Summary Basis of Decision for Yervoy ™
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:
YervoyTM
Ipilimumab, 5 mg/mL, Liquid, Intravenous infusion
Bristol-Myers Squibb Canada
Submission control no: 138178
Date issued: 2012-07-06
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):
- 02379384
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
TM of Bristol-Myers Squibb Company used under licence by Bristol-Myers Squibb Canada.
2 Notice of decision
On February 1, 2012, Health Canada issued a Notice of Compliance to Bristol-Myers Squibb Canada for the drug product, Yervoy.
Yervoy contains the medicinal ingredient ipilimumab, a recombinant human monoclonal antibody (IgG1) that belongs to the class of antineoplastics.
Yervoy is indicated for the treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease. Yervoy binds to the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and specifically blocks the inhibitory signal of CTLA-4, resulting in T-cell activation, proliferation, and lymphocyte infiltration into organ tissues and tumours, presumably leading to tumour cell death. The mechanism of action of Yervoy is indirect, through enhancing T-cell mediated immune responses that may involve any organ systems and cause immune-mediated adverse drug reactions.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Yervoy were evaluated primarily in one Phase III, double-blind study which randomized 676 patients with unresectable or metastatic melanoma who had previously been treated with regimens containing one or more of the following: interleukin-2 (IL-2); dacarbazine; temozolomide; fotemustine; or carboplatin. Patients were randomized in a 3:1:1 ratio to receive either Yervoy 3 mg/kg in combination with an investigational gp100 peptide vaccine (gp100), Yervoy 3 mg/kg monotherapy, or gp100 alone. The primary endpoint was overall survival (OS) in the Yervoy + gp100 group versus (vs.) the gp100 group. Key secondary endpoints were OS in the Yervoy + gp100 group vs. the Yervoy monotherapy group and in the Yervoy monotherapy group vs. the gp100 group. Results of the study showed, there was a reduction in the mortality risk by 32% in the Yervoy + gp100 treatment group (p = 0.0004) and 34% in the Yervoy monotherapy treatment group compared to the gp100 alone treatment group (p = 0.0026 without multiplicity adjustment). Therefore, both Yervoy-containing regimens demonstrated a statistically significant advantage for OS compared to gp100 alone.
Yervoy (5 mg/mL, ipilimumab) is supplied as either a 10 mL or 40 mL sterile solution contained in a single-use glass vial to deliver 50 mg or 200 mg of ipilimumab per vial, respectively. The recommended induction regimen of Yervoy is 3 mg/kg administered intravenously over a 90-minute period every 3 weeks for a total of four doses. Liver function tests, thyroid function tests, and electrolytes should be assessed before initiation of Yervoy treatment and before each subsequent dose administered. In addition, any signs or symptoms of immune-related adverse reactions, including diarrhoea and colitis should be assessed during treatment. Yervoy should be administered under the supervision of physicians experienced in the treatment of cancer. Further dosing guidelines are available in the Product Monograph.
Yervoy can cause severe and fatal immune-mediated adverse reactions, including enterocolitis; intestinal perforation; hepatitis; dermatitis; neuropathy; endocrinopathy; as well as toxicities in other organ systems. While most of these reactions occurred during the induction period, onset months after the last dose have been reported. For severe immune-mediated adverse reactions, Yervoy should be permanently discontinued; systemic high-dose corticosteroid with or without additional immunosuppressive therapy may be required for treatment.
Yervoy is contraindicated for patients who are hypersensitive to ipilimumab or to any ingredient in the formulation or component of the container. Yervoy is also contraindicated in patients with active, life-threatening autoimmune disease, or with organ transplantation graft where further immune activation is potentially imminently life-threatening. Yervoy should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Yervoy are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Yervoy is favourable for the treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease.
3 Scientific and Regulatory Basis for Decision
In August 2010, a Priority Review Request filed by the sponsor was rejected by Health Canada because of insufficient information provided to justify issuing a priority review in accordance with Health Canada Policy "Guidance for Industry -Priority Review Request" (2006/03/01).
A Notice of Non-Compliance (NON) was also issued during the review process for this submission. The NON was issued on October 6, 2011 pertaining mainly to issues regarding appropriate risk communications.
After a series of communications with the sponsor, new information was assessed in detail and the deficiencies that had been identified were deemed to be appropriately resolved.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Ipilimumab, the medicinal ingredient of Yervoy, is an antineoplastic agent. It is a fully human monoclonal immunoglobulin that binds specifically to the cytotoxic T-lymphocyte antigen 4 (CTLA-4) expressed on a subset of T cells in human and non-human primates. The interaction of CTLA-4 with its natural ligands, CD80/CD86, expressed on antigen-presenting cells results in an inhibitory signal for T cell activation. The proposed mechanism of action for ipilimumab is interference with this interaction, thus allowing potentiation of the T-cell response.
Manufacturing Process and Process Controls
The manufacture of ipilimumab comprises a series of steps which include cell culture, product harvest, purification, virus inactivation, removal and formulation. The consistency of the manufacturing process is ensured through defined production procedures, critical quality tests, in-process limits and ipilimumab certificate of analysis specifications. Process validation data demonstrate that the manufacturing processes operate in a consistent manner, yielding product of acceptable quality. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during the manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that ipilimumab 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 at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of ipilimumab are considered acceptable.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
Batch analysis results were reviewed and all results comply with specifications, demonstrating consistent quality of the batches produced. The drug substance container closure is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life and storage conditions for the drug substance were adequately supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Yervoy is a sterile, non-pyrogenic, clear to slightly opalescent, colourless to pale yellow, preservative-free, isotonic aqueous solution for intravenous (IV) injection. It is supplied in 50-mg and 200-mg single-use vials at a nominal concentration of 5 mg/mL ipilimumab [each milliliter (mL) contains 5 milligrams (mg) of ipilimumab; 3.15 mg tris hydrochloride; 5.85 mg sodium chloride; 10 mg mannitol; 0.04 mg diethylene triamine pentaacetic acid (DTPA); 0.1 mg polysorbate 80 and Water for Injection (USP); and sodium hydroxide or hydrochloric to adjust to an approximate pH of 7].
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Yervoy, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Yervoy. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not affected by the changes described.
Manufacturing Process and Process Controls
The drug product manufacturing process consists of pooling and mixing of the drug substance followed by sterile filtration, and aseptic filling into sterile glass vials. All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
The drug product manufacturing process has been adequately validated and is capable of consistently generating product that meets release specifications.
Control of Drug Product
Each lot of Yervoy drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.
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.
Stability
Based on the long-term, accelerated, and stress stability data submitted, the proposed 36-month shelf-life at 2-8°C for Yervoy 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.
3.1.3 Facilities and Equipment
An on-site evaluation of the facilities involved in the manufacture and testing of Yervoy was not warranted since the facilities were recently evaluated for other products produced by the company. All sites are compliant with Good Manufacturing Practices (GMP).
The design, operations and controls of the facility and equipment that are involved in the production of Yervoy are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
The ipilimumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
A number of issues related to the manufacturing process and quality control of Yervoy were raised during this review. Some issues were resolved, however, many necessitated the implementation of commitments to perform additional studies; provide results of on-going studies; improve or replace release/stability testing methods; and reassess release/stability specifications. This approach was taken as similar issues were also raised and resolved through the implementation of commitments by the United Stated Food and Drug Administration (FDA).
However, overall, the Chemistry and Manufacturing information submitted for Yervoy has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Ipilimumab is a fully human monoclonal antibody (mAb), of the immunoglobulin (Ig) G subclass 1, kappa light-chain, and specific for CTLA-4. Ipilimumab binds with high affinity to human CTLA-4-Ig with an apparent Kd (avidity) of 10.5 nM, and demonstrates relatively slow binding and dissociation kinetics.
In vitro pharmacodynamic (PD) studies demonstrated that ipilimumab binding to activated CD4+ T cells was elevated by Day 3 and was maintained through Days 4 and 5, but declined by Day 7. Resting T cells expressed very low or undetectable levels of CTLA-4. Ipilimumab binding to activated T cells resulted in low to moderate antibody-dependent cellular cytotoxicity (ADCC) at higher concentrations of antibody. The process of binding was also dependent on FcγRIII function. Ipilimumab binding to FcrRI/CD64 was stronger when compared to binding with either FcγRII/CD32 or FcγRIII/CD16 [that is (i.e.) receptors for the Fc portion of IgG]. There was no measurable ADCC activity on resting T cells. The potency of ipilimumab-mediated ADCC activity varied among individuals, which is related in part to the level of CTLA-4 expression. Overall, there was low expression of CTLA-4 on activated T cells, indicating that treatment with ipilimumab would not result in depletion of activated T cells in vivo. Ipilimumab demonstrated no significant complement-dependent cytotoxic activity.
In vivo studies were conducted to investigate the effect of ipilimumab on tumour growth. In the MC38 tumour model using transgenic mice, ipilimumab provided some anti-tumour benefit, which was more pronounced when there were fewer tumour cells inoculated into the mice, and was also dependent on the number of doses administered. In a therapeutic SAI/N tumour model, there were no significant statistical differences in tumour growth between mice treated with anti-CTLA-4 alone, or in combination with dexamethasone. Dexamethasone treatment alone did not significantly affect tumour volume in any of the studies. When co-administered with dexamethasone, the anti-tumour effect of anti-CTLA-4 declined more gradually at higher dose levels. This data supports the use of corticosteroids in the treatment of adverse events following anti-CTLA-4 immunotherapy.
In the murine MC38 colon adenocarcinoma model, there was modest tumour growth delay with anti-PD-1 and anti-CTLA-4 monoclonal antibodies (mAbs). However, combined anti-PD-1 and anti-CTLA-4 blockade revealed a synergistic effect with potent inhibition of tumour growth and complete tumour regression in many animals. The majority of surviving mice withstood a subsequent MC38 challenge while none showed immunity to a B16 melanoma cell challenge. This indicates that durable and specific tumour immunity was established in mice treated with the combined mAbs. Concurrent dosing also proved superior to sequential dosing. Potent anti-tumour responses were retained upon varying the doses of anti-PD-1 and anti-CTLA-4 mAbs as combined therapy, suggesting that dosing of each mAb can be altered relative to the other while maintaining the overall anti-tumour effect.
It was also demonstrated in the murine CT26 colon adenocarcinoma model that combined treatment with anti-mouse PD-1 mAb and anti-mouse CTLA-4 mAb resulted in significantly greater tumour growth inhibition than single agent therapy. The murine SAI/N fibrosarcoma model revealed that optimal doses of anti-mouse PD-1 mAb and anti-mouse CTLA-4 mAb as single agents resulted in complete tumour regression in 40% of the tumours. Combination of a sub-optimal dose of anti-mouse CTLA-4 mAb, which had minimal anti-tumour activity when administered alone, with an optimal dose of anti-mouse PD-1 mAb resulted in a 2-fold increase in the number of mice that were tumour-free at the end of the study as well as an increase in tumour growth inhibition over either single agent alone. Under the conditions of these in vivo studies, it was concluded that the combination of anti-CTLA-4 and anti-PD-1 antibodies may increase anti-tumour activity when compared to anti-PD-1 mAb monotherapy and may allow for a reduction in the relative dosing of anti-CTLA-4 mAb and anti-PD-1 mAb in combination therapy.
The murine FcγRIIb-/- autoimmune model conducted in FcγRIIb-deficient mice revealed that the combination of anti-PD-1 mAb and anti-CTLA-4 mAb had little effect on the induction of autoimmune phenotypes in FcγRIIb-/- mice. The murine non-obese diabetic mouse model revealed that anti-mouse PD-1 antibody monotherapy induced diabetes; however, the combined use of anti-mouse PD-1 and anti-mouse CTLA-4 mAbs resulted in a more rapid induction of diabetes in male mice. These findings suggest that anti-mouse CTLA-4 mAb can potentiate destructive T cell responses to pancreatic islets that are elicited by anti-PD-1, despite having no diabetogenic activity on its own.
In two different models of immune-mediated colitis (murine ulcerative colitis and murine Crohn's disease), it was demonstrated that treatment with an anti-CD137 agonistic mAb prior to treatment with CTLA-4 mAb significantly reduced the clinical signs associated with CTLA-4 mAb treatment. The simultaneous administration of a CD137 agonistic antibody and an anti-CTLA-4 antibody enhanced the activity against inherently immunogenic tumours when compared with the activity elicited by each antibody as monotherapy. CD137 mAb also showed activity against the EMT-6 mammary tumour model, whereas CTLA-4 mAb was inactive. The combination of both antibodies against EMT-6 tumours was similar to that observed with CD137 mAb, indicating that addition of CTLA-4 mAb did not affect CD137 mAb activity. Finally, in tumour models where CD137 mAb or CTLA-4 mAb showed no activity, simultaneous treatment with both mAbs did not result in a measurable anti-tumour effect.
After administration to cynomolgus monkeys, ipilimumab augmented intramuscular deoxyribonucleic acid (DNA) immunizations with poly-optimized simian immunodeficiency virus DNA constructs, as evidenced by an increase in CD4+ T cells. It was concluded that the data obtained from the tumour models demonstrating the activity of CTLA-4 mAbs, and the data from the in vitro studies, support the use of ipilimumab for treatment of certain human cancers.
Drug Interactions
Ipilimumab is not expected to interact with cytochrome P450 isoenzymes and, therefore, should not be associated with drug-drug interactions.
3.2.2 Toxicology
Toxicology studies with ipilimumab were conducted in cynomolgus monkeys since they were shown to be a pharmacologically relevant species for non-clinical safety evaluations. Ipilimumab binds to human and macaque CTLA-4, but does not cross-react with murine or rat CTLA-4, and has pharmacologic activity only in monkeys.
Repeat-Dose Toxicity
Ipilimumab was generally well tolerated in repeat-dose toxicity studies at doses up to 30 mg/kg body weight (bw). One female monkey developed severe treatment-related colitis and was sacrificed moribund following the intravenous (IV) administration of two monthly doses of 10 mg/kg bw. A male monkey in a separate study developed a rash covering the lower abdomen approximately 4 weeks following 3 monthly doses of ipilimumab. Although these findings occurred in monkeys also receiving vaccine antigens, they were considered immune-related events and are consistent with the pharmacology of the drug. Ipilimumab did not result in adverse toxicity in any other monkeys when administered IV at doses up to 30 mg/kg bw for 1 week, 10 mg/kg bw administered weekly for 1 month, 1 mg/kg bw weekly for 10 weeks, or 10 mg/kg bw monthly for up to 6 months.
Genotoxicity
As detailed in the International Conference on Harmonisation (ICH) guideline S6 (Guideline for Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals), the range and type of genotoxicity studies routinely conducted for pharmaceuticals are not applicable to biotechnology-derived pharmaceuticals since it is not expected that these substances would interact directly with DNA or other chromosomal material. Thus, genotoxicity studies were not conducted for ipilimumab.
Carcinogenicity
As detailed in ICH guideline S1A (Guideline on The Need for Carcinogenicity Studies of Pharmaceuticals), carcinogenicity studies are generally not needed for oncolytic agents intended for treatment of advanced systemic disease. In addition, rodents are the generally accepted model for carcinogenicity testing, and these species are not suitable for toxicity testing of ipilimumab owing to their lack of cross-reactivity to ipilimumab. Thus, carcinogenicity studies for ipilimumab were not conducted.
Reproductive and Developmental Toxicity
Reproductive, developmental, or juvenile toxicology studies have not been performed with ipilimumab. Owing to the lack of specific target binding of ipilimumab in rodent or rabbit tissues, evaluation of ipilimumab in standard reproductive toxicology and juvenile models using these species would not be relevant.
Given the short life expectancy and physiologic status of adult patients with advanced melanoma and the potential benefits from the use of ipilimumab in pregnant women despite its potential risks, no formal reproductive, developmental, or juvenile studies were conducted to support the proposed indication. Potential reproductive risks are addressed in the product labelling.
Local Tolerance
In the IV repeat-dose studies in monkeys with ipilimumab, no substantial irritation was observed at the injection sites. Ipilimumab was administered from pre-formulated (ready-to-use) vials at the clinical concentration (generally ~5 mg/mL). However, injection rates were faster and varied from ~3 to 10 mL/min (up to 50 mg/min) in the non-clinical studies compared with 90-minute clinical infusion (total dose of 210 mg for a 70 kg person, up to 2.3 mg/min); thus, providing a safety factor of ~22-fold based on infusion rate.
Other Studies
Tissue cross-reactivity studies conducted utilizing a panel of normal human tissues did not result in the identification of any unexpected target tissues. Tissue reactivity was consistent with its target antigen specificity. Hence, it is therefore unlikely that ipilimumab administration will have secondary pharmacological effects as a result of off-target binding to tissues.
3.2.3 Summary and Conclusion
The pharmacology data obtained from the tumour models demonstrating the activity of CTLA-4 mAbs, together with the data from the in vitro studies, support the use of ipilimumab for treatment of certain human cancers.
The non-clinical toxicology database was considered adequate to assess the safety profile of ipilimumab and support its use for cases of advanced melanoma in humans, provided adequate safety precautions are taken against the possible immunopotentiating effect of treatment such as the potential for, colitis and dermatitis. Standard reproductive toxicology studies were not conducted with ipilimumab. Hence, potential reproductive risks have been addressed in the product labelling. Currently, an ongoing pre- and post-natal development study in cynomolgus monkeys is being conducted. As with any IV administered protein, ipilimumab also has the potential to evoke an infusion reaction.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In patients with melanoma who received ipilimumab, mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. In Phase II studies, this increase occurred in a dose-dependent fashion. In a Phase III study (see section 3.3.3 Clinical Efficacy), ipilimumab given with or without gp100 peptide vaccine at 3 mg/kg increased ALC throughout the induction dosing period, but no meaningful change in ALC was observed in the control group of patients who received an investigational gp100 peptide vaccine alone.
In peripheral blood of patients with melanoma, a mean increase in the percent of activated human leukocyte antigen (HLA)-DR+ CD4+ and CD8+ T cells and a mean decrease in the percent of naive (CCR7+ CD45RA+) CD4+ and CD8+ T cells was observed after treatment with ipilimumab, consistent with its mechanism of action. A mean increase in the percent of central memory (CCR7+ CD45RA-) CD4+ and CD8+ T cells and a smaller, but significant, mean increase in the percent of effector memory (CCR7- CD45RA-) CD8+ T cells also was observed after treatment with ipilimumab.
3.3.2 Pharmacokinetics
Pharmacokinetic (PK) data from 3 Phase II studies have been combined in the context of developing a population PK model. The PK of ipilimumab was studied in 499 patients with advanced (Stage III or IV) melanoma. Based on population PK analysis, the following PK parameters were obtained: a mean terminal half-life of 14.7 days; a mean systemic clearance of 15.3 mL/h; and a mean volume of distribution at steady-state of 7.21 L. The average serum trough concentration achieved at steady-state with a 3 mg/kg induction regimen was 21.8 mcg/mL.
The PK of ipilimumab is linear and time-invariant, and exposures are dose-proportional over the 0.3-10 mg/kg dose range. Clearance of ipilimumab increases with increasing body weight, supporting a weight-based dose of ipilimumab. Clearance of ipilimumab also increases with increasing baseline lactate dehydrogenase. Clearance was not affected by age, gender, hepatic function, or renal function.
Throughout this submission there was a very heavy reliance on the estimates from this population PK model, to the extent that there were only 15 subjects whose drug profiles could be considered 'densely' sampled.
In the case of ipilimumab, the later dose at 43 days was consistently associated with a higher infusion exposure and half-life when compared with the first dose. This would suggest a number of mechanisms that should have been reflected in the equations comprising the population PK model if it was expected to have any 'face validity'.
The observations regarding time-invariance, accumulation and time to steady state were based on simulations using the population PK model for each subject in the final dataset. Inasmuch as population PK summarizes the observed values, it serves some valid function.
In conclusion, the final population PK model parameters were robustly estimated and the final population PK model provided an adequate description of the overall concentration-time profile of ipilimumab.
3.3.3 Clinical Efficacy
The clinical program for Yervoy comprised one pivotal Phase III study; four supportive Phase II studies; and three additional non-pivotal studies.
A pivotal Phase III, randomized, placebo-controlled multicentre study was conducted to primarily demonstrate superior efficacy of ipilimumab plus gp100 melanoma vaccine compared with gp100 vaccine alone. Total of 676 patients were randomized into three treatment groups to receive gp100 vaccine [Number (n) = 136], ipilimumab monotherapy (n = 137) or gp100 vaccine plus ipilimumab (n = 403). Gp100 vaccine is an experimental medicine that has not been authorized in any jurisdictions to date. The median age of the patients enrolled was 57 (range 19-90) with 59% males and 41% females. At study entry, 98.2% of the patients had unresectable Stage IV malignant melanoma; 71.4% of the patients were stage M1c; and over one-third had an elevated lactase dehydrogenase (an indicator of metastases). Enrolled patients were tested positive for HLA-A2*0201. This HLA phenotype is to ensure the effective antigen presentation for the gp100 peptides, and accounts for 40-50% of the general population.
Overall survival (OS) was the primary endpoint. Compared with the gp control arm, there was a 32% reduction in the mortality risk in the ipilimumab+gp arm [hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.55, 0.85, probability (p) = 0.0004] and a 34% reduction in the ipilimumab monotherapy arm (HR = 0.66, 95% CI: 0.51, 0.87, p = 0.0026; not adjusted for multiple comparisons). For the secondary endpoints, progression-free survival (PFS) and best overall response rate (BORR) were modest and did not appear to be consistent with the magnitude of OS benefits in the ipilimumab arms. Nevertheless, BORR and the disease control rate were higher in the ipilimumab arms compared with the gp arm, with the highest rates observed in the ipilimumab monotherapy arm. The ipilimumab-induced response appeared to be durable. No improvement was reported for health-related quality of life.
| Treatment Arms | Overall Survival (OS) median (months) [(95% Confidence Interval (CI)],Hazard Ratio (HR) (95% CI) | Progression Free Survival (PFS) (median month) | Best Overall Response Rate (BORR)(%) | Disease Control Rate (DCR)(%) |
|---|---|---|---|---|
| ipi+gp (n = 403) | 9.95 (8.5-11.5) HR = 0.68 (0.55, 0.85) p = 0.0004 | 2.76 | 5.7 | 20.1 |
| ipi (n = 137) | 10.12 (8-13.8) HR = 0.66 (0.51, 0.87), p = 0.0026 | 2.86 | 10.9 | 28.5 |
| gp (n = 136) | 6.44 (5.5, 8.7) | 2.76 | 1.5 | 11.0 |
The magnitude of OS benefit appeared to vary by tumour stage and by prior treatment. However, the sub-group analyses by tumour stage and prior treatment are based on limited patient numbers and should be interpreted with caution. Although cases of delayed response to ipilimumab were reported in the pivotal study, the trial design did not permit a systemic evaluation of this phenomenon. In the pivotal study, patients were excluded if they had ocular melanoma; active central nervous system metastases; concurrent use of immunosuppressants; certain types of infectious diseases; autoimmune diseases or organ transplants; those with poor performance status; shorter life expectancy; or inadequate organ function reserve at baseline were thus under-represented. Therefore, the efficacy and safety information in these sub-patient populations is limited.
Four supportive Phase II studies were submitted with a total of 560 patients enrolled. Patient population in these 4 studies was similar to that of in the pivotal study. These 3 Phase II studies provided data for dose selection including efficacy and safety information to support the pivotal Phase III study.
Three additional Phase II studies were submitted. Information obtained from these 3 studies was limited because of the relatively small sample sizes enrolled in each study, as well as variations in patient population, study design, study duration, dose regimen, and endpoints.
3.3.4 Clinical Safety
Clinical safety was assessed in the Phase III pivotal study described in section 3.3.3 Clinical Efficacy.
In patients who received 3 mg/kg ipilimumab monotherapy, the most frequently reported adverse events [(AEs) occurring at ≥10%] were diarrhoea; rash; pruritus; fatigue; nausea; vomiting; decreased appetite; and abdominal pain. Ipilimumab therapy was discontinued because of AEs in 10% of patients; colitis and diarrhoea were the most common AEs that led to discontinuation of the therapy.
Ipilimumab has a unique safety profile characterized by autoimmune-like AEs termed immune-mediated adverse drug reactions (imADRs). Ipilimumab can cause severe and fatal imADRs, including enterocolitis; intestinal perforation; hepatitis; dermatitis; neuropathy; endocrinopathy; as well as toxicities in other organ systems. The incidences of severe to fatal imADRs in the pivotal study were 15% and 12% in the ipilimumab monotherapy and ipilimumab+gp100 arms, respectively. There were 8 deaths (1.6%) due to imADRs: 2 (1.5%) occurred in the ipilimumab monotherapy arm (large intestine perforation and hepatic failure); and 6 (1.6%) in the ipilimumab+gp100 arm (toxic epidermal necrolysis with acute respiratory distress syndrome; colitis with gastrointestinal perforation; intestinal perforation; multi-organ failure due to peritonitis; Guillain-Barré syndrome; and pericardial effusion). An additional 5 (1.0%) ipilimumab-related deaths were reported: 2 (1.5%) in the ipilimumab monotherapy arm (angiopathy, infection and renal failure with septic shock); and 3 (0.8%) in the ipilimumab+gp100 arm (sepsis, myelofibrosis, severe colitis and hyponatremia associated with fatal sepsis).
Sixty-seven percent of the patients who experienced severe imADRs (≥ grade 3) were treated with high-dose corticosteroids. Of those, 74% of the imADR events were resolved with treatment of high-dose corticosteroids alone, and 11% were resolved with additional treatment of an immune-suppressant, infliximab. Three patients (6.8%) died while receiving high-dose corticosteroids for treatment of imADRs.
Safety data from a recently completed Phase III study in patients treated with 10 mg/kg ipilimumab plus dacarbazine was reviewed. No new types of imADRs were identified.
Owing mainly to issues regarding appropriate risk communication, a NON was issued on October 6, 2011.
After a series of communications with the sponsor, new information was assessed in detail and the deficiencies that had been identified were deemed to be appropriately resolved. The final Canadian Product Monograph captures the updated safety information of Yervoy therapy and provides management guidelines for ipilimumab-specific imADRs.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Advanced melanoma is a serious, life-threatening disease with a median OS of less than one year and represents 1% of all cancer deaths in Canada in 2011. The authorized first-line therapies for advanced melanoma, such as dacarbazine and interleukin-2, have not demonstrated an impact on OS in controlled randomized studies. Currently, there is no authorized therapy for patients with advanced melanoma who failed, or could not tolerate first-line therapies.
Yervoy demonstrates a statistically significant and clinically relevant improvement in OS in patients with advanced melanoma. Yervoy monotherapy significantly improved OS by 3.68 months compared with the control gp100 vaccine in patients with advanced melanoma who have failed or do not tolerate other systemic therapies.
Yervoy can cause severe and fatal imADRs, including enterocolitis; intestinal perforation; hepatitis; dermatitis; neuropathy; endocrinopathy; as well as toxicities in other organ systems. Based on the currently available information, the risks of ipilimumab-specific AEs, in particular imADRs, are appropriately captured in the Product Monograph. Moreover, the management guidelines of ipilimumab-specific imADRs are also included in the Product Monograph.
The overall benefit/risk profile of Yervoy is judged favourable as a second-line therapy in the treatment of patients with advanced melanoma provided that the risks, in particular the risks of imADRs, are effectively communicated to physicians and patients, and will be adequately monitored and managed post marketing.
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 Yervoy is favourable in the treatment of advanced melanoma in patients who have received prior therapy. 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: YervoyTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-06-03 |
| Request for priority status | |
| Filed: | 2010-07-13 |
| Rejection issued by Director, Biologics and Genetic Therapies Directorate/Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: | 2010-08-09 |
| Submission filed: | 2010-10-13 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2010-12-10 |
| Review 1 | |
| Quality Evaluation complete: | 2011-10-06 |
| Clinical Evaluation complete: | 2011-10-06 |
| Labelling Review complete: | 2011-10-05 |
| Notice of Non-Compliance (NON) issued by Director General (pertaining mainly to issues regarding appropriate risk communications): | 2011-10-06 |
| Response filed: | 2011-11-03 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2011-11-25 |
| Review 2 | |
| Quality Evaluation complete: | 2012-01-30 |
| Clinical Evaluation complete: | 2012-01-31 |
| Notice of Compliance (NOC) issued by Director General: | 2012-02-01 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| YERVOY | 02379384 | BRISTOL-MYERS SQUIBB CANADA | IPILIMUMAB 5 MG / ML |