Summary Basis of Decision for Kepivance ®
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:
Kepivance®
Palifermin, 6.25 mg/vial, Powder for solution, Intravenous
Amgen Canada Inc.
Submission control no: 092866
Date issued: 2007-02-14
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrKEPIVANCEMD, palifermine, 6,25 mg/flacon, poudre pour solution, Amgen Canada Inc., No. de contrôle de la présentation 092866
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):
- 02274221
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
® Registered Trademark of Amgen
2 Notice of decision
On December 9, 2005, Health Canada issued a Notice of Compliance to Amgen Canada Inc. for the drug product Kepivance®.
Kepivance® contains the medicinal ingredient palifermin, a recombinant human keratinocyte growth factor (rHuKGF).
Kepivance® is indicated to decrease the incidence and duration of severe oral mucositis in patients with haematologic malignancies receiving myelotoxic therapy and requiring haematopoietic stem cell support. Acute oral mucositis is a common, serious, dose-limiting side effect of myelotoxic chemotherapy and radiation therapy conditioning regimens with bone marrow/peripheral blood stem cell transplantation. This painful and debilitating complication compromises the patient's ability to perform basic functions and negatively impacts quality of life with a potential deleterious effect on clinical outcome. Kepivance® stimulates the growth of epithelial cells in tissues expressing the keratinocyte growth factor receptor (KGFR), but has no effect in cells that do not express KGFR (e.g. hematopoeitic cells). Treatment with Kepivance® has been shown to substantially reduce injury to the oral and gastrointestinal tract mucosa and salivary glands in numerous animal models of radiation and chemotherapy-induced injury.
Kepivance® was reviewed under the Priority Review Policy, taking into consideration the debilitating nature of the indication and the fact that no other drug is presently marketed in Canada to decrease the incidence, duration, and severity of oral mucositis in patients with haematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support.
The market authorization was based on quality, pre-clinical, and clinical information submitted. Three clinical studies, including two pivotal studies and one non-pivotal study, were submitted/performed to evaluate the efficacy and safety of Kepivance® in patients with haematological malignancies treated with myelotoxic chemo/radiation therapy and haematopoietic stem cell support. The data from these studies demonstrated statistically significant efficacy and safety for Kepivance® in the intended indication in patients with haematological malignancies. Improvement was seen in the incidence and duration of oral mucositis as well as its related sequelae.
Kepivance® (6.25 mg/vial palifermin) is presented as a lyophilized powder for reconstitution. The recommended dosage of Kepivance® is 60 µg/kg/day, administered as an IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. Dosing guidelines are available in the Product Monograph.
Kepivance® is contraindicated in patients with known hypersensitivity to Escherichia coli (E. coli)-derived proteins, palifermin, or any other component of the product. Kepivance® 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 Kepivance® 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 Kepivance® is favourable to decrease the incidence and duration of severe oral mucositis in patients with haematologic malignancies receiving myelotoxic therapy and requiring haematopoietic stem cell support.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Description
Kepivance® contains the medicinal ingredient palifermin, a recombinant human keratinocyte growth factor (rHuKGF). Palifermin mimics endogenous keratinocyte growth factor (KGF), an epithelial cell-specific growth factor that is naturally upregulated in response to epithelial tissue injury. KGF binds to epithelial cells via KGF receptors (KGFR) on the cell-surface, thereby stimulating proliferation, differentiation, and upregulation of cytoprotective mechanisms (e.g. induction of antioxidant enzymes). Treatment with palifermin is focused on decreasing the incidence, duration, and severity of oral mucositis and related sequelae (such as mouth and throat soreness, use of parenteral nutrition, and incidence of febrile neutropenia) to improve function in patients with haematologic malignancies receiving myelotoxic therapy requiring haematopoietic stem cell (HSC) support.
Manufacturing Process and Process Controls
Palifermin is produced in E. coli through recombinant DNA technology. Manufacturing consists of fermentation, cell processing, and purification processes. The materials used to produce the drug substance are considered suitable for their intended use. Certificates of suitability have been provided for animal-derived materials used in the production of the palifermin drug substance.
Analytical procedures used for validating the fermentation and purification processes were described. Validation data for five consecutive fermentation lots and four consecutive purification lots were obtained and are considered acceptable.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterisation
Palifermin is a water-soluble, 140 amino acid protein with a molecular weight of 16.3 kDa. It differs from endogenous KGF in that the first 23 N-terminal amino acids have been deleted to improve protein stability.
Although impurities and degradation products generated from the manufacturing process were reported and characterized, they were found to be within established limits and are 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 comparability of the material manufactured at the clinical and the commercial sites was fully investigated. The results of these analyses confirm that the two lots, representative of the clinical and commercial scales, were highly comparable with respect to primary and higher-order structures, variant profiles, and potency.
The proposed packaging components are considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Kepivance® (palifermin) is therapeutically classified as a keratinocyte growth factor (KGF) proposed for the treatment of mucositis. It is the first product in this class of drugs.
Kepivance® is supplied as a sterile, white, lyophilized powder. It is reconstituted with 1.2 mL of sterile water for injection and administered as an intravenous (IV) bolus injection. Kepivance® is packaged in single use vials as an isotonic formulation consisting of 6.25 mg palifermin, 50 mg mannitol, 25 mg sucrose, 1.94 mg L-histidine, and 0.13 mg polysorbate 20. Reconstitution yields a clear, colourless solution of Kepivance® (5 mg/mL) with a pH of 6.5. No preservatives are included in the formulation as the drug product is intended for single use only.
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of palifermin with the excipients was demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Several studies which justified the type and proposed concentration of excipients to be used in the drug product were reviewed and these verified that there are no potential toxicological or immunological effects expected. A lyophilized product formulation was developed. Based on previous lyophilization studies with rHuKGF analogs, L-histidine was chosen as the buffer of choice due to the stability that it provides, its effective buffering capacity, and its suitability for lyophilization. Polysorbate 20 was chosen as the surfactant of choice due to its known parenteral safety profile.
The current formulation (manufactured at both clinical and commercial scale) was used for Phase III clinical trials and is intended for the commercial product. The purity and potency of the drug product were not affected by adjustments to the lyophilization cycle from the clinical process to the commercial process. The overall results suggest that the drug products produced at commercial scale and clinical scale are analytically comparable.
Although different vendors have supplied 5 mL glass vials for the clinical and commercial processes, the vials are identical dimensionally and meet compendial physicochemical requirements for Type I, Class A, borosilicate glass. The glass vials and stoppers meet current USP and Ph.Eur. requirements.
Manufacturing Process and Process Controls
The drug product manufacturing process involves the following steps: buffer preparation and cooling; thawing of drug substance; formulation; sterile filtration, fill, and lyophilization; and inspection, labelling, and packaging.
The specifications for all the ingredients are either approved in accordance with USP/NF or Ph.Eur. standards. The acceptance criteria needed for validation of formulated buffer, formulated drug substance, and drug product were successfully met. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Kepivance® is tested to verify its identity, appearance, content uniformity, and the presence of degradation products and microbiological impurities. The test specifications and analytical methods are considered acceptable and the shelf-life and release limits for individual and total degradation products are within acceptable limits.
Data from the validation reports for the analytical procedures used for release testing of the drug product were satisfactory. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the submitted real-time and accelerated stability study data, the proposed 24-month shelf-life at 2° to 8°C for Kepivance® is considered acceptable. Vials should be kept in their carton to protect them from light until time of use.
The reconstituted solution of Kepivance® contains no preservative and is intended for single use only. It should therefore be administered immediately (within 3 hours). When reconstituted by a health care professional under aseptic conditions, Kepivance® may be stored refrigerated in the carton at 2° to 8°C for up to 24 hours. Before injection, Kepivance® may be allowed to reach room temperature for a maximum of 1 hour, but should be protected from light.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment involved in the production of Kepivance® are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Certificates of suitability were provided for all animal-derived materials used in the manufacture of the drug substance.
3.1.5 Summary and Conclusion
At the request of Health Canada's Biologics and Genetic Therapies Directorate, the sponsor provided a foreign review communication/report related to Kepivance®. The foreign communication came from the United States Food and Drug Administration (FDA). It summarized key review issues raised by the FDA and resolutions submitted by the sponsor that the FDA considered acceptable.
The Chemistry and Manufacturing information submitted for Kepivance® has demonstrated 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
A non-clinical program to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs), and toxicology of palifermin was conducted. The program assessed the use of palifermin in the treatment of epithelial/mucosal tissue injury induced by radioligand or chemotherapy. Non-clinical studies used the intravenous (IV) route to model the intended clinical administration. The subcutaneous (SC) route was explored as a potential route of administration, but was subsequently abandoned following local reactions observed in an early Phase I clinical trial. Studies were conducted in a variety of species including mice, rats, and rhesus monkeys.
Models of chemotherapy and radiation induced gastrointestinal tract (GIT) injury included:
- Rat models of acute and chronic salivary gland toxicity induced by radiation.
- Murine models of oral mucosal toxicity induced by radiation or combination radiation/chemotherapy.
- Mouse models of survival following lethal irradiation and bone marrow or peripheral blood progenitor cell transplantation (PBPCT).
- Non-human primate models of lethal irradiation and bone marrow transplantation.
3.2.1 Pharmacodynamics
Primary PD studies were designed to evaluate epithelial protection by exogenously administered palifermin. In vivo animal models of injury to the upper and lower GIT, lung, urinary bladder, and skin (hair follicles) were conducted. Mechanisms of protection appeared to include stimulation of epithelial cell proliferation, maintenance of intercellular junctions and epithelial barrier (e.g. mucosal) integrity, and increased epithelial cell expression of various proteins having protective actions (e.g. antioxidant enzymes). These results are consistent with the role for KGF in the organism's response to such injury and indicate that palifermin could have therapeutic activity in a clinical setting of ameliorating cancer therapy-induced oral and GIT mucositis.
Results from the PD studies have shown that palifermin reduces the effects of injury to the mucosal lining of the oral cavity and aerodigestive tract induced by radiation and/or chemotherapeutic agents. The mechanism of action appears to be bimodal: a growth-enhancing differentiation and a cytoprotective effect throughout the GIT, both of which result in a thickening of the epithelial tissues.
The effects of palifermin on behaviour, pain sensation, convulsing activity, body temperature, respiration and cardiovascular function, smooth muscle activity, and renal and GIT activity, were assessed in mice, rats, guinea pigs, and/or monkeys. The broad species activity of rHuKGF allowed for completion of a comprehensive pre-clinical safety program. It was concluded that palifermin did not adversely affect the central or autonomic nervous systems, the cardiovascular or respiratory systems, the GIT, or the genitourinary system of any of the evaluated species. Most of the observed effects (including acanthosis, hyperkeratosis, and hyperplasia in a variety of tissues) can be attributed to an exaggerated pharmacological response to palifermin.
Understanding the behavior of palifermin in the biologic matrix (eg. plasma, serum, cerebral spinal fluid, etc.) and the possible influence of binding proteins may be important for a complete understanding of the PD effect. Overall, pharmacological experiments demonstrated the PD properties of palifermin, confirming its role in the healing process of epithelial tissues. Of interest, was the fact that the PD effect lasted longer than the elimination half-life of palifermin.
3.2.2 Pharmacokinetics
The PKs of palifermin have been characterized following single-dose IV and/or SC administrations, and multiple-dose IV administration in mice, rats, and monkeys.
Results in all three species demonstrated dose linearity, a half-life range of 1 to 4 hours, and evidence of extravascular distribution of palifermin.
Distribution
Rat tissues containing the highest percentage of total radioactivity following IV administration of 125I-rHuKGF included liver, skin, carcass, kidney, small intestines, blood, stomach, and thyroid.
Average values for volume of distribution at steady state were approximately 45 mL/kg, 1050 mL/kg, and 5400 mL/kg in rats, monkeys, and mice respectively. The large volume of distribution observed in mice and monkeys is indicative of extravascular distribution of palifermin in these species.
In monkeys, a sharp decrease in serum concentration of palifermin was evident between 0.5 and 1.0 hours following an IV bolus injection. After this first phase, a slight increase or plateau in concentrations was observed between 1.0 and 2.0 hours post dosing, followed by a consistent decline in concentrations for the remainder of the sampling time. As was expected from the relatively short half-life of palifermin, no accumulation was observed following multiple dosing to monkeys and mice in the PK studies. AUC measurements decreased over time, probably as a result of antibody interference.
Metabolism
In rats, exposure was the same following administration into the portal vein versus the femoral vein, indicating low hepatic extraction of palifermin.
No formal metabolism studies were conducted as it is believed that palifermin follows the metabolic pathways for metabolism of biotechnology-derived pharmaceuticals (i.e. degradation to small peptides and individual amino acids).
Excretion
Average clearance values were approximately 56 mL/hr/kg, 420 mL/hr/kg, and 2500 mL/hr/kg in rats, monkeys, and mice, respectively.
Approximately 11% of the radioactive dose administered to rats was recovered in the urine as trichloro-acetic acid precipitable radioactivity over 24 hours, suggesting that some intact palifermin and/or smaller fragments may be excreted in the urine. It is therefore evident that renal elimination plays a role in the clearance of radio-labelled palifermin in rats. Exposure to palifermin, as measured by AUC, increased approximately 2-fold in bilaterally-nephrectomized rats compared to that observed in sham-operated rats. This is notable as it indicates the role of the kidney in the elimination of palifermin. This finding led to caution in cases of renal impairment. A clinical study in patients with renal impairment was ongoing at the time of this drug submission. The completed study report was provided by the sponsor in response to a clarification request from Health Canada. The results indicated that the level of renal function in a subject does not affect the clearance of Kepivance® (palifermin) in humans. Accordingly, dose adjustment is not indicated for patients with renal dysfunction who receive Kepivance®.
It is possible that other organs may also participate in the elimination of palifermin through its binding to KGF receptors and internalization/breakdown within epithelial cells.
Safety Margins
Safety margins have been calculated based on the highest intended clinical dose of 60 µg/kg/day palifermin administered via IV for 3 consecutive days. The repeat-dose safety exposure margin for IV administration based on the no observed adverse effect level (NOAEL) dose in the 28-day cynomolgus monkey study is 8-fold the clinical exposure.
Toxicokinetics
Toxicokinetic analyses have been carried out in a range of repeat-dose toxicology studies in rats. Toxicokinetics were also investigated in embryo/foetal developmental toxicity studies in rats and rabbits. There was no evidence of accumulation of palifermin in pregnant rats. Palifermin was administered late in gestation at single IV doses of 1000 µg/kg in pregnant rats and 500 µg/kg in pregnant rabbits. The levels of palifermin detected in foetal serum and amniotic fluid were generally below the assay's limit of quantification suggesting negligible trans-placental transfer.
Drug Interactions
No formal drug interaction studies were conducted with palifermin, however, this possibility was addressed as part of animal model evaluations. When granulocyte colony-stimulating factor was used in combination with palifermin in murine and non-human primate chemotherapy/radiotherapy models, there was no evidence of drug interaction.
It is known that endogenous KGF is a heparin binding protein, therefore, it binds to heparin sulfate proteoglycans.
3.2.3 Toxicology
Acute Toxicity
Toxicology studies conducted in mice, rats, guinea pigs, rabbits, and monkeys, provided information on the safety of palifermin to support its use in humans. The studies demonstrated the pharmacological effects of palifermin including its effect on various organs. Generally, these effects tended to be mild, moderate, and usually reversible.
Reproductive and Development Toxicity Studies
Though toxicology studies did not demonstrate trans-placental transfer of palifermin, caution is recommended in the treatment of pregnant or lactating women. Currently, the drug indication excludes such patients.
No adverse effects (AEs) on mating or fertility were observed at dose levels ≤ 100 µg/kg/day, however, AEs related to reproductive parameters and fertility were seen at doses ≥ 300 µg/kg/day concomitantly with signs of toxicity. Embryo/foetal developmental toxicity was observed in rats at a dose of 1000 µg/kg/day, and rabbits at 150 µg/kg/day. In addition, the no-effect doses for developmental effects were 60 µg/kg/day for rabbits, and 300 µg/kg/day for rats. The observed treatment-related effects for both species included intra-uterine growth retardation and survival. Rats also showed decreased foetal weight.
Genotoxicity Studies
Palifermin was not genotoxic in any of the assays conducted
Mutagenicity and Carcinogenicity Studies
No mutagenic or carcinogenic effects were noted in the appropriate tests, however, these effects need to be monitored with ongoing clinical use.
Tumour interaction studies were important in order to assess the effect of palifermin on epithelial tissues expressing KGFR. Though KGFR is not expressed on haematopoietic cells, the potential of secondary malignancies including solid tumours that express KGFR could be affected by the administration of the drug. Experiments demonstrated a minimal risk particularly with the short administration schedule in the present indication. It is important that the long-term effect of palifermin in patients be monitored in the post-marketing phase as only clinical experience can provide the appropriate assurance of the long-term safety of the drug in this context.
KGF demonstrated a limited ability to enhance the growth of KGFR expressing human tumour cells, causing a modest growth enhancement of only 1 of 7 KGFR expressing human tumour cell lines in mouse xenograft models at high doses ≥ 1500 µg/kg/day. The pharmacological effects seen in toxicity studies reversed in some cases. Changes of thyroid hyperplasia and scarring, plus degeneration of the thymus, were toxicological effects that did not reverse. In some studies, liver weight and morphology did not return to normal following recovery.
Physiological Effects
The epithelial proliferative effects of palifermin in the skin and mucosa manifested as widespread acanthosis and hyperkeratosis. The GIT showed acanthosis and hyperkeratosis in the buccal mucosa, esophagus, stomach and intestine. Mammary glands illustrated enlarged mammary tissue, gland hyperplasia, and ductal hyperplasia. Effects on the bladder urothelium included hemorrhage and hyperplasia, whereas, the pancreatic ducts showed ductular hyperplasia with transient elevations of serum amylase and lipase. Submandibular gland acinar cell hypertrophy and increased gland weight may have contributed to the elevation in serum amylase. The liver showed increased liver weight, apoptosis, and associated changes in serum chemistry parameters in rats.
Other effects included thymic gland depletion, seen at low doses in monkeys and in rats, and increases in the number and size of thyroid follicles in rats. No ophthalmologic or cardiographic effects were observed. Epithelial hyperplasia, attributed to the pharmacological action of palifermin, was seen at dose levels ≥ 100 µg/kg in rats and ≥ 30 µg/kg in monkeys.
While the cornea is known to express the KGFR, no ophthalmic effects were apparent in examinations or in histopathological evaluations of the eye in rats or monkeys.
3.2.4 Summary and Conclusion
Pharmacological studies have demonstrated that administration of palifermin in a number of different chemotherapy/radiotherapy models provides significant anatomical and functional protection to epithelial tissues in animals. The primary pharmacological effect appears to be enhancement of the structural integrity of the epithelium through stimulation of proliferation, cytoprotection, and repair of tissues. This pharmacological response has been shown to translate clinically into protection of the barrier and absorptive functions of the oral mucosa and gut in subjects exposed to cytotoxic therapies.
The non-clinical PD and PK studies provided an understanding of the drug kinetics that formed the basis for clinical evaluation. Data demonstrated dose-linear PKs with a short half-life. Extravascular distribution was apparent and no drug accumulation was seen following multiple dose administrations.
Endogenous KGF is a heparin binding protein, therefore, IV lines using heparin should be rinsed with saline prior to administration of palifermin. This is clearly indicated in the Product Monograph.
Toxicities were not observed in the repeat-dose studies of carcinogenicity, genotoxicity, or drug interactions. In vivo, palifermin demonstrated limited ability to enhance the growth of tumour cells expressing KGFR. It should be noted, however, that overt toxicity was observed only at the highest evaluated doses in the repeat-dose toxicity studies (up to 28 days in duration). The toxicology program, therefore, proved an adequate risk for use in humans. The safety of palifermin with regard to potential effects on tumour outcome, however, can only be established with clinical experience.
Adverse reproductive effects of palifermin were noted in embryo/foetal developmental toxicity studies, however, an NOAEL of 300 µg/kg/day and 60 µg/kg/day was identified in rats and rabbits, respectively. Adverse effects on fertility/reproductive parameters were observed in female and male rats, but an NOAEL dose of 100 µg/kg/day was identified. Throughout the various toxicology studies, animals were exposed to doses of palifermin that were higher than the maximum therapeutic dose in humans (60 µg/kg/day). The results of these studies, therefore, provide assurance of safety in humans. With few exceptions, findings in the toxicology studies were reversible and attributable to the pharmacological activity of palifermin. The observations were consistent with the known activity of KGF, and returned to baseline during recovery (with the exception of the thyroid effects). The lack of interaction between palifermin and granulocyte-colony stimulating factor, routinely used in the transplant setting, was noted.
Kepivance® (palifermin) is contraindicated in patients with known hypersensitivity to Escherichia coli (E. coli)-derived proteins, palifermin, or any other component of the product.
Overall, the non-clinical studies provided adequate information on the safety and efficacy of palifermin.
3.3 Clinical basis for decision
Kepivance® (palifermin) is indicated to decrease the incidence and duration of severe oral mucositis in patients with haematologic malignancies receiving myelotoxic therapy and requiring haematopoietic stem cell (HSC) support. Haematological malignancies include Hodgkin's disease (HD) and Non-Hodgkin's lymphomas (NHL); Acute and Chronic Myeloid (AML, CML) and Lymphocytic Leukemias (ALL, CLL); and Multiple Myelomas (MM).
Therapeutic regimens used with HSC support include combinations of high doses of chemotherapeutic agents, with or without radiation therapy. A major complication of radiation and chemotherapy is damage to the epithelial lining of the GIT, particularly the oropharyngeal mucosa. Severe oral mucositis is common in patients receiving myelotoxic chemotherapy and/or radiotherapy. Acute oral mucositis is a significant clinical problem across high-dose myelotoxic treatments with HSC support. The clinical consequences of oral mucositis are numerous. Currently, no standard, adequate, preventative measures are available. Therapy that could reduce the incidence, duration, and severity of oral mucositis would provide significant benefit to these patients.
Based on the proliferative, differentiative, and cytoprotective effects of Kepivance® on the epithelial lining of the GIT, it is hypothesized that Kepivance® may significantly reduce or prevent oral and intestinal mucositis in clinical settings where radiation and/or chemotherapy are used therapeutically in malignancies. Kepivance® has the potential to act at several stages in the pathogenesis and resolution of oral mucositis.
In evaluating preventative agents such as Kepivance®, a reliable scale to assess the incidence and grades of oral mucositis is important. The clinical efficacy studies described in this submission were evaluated based on the World Health Organization (WHO) scale as defined below:
Table 1: WHO - Oral Mucositis Scale
| Grade | 0 | 1 | 2 | 3 | 4 |
|---|---|---|---|---|---|
| WHO Scale | No Symptoms | Soreness and erythema | Erythema, ulcers, ability to eat a solid diet | Extensive ulcers, erythema, requirement of a liquid diet | Alimentation not possible |
While reductions in grade 3-4 oral mucositis would be of highest importance, reductions of grade 2 mucositis could provide a meaningful clinical benefit.
3.3.1 Human Pharmacology
A total of eight clinical pharmacology studies were conducted to evaluate the safety, PK, and PD properties of Kepivance®. Six studies were conducted in healthy subjects and two studies were conducted in subjects with haematologic malignancies undergoing total body irradiation (TBI).
3.3.2 Pharmacodynamics
The effect of Kepivance® on the proliferation of epithelial cells was assessed in buccal mucosal biopsies collected from healthy volunteers. In the multiple-dose study (once daily for 3 consecutive days), a significant increase in Ki67 staining (a surrogate measure of epithelial cell proliferation) relative to baseline was observed up to 72 hours following administration of the first dose of Kepivance® at a dose level as low as 40 µg/kg/day. In the single-dose study, buccal mucosal epithelial cell proliferation was augmented with increased Kepivance® exposure at doses ranging from 60 µg/kg to 250 µg/kg, with a plateau at 160 µg/kg.
Of note, at 48 hours following dosing, most of the quantifiable Kepivance® concentration values were less than twice the lower limit of quantification of the assay, indicating that the pharmacologic effect (measured by Ki67 staining) persists after active drug levels have dissipated. Of particular interest was the demonstration that the PD effect of Kepivance® (with Ki67 staining in buccal mucosa) lasted up to 72 hours compared to a Kepivance® half-life of 4.5 hours. This is important for future assessment of optimizing the schedule of Kepivance® in the post-marketing phase.
3.3.3 Pharmacokinetics
Six PK studies were conducted in 210 healthy volunteers receiving doses of Kepivance® ranging from 0.2 µg/kg to 250 µg/kg Kepivance®. Two other studies enrolled 26 patients with haematological malignancies receiving therapeutic doses of 60 µg/kg/day of Kepivance®. It is important to note that the studies conducted in healthy volunteers enrolled a population of mostly young, white men, and were therefore not fully representative of the patient population, particularly with respect to age. In healthy volunteers, Kepivance® exhibited linear PK in the dose range of 10 µg/kg to 250 µg/kg. Following the first PK study, a SC route was abandoned in view of local irritation in most treated cases. The IV schedule was established in all clinical studies.
A single dose of 250 µg/kg/day was studied. This was well tolerated but the efficacy of this schedule has not been evaluated and is not recommended at this time. In the future, additional data should be collected to evaluate the efficacy and safety of this potentially simpler schedule.
Distribution
Volume of distribution at steady state (Vss) was greater than total body water volume, indicating extravascular distribution of Kepivance® following IV administration.
No accumulation of Kepivance®, as measured by area under the concentration time curve (AUC), occurred following 3 consecutive daily doses to healthy volunteers (20 µg/kg/day and 40 µg/kg/day) or to patients with haematologic malignancies (60 µg/kg/day).
Metabolism
The mean AUC from time zero to the time of last quantifiable concentration value after dose 6 (last dose after chemo- and radiotherapy) was approximately 46% lower, on average, than that after dose 3 (last dose before chemo- and radiotherapy). The reason for this low exposure following the sixth dose rather than after the third dose is not known.
Excretion
The elimination portion of the PK profile was similar in healthy volunteers and in patients with haematologic malignancies. Data from both populations demonstrated a rapid decline of Kepivance® concentrations in the first 30 minutes post-dose and a slight increase or plateau in concentrations approximately 1- to 4-hours post-dose followed by a terminal decline phase. The average elimination half-life was approximately 4.5 hours.
At the 60 µg/kg/day dose level, patients with haematologic malignancies demonstrated clearance levels approximately 2- to 4-fold higher and Vss levels approximately 2-fold higher than those in healthy volunteers. The cause of this difference is unknown.
Special Populations
No differences between men and women in the PK of Kepivance® were observed in healthy volunteers or in subjects with haematologic malignancies.
Inter-subject variability of approximately 69% was observed in the PK parameters of the studies conducted in both healthy subjects and in patients with haematologic malignancies. The reason for this variability was not further explored.
3.3.4 Clinical Efficacy
Three clinical studies, including two pivotal studies (study 20000162 and study 980231) and one non-pivotal study (study 20010182) were conducted to evaluate the efficacy and safety of Kepivance® in patients with haematological malignancies treated with myelotoxic chemotherapy/radiation therapy and HSC support. The myelotoxic regimen was the same in all studies, and consisted of TBI (12 Gy total dose) in 6, 8, or 10 fractions over 3 or 4 days, followed by high-dose chemotherapy (etoposide and cyclophosphamide). The studies were conducted in North America where this conditioning regimen is used and is associated with a high rate (60-70%) of severe oral mucositis.
The primary endpoint of each study was to evaluate the efficacy of Kepivance® in reducing the duration of WHO grade 3-4 oral mucositis, conducted on a modified intent-to-treat (mITT) population consisting of patients who received at least one dose of investigational product (defined as a dose of palifermin or placebo). Secondary efficacy endpoints included the incidence and duration of grades 2, 3, and 4 oral mucositis and the measurement of sequelae of mucositis including mouth soreness, use of opioid analgesia, parenteral nutrition, and incidence and treatment of infections.
Study Design
Both study 980231 (Phase II) and study 20000162 (Phase III) were randomized, double-blind, placebo-controlled, multicentre trials.
In study 980231, 12 centres randomized 169 patients (52 placebo, 117 palifermin) with haematologic malignancies in a 1:1:1 ratio to 1 of 3 treatment regimens. Under the original protocol, patients were randomized to receive 7 doses of investigational product (60 µg/kg/day palifermin or placebo):
- Palifermin pre-post: palifermin administered for 3 consecutive days prior to the conditioning regimen; 1 dose on the last day of TBI immediately following the administration of the last radiation fraction; and for 3 consecutive days beginning immediately after peripheral blood progenitor cell (PBPC) infusion.
- Palifermin pre: palifermin administered for 3 consecutive days prior to the conditioning regimen; 1 dose on the day of the last TBI fraction immediately following the administration of the last radiation fraction; and placebo administered for 3 consecutive days immediately after PBPC infusion.
- Placebo: placebo administered for 3 consecutive days prior to the conditioning regimen; on the day of the last TBI fraction immediately following the administration of the last radiation fraction, and for 3 consecutive days beginning immediately after PBPC infusion.
An interim Safety Committee review (including data from 19 subjects randomized to this treatment schedule) resulted in an amendment which eliminated the dose of investigational product administered on the day of the last TBI fraction from the treatment schedule. This was due to theoretical concerns (supported by animal data) of the elimination of benefit or the possible worsening of mucosal injury under certain conditions. This resulted in the selection of a 6-dose schedule consisting of 3 doses of investigational product prior to TBI and 3 doses of investigational product following PBPC infusion.
In addition, of the 169 patients who were randomized, 1 patient from the placebo group and 5 patients from the Kepivance® group never received investigational product. This left 163 patients who received investigational product (51 from the placebo group and 112 from the Kepivance® group). Of the 163 patients who received investigational product, 34 were randomized under the original protocol to receive 7 doses of investigational product (11 placebo, 12 palifermin pre, 11 palifermin pre-post). The remaining 129 patients were randomized under the amended protocol to receive 6 doses of investigational product (40 placebo, 43 palifermin pre, 46 palifermin pre-post).
Assessments of oral mucositis severity were performed daily, commencing on the first day of radiotherapy until resolution of oral mucositis (WHO grade 2 or less). Patients were observed until day 28 following PBPC infusion. Follow-up assessment of disease response was performed 60-100 days following PBPC infusion when consenting patients were enrolled in the long-term follow-up study 960226.
In the second pivotal study (20000162), a total of 212 patients were randomized in a 1:1 ratio at 13 centres, with 106 receiving palifermin and 106 receiving placebo via IV for 3 consecutive days both prior to the conditioning regimen (pre) and for 3 days immediately following autologus PBPC transplantation (post).
To avoid biases in the assessment of efficacy, the following measures were implemented:
- The two pivotal studies were placebo-controlled and double-blind.
- As palifermin-related skin reactions and oral events (taste alterations, tongue thickness, etc.) could possibly lead to unblinding, sensitivity analyseswere performed on the primary endpoint in both studies. Subjects who had such skin/oral events were excluded and where data was missing a "worse case scenario"was applied. In addition, because palifermin can cause transient elevations in serum amylase and lipase, amylase and lipase analyses were performed by a central laboratory in study 20000162.
- The same patient population was evaluated (i.e. patients with NHL, HD, AML, ALL, CML, CLL, or MM), thus covering the spectrum of patients with haematologic malignancies for whom high-dose myelotoxic therapy with HSC support has been proven to be an effective treatment.
- Patients were stratified by centre and type of haematologic malignancy. Stratification by centre was important as each centre used different mucositis assessors and a specific number of TBI fractions. The need for stratification by type of haematologic disease was related more to long-term safety than to efficacy, since different malignancies have different prognoses. Significant imbalances between treatment arms in prognostic characteristics could confound interpretation of long-term safety data.
Efficacy Results
In study 980231, the 6-dose schedule (with Kepivance® administered before the conditioning regimen and following HSC support) demonstrated significant efficacy in reducing oral mucositis and related sequelae. Of note, is that the outcome for most efficacy endpoints was consistently numerically better in the pre-post group than the pre group, suggesting that the pre-post administration of Kepivance® may provide more benefit in this patient population. The potential benefit of the pre-post schedule will need to be confirmed in a post-marketing phase.
Study 20000162 demonstrated a statistically significant improvement in the incidence, duration, and severity of oral mucositis as well as its related sequelae. The study therefore met its primary and secondary efficacy endpoints.
The protocol-specified populations of the two pivotal efficacy studies were the same. Baseline characteristics were representative of this population of patients. Demographic characteristics were well balanced between the two groups. Within study 20000162, more men were enrolled (n=131) than women (n=81). Based on what is known about the pathophysiology of oral mucositis and an efficacy analysis by gender, this demographic characteristic does not have an influence on the duration or incidence of oral mucositis. As expected, most patients were diagnosed with NHL (65% of the placebo and 68% of the palifermin group).
Integrated analysis of efficacy was evaluated in both study 20000162 and in a primary efficacy pool. The composition of the primary efficacy pool included mostly patients from study 20000162, including all subjects under the 6-dose pre-post schedule of Kepivance® or placebo. Study 20000162 contributed 212 (71%) of the 298 patients in this pool. The remainder included the 86 patients in study 980231. All analyses were performed for the mITT population.
In both study 20000162 and the primary efficacy pool, nearly all subjects received the planned 6 doses of investigational product, with slightly more subjects in the placebo group than the Kepivance® group receiving all 6 doses (in study 20000162, 97% and 95% of subjects in the placebo and Kepivance® groups, respectively, and in the primary efficacy pool, 98% and 95% of subjects in the placebo and Kepivance® groups, respectively).
The results for patients treated under the 7-dose schedule with an additional dose of Kepivance® on the last day of TBI given in proximity to the cytotoxic therapy resulted in loss of protective activity and/or worsening of mucositis. These results support the concern that proximity in the time of Kepivance® administration and chemotherapy negates any potential benefit of Kepivance® and justifies the change and recommendation of the 6-dose schedule.
Comparison of Efficacy Results of All Studies
In both study 20000162 and the primary efficacy pool, Kepivance® produced statistically significant decreases in the duration of WHO grade 3 or 4 oral mucositis (the primary endpoint). In study 20000162, the mean duration in the Kepivance® group was 3.7 days and in the placebo group was 10.4 days. In the primary efficacy pool, the duration in the Kepivance® group was 4.0 days and in the placebo group 9.9 days.
Since the primary efficacy endpoint consisted of two distributions (one for the incidence of severe oral mucositis, and one for duration for those who had severe oral mucositis), the Lachenbruch's two-part model, which simultaneously tests these two distributions, was performed. Results of the analysis showed statistically significant improvement (p<0.001) for the Kepivance® treatment group compared with the placebo group for both distributions considered simultaneously.
Secondary endpoint analyses yielded similar results. There was a significant improvement in the duration of grades 2, 3, and 4 mucositis. In the mITT population in study 20000162 the mean duration in the Kepivance® group was 8.4 days versus 15.7 days in the placebo group. In the primary efficacy pool, the duration was 8.7 days in the Kepivance® group versus 15.5 days in the placebo group. Finally, in the analysis of clinical sequelae, the mouth/throat soreness AUC mean in study 20000162 was 32.6 days in the Kepivance® group versus 52.5 days in the placebo group. In the primary efficacy pool, it was 33.3 days in the Kepivance® group versus 50.4 days in the placebo group.
Summary
The primary endpoint was met in that the duration of severe (WHO grade 3 or 4) oral mucositis was significantly reduced in subjects who received Kepivance® compared with placebo. The incidence of grade 3 and 4 oral mucositis was also significantly reduced in the Kepivance® group compared with the placebo group. The significant reductions in incidence, duration, and severity of oral mucositis were associated with clinically and statistically significant reductions in the patient-reported outcomes of mouth and throat soreness and limitations in related daily activities, as well as decreases in the use of opioid analgesics, the incidence of febrile neutropenia, and total parenteral nutrition.
Reproducible results were obtained for all sensitivity analyses performed. The distribution of patients by incidence at each WHO grade indicates a shift from grade 4 to grade 3 in patients treated with Kepivance® compared with placebo. Results were reproducible across: 1) study centers, 2) underlying haematologic diseases, and 3) number of radiotherapy fractions in the conditioning regimen.
The general design of the studies was adequate with a meticulous approach to the collection of data relating to oral mucositis (daily collection by patients and by well trained assessors). The double-blind, randomized design and sensitivity analyses applying worst-case imputation rules were suitable for the objectives and the statistical design used adequate sample sizes and power. The training of the assessors and the patients in the daily evaluation of oral mucositis including daily patients' questionnaires and diaries to evaluate the clinical impact of therapy were well planned and led to comprehensive and reliable data collections.
The results of the individual clinical studies and the pooled efficacy analyses provided statistically significant evidence for the proposed indication of Kepivance® in patients with haematological malignancies receiving high dose myelotoxic chemotherapy/radiation therapy followed by HSC cell support. The approved dosage schedule should consist of the administration of Kepivance® at a dose of 60 µg/kg/day given as a bolus intravenously for 3 consecutive days before myelotoxic conditioning chemo/radiation regimen and for 3 consecutive days following HSC support (i.e. a total of 6 doses). The data demonstrates statistically significant improvement in the incidence, duration and severity of acute oral stomatitis and also demonstrates a significant benefit in related sequelae and functioning of patients receiving the drug when compared to placebo. The treatment was relatively simple to administer over a short period of time and was generally well tolerated.
3.3.5 Clinical Safety
The safety of Kepivance® was assessed in more than 1000 patients enrolled in 15 clinical studies: 5 studies conducted to evaluate the efficacy of Kepivance® in patients with haematologic malignancies receiving myelotoxic therapy with HSC support (650 patients), 3 studies in head and neck cancer patients receiving fractionated chemoradiotherapy (159 patients), 3 studies in metastatic colorectal cancer patients receiving cyclic chemotherapy (145 patients), and 6 studies that provided PK and safety information for healthy volunteers.
Six groupings or "pools" of data have been analyzed for the integrated analysis of safety. Analyses of the clinical studies, the safety pools of over 1000 patients, and the results of an ongoing long-term disease outcome study demonstrated that:
- Adverse events (AEs) were consistent with those seen in the patient population receiving high dose myelotoxic therapy.
- The main toxicity attributed to Kepivance® was related to its pharmacologic effect and consisted of skin and oral AEs. These were mild to moderate, reversible, and did not lead to discontinuation of the drug.
- Kepivance® was associated with asymptomatic elevation of lipases and salivary amylase with no associated clinical consequences. There was no untoward effect on the cornea (known to have a high expression of KGFR), and no evidence of the development of anti-palifermin antibodies in all patients evaluated.
- Kepivance® did not interact with filgrastim usage and did not interfere with haematologic recovery HSC support.
- Long term follow-up data revealed no significant difference in overall survival, progression-free survival, or the incidence of secondary malignancies.
The occurrence of visual AEs with palifermin administration is a theoretical possibility as KGFRs are present on the lens of the eye. Adverse events reported in vision disorders were reversible, infrequent, and occurred in similar proportions in both groups. Two trials in myelotoxic therapy prospectively assessed cataract formation using slit-lamp eye examinations before and after Kepivance® administration. No trend toward an increase in cataract formation was detected.
Kepivance® is not for use in patients with non-haematological cancer.
Across the clinical program, Kepivance® was generally well tolerated. The safety of Kepivance® was similar across all populations. Deaths and serious AEs occurred in a similar proportion in the placebo and Kepivance® groups, and occurred at rates usually observed in these patient populations.
3.3.6 Issues Outstanding
Although it is biologically plausible that administration of Kepivance® pre-myelotoxic therapy could result in a protective effect based on proliferation of the epithelia and administration after the insult could accelerate the rate of healing, further investigation comparing different dosing schedules for optimal therapy should be conducted. Additional doses and schedules for Kepivance® in various settings are under investigation. The sponsor is planning to conduct an exploratory clinical study examining the pre- versus the pre-post dosing schedule.
The sponsor pointed out that the biological/therapeutic effect of Kepivance® persisted after the drug level dissipated, however, the full response-time curves were not clearly determined. It is not known when the peak response is and how long the persisting effect can last. Clarification of this issue will help optimize the dosing schedule to avoid excessive Kepivance® administration.
Apparently, the peptide used in the non-clinical PK/PD program was different from that used in clinical trials (including Phase I trials). Bridging studies to demonstrate similar receptor binding and biological activities of the peptides should be provided.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Patients have rated mucositis as one of the most debilitating side effects, as it seriously compromises their ability to perform basic functions such as swallowing, speaking, eating, and drinking. This negatively affects quality of life, and can have economic consequences by increasing hospitalization days, use of parenteral feeding, narcotic analgesia, and antibiotics. Some sequelae, such as significant infections, are potentially life-threatening.
No authorised treatment is available that targets the pathophysiology of oral mucositis. All current approaches address symptom improvement and are associated with inherent complications. Oral mucositis represents a dose-limiting toxicity for many chemo/radiotherapy regimens, and any product that can reduce this toxicity could enable the use of regimens associated with higher anti-tumour activity.
Clinical data presented for the proposed indication clearly demonstrate that:
- Kepivance® has significant activity in reducing the incidence, duration, and severity of oral mucositis and related clinical sequelae.
- Kepivance® demonstrates meaningful benefits using objective measurements of mucositis, paralleled by the subjective assessment of mouth and throat soreness and related sequelae.
- The observed safety profile of Kepivance® is predictable, manageable, and appropriate for a supportive care agent.
- No differences in overall survival, time to progression, or progression free survival rates have been observed between Kepivance® and placebo groups for up to 2 years of follow-up. Significantly, no differences in the incidence of secondary malignancies have been observed between the Kepivance® and placebo groups.
In the evaluation of supportive care drugs such as Kepivance®, it is important that in the design of studies one is able to differentiate between the toxicities associated with the underlying disease and its therapy from the toxicities associated with new supportive agent. This was well addressed in the safety evaluation of Kepivance®. The design of the pivotal clinical trials as double blinded, placebo-controlled, randomized trials, and the implementation of appropriate sensitivity analyses addressed these safety issues effectively and allowed the definition of the safety profile associated with Kepivance®. The number of patients analyzed in the pooled data exceeds 1000 and thus provides sufficient power and validity to the safety conclusions.
In general Kepivance® was well tolerated. Most of the severe AEs were related to the haematological malignancies and their treatment with high dose myelotoxic therapy and HSC support. These were equal in both the Kepivance® and placebo groups. Toxicities related to Kepivance® were clearly identified and were the result of the pharmacologic effects of Kepivance®. These included mainly oral and cutaneous effects. They were mild to moderate in severity, were reversible and did not lead to drug discontinuation.
Data did not indicate any deleterious effect of Kepivance® on bone marrow recovery or any effect of Kepivance® on the effectiveness of therapy administered to haematological malignancies.
No neutralizing antibodies were identified in any of the patients treated with Kepivance®.
Other specific toxicities were addressed effectively, albeit with certain limitations due to either insufficient numbers or, more particularly, an insufficient period of follow up. A particular concern regarding growth factors is that they may enhance the growth of existing tumours, promote the growth of new tumours, or protect tumours against the cytotoxic effects of chemo/radiotherapy. Kepivance® stimulates the growth of epithelial cells through the KGFR. In some in vitro and in vivo non-clinical models, palifermin has been shown to enhance the growth rate of human cancer tumour cell lines, however, the effects of palifermin appear to be limited to those tumour cells demonstrating expression of the KGFR.
It was recommended that in a post-marketing phase, the following be undertaken:
- Monitoring of the incidence of secondary malignancies, in particular epithelial tumours known to express KGFR.
- Monitoring of the long term effect of Kepivance® on organs known to express KGFR such as the cornea and pancreas.
- Provide results of the ongoing study in patients with impaired renal function.
- Provide updates on the long-term follow up study.
- Evaluate the development of neutralizing antibodies to palifermin over a longer period of time.
- Optimize Kepivance® schedule with confirmation of the value of the post-dose component and evaluate shorter or higher single-dose schedules, taking into account the PK and PD properties of Kepivance®.
- Evaluate Kepivance® therapy in elderly patients and in ethnic groups not adequately represented in the clinical studies.
- Ongoing monitoring for any long-term unforeseen AEs.
Kepivance® was reviewed under the Priority Review Policy, taking into consideration the debilitating nature of the indication and the fact that no other drug is presently marketed in Canada to decrease the incidence, duration, and severity of oral mucositis in patients with haematologic malignancies receiving myelotoxic therapy requiring HSC support.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Kepivance® is favourable to decrease the incidence and duration of severe oral mucositis in patients with haematologic malignancies receiving myelotoxic therapy and requiring haematopoietic stem cell support. 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: Kepivance®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2004-06-29 |
| Request for priority status | |
| Filed: | 2004-06-14 |
| Approval issued by BGTD: | 2004-07-07 |
| Submission filed: | 2004-07-19 |
| Screening | |
| Screening Acceptance Letter issued: | 2004-08-13 |
| Review | |
| On-Site Evaluation: | 2004-09-21 - 2004-09-24 |
| Quality Evaluation complete: | 2005-10-13 |
| Clinical Evaluation complete: | 2005-11-30 |
| Labelling Review complete: | 2005-11-24 |
| NOC issued by Director General: | 2005-12-09 |