Summary Basis of Decision for Somavert
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:
Somavert
Pegvisomant, 10 mg, 15 mg, and 20 mg per vial, Lyophilized powder for reconstitution, Subcutaneous injection
Pfizer Canada Inc.
Submission control no: 082148
Date issued: 2006-11-06
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrSOMAVERT*, pegvisomant, 10mg, 15mg, et 20 mg par flacon, poudre lyophilisée pour reconstitution, Pfizer Canada Inc., No de contrôle de la présentation 082148
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02272199 - 10 mg/vial
- 02272202 - 15 mg/vial
- 02272210 - 20 mg/vial
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
™ Pfizer Enterprizes SARL Pfizer Canada Inc., licensee © Pfizer Canada Inc. 2005
2 Notice of decision
On October 17, 2005, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product Somavert.
Somavert contains the medicinal ingredient pegvisomant, which is a human growth hormone (GH) receptor antagonist manufactured by recombinant DNA technology.
Somavert is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery, and/or radiation therapy, and other medical therapies, or for whom these therapies are not appropriate. Acromegaly is a rare endocrine condition caused by the excessive secretion of GH. The resulting clinical effects are attributable to high serum concentrations of both GH and insulin-like growth factor-I (IGF-I), which is GH dependent. Treatment with Somavert aims to restore normal serum IGF-I levels and to improve clinical signs and symptoms. Somavert acts by blocking the cell surface GH receptor preventing its activation by the elevated levels of circulating GH.
Priority review status was granted for Somavert taking into consideration the severity of the disease that it treats, the lack of adequate treatment available, and the clinical evidence of efficacy (based on Health Canada's clinical evaluation). Somavert is an innovative therapy for acromegalic patients with a significantly better safety profile than that of other medical therapies.
The market authorization for Somavert was based on quality, pre-clinical, and clinical information submitted. It has exhibited adequate evidence of efficacy for the authorized indication and the data have shown that it is an effective therapy for normalizing IGF-I levels as well as improving the symptoms of acromegaly. Somavert should be administered under the conditions stated in the Product Monograph taking into consideration all potential risks associated with the administration of this drug product.
Somavert (10 mg, 15 mg or 20 mg per vial) is presented as a lyophilized powder. Each vial must be reconstituted with 1 mL of diluent provided in the package. A loading dose of 40 mg of Somavert should be administered subcutaneously under physician supervision. The patient should then be instructed to begin daily subcutaneous injections of 10 mg of Somavert. Serum IGF-I concentrations should be measured every 4 to 6 weeks and appropriate dose adjustment should be made in increments of 5 mg/day (or decrements of 5 mg/day if IGF-I levels have decreased below normal range) in order to maintain the serum IGF-I concentration within the age-adjusted normal range and alleviate the signs and symptoms of acromegaly. The maximum dose should not exceed 30 mg/day. Further dosing guidelines are available in the Product Monograph.
Somavert is contraindicated for patients with a history of hypersensitivity to any of its components. The stopper on the vial of Somavert contains latex. Detailed conditions for the use of Somavert are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Somavert is favourable for the treatment of acromegaly in patients who have had an inadequate response to surgery, and/or radiation therapy, and other medical therapies, or for whom these therapies are not appropriate.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Somavert contains the medicinal ingredient pegvisomant, which is a pegylated human growth hormone (GH) receptor antagonist manufactured by recombinant DNA technology. It is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery, and/or radiation therapy, and other medical therapies, or for whom these therapies are not appropriate. Acromegaly is a serious, chronic, and debilitating condition characterized by excessive secretion of human growth hormone (hGH) and elevation of serum insulin-like growth factor-I (IGF-I), usually resulting from a benign adenoma of the pituitary gland. The goal of the treatment is to normalize serum IGF-I levels to improve clinical signs and symptoms of the disease. Pegvisomant is an analogue of hGH that has been structurally changed to bind to hGH receptors without triggering signal transduction and to block the binding of endogenous hGH. Inhibition of hGH action results in decreased serum concentrations of IGF-I, as well as other GH-responsive serum proteins including IGF-binding protein-3 (IGFBP-3) and acid labile sub-unit (ALS). This results in the arrest and/or partial reversal of the symptoms and signs of acromegaly.
Manufacturing Process and Process Controls
Pegvisomant is produced by the pegylation of a human Growth Hormone analogue produced by recombinant DNA technology in E. coli cells using a well characterized Master and Working cell bank system. The manufacturing process has been divided into three phases: fermentation, purification of the bulk intermediate and pegylation. The materials used in the manufacture are considered to be suitable and meet the standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Pegvisomant contains 191 amino acid residues to which polyethylene glycol (PEG) polymers are covalently bound. The amino acid sequence for pegvisomant is identical to that of hGH except for substitutions at nine residues.
The physicochemical characteristics of pegvisomant were determined using appropriate methods. The biological activity of pegvisomant is limited to blocking hGH receptor activation. Mutations introduced to increase the affinity of pegvisomant to the hGH receptor also increase receptor specificity. Although native hGH can bind and activate the human prolactin receptor, pegvisomant does not interact with it in any way.
Detailed characterization studies were performed to provide assurance that pegvisomant is consistently manufactured with the appropriate structure, including biological activity. Results from the testing of numerous lots of pegvisomant have demonstrated that the specific activity and pegylation profiles are consistent. Several studies were conducted using appropriate methods to analyze molecular structure.
The results of the characterization studies show that pegvisomant possesses the predicted structure and biological activity. Batch consistency was demonstrated by process validation studies and batch analysis. Potential impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These impurities were found to be within established limits and are therefore considered to be acceptable.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for release testing of the drug substance, and to justify the specifications of the drug substance.
The proposed packaging components are considered acceptable.
Stability
Based on the real-time and accelerated stability studies, the proposed shelf-life, storage and shipping conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Somavert is supplied as a sterile, white, lyophilized powder intended for reconstitution with 1 mL of Sterile Water for Injection. It is available in 6 mL Flint USP Type I tubing glass, single-dose vials containing 10 mg, 15 mg, or 20 mg of pegvisomant protein. Each vial also contains 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous and 0.36 mg of sodium phosphate monobasic monohydrate. No preservative is added. Vials are sealed with a 20 mm gray rubber stopper and a 20 mm flip off aluminum seal. The stopper in the vial contains latex. The composition has been tolerated well in clinical trials and is stable both as a freeze-dried product and as a reconstituted solution.
The water for injection is provided in 15 mL glass vials that meet Ph. Eur. requirements for hydrolytic glass class I. The vials are sealed with 20 mm red butyl rubber stoppers and plastic 20 mm red/gold coloured caps.
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The suitability of the Somavert formulation was demonstrated by the results of the stability and validation studies.
Pharmaceutical Development
Somavert is formulated in three strengths to meet variable dosage demands. The drug product was formulated with glycine and mannitol and lyophilized to enhance its stability.
The selected formulation retains the potency and structural integrity of pegvisomant during the proposed shelf-life. The excipients used for formulation comply with USP standards.
Changes were made to the manufacturing process during development. Data pertaining to the physicochemical and biological characteristics demonstrated biocomparability between the various developmental batches and commercial batches.
Manufacturing Process and Process Controls
Somavert is formulated, sterile filtered, filled, lyophilized, and capped. All equipment, operating parameters, in-process manufacturing steps and detailed instructions are adequately defined in the documentation.
The water for injection is filtered through a 0.22 µm sterile membrane filter. The bulk is then filled aseptically into vials that have been sterilized and depyrogenated. Vials are closed with sterilized rubber stoppers and the filled product is sterilized in the final container.
It was demonstrated that the commercial manufacturing process results in a consistent product and is considered to be adequately controlled within justified limits.
Control of Drug Product
Somavert is tested to verify its appearance, identity, purity, sterility, and potency as well as the formulation-related parameters such as protein content and pH. The test specifications and analytical methods were justified and considered acceptable. Validation reports are considered satisfactory and in compliance with ICH guidelines for all analytical procedures used for release testing of the drug product.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed 24 month shelf-life at 2-8oC for Somavert is considered acceptable. Somavert does not contain a preservative in either the lyophilized drug product or the diluent. Somavert should therefore be administered within three hours of reconstitution.
The shelf-life for the water for injection is 60 months when stored under the same conditions.
3.1.3 Facilities and Equipment
On-Site Evaluations (OSE) of facilities involved in the manufacture and testing of pegvisomant and Somavert have been conducted by the Biologics and Genetic Therapies Directorate, Health Canada. 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. All facilities are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Adequate measures have been taken to ensure that raw materials used in the production of Somavert pose minimal risk of contamination with adventitious agents. Excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Summary and Conclusion
Somavert (pegvisomant) has undergone Chemistry and Manufacturing review and complies with the requirements of Division C.08.002 of the Food and Drug Regulations insofar as the Quality (Chemistry and Manufacturing) information is concerned.
The information provided for Somavert demonstrates that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
Eleven non-clinical pharmacological studies were conducted including three primary pharmacodynamic (PD), two secondary PD, five pharmacokinetic (PK), and one drug interaction study.
3.2.1 Pharmacodynamics
The binding affinity of pegvisomant to hepatic GH receptors was studied in vitro in the mouse, rat, rabbit, dog, monkey and human. An 125I radio-labelled hGH competitive binding method was used. Results indicated that pegvisomant had a higher affinity for the GH receptor in the monkey, rabbit, and human, compared to that in the mouse, rat, and dog. This may indicate a species-specific difference, however, the data are considered preliminary as the experiment was only run once for each receptor.
The ability of pegvisomant to reduce IGF-I levels was studied in vivo in rabbits and rhesus monkeys (RM) following repeat subcutaneous (SC) (rabbits and monkeys) or intravenous (IV) (monkeys only) administration. In the rabbit study, three female New Zealand rabbits were dosed for two periods separated by a three day interval. Results indicated that during the first dosing period, the mean serum IGF-I concentrations decreased >50% two hours after dosing as compared to a 20-33% decrease in the placebo group. No further reductions were noted after the second dosing period and the IGF-I levels rebounded in both groups.
In the RM study, pegvisomant was superior to other GH antagonists in reducing serum IGF-I levels following a single SC or IV dose. Additionally, pegvisomant lowered the level of IGFBP-3, a protein that sequesters IGF-I. Single SC administration of pegvisomant at doses ranging from 0.3-1.0 mg/kg had dose-related effects in lowering IGF-I concentration. The levels of IGF-I reached their lowest point 6-7 days after dosing and returned to the pre-dose level by day 14 post-dose. The maximum effect, an approximately 80% mean decrease from baseline levels for IGF-I, was observed in RMs that received 1.0 mg/kg pegvisomant. Following repeated SC administration (0.21 or 0.15 mg/kg once daily for 14 days), the IGF-I concentration was decreased to 80% of the baseline level from day 7 to day 21 after the first dose and then started to rebound toward baseline. The effect appeared selective as there was a lack of change in insulin, glucose, and cholesterol levels following treatment with pegvisomant.
3.2.2 Pharmacokinetics
The PK profile of pegvisomant was investigated following single or multiple SC or IV doses in the mouse, rat, and RM. Clearance and volume of distribution were low in all species, and the terminal elimination half-life ranged from 17-39 hours. There was some evidence of non-linear elimination after a 1 mg/kg dose in the monkey. Absorption of pegvisomant after SC administration was high. Bioavailability was approximately 70% in the monkey and slightly lower in the mouse.
In the rat, pegvisomant is eliminated primarily by the kidney.
3.2.3 Toxicology
Toxicology studies were carried out in mice, rats, and monkeys.
Acute and Long-term Studies
In acute studies, Somavert was given to mice as single doses of up to 10 mg/kg by IV or SC route and to cynomolgus monkeys (CM) by IV at 15 mg/kg or 100 mg/kg. In both instances, there were no toxic findings.
Long-term Toxicity
The study of longer-term toxicity was carried out at 2 weeks in mice and at 4 and 26 weeks in CMs. Irritation at the injection site was observed in mice and CMs. Some hepatic changes were also observed, however, these were not considered to be related directly to pegvisomant. In rats given pegvisomant for 26 weeks, the same changes occurred in addition to increases in kidney size. Some microscopic effects such as vacuolation of liver cells were also seen, but most were reversible at lower doses. In CMs treated for 26 weeks, the changes were attributable to the pharmacologic effects of Somavert. The no observable effect level (NOEL) was 1.0 mg/kg/day in rats; in monkeys, the overall NOEL was 0.3 mg/kg/week and the no observable adverse effect level (NOAEL) was 1.0 mg/kg/week SC. In the CM study, pegvisomant was administered weekly for 6 months whereas it is injected daily in humans. Thus, exposure in CM was not higher than in patients at the therapeutic dose.
Genotoxicity
Based on the findings of two Ames tests and an in vitro chromosomal aberration assay in human lymphocytes, it was determined that pegvisomant was not genotoxic. In animal studies, pegvisomant had an anti-tumour effect and did not show mutagenicity in the Ames test.
Reproductive Toxicity
No evidence of teratogenicity was observed in embryonic/fetal studies when exposure to pegvisomant occurred during organogenesis, however, implantation loss was seen in rabbits.
3.2.4 Summary and Conclusion
The pharmacological and toxicological data were considered to be sufficient to support positive conclusions regarding the PD, PK, and toxicological safety of pegvisomant.
The lack of long-term toxicity and carcinogenicity studies with pegvisomant was questioned by the European Medicines Agency (EMEA). The manufacturer argued however, that due to the nature of acromegaly and the specificity of the product, there was little to be gained by conducting additional non-clinical studies lasting over one year. Indeed, there is flexibility in the toxicity guidelines of ICH that allow studies of no longer than six months duration to be considered adequate if the disease justifies the circumstances and when little more could be gained from these studies. Nonetheless, this was one of the issues discussed with both the FDA and the EMEA and commitments were made by the sponsor to the FDA to conduct carcinogenicity studies.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
The level of IGF-I is a biochemical marker for determining hGH excess. The antagonistic action of pegvisomant blocks GH receptors, inhibiting the action of hGH. This results in decreased serum concentrations of IGF-I, as well as other GH-responsive serum proteins, including IGFBP-3. The ability of pegviomant to facilitate this action was assessed in three clinical pharmacological studies. Data from these studies were characterized by substantial inter-subject variability as well as small sample sizes and therefore could not be considered conclusive.
There were some differences in opinion between the EMEA and the FDA concerning the clinical PK/PD studies. As there is no exact dose-response relationship for a single dose of pegvisomant, the initial doses of Somavert differed between the EMEA and the FDA, with the latter having a smaller loading dose of 40 mg. A 40 mg loading dose was selected based on the PK profile and clinical evidence.
3.3.2 Pharmacodynamics
Data from healthy subjects indicated that doses of approximately 0.3 mg/kg to 1.0 mg/kg Somavert did demonstrate a decrease of serum IGF-I levels following single SC administration. Further evidence of the impact of Somavert pharmacodynamics on serum IGF-I levels were provided in repeated dosing in acromegaly patients following multiple dosing. In these patients, a dose-dependent decrease of IGF-I was observed similar to that which occurred in the healthy subjects, however, the PD data had to be interpreted carefully as no placebo controls were included in the study.
3.3.3 Pharmacokinetics
The PK profile in relation to dose values was studied in healthy male subjects. Tmax varied from 9 hours to 72 hours following single SC administration of Somavert at doses ranging from 0.03 mg/kg - 1.0 mg/kg. Greater than dose-proportional increases in Cmax and AUC were observed, raising concern for the possibility of an underestimation of the drug concentration.
A gender effect was obvious from a bioavailability study in six male and six female subjects. With the exception of Tmax, all other PK parameters determined from the study showed gender-differences following single SC administration of 20 mg. Male subjects had greater Cmax and AUC, shorter half-life, and a slower clearance than female subjects. The sample size for this study was small, therefore the results were not significant in population PK analysis, however the issue may be worth monitoring during clinical practice. Very little difference was observed in most PK parameters between the male and female subjects following single IV infusion at 10 mg with the exception of a greater AUC in males. Bioavailability was approximately 59% for male and 48% for female subjects.
PK data determined from a small number of patients with acromegaly (n=3/dose group) were comparable with that from healthy subjects following the same dose regimen (i.e. single SC injection of 0.3 or 1.0 mg/kg).
3.3.4 Clinical Efficacy
In clinical studies, Somavert has been shown to normalize IGF-I levels. A total of four studies (two pivotal and two non-pivotal) were conducted to assess clinical efficacy.
Non-Pivotal Trials
The first non-pivotal trial was a 6-week, double-blind, placebo-controlled, multiple-dose, Phase IIb trial. The objective of the trial was to determine the safety and efficacy of Somavert at two different dose levels in patients with acromegaly over the age of 18. Forty-six patients were randomized into three groups: placebo (n=15), 30 mg/week Somavert (n=16), and 80 mg/week Somavert (n=15). Somavert or the placebo was administered by SC injection during each weekly treatment visit. More than 80% of the patients that took part in the trial had been previously treated with surgery, radiotherapy, and/or octreotide acetate. The primary efficacy endpoints were the percent change from baseline in IGF-I levels after 6 weeks of therapy and the percent of patients in whom serum IGF-I levels were normalized. The secondary efficacy endpoints were improvement in the signs and symptoms of acromegaly, ring size, and additional data.
At the beginning of the trial IGF-I levels were comparable among all patients. Following 6 weeks of treatment the mean percent change from baseline was -15.7% for the 30 mg group, -31.3% for the 80 mg group, and -0.4% for the placebo group. The changes for the two active treatment groups were statistically significant. No statistically significant changes in the signs and symptoms of acromegaly or ring size were observed in any group.
An open-label, dose-titration, multi-centre, Phase IIb, extension study in patients who successfully completed the previous study followed. The objective was to determine the long-term safety profile for Somavert in patients with acromegaly. On the first visit, each patient received 30 mg of the study drug followed by 30 mg or more weekly. Dosage could be adjusted in 10 mg increments each week to a maximum of 80 mg/week based on the investigator's clinical assessment of the subject's condition. Investigators took into consideration tolerability of the study medication, IGF-I concentrations, signs and symptoms of acromegaly, ring size, etc. Doses could also be adjusted downward at any time. The study protocol was amended several times during the trial eventually being changed from a maximum of 80 mg per week to a maximum of 40 mg per day. Drug shortages forced some subjects to interrupt their treatment.
There were 36 patients enrolled in the extension study. The treatment duration per patient was variable with the mean duration of Somavert therapy being 84.7 weeks. The primary efficacy and secondary efficacy endpoints were the same as those for the previous study. Of the patients enrolled, 17 had IGF-I concentrations that normalized during the course of the weekly dosing part of the study. All 36 patients had IGF-I levels that decreased to within normal limits for age-matched controls by the time of the final visit of the daily dosing part of the study. During daily dosing, the majority of subjects achieved normal IGF-I concentrations at a dose of 10 mg/day pegvisomant. Slight improvements were noted in the signs and symptoms of acromegaly and in ring size by the end of the study. Although these studies may suggest therapeutic potential, neither was considered to be an adequate measure of therapeutic utility in this patient population. The adequacy of the treatment should be judged by its capacity to maintain IGF-I serum levels in the normal range. Neither study was designed to prove that treatment with Somavert results in sustained normalization of IGF-I levels.
Pivotal Trials
The first pivotal trial was a 12 week, randomized, multi-centre, double-blind, placebo-controlled, Phase III trial. The objective of the trial was to determine the tolerability and efficacy of Somavert therapy in patients with acromegaly. A total of 112 patients over the age of 18 who had been diagnosed with acromegaly were randomized into four groups: placebo (n=26), 10 mg/day Somavert (n=26), 15 mg/day Somavert (n=26), or 20 mg/day Somavert (n=26). Subjects received either the placebo or Somavert by SC injection in a single bolus loading dose and then once daily for 12 weeks.
The primary efficacy endpoint was the percent suppression in IGF-I levels from baseline. The secondary efficacy endpoints included the incidence of normalization of IGF-I concentrations, the reduction in acid labile sub-unit (ALS), free IGF-I levels, and the signs and symptoms of acromegaly.
All three treatment groups had reductions in IGF-I levels from baseline that were statistically significant, as compared to the placebo treatment group, at each post-treatment time point. A serum IGF-I level within the age-adjusted reference range was achieved in 54%, 81%, and 89% of patients receiving 10 mg/day, 15 mg/day, and 20 mg/day respectively. By the end of the trial, the percentage of subjects with normalization of IGF-I levels was 38.5%, 75%, and 82.1% in the 10 mg/day, 15 mg/day, and 20 mg/day group respectively. The fall in serum IGF-I levels was accompanied by significant improvement in the signs and symptoms of active acromegaly, in particular soft tissue swelling (as measured by ring size), excessive sweating, and fatigue. In only 12 weeks, the mean ring size decreased in a dose-dependent manner up to 2.5 sizes in patients receiving 20 mg/day.
Sub-group analyses of subjects previously treated with somatostatin analogue or dopamine agonist therapy were conducted. Following a washout period, treatments with 15 mg/day and 20 mg/day Somavert reduced IGF-I concentrations to lower levels than had previously been achieved with either of the two therapies. It is to be noted that this was in patients who had previously failed other modes of therapy.
Following the 12-week trial, a multi-centre, open-label, dose titration, Phase III, extension trial of Somavert was conducted. The objective of this trial was to evaluate the long-term safety, tolerability, and efficacy of Somavert (5-40 mg/day) therapy in subjects with acromegaly. The study was designed with a dose titration phase (to normalize IGF-I concentrations) and a maintenance phase to mimic eventual clinical practice. The study included 108 patients, 103 of whom had participated in the previous study. Subjects were treated for up to 82 weeks (mean=42.6 weeks, range=1-82 weeks) with Somavert administered by a daily SC injection. Each dose was titrated until the serum IGF-I level became normal or a maximum dose of 40 mg was reached. The primary efficacy endpoint was the percent suppression in IGF-I concentration from the baseline of the previous study. The secondary efficacy endpoints were: the normalization of IGF-I, acromegaly severity score, and ring size.
Of the patients treated, 92.6% (100 of 108) achieved normal IGF-I levels. Only 84 patients actually completed the study, with the most common reason for withdrawal being drug shortage. The majority of the subjects (63%) achieved normal IGF-I concentrations at the initial Somavert dose level of 10 mg/day. Improvements in biochemical control were once again associated with reductions of ring size and improvements in the signs and symptoms of acromegaly scores.
In summary, Somavert has been shown to be an effective medical therapy for normalizing serum IGF-I levels as well as improving signs and symptoms of acromegaly.
3.3.5 Clinical Safety
There were a number of studies that rounded out the safety and efficacy profile of Somavert. The main issues surrounding safety and for which the product is labeled are the following: liver function impairment with needed dose-adjustments provided for immunogenicity (low titre, non-neutralizing antibodies with no effect on efficacy), and some drug-interactions in diabetics or those on opioids. Somavert cross-reacts with GH in conventional GH radioimmunoassays (RIAs). In addition, there is a rise in GH levels following the start of Somavert treatment that plateaus at around 2 weeks. For this reason, GH measurement cannot be used to titrate the dose of Somavert. Dose titration should be on the basis of normalizing IGF-I levels.
Non-Pivotal Trials
Several assessments were conducted throughout the 6-week trial in order to analyze the safety of Somavert. Adverse events (AEs) were reported, laboratory tests were conducted for various assessments, anti-pegvisomant and anti-GH antibodies were quantified, and magnetic resonance images (MRI), chest x-rays, and electrocardiograms (ECG) were carried out pre- and post- treatment. A total of 107 AEs were reported but only one was serious in nature. There were no deaths or withdrawals due to AEs. No clinically significant changes in pituitary MRIs were noted. Finally, no patients developed treatment-emergent anti-GH antibodies.
In the 12-week extension study the same safety assessments were conducted. Of the 36 patients enrolled, 29 experienced 151 AEs with 5 of these being serious and 20 being severe. There were no deaths.
Pivotal Trials
In the first pivotal trial, safety was evaluated through clinical laboratory tests, pituitary MRI analysis, ECGs, physical examinations, vital signs, AEs, and measurement of levels of GH and GH antibodies. The incidence of AEs was similar in all four treatment groups with the most common being: asthenia, flu syndrome, headache, infection, injection site reaction, pain, abnormal liver function, diarrhoea, nausea, dizziness, somnolence, and sweating. One patient in the 15 mg/day group had elevated liver transaminases and was withdrawn from the study. There were eight serious AEs that required hospitalization but none were considered to be related to the study drug. No clinically significant changes in pituitary tumour size were observed. In addition, no subjects developed clinically significant treatment emergent GH antibodies.
During the extension study, no clinically significant changes were observed in mean safety laboratory parameters. One subject was withdrawn due to transaminase elevation. Mild or moderate transaminase elevation was seen in ten additional subjects. Hypercholesterolemia was seen in 14 subjects, most mild or not higher than baseline. Increases in pituitary tumour volume were not generally observed. Three subjects experienced weight increases >10 kg.
The number of patients (n=109) and duration of treatment with Somavert remains relatively small (range=1 day to 82 weeks, mean=42.6 weeks). Long-term studies are required to adequately assess the safety of Somavert. One subject experienced a clinically significant increase in tumour size while on this agent. Patients receiving Somavert should have adenoma size assessed by MRI yearly. In addition, two patients experienced Somavert induced liver function disturbance. It is therefore important that patients with abnormal liver function not be prescribed Somavert. Additionally, patients who are treated with Somavert should have their liver function tests (LFT) monitored once a month, for the first six months of treatment.
In summary, there remains a clear need for a long-term follow up program for all patients treated with Somavert to assess adequately its safety and detect AEs. No comparative studies between Somavert and somatostatin analogs had been conducted at the time of review of the New Drug Submission. Given the fact that somatostatin analogues are the current standard of care, these studies would be very useful in providing advice for clinical practice purposes.
3.3.6 Issues Outstanding
The clinical trials were not controversial. The main issue presented was their size; however, given the prevalence of acromegaly, it is not possible to conduct large clinical trials of the size regulatory agencies are generally accustomed to.
The clinical issues raised in all three jurisdictions: Health Canada, the FDA, and the EMEA, were also comparable. Thus the responses provided by Pfizer to the EMEA and the FDA were considered adequate and few additional questions were raised.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Acromegaly is a serious and debilitating condition characterized by excessive secretion of GH and IGF-I, usually resulting from a benign adenoma in the anterior portion of the pituitary gland. The average annual incidence of the disease is 3-4 cases per million with a prevalence of approximately 60 per million. There are roughly 1700 confirmed cases of acromegaly in Canada. If left untreated, this condition is associated with a significant morbidity and mortality rate. With adequate treatment, the survival of patients is similar to that of the general population.
The currently available treatment options for acromegaly are surgery, radiation therapy, or medical therapy with dopamine agonists or somatostatin analogues. Based on the biochemical approach to normalize IGF-I levels, at minimum, 35% of patients do not achieve IGF-I normalization with currently approved therapies.
The safety/efficacy trials for Somavert comprised a total of 112 patients previously treated with surgery, radiation therapy, and/or medical therapies. The trials compared Somavert with a placebo treatment and utilized an 80 mg loading dose followed by doses of 10 mg, 15mg, or 20 mg per day via the SC route. Groups demonstrated dose-dependent, statistically significant reductions in serum levels of IGF-I, free IGF-I, IGFBP-3, and ALS as compared to the placebo group. Following 12 weeks of treatment, serum IGF-I levels were normalized in up to 82% of the patients, proving that Somavert is an effective therapy for acromegalic patients who have not responded to previous therapy. Somavert represents a significant advance over existing medical therapies due to its improved safety and efficacy profile.
Although acromegaly is a rare condition, it is indeed severe and devastating. Standard therapies have failed to provide adequate clinical control in almost 30% of affected patients. There are no treatment alternatives for such patients. Data from the pivotal trial, in which 93 of the 112 patients enrolled had undergone surgery, radiotherapy, and/or previous drug therapy, demonstrated that these patients continued to present IGF-I levels 30% above the upper normal limits despite the treatments. Statistically significant reductions in IGF-I levels as well as improvement in signs and symptoms in more that 90% of the patients in that treatment group were observed following treatment with Somavert. This study proved that Somavert was effective for patients who have failed previous standard therapies.
Somavert provides a significantly diminished risk over existing therapies. According to the safety data provided, Somavert was well tolerated and appeared to have a better safety profile than that of the standard medical therapy (somatostatin analogues). Most AEs reported with Somavert were considered to be mild and dose-related.
The sponsor has committed to the same post-NOC studies as for the EMEA and/or the FDA, namely:
- A randomized clinical trial to study the combination of somatostatin and Somavert.
- Post-market surveillance of acromegalic patients in order to monitor: liver function tests, renal function, IGF-I levels, GH levels, MRI scans of the sella turcica to confirm whether Somavert stimulates pituitary tumour growth, incidence of hypoglycemic reactions and decrease of antidiabetic medication requirements when diabetes mellitus is part of the disease.
- Feasibility of developing new anti-pegvisomant/GH assays to detect specific antibodies.
- A standard carcinogenicity study in a single species.
Priority review status was granted for Somavert taking into consideration the severity of the disease that it treats, the lack of adequate treatment available, and the clinical evidence of efficacy (based on the Health Canada's clinical evaluation). In addition, Somavert is an innovative therapy for acromegalic patients with a significantly better safety profile than that of other medical therapies for this condition.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Somavert is favourable for the treatment of acromegaly in patients who have had an inadequate response to surgery, and/or radiation therapy, and other medical therapies, or for whom these therapies are not appropriate.
The 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.
4 Submission Milestones
Submission Milestones: Somavert
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting (Quality) : | 2002-07-10 |
| Pre-submission meeting (Clinical): | 2002-10-07 |
| Request for priority status | |
| Filed: | 2002-10-25 |
| Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: | 2002-11-21 |
| Submission filed: | 2003-01-16 |
| Screening | |
| Screening Acceptance Letter issued: | 2003-02-10 |
| Update Notice issued: | 2003-08-28 |
| Response filed: | 2003-12-01 |
| Review | |
| On-Site Evaluation: | 2004-05-25 |
| Quality Evaluation complete: | 2004-11-03 |
| Clinical Evaluation complete: | 2005-10-06 |
| Labelling Review complete: | 2005-08-26 |
| NOC issued by Director General: | 2005-10-17 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SOMAVERT | 02272199 | PFIZER CANADA ULC | PEGVISOMANT 10 MG / VIAL |
| SOMAVERT | 02272210 | PFIZER CANADA ULC | PEGVISOMANT 20 MG / VIAL |
| SOMAVERT | 02272202 | PFIZER CANADA ULC | PEGVISOMANT 15 MG / VIAL |