Issued NOC 2021-10-14

Submission filed as a Level I – Supplement to update the Dosage and Administration section of the PM to facilitate dosing with a unit-based syringe. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02509733) market notification

Not applicable

Date of first sale: 2021-03-01

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 235023

2020-01-09

Issued NOC 2020-12-17

NOC issued for New Drug Submission.

 

Summary Basis of Decision (SBD) for Increlex

Date SBD issued: 2021-03-25

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

Mecasermin

Drug Identification Number (DIN):

  • DIN 02509733 - 40 mg/4 mL mecasermin, solution, subcutaneous administration

Ipsen Biopharmaceuticals Canada Inc.

New Drug Submission Control Number: 235023

 

On December 17, 2020, Health Canada issued a Notice of Compliance to Ipsen Biopharmaceuticals Canada Inc. for the drug product Increlex.

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 Increlex is favourable for the treatment of growth failure in children and adolescents from 2 to 18 years of age with confirmed severe primary insulin-like growth factor-1 deficiency. Severe primary insulin-like growth factor-1 deficiency is defined by:

  • height standard deviation score ≤-3.0 and;
  • basal insulin-like growth factor-1 (IGF-1) levels below the 2.5th percentile for age and gender and;
  • growth hormone (GH) sufficiency.
  • Exclusion of secondary forms of IGF-1 deficiency, such as malnutrition, hypopituitarism, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.

Severe primary insulin-like growth factor-1 deficiency includes patients with mutations in the GH receptor (GHR) gene (Laron syndrome), post-GHR signalling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.

 

1 What was approved?

 

Increlex, a recombinant deoxyribonucleic acid (DNA)-derived human insulin-like growth factor-1 (IGF-1), was authorized for the treatment of growth failure in children and adolescents from 2 to 18 years of age with confirmed severe primary insulin-like growth factor-1 deficiency. Severe primary insulin-like growth factor-1 deficiency is defined by:

  • height standard deviation score ≤-3.0 and;
  • basal insulin-like growth factor-1 (IGF-1) levels below the 2.5th percentile for age and gender and;
  • growth hormone (GH) sufficiency.
  • Exclusion of secondary forms of IGF-1 deficiency, such as malnutrition, hypopituitarism, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.

Severe primary insulin-like growth factor-1 deficiency includes patients with mutations in the GH receptor (GHR) gene (Laron syndrome), post-GHR signalling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.

Increlex is not authorized for use in pediatric patients younger than two years of age as its safety and efficacy have not been established in this population.

Increlex is contraindicated in:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
  • Children and adolescents with active or suspected neoplasia, or any condition or medical history which increases the risk of benign or malignant neoplasia.

Furthermore, as Increlex contains benzyl alcohol, it must not be given to premature babies or neonates. In addition, Increlex should not be used for growth promotion in patients with closed epiphyses.

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

Increlex will be distributed through a restricted distribution network in order to mitigate the potential risk of a medication error due to brand name confusion.

Increlex (40 mg/4 mL mecasermin) is presented as a solution. In addition to the medicinal ingredient, the solution contains benzyl alcohol, sodium chloride, polysorbate 20, glacial acetic acid, sodium acetate, trihydrate, and 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 Increlex Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Increlex approved?

 

Health Canada considers that the benefit-risk profile of Increlex is favourable for the treatment of growth failure in children and adolescents from 2 to 18 years with confirmed severe primary insulin-like growth factor-1 deficiency (SPIGFD). Severe primary insulin-like growth factor-1 deficiency is defined by:

  • height standard deviation score ≤-3.0 and;
  • basal insulin-like growth factor-1 (IGF-1) levels below the 2.5th percentile for age and gender and;
  • growth hormone (GH) sufficiency.
  • Exclusion of secondary forms of IGF-1 deficiency, such as malnutrition, hypopituitarism, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.

Severe primary insulin-like growth factor-1 deficiency includes patients with mutations in the GH receptor (GHR) gene (Laron syndrome), post-GHR signalling pathway, and IGF-1 gene defects. These patients are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.

Severe primary insulin-like growth factor-1 deficiency is a rare disease. It is estimated that there are only 10 to 100 individuals with SPIGFD in Canada. Growth failure in children with SPIGFD is a serious and chronically debilitating condition. If untreated, SPIGFD impacts development and can lead to an extremely short adult stature (a final adult height that can be 4 to 10 standard deviations below average). This can lead to a range of health conditions such as obesity, hyperlipidemia, insulin resistance, muscle weakness or undeveloped muscles and osteoporosis. Current recommendations suggest that optimal therapy for SPIGFD is replacement of the missing hormone through the administration of recombinant human insulin-like growth factor-1, as recombinant human growth hormone may not be an appropriate therapy for these patients.

Increlex (mecasermin), a recombinant human insulin-like growth factor-1, is the only approved therapy worldwide for the treatment of growth failure in children with SPIGFD. The United States Food and Drug Administration, the European Medicines Agency and Australia's Therapeutic Goods Administration approved Increlex for the proposed indication in 2005, 2007 and 2019, respectively. Presently, there is no approved treatment available in Canada for the treatment of SPIGFD; however, Increlex has been available for patients via the Special Access Program since 2014.

Increlex has been shown to be efficacious in patients with SPIGFD. The market authorization was based on the results of one pivotal, Phase III study (Study 1419) including data from predecessor studies that evaluated the safety and efficacy of long‑term replacement therapy with Increlex in 92 children with SPIGFD. Patients in the pivotal study received doses of 0.06 to 0.12 mg/kg subcutaneously twice a day.

The primary efficacy endpoint was the change in height velocity from pre-treatment during each year of treatment in patients naïve to Increlex. The primary efficacy endpoint of the pivotal study was met as demonstrated by an increase in mean height velocity to 8.0 cm/year in the first year of treatment as compared to the pre-treatment mean height velocity of 2.6 cm/year. This effect was sustained for seven years. Secondary endpoints were also met as the mean height velocity and height standard deviation scores improved from -3.4 to 1.7 and -6.9 to -6.1, respectively, following one year of treatment. This effect was sustained for ten years. In addition, real world evidence was obtained from the European (EU) Registry 2‑79‑52800‑002. Results from this study were consistent with those from Study 1419.

The safety profile of Increlex is generally consistent with the known mechanisms of action of IGF-1. The most common treatment emergent adverse event was hypoglycemia. An increased risk of benign and malignant neoplasia in children and adolescents treated with Increlex was noted, however the increased risk of neoplasia may be higher in patients who receive Increlex for unapproved uses, at higher than recommended doses or at doses that produced serum IGF-1 levels above the normal reference ranges for age and sex. Other safety issues identified in the submission included allergic reactions, including anaphylaxis, intracranial hypertension, tonsillar hypertrophy, injection site hypertrophy, slipped capital femoral epiphysis, worsened scoliosis, organomegaly, and immunogenicity.

Increlex 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 Increlex Product Monograph to address the identified safety concerns.

A Risk Management Plan (RMP) for Increlex was submitted by Ipsen Biopharmaceuticals Canada 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Increlex Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for look‑alike sound‑alike attributes, was conducted and the proposed name Increlex was accepted.

Overall, the therapeutic benefits of Increlex seen in the pivotal study and supportive studies are promising. Considering the clinical consequences of untreated SPIGFD and the unmet treatment need, the benefits of increased height and height velocity outweigh the known or potential risks associated with Increlex treatment. The benefit-risk profile of Increlex is considered to be favourable for patients with SPIGFD.

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 Increlex?

 

Submission Milestones: Increlex

Submission Milestone Date
Pre-submission meeting 2019-09-24
Submission filed 2020-01-09
Screening  
Screening Acceptance Letter issued 2020-02-24
Review  
Clinical/Medical Evaluation complete 2020-12-01
Review of Risk Management Plan complete 2020-12-01
Biostatistics Evaluation complete 2020-12-01
Labelling Review complete 2020-12-15
Quality Evaluation complete 2020-12-16
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2020-12-17

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Increlex was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the European Medicines Agency (EMA) and Australia's Therapeutic Goods Administration were used as an added reference.

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

 

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

 

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 decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Increlex 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

Increlex (mecasermin) is a deoxyribonucleic acid (DNA)-derived recombinant human insulin-like growth factor-1 (rhIGF-1) produced in Escherichia coli. Increlex is identical to the naturally occurring human peptide, insulin-like growth factor-1 (IGF-1), which is a key hormonal mediator of statural growth.

Under normal circumstances, growth hormone (GH) binds to its receptor in the liver and other tissues. This binding stimulates the synthesis and secretion of IGF-1. In target tissues, IGF-1 activates the type 1 IGF-1 receptor. The ensuing intracellular signalling stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 also include stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.

The pharmacokinetics (PK) of mecasermin following subcutaneous (SC) administration were characterized based on two PK studies conducted in pediatric patients with primary insulin-like growth factor-1 deficiency (IGFD), and a population PK modeling analysis based on PK data collected across two Phase II PK studies and two Phase III studies.

Mecasermin exhibited non-linear pharmacokinetics. Exposure increased less than proportionally with single SC doses over the range of 0.015 mg/kg to 0.12 mg/kg in patients with primary IGFD. The absolute bioavailability of IGF-1 following SC administration in healthy subjects was estimated to be close to 100% based on cross-study comparison. Following single SC administration of 0.12 mg/kg mecasermin, the clearance was 0.053 L/h/kg (69% coefficient of variation [CV]), the half-life was 5.8 h (64% CV), and the volume of distribution was approximately 0.31 L/kg in patients with severe primary insulin-like growth factor-1 deficiency. Following subcutaneous administration of 0.04 mg/kg to 0.12 mg/kg twice daily of mecasermin, steady state was achieved by approximately 4 days with an accumulation ratio of approximately 1.1 to 1.5, based on the population PK analysis. The IGF-1 standard deviation scores (SDS) were derived from IGF-1 concentrations relative to the age- and gender-adjusted population mean. At steady state, the mean IGF-1 SDS were within the normal range (-2 to +2) for pediatric patients with SPIGFD, with higher SDS reached at higher doses.

The clinical pharmacology data support the use of Increlex for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Increlex was primarily supported by data from the pivotal Phase III extension Study 1419 which included data from four predecessor studies. Data from these studies were pooled to evaluate the efficacy of long-term replacement therapy with Increlex in patients with growth failure due to SPIGFD.

Additional supportive data were analysed from the ongoing European (EU) Registry 2‑79‑52800‑002 study currently obtaining long-term safety and effectiveness data for Increlex in children with growth failure.

Study 1419

Study 1419 was a Phase III, open-label, multicentre, extension study in patients with growth failure due to SPIGFD. The study was designed to follow patients until they reach adult height. Most patients had been treated continuously with Increlex for several years in four predecessor studies (Phase II Study F0206s and Phase III Studies F0375g, F0632g and F0671g). Each patient's results were linked with their results from the predecessor studies.

Study 1419 and the predecessor studies evaluated the safety and efficacy of replacement therapy with Increlex (dose of 0.06 mg to 0.12 mg/kg subcutaneously twice a day) in 92 children with growth failure due to SPIGFD.

The primary efficacy endpoint was the change in height velocity (cm/year) from pre-treatment measurement in patients naïve to Increlex (those who had not received Increlex treatment prior to enrolment in this study or any of the predecessor studies). Eighty-one of the 92 patients were treatment-naïve at initiation of study treatment and completed at least one year of Increlex treatment. Seventy-five of these 81 patients had baseline height velocities and post-treatment height velocities.

The secondary efficacy endpoints were height velocity standard deviation (SD) scores and height SD scores in treatment-naïve patients. Height velocity and height were compared to that expected for age- and gender-matched children in the general population by calculating SD scores.

At baseline, patients were severely short with a mean height SD score of -6.9 (range ‑12.1 to ‑2.8) and a mean baseline IGF-1 SD score of ‑3.9 (range ‑9.5 to ‑0.6). Also at baseline, patients had a mean chronological age of 6.8 years (range 1.7 to 15.2 years) with a corresponding mean bone age of 3.8 years (range 0.1 to 12.3 years). Ninety-one percent (91%) of patients were prepubertal at baseline (pubertal stage 1).

The results for the primary efficacy endpoint demonstrated that the mean height velocity increased to 8.0 cm/year from 2.6 cm/year (±1.7 cm/year) at baseline after one year of Increlex treatment. These results were from 75 children naïve to Increlex. The mean height velocities for years 2 to 7 remained better than at baseline (5.9, 5.5, 5.2, 4.9, 4.8, 4.3, and 4.4 cm/year, respectively).

With respect to the secondary efficacy endpoint results, the mean pre-treatment height velocity SD score was -3.4 compared to a mean of 1.7 after one year of Increlex treatment in children naïve to Increlex. The mean height velocity SD score for years 2 through 8 remained better than at baseline (‑0.0, ‑0.1, ‑0.2, ‑0.3, ‑0.2, ‑0.5, and ‑0.2 respectively). Secondly, the mean baseline height SD score was -6.9 compared to a mean of -6.1 after one year of Increlex treatment in children naïve to Increlex. The mean height SD score for years 2 through 8 remained better than at baseline (‑5.6, ‑5.3, ‑5.1, ‑5.0, ‑4.9, ‑4.9, and ‑5.1, respectively).

After five years of Increlex therapy, bone age advanced by an average of 0.9 years compared to chronological age. Twenty-six (21 of whom were Increlex-naïve) of the 91 patients attained near-adult height, 57 patients withdrew before reaching near-adult height, and 8 patients were still on treatment when study data were collected.

The number of patients decreased as Study 1419 progressed. Despite the small number of study participants, which is expected in the context of a rare disease, the trends of the primary and secondary endpoint findings are considered clinically meaningful and support the proposed indication for Increlex.

Supportive Studies

European Registry

Additional supportive efficacy data were obtained from an ongoing registry. The European (EU) Registry 2‑79‑52800‑002 is a descriptive, multicentre, observational, prospective, open-ended, non-interventional, post-authorization surveillance registry study designed to obtain real world evidence for the safety and effectiveness of Increlex treatment in children with SPIGFD.

A total of 242 patients from 10 European countries were enrolled in the registry. The patients had a mean chronological age of 10.2 years for boys and 8.9 years for girls. The initial mean dose administered was 0.04 mg/kg (range 0.01 mg/kg to 0.27 mg/kg) twice daily. This was increased up to 0.12 mg/kg twice daily between months 18 and 114. Despite various limitations, following one year of Increlex treatment the overall findings for height velocities and height SD scores in Increlex-naïve children with SPIGFD were consistent with those of Study 1419.

Overall Analysis of Efficacy

In conclusion, Study 1419 demonstrated efficacy of Increlex for treating SPIGFD at the recommended dose administered twice daily. The EU Registry 2-79-52800-002 confirmed the effectiveness of Increlex administered twice daily under conditions of routine clinical care at the recommended dose. Results, in terms of height velocity during the first year of treatment, are concordant across the pivotal and supportive studies.

Indication

The New Drug Submission for Increlex was filed by the sponsor with the following indication:

  • Increlex (mecasermin) is indicated for the long-term treatment of growth failure in children and adolescents from 2 to 18 years of age with confirmed severe primary insulin-like growth factor-1 deficiency. Severe primary insulin-like growth factor-1 deficiency is defined by:
    • height standard deviation score ≤ -3.0 and;
    • basal insulin-like growth factor-1 (IGF-1) levels below the 2.5th percentile for age and gender and;
    • growth hormone (GH) sufficiency.
    • Exclusion of secondary forms of IGF-1 deficiency, such as malnutrition, hypopituitarism, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids.
       
  • Severe primary insulin-like growth factor-1 deficiency includes patients with mutations in the GH receptor (GHR) gene (Laron syndrome), post-GHR signaling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.

To ensure safe and effective use of the product, Health Canada approved the indication above with the removal of "long-term" from the first sentence. The duration of Increlex treatment will be determined by the physician based on each patient's response.

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

Clinical Safety

Data from the pivotal Study 1419 (described in the Clinical Efficacy section) and four predecessor studies were pooled for safety analyses and formed the integrated safety database, which included 92 children with SPIGFD who received at least one dose of Increlex. The mean duration of exposure for patients in Study 1419 was 6.0 years (516 patient-years). In addition, supportive data was provided from a United States (US) registry study and a European (EU) registry study. There were 1,342 patients and 246 patients with growth failure due to various causes (some for reasons other than SPIGFD) in the US and EU registry studies, respectively, who received at least one dose of Increlex. A safety database of this size is considered sufficient for a rare disease; however, the safety database contained results from different patient populations. Most studies, including the pivotal Study 1419, were uncontrolled which made it challenging to assess if the reported adverse events were attributable to Increlex or other factors.

In Study 1419, 76 patients (83%) had at least one reported treatment emergent adverse event (TEAE) during treatment. The most common TEAEs were hypoglycemia (47%), hypersensitivity (35%), injection site hypertrophy (35%), headache (27%) and snoring (22%). Within the same study, 18 patients (20%) experienced at least one serious adverse event (SAE). The most common serious adverse events reported were tonsillar hypertrophy and adenoidal hypertrophy in 6 (6.5%) patients. All six cases were reported as related to Increlex.

There were no deaths in clinical studies. There were four deaths in the registry studies with one recorded as sudden, unexpected, and possibly related to Increlex. The other three deaths were not considered as related to Increlex.

Malignancy

In Study 1419, there were no reports of malignant neoplasms. Seven patients (8%), however, reported benign neoplasms: melanocytic nevus in 4 patients (4%, 2 were considered as related to treatment), acrochordon (skin tags) in 3 patients (3%, 1 was considered as related to treatment) and skin papilloma (warts on toes) in 2 patients (2%, unrelated).

A case of papillary thyroid cancer was detected in the EU registry study. In the post-marketing data, 23 benign neoplasia and 19 malignant neoplasia cases were reported, which represented a variety of different malignancies and included rare malignancies usually not seen in children.

One of the limitations of the safety data was the fact that cases reported from post-marketing sources were derived from several sources and were based mainly on spontaneous reporting. As such, it was not possible to reliably estimate the incidence of neoplasms, the magnitude of the risk, or to identify particular patient groups at higher risk. As IGF-1 is known to be a mitogen, a causal association between the use of Increlex and neoplasia/malignancies cannot be excluded. As such, neoplasm/malignancy is considered an identified risk of Increlex.

Hypoglycemia

Hypoglycemia, hypoglycemic seizure or convulsion were the most frequently reported TEAEs. In Study 1419, 43 (47%) patients experienced at least one episode of hypoglycemia during treatment with Increlex. Seven (8%) patients experienced severe hypoglycemia (requiring assistance and treatment) and 7 (8%) patients experienced hypoglycemic seizure/loss of consciousness on one or more occasions.

Hypoglycemia analyses suggested that the frequency of hypoglycemia was highest in the first month of treatment and episodes were more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a meal was consumed shortly before or after the administration of Increlex.

Hypersensitivity Reactions

All therapeutic proteins, including Increlex, have a potential risk of causing hypersensitivity reactions. Hypersensitivity reactions to Increlex have been reported in clinical studies and post-marketing experience. These ranged from localized (injection site) reactions (e.g., urticaria, pruritus, erythema, etc.) to systemic reactions, including anaphylaxis, generalized urticaria, angioedema and dyspnea. Some patients required hospitalization.

In Study 1419, 33 patients (35%) reported a local and/or systemic hypersensitivity reaction, including cough, rash, dyspnea, pruritic rash, drug hypersensitivity, hypersensitivity, pruritus, asthma, urticaria and injection site urticaria. In the post-market setting, the frequency of cases indicative of anaphylaxis was estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnea. Some patients required hospitalization.

Intracranial Hypertension

In Study 1419, intracranial hypertension and headache were reported in 6 patients (7%) and 25 patients (27%), respectively. One patient had severe benign intracranial hypertension classed as a related SAE. In Registry studies, two events of intracranial hypertension were life threatening and involved hospitalization.

Tonsillar Hypertrophy

Insulin-like growth factor-1 may stimulate the immune system and cause tonsillar hypertrophy/adenoidal hypertrophy. Tonsillar/adenoidal hypertrophy was one of the common TEAEs and the most common SAE in Study 1419. Tonsillar hypertrophy was noted in 19 (21%) patients, particularly in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years. Snoring occurred generally in the first year of treatment and was reported in 20 patients (22%).

Lipohypertrophy

In Study 1419, 32 patients (35%) experienced injection site hypertrophy. None of these events were serious. In general, this event was resolved when injections were properly dispersed.

Slipped Capital Femoral Epiphysis and Scoliosis

Slipped capital femoral epiphysis (with the potential to lead to avascular necrosis) and progression of scoliosis can occur in patients who experience rapid growth. One scoliosis and one spinal deformity were reported in Study 1419.

Cardiomegaly/Organomegaly

Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals without associated clinical symptoms. The relation of these cardiac changes to Increlex treatment cannot be fully assessed at this time due to underlying disease and the lack of a control group.

Clinical Laboratory Evaluations

Mild elevations in the serum aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were found in a significant proportion of patients before and during treatment. Rises in serum levels of these enzymes did not lead to treatment discontinuation. Alanine aminotransferase (ALT) elevations were occasionally noted during treatment. Elevations in cholesterol and triglycerides to above the upper limit of normal were observed before and during treatment. The relation of these changes to Increlex treatment cannot be fully assessed at this time due to underlying disease and the lack of a control group.

Immunogenicity

Anti-IGF-1 antibodies were only analyzed in the predecessor studies. Of the 23 pediatric patients with SPIGFD, 11 patients were positive for anti-IGF-1 antibodies at one or more times during the first year of treatment. There was no statistically significant difference between the mean height velocities during the first year for anti-drug antibody (ADA)-positive and ADA-negative patients.

Overall Analysis of Safety

The safety profile of Increlex in the clinical studies seems to be consistent with the known mechanisms of action of IGF-1. The most common treatment emergent adverse event was hypoglycemia. There is an increased risk of benign and malignant neoplasia in children and adolescents treated with Increlex. Other safety issues identified in the submission included allergic reactions/anaphylaxis, intracranial hypertension, tonsillar hypertrophy, injection site hypertrophy, slipped capital femoral epiphysis, worsened scoliosis, organomegaly and immunogenicity.

The safety issues identified are managed through specific warnings and precautions included in the approved Increlex Product Monograph and the Risk Management Plan.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The results of the non-clinical studies as well as the potential risks to humans have been included in the Increlex Product Monograph. In view of the intended use of Increlex, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

In vivo studies were conducted to assess the efficacy of mecasermin in restoring growth in animals that were GH- and IGF-1-deficient.

In pharmacodynamic studies, hypophysectomised rats treated with recombinant human IGF-1 (rhIGF-1) demonstrated a dose-dependent increase in rescued bone growth and a partial recovery of mean body weight when compared to wild-type rats of the same age.

Mecasermin was administered subcutaneously to Sprague Dawley rats (at doses up to 4.0 mg/kg/day) and Beagle dogs (at doses up to 0.6 mg/kg/day) for 6 months. In rats, a reversible change in thymic pathology, which corresponded to changes in the weight of the organ, was noted at the highest dose (4.0 mg/kg/day). The no‑observed‑adverse‑effect level (NOAEL) for this study was determined to be 1.0 mg/kg/day (below the maximum recommended human dose [MRHD] based on body surface area). In dogs, adrenal changes were reported at a dose of 0.3 mg/kg/day and hypoglycemia-related deaths were reported at a dose of 0.6 mg/kg/day. In general, the effects noted in dogs were consistent with the known pharmacological effects of mecasermin. The NOAEL was determined to be 0.15 mg/kg/day (below the MRHD based on the total drug exposure across time [area under the curve, AUC]).

In a carcinogenicity study, mecasermin was administered subcutaneously to Sprague Dawley rats at doses of 0.25 to 10 mg/kg/day for up to 2 years. Increased incidences of medullary hyperplasia and pheochromocytoma in the adrenal gland, keratoacanthoma in the skin, and carcinoma in the mammary gland were observed along with excess mortality secondary to IGF‑1-induced hypoglycemia. An NOAEL for this study could not be established due to neoplasms observed at the lowest dose (below the MRHD based on AUC).

No evidence of genotoxicity was observed with mecasermin in a chromosomal aberration test at concentrations of up to 487 µg/mL or in an in vivo mouse micronucleus test at intravenous doses of up to 97.4 mg/kg.

Embryo-fetal development studies were conducted with pregnant rats and rabbits in which mecasermin was administered intravenously during the period of organogenesis. No effects were observed in rat fetuses at doses up to 16.0 mg/kg/day (11‑fold greater than the MRHD based on body surface area). Reduced fetal viability was reported in pregnant rabbits administered 2.0 mg/kg/day. The NOAEL was determined to be 0.5 mg/kg/day in rabbits (below the MRHD based on body surface area). Placental transfer of mecasermin was not studied. No juvenile toxicity studies have been conducted with mecasermin. Mecasermin had no effects on the fertility of male and female rats administered intravenous doses of up to 4 mg/kg/day (3-fold the MRHD based on AUC).

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Mecasermin (recombinant human insulin-like growth factor-1 [rhIGF-1]) is a non-glycosylated basic polypeptide structurally identical to naturally occurring human insulin-like growth factor-1 (IGF-1) or somatomedin C. Its amino acid sequence delineates a single chain of 70 amino acid residues with a calculated molecular mass of 7,649 Daltons.

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

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 or Final Product

The drug substance is manufactured in Escherichia Coli using recombinant deoxyribonucleic acid (DNA) technology. The manufacture 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 contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance consists of three major stages, starting with a fermentation stage, followed by a primary recovery and protein refolding stage, and ending with a purification and bulk formulation stage. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

Increlex drug product is manufactured from the rhIGF-1 formulated bulk drug substance by sterile filtration and aseptic filling processes using conventional pharmaceutical equipment and facilities. In addition, each vial of product contains the following excipients: benzyl alcohol, sodium chloride, polysorbate 20, glacial acetic acid, sodium acetate trihydrate, and water for injection. The materials used in the manufacture of the drug substance and drug product (including biological materials) are considered 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 method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Increlex is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Through Health Canada's lot release testing and evaluation program, one manufactured final product lot was tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Each lot of Increlex drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

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 36-month shelf life at 2-8 °C for Increlex is considered acceptable.

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 facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

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

Adventitious Agents Safety Evaluation

Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. Certification letters attesting to these claims were provided by the sponsor.

 

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