Summary Basis of Decision for Sebivo
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:
Sebivo
Telbivudine, 600 mg, Tablets (film-coated), Oral
Novartis Pharmaceuticals Canada Inc.
Submission control no: 104469
Date issued: 2008-04-18
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), PrSEBIVO*, Telbivudine, 600 mg, comprimés, Novartis Pharmaceuticals Canada Inc., No de contrôle de la présentation 104469
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):
- 02288389
Therapeutic Classification:
Non-medicinal ingredients:
Tablet coating: titanium dioxide, polyethylene glycol, talc, hypromellose
Submission type and control no:
Control No. 104469
Date of Submission:
Date of authorization:
* Trademark
2 Notice of decision
On November 28, 2006, Health Canada issued a Notice of Compliance to Novartis-Pharmaceuticals Canada Inc. for the drug product Sebivo*.
Sebivo* contains the medicinal ingredient telbivudine, a thymidine nucleoside analogue, which is an antiviral agent.
Sebivo* is indicated for the treatment of chronic hepatitis B virus (HBV) in adults 16 years and older with compensated liver disease and evidence of viral replication and active liver inflammation. HBV is a serious disease that attacks the liver and can cause infection, cirrhosis or scarring, liver cancer, liver failure, or death. Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase, thereby preventing the virus from replicating.
Priority Review status was granted for the evaluation of Sebivo* as it appeared to provide a significant increase in efficacy for a serious, life-threatening, or severely debilitating illness not adequately managed by a drug marketed in Canada. Telbivudine indicated a potential superiority to lamivudine in Hepatitis B e antigen positive patients for both a primary endpoint of therapeutic response and also for histologic response.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. Safety and efficacy were examined in one active-controlled pivotal study comprised of 1367 treatment-naive patients, aged 16 years and over. In HBV antigen positive patients, significantly higher response rates for therapeutic, histologic, and virologic responses were observed over lamivudine. In HBV antigen negative patients, therapeutic response and histologic response were non-inferior to those of lamivudine, while virologic response was superior to lamivudine.
A risk of muscular adverse events and associated creatine kinase (CK) elevations was observed in conjunction with the use of Sebivo*, including cases of myopathy, muscle weakness, and muscle pain. A warning about the risk of muscular adverse events has been included in the Product Monograph, including cautionary statements regarding co-administration with other drugs known to cause myopathy.
Sebivo* (600 mg, telbivudine) is presented as film-coated tablets. The recommended dose of Sebivo* for the treatment of chronic HBV is 600 mg once daily, taken orally, with or without food. The optimal treatment duration has not been established. Dose interval adjustment is recommended in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min), including those with end stage renal disease (ESRD) on hemodialysis. Dosing guidelines are available in the Product Monograph.
Sebivo* is contraindicated in patients with previously demonstrated hypersensitivity to telbivudine or any component of the product. Sebivo* 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 Sebivo* 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 Sebivo* is favourable for the treatment of chronic hepatitis B in adults 16 years and older with compensated liver disease and evidence of viral replication and active liver inflammation.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Telbivudine, the medicinal ingredient of Sebivo is an antiviral agent for the treatment of hepatitis B virus (HBV). HBV is a serious disease that attacks the liver and can cause infection, cirrhosis or scarring, liver cancer, liver failure, or death. Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase, thereby preventing the virus from replicating.
Manufacturing Process and Process Controls
Telbivudine is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Detailed characterization studies were performed to provide assurance that telbivudine consistently exhibits the desired characteristic structure. Results from process validation studies also indicate that the methods used during processing adequately control the levels of product and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
The structure of telbivudine has been adequately explained and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory. Comparability of telbivudine lots produced by three different manufacturers, different processes, and different clones was performed and comparable physicochemical characteristics and immunoreactivity were demonstrated.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of the drug substance. The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and were within the proposed acceptance criteria.
The drug substance packaging is considered to be acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed retest period, shelf-life, and storage conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Sebivo* 600 mg film-coated tablets are an immediate-release dosage form for oral administration. The dosage form consists of a white to slightly yellowish, ovaloid, slightly curved film-coated tablet with bevelled edges, debossed with "LDT" on one side. Sebivo* is packaged in polyvinylchloride (PVC) blister packs backed with a heat-sealed aluminium lid foil.
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of telbivudine with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Sebivo*, manufacturing process including packaging, information on batches used in in vitro studies for characterization, rationale for choice of formulation, and discussion on the effect of formulation change on the safety and/or efficacy of Sebivo*. Changes to the manufacturing process and formulation made throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
The drug product is formulated, blended, compressed, coated, and packaged. The specifications for all of the ingredients are either approved in accordance with USP/NF or Ph. Eur. standards.
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 and can consistently yield a drug product which meets the pre-determined quality characteristics.
Control of Drug Product
Sebivo* is tested to verify that the identity, appearance, purity, content uniformity, and the levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are satisfactory and justify the specifications of the drug product.
Stability
Based upon the real-time and accelerated stability data submitted, the proposed 24-month shelf-life at 15-30°C for Sebivo* is considered acceptable. Sebivo* is photostable.
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
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations. The facilities involved in the production of Sebivo* are rated Good Manufacturing Practices (GMP) compliant for the manufacturing activities conducted.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Sebivo* 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
Preliminary primary pharmacodynamic (PD) studies showed that telbivudine was effective in reducing virion-associated extracellular HBV DNA production in the human hepatoma cell line 2.2.15 (routinely used to determine the anti-HBV activity of potential antiviral agents) with a mean effective concentration (EC50) of 0.19 μM and an EC90 of 0.98 μM. Telbivudine, however, did not inhibit replication of any viruses other than HBV and duck hepatitis B virus (DHBV) in vitro, including human immunodeficiency virus type-1. When tested against transfected mutant and wild-type HBV producer cell lines, telbivudine exhibited slightly better activity against the N236T mutant than the wild type with lesser changes than lamivudine and adefovir.
Telbivudine failed to exhibit antiviral activity against the m204I and L180M/m204V mutants (changes to wildtype were >1360±363 fold) and demonstrated only marginal activity against the L180M/m204I double mutant (change of >1049±226 fold). However, against the m204V virus alone, telbivudine retained almost full activity. Telbivudine had preferential inhibition against HBV nucleocapside-producing 2.2.1.5 cells compared to lamivudine, but lamivudine was a preferential inhibitor in HBV minus (-) DNA strand synthesis.
Telbivudine was 8.8-fold more potent in inhibiting replication in growing cells than in resting cells. When tested against woodchuck hepatitis virus (WHV), telbivudine produced significant dose-dependant viral load reductions (up to 8 logs between days 14 and 28) and decreases in woodchuck hepatitis surface antigen (WHsAg) levels. These decreases were superior to the comparator, lamivudine.
Telbivudine showed no signs of cytotoxicity in human peripheral blood mononuclear cells or in numerous other cell lines of human and mammalian origin including human bone marrow cells and HepG2 cells.
Telbivudine was shown to be negative for adverse effects on the respiratory, cardiovascular, and central nervous system (CNS) function tests in rats and monkeys. Additionally, in human ether-a-go-go-related gene (hERG) cells in vitro, no effects on hERG currents were observed. The sponsor performed the minimum battery of safety pharmacology tests according to the ICH S7 guidelines; these were cardiovascular, respiratory, and CNS safety. Due to the fact that there are no outstanding pharmacological effects associated with this class of drug, these tests are considered acceptable. The lack of cytotoxicity and lack of effect on respiratory and cardiovascular parameters suggest little effect on mitochondrial function and the potential for lactic acidosis.
3.2.2 Pharmacokinetics
Absorption
Telbivudine was reasonably well absorbed with the absorption ranging from 34.9-43.4% in woodchucks, 57.4-63.5% in rats, and approximately 59% in monkeys. Levels of the drug exposure parameters Cmax and AUC differed among the species tested; a 10mg/kg dose in rats produced Cmax concentrations ranging between 1520 and 1620 ng equivalents/mL, and approximately 8.58 μM. in woodchucks. Tmax generally ranged from 1.67 hours in monkeys to approximately 3 hours in woodchucks. Plasma concentrations were found to decline rapidly after Tmax in monkeys. In rabbits, systemic exposure appeared to be dose-proportional up to 250 mg/kg/day but not beyond. Cmax values in rabbits were 12.3, 38.9, and 66.4 μg/mL based on 50, 250, and 1000 mg/kg/day doses, respectively. Telbivudine exposure in the fetuses of pregnant rabbits was similar to the concentration in circulating plasma. Telbivudine had medium permeability of Caco-2 cell monolayers and traverses by passive diffusion or paracellular diffusion due to high water solubility.
Distribution
When administered to rats, radiolabelled telbivudine was extensively distributed and detected in all areas of the body by 3 hours post-dose and cleared by 72 hours post-dose. Tissues with the highest concentrations were the small and large intestine, urinary bladder, kidneys, prostate gland, mesenteric lymph nodes, stomach, and pancreas. The lowest concentrations were found in the spinal cord. Telbivudine was able to cross the blood/brain and blood/testes barriers. Telbivudine did not appear to bind to melanin. Exposure of telbivudine increased with dose up to 4.0 g/kg in rats but became less than dose-proportional after this. This may be due to absorption site saturation. Plasma protein binding was generally low in rat, monkey, and human plasma and was independent of concentration.
When radiolabelled telbivudine was administered to pregnant and lactating rats, radioactivity was detected in maternal tissues, fetal tissues, whole fetuses, milk, and plasma through 8 hours post-dose. Exposure was highest in the kidneys, liver, uterus, placenta, and ovaries, and lowest in the brain. Fetal brain concentrations exceeded maternal brain concentrations but otherwise fetal tissues had the lowest concentrations.
Metabolism
When tested in human hepatic microsomal cytochrome P450 enzymes, telbivudine was shown to not be an inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. A slight decrease in P450 content was noted in rats but no changes in EROD (CYP1A), PROD (CYP2B), END (CYP3A), or LAH (CYP4A) activities were observed. The slight decrease was not treatment-related, so telbivudine is not considered a P450 inducer.
In rats, telbivudine was excreted primarily in unchanged form and only one metabolite was found in urine or feces (M4) in trace amounts. No metabolites were observed in monkeys.
Telbivudine was metabolized to the 5'-monophosphate, 5'-diphosphate and 5'-triphosphate derivatives, with the 5'-triphosphate being the predominant intracellular metabolite. Formation of phosphate derivatives occurred in a dose-dependent manner.
Excretion
Urinary excretion was found to be the primary excretion pathway and accounted for 67.6-72.8% of the excreted dose after a 10 mg/kg dose in rats. Telbivudine was also found to be secreted in milk at levels comparable to plasma concentrations.
3.2.3 Toxicology
Acute Toxicity
Telbivudine was tested in acute toxicity studies in rats and monkeys. No significant or drug-related effects were noted in rats at doses up to 2000 mg/kg. In monkeys, some changes in hematology parameters were noted on day 17 in the treatment animals. These included decreases in erythrocyte, hemoglobin, and hematocrit values; additionally, incidents of anisocytosis, poikilocytosis, hypochromasia, and/or polychromasia were noted. Increases in leukocytes and neutrophils were also seen in some animals. Minor decreases in alkaline phosphatase and potassium were also noted. None of these events were attributed treatment. The no observed adverse effect level (NOAEL) in monkeys was 2000 mg/kg.
Repeat-Dose Toxicity
The repeat-dose toxicity testing was acceptable according to ICH guidelines, which recommends a 6-month rodent study and a 9 month non-rodent study.
The longest repeat-dose study was the 9-month study in monkeys. The NOAEL was
1000 mg/kg which produced a Cmax ranging from 29.1 to 31.7 μg/mL, a Tmax of approximately 2 hours, and an AUC ranging from 168 to 339 μg/hr/ml. A toxicokinetic analysis for the 6-month rodent study was not provided, however exposures in rats from the 28-day study showed that a 1000 mg/kg dose resulted in a Cmax ranging from 29.6 to 45.3 μg/mL, an AUC from 167 to 212 μg/hr/mL and a Tmax of approximately 1-2 hours. Exposures at doses comparable to those in the 6-month study would be well above human therapeutic levels.
Statistically significant and potentially treatment-related effects that were most commonly observed in the repeat-dose toxicity studies included the following:
a) Hematology
Statistically significant increases in leukocyte and lymphocyte counts were noted in male mice that received high doses (2000 mg/kg) of telbivudine. At the same dose, female mice also had elevated erythrocyte counts, hemoglobin concentrations, and hematocrit values. In rats, decreases in mean absolute polymorphonuclear neutrophil counts were observed in males given 2000 mg/kg. In the 6-month chronic toxicity study in rats, decreases in eosinophils and absolute and relative values for large unstained cells were noted, as well as increases in absolute white blood cell counts. Statistically significant increases in prothrombin (PT) time were also noted in male rats that recieved the high dose. In the 9-month toxicity study in monkeys, significant changes in lymphocyte counts were noted at day 273, although the sponsor notes these changes were mostly influenced by one animal and were not common in other monkey studies. These changes mostly occurred at high dose levels of the drug, but there was little pattern in their occurrence.
b) Organ Effects
In the 13-week oral gavage study in mice, statistically significant increases in mean liver/gall bladder weights were noted in high-dose females. Spontaneous lesions were noted in the liver, kidneys, adrenal glands, and ovarian cysts. These effects were not considered to be related to the study drug.
In rat studies, statistically significant increases in adrenal gland weights were noted in mid- and high-dose females. In the 6-month toxicity study in rats, predominantly at higher doses, brain weight was noted to have increased while kidney, heart, lung, and salivary gland weights decreased. No pattern was detected in these effects and therefore they were not considered toxicologically relevant. Incidences of apoptosis/single cell necrosis, inflammatory cell infiltration, and acinar cell atrophy in the pancreas and interstitial nephritis and inflammation of the urinary bladder were also observed in one rat study at higher doses.
In the 9-month monkey study, a decrease absolute brain weight was noted in high-dose males. Additionally, two high-dose females at the three-month necropsy and one at the nine-month necropsy had sciatic nerve degeneration. The sponsor had no explanation for this effect.
c) Laboratory Parameters
Significant changes in laboratory parameters in mice included increases in albumin, total protein, globulin, AST, and ALT values. These changes were not considered to be treatment-related.
In the 6-month chronic toxicity study in rats, increases in serum chloride and sodium, total protein, alkaline phosphatase and decreases in albumin/globulin were observed. The changes occurred at the high-dose levels and were generally small, and therefore not considered toxicologically relevant.
In the 28-day study in monkeys, slight increases in ketone and protein levels in urine were noted but considered to be unlikely to be related to the study drug. In the 9-month monkey study, decreases in alkaline phosphatase and chloride at 83 days were noted in the mid- to high-range dose groups.
d) Cardiovascular effects
Mild QT-QTc prolongation in one high-dose male and female in the 14-day monkey study were noted but were not observed in any other animals or studies. This event was not considered related to the test drug telbivudine.
Genotoxicity
Telbivudine was found to be non-genotoxic in Salmonella typhimurium / Escherichia coli mutation assays and chromosome aberration tests in Chinese hamster ovary cells at concentrations up to 5000 µg/plate. In the chromosome aberration tests, there were no statistically significant increases in the incidence of cells with aberrant metaphases at levels up to 2422 µg/mL, although some inhibition was noted at the highest dose levels. Overall, telbivudine was determined to be negative for genotoxicity.
Carcinogenicity
The ICH requirements for non-clinical carcinogenicity studies have been satisfied in that the sponsor has conducted one 2-year study in rats (an acceptable rodent model) as well as a 26-week study in CBgF1-TgrasH2 transgenic mice.
In the 2-year rat study, telbivudine was administered for 85 weeks at a dose of 2000 mg/kg/day, 95 weeks at 1000 mg/kg/day, and 104 weeks at 500 mg/kg/day. Dosing at 2000 mg/kg/day was stopped at week 85 due to high mortality. Although there was no evidence of increased neoplasia-related mortality associated with treatment, the main cause of death in all groups (including control) was neoplasm. There was a comparable incidence between the control and treated groups. Other deaths in this study were a result of chronic progressive rat nephropathy that occurred in 12% of the 1000 mg/kg/day group and 14% of the 2000 mg/kg/day group in males (to a lesser extent in females). This event was fairly common and is also a common disease in aging rats, although the sponsor acknowledges that treatment may have enhanced the progression of the disease due to renal clearance being the primary route of excretion of the drug.
Secondary effects of nephropathy affected the aorta, lung, stomach, heart, and femurs in the high-dose groups. Pelvic calculi and lymphoid depletion of the spleen were also noted in the high-dose groups and were found in many of the deaths. Microscopically, the tissues from all groups showed no evidence of increased oncogenicity associated with treatment. Neoplasms observed included pituitary adenomas, pheochromocytomas, thyroid c-cell adenomas, and mammary gland fibroadenomas and carcinomas, but there was no increased incidence associated with treatment. Increased pancreatic acinar cell adenomas were noted in male rats at the 500 and 2000 mg/kg/day doses. The incidence of this event was higher in the 2000 mg/kg/day but still within historical range for the species. The study NOEL was 500 mg/kg/day.
The 26-week study in transgenic mice demonstrated statistically significant increases in the incidence of tumours up to the 2000 mg/kg/day dose group. In this study the Cmax ranged from 43.0 to 131 μg/ml with both Cmax and AUC increasing with dose level. These dose levels are higher than the expected human exposure.
Reproductive and Developmental Toxicity
In studies of treatment effect on fertility and early embryonic development in rats, telbivudine treatment showed no changes in mating or fertility parameters at doses up to 1000 mg/kg/day. The only noted effects of treatment were a significantly increased number of rats with soft or liquid feces in the 1000 mg/kg/day group, and increases in body-weight gains and feed consumption in all groups. A slight reduction in fertility was noted in the 500 and 1000 mg/kg/day dose groups but these results were within historical range. Minor fetal alterations were observed and included folded retinas, undescended testes, dilation of the renal pelvis, and some skeletal abnormalities, however none of these changes were dose related and were considered unrelated to treatment. The NOAEL was 1000 mg/kg/day.
In the examination of embryo-fetal development in rabbits there was an increased incidence of abortion and early delivery (day 29) in the 1000 mg/kg/day dose group. These events were accompanied by maternal toxicity which included scant feces, ungroomed coat, weight loss, and localized alopecia. Abnormal feces events were significantly increased in the 1000 mg/kg/day group. Additional toxicity also included significant body-weight loss and reductions in feed consumption.
Alterations in fetuses included irregular ossification of the skull, reduced metacarpals, distended aorta, and displaced innorminate artery. These were not considered treatment-related however, and the NOAEL was set at 250 mg/kg/day due to body weight alterations. The 1000 mg/kg/day dose caused a slight increase in the incidence of abortion and early delivery of litters. This was likely an effect of the reduced feed consumptions and gastrointestinal (GI) effects. The developmental NOAEL was 1000 mg/kg/day.
No effects related to maternal treatment were noted in the F1 rats in the pre-natal and post-natal development studies. Effects that were observed in the F1 generation included small, flaccid purple testes in a 1000 mg/kg/day rat and distended small intestine in a 100 mg/kg/day rat. Observations of laboured breathing, swollen snout, misaligned incisors, chromodacryorrhea, decreased motor activity, and ungroomed coat were noted in some F1 males and females but were not considered treatment-related as they were not dose-dependent and occurred only sporadically. Delays in mating were observed in the 100, 250, and 1000 mg/kg/day groups vs. control but these changes were not considered biologically significant.
3.2.4 Conclusion
Telbivudine was tested in acute toxicity studies in rats and monkeys. No significant or drug-related effects were noted in rats at doses up to 2000 mg/kg. Repeat-dose toxicity studies included a 6-month rat study and a 9-month monkey study as well as some shorter duration studies in rats and mice. The NOAEL was determined to be 1000 mg/kg in most species. Statistically significant toxicological effects included increases in leukocytes and lymphocytes and increases in prothrombin time in mice at high doses (216% to 252% of control). The main organs of toxicity appeared to be the liver and adrenal glands. Incidents of unexplained sciatic nerve degeneration were noted in some high dose monkeys.
Carcinogenicity studies of 104 weeks were conducted in rats at doses up to 2000 mg/kg/day. The 2000 mg/kg/day dose was discontinued at week 85 due to high mortality. The main cause of death in all groups of this study was neoplasm, however the incidence between treatment and control groups was comparable. Carcinogenicity studies of 26 weeks in transgenic mice were also conducted and showed a statistically significant increase in the incidence of tumours at the 2000 mg/kg/day dose. This dose, however, was well above the expected human exposure levels.
An increased rate of abortion and early delivery were noted in rabbits at the 1000 mg/kg/day dose in the embryo-fetal development studies and these incidents were accompanied by signs of toxicity that included scant feces, ungroomed coat, weight loss, and localized alopecia.
Overall, the non-clinical toxicity studies were acceptable and adequately met ICH requirements.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology/Bioequivalence
The initial dose-ranging clinical study of telbivudine utilized tablets of 25, 100, and 200 mg strengths to cover the range of daily doses examined, from 25 to 800 mg/day. Based on dose-response data, the telbivudine dose of 600 mg once a day was selected for use in Phase III clinical studies. The 600 mg dose was administered as 3 x 200 mg Clinical Service Formulation (CSF) tablets. The 200 mg CSF tablet was used in most clinical pharmacology studies, i.e. Phase IIb and Phase III studies. A 600 mg tablet formulation was developed to provide dosing convenience in the form of a single, once-daily tablet. Two formulations of uncoated 600 mg tablets (designated as variants 005 and 006) were selected and tested in pilot comparative bioavailability study NV-02B-014. Both variants were found to exhibit comparable rate and extent of absorption to the 200 mg CSF tablet formulation and to an oral solution formulation (20 mg/mL). Formulation variant 005 was selected for further testing in the pivotal comparative bioavailability study NV-02B-025. Further, an effect of food on the pharmacokinetics of telbivudine was examined in study NV-02B-008.
The results of the pilot comparative bioavailability study NB-02B-014 met the recommended standards for comparative bioavailability based on both measured data and potency-corrected data: the 90% confidence interval of the relative mean of AUC0-32 and the relative mean Cmax of the proposed FMI formulations (i.e., FMI-1 and FMI-2 600 mg tablets) as compared to 3 x 200 mg CSF tablet formulation were within 80 to 125%.
The results of the pivotal comparative bioavailability study NV-02B-025 demonstrated that the rate and extent of absorption from the proposed FMI 600 mg tablets (administered as 1 x 600 mg) as compared to the CSF 200 mg tablets (administered as 3 x 200 mg) are comparable under fasted conditions: the 90% confidence interval of the relative mean of AUC0-72 and the relative mean Cmax of FMI 600 mg tablets as compared to 3 x 200 mg CSF were within 80 to 125% calculated from the measured data, and data corrected for measured drug content.
Absorption
Following oral administration of a 600 mg single dose of telbivudine to healthy subjects, the peak plasma concentration (Cmax) was 3.69 ug/mL and occurred at a median of 2.0 hours post-dose. Absorption and exposure were unaffected when telbivudine was administered with food.
Distribution
In vitro binding of telbivudine to human plasma proteins was low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues.
Metabolism
No metabolism or metabolite formation was detected.
Excretion
Telbivudine is renally excreted, and is considered to have a long elimination half-life. Based on the clinical PK data, it was determined that a dosage adjustment is recommended in patients with renal impairment (with creatinine clearance <50 mL/min). A dosage interval adjustment has been recommended in the Product Monograph as a 600 mg film coated tablet is the only formulation available at the present time.
Drug-Drug Interactions
Telbivudine is neither a substrate nor an inhibitor of human hepatic CYP450, thus it is unlikely to interfere with co-administered drugs that are metabolized via the liver. Thus, the sponsor focussed the drug-drug interaction studies on drugs that are likely to be co-administered with telbivudine on a chronic basis, e.g, other HBV treatments such as nucleoside/nucleotide antivirals (LAM, adefovir dipivoxil), peginterferon alfa-2a, and cyclosporine (an immunosuppressive used in HBV-infected patients undergoing solid organ transplantation or with autoimmune disorders). The PK of telbivudine does not appear to be affected by co-administration with other antiviral drugs; however, telbivudine did increase the Cmax of CsA and both the Cmax and AUC of PegIFN. No conclusions can be made with respect to an interaction or lack thereof between LAM and telbivudine as only a sub-therapeutic dose (200mg) of telbivudine was used. In addition, the results of the interaction between CsA and telbivudine are also dubious because a low (maintenance) dose of CsA was used. The PK information has been expanded in the Product Monograph to provide more detail including the limitations of the studies (e.g., low doses).
3.3.2 Clinical Efficacy
The clinical program for Sebivo* consisted of a single pivotal trial, Study 007, enrolling more than 1300 patients. The non-pivotal clinical study (Study 003), a dose-confirmatory study, was divided into five arms of approximately 20 patients each. The large pivotal trial included both HBe antigen-positive and HBe antigen-negative patients, but the smaller non-pivotal trial included HBe antigen-positive patients only. Though the demonstrated efficacy for telbivudine in compensated HBV patients with evidence of viral replication is based only on a single large pivotal study, this was considered acceptable, although not ideal. There were no completed clinical studies in patients with decompensated liver disease, co-infected patients (HIV or hepatitis C/D), or patients in the transplant setting. There were also no studies in patients with lamivudine resistance.
Novel Endpoint for Anti-HBV Agent
The primary endpoint in the pivotal trial (Study 007) was a novel composite endpoint, termed Therapeutic Response. This was defined as HBV DNA suppression to <5 log10 copies per mL combined with either HBe antigen loss or ALT normalization. All other anti-HBV agents up to this time used histology as the primary endpoint. Secondary endpoints included histologic response, and individually each of the three elements of the composite endpoint: reduction in HBV DNA, ALT normalization, and HBe antigen seroconversion. This is important to note because, as mentioned previously, histology has been the standard primary endpoint in clinical trials for other anti-HBV agents, and the novel endpoint used in this trial is the first time this endpoint has been used in a clinical trial of an anti-HBV therapeutic agent. Since it appears that this composite endpoint is not really a composite endpoint, but more accurately only reflects HBV DNA reduction, there is truly a greater need for consensus as to whether this is an acceptable endpoint. Although this endpoint is convenient, non-invasive, and capable of providing multiple measurements over time, the clinical utility and correspondence with histological evidence has not been widely established.
Differential Results Based on HBe Antigen Strata
Results from Study 007 were presented separately for HBe antigen-positive and HBe antigen-negative patients because significant statistical interactions were found between the patients' pre-treatment HBe antigen status (positive or negative) and the results of Therapeutic Response and Histologic Response. Overall, at Week 52, 75.3% of telbivudine-treated patients achieved a primary endpoint of Therapeutic Response compared to 67% of lamivudine-treated patients. In the HBe antigen-negative patients, 75.2% of telbivudine-treated patients achieved a Therapeutic Response at Week 52 compared to 77.2% of lamivudine-treated patients.
With regards to the primary endpoint, when the data was subanalyzed for the strata HBe antigen-negative patients with ALT levels >2.5x the upper limit of normal (ULN), telbivudine did not meet the non-inferiority criteria in comparison to lamivudine. In all three other strata of this subanalysis, (HBe antigen-positive patients [2 strata] and HBe antigen-negative patients with ALT levels <2.5x ULN), telbivudine was able to meet the established criteria for non-inferiority.
Histology
Histology, which has been the primary endpoint for all other anti-HBV drugs, was only a secondary endpoint in this submission. With regards to reduction in necroinflammatory scores for histological evaluation, telbivudine was found to be non-inferior to lamivudine for HBe antigen-negative patients and HBe antigen-positive patients. For HBe antigen-positive patients, 64.7% of telbivudine-treated patients achieved histologic response compared to 56.3% of lamivudine-treated patients, and in the HBe antigen-negative patients, 66.% in each arm achieved histologic response. However, based on Ishak fibrosis data, a greater percentage (not powered to provide a statistical comparison) of patients were found to have worsening Ishak fibrosis scores. This finding was difficult to evaluate further due to the lack of statistical analysis available.
Resistance
Study NV-02B-007 examined a panel of aligned, full HBV RT sequences from 1369 patients (out of 1376 enrolled patients) at baseline and then after 104 weeks of therapy. At baseline, the sponsor reported that the most prevalent genotypes seen in the study were genotype C (695 pts, 50.77%); genotype B (359 pts, 26.22%); genotype D (217 pts, 15.85%) and genotype A (81 pts, 5.92%).
The results of this analysis revealed more clinical virologic breakthrough in the lamivudine treatment group than in the telbivudine treatment group (10.4% for HBe-positive and 8.5% for HBe-negative vs. 3.4% and 2.1%, respectively). In the telbivudine resistant patients, the majority (94%) were genotype M204I and none were M204V. In the lamivudine resistant group, 48% were genotype M204I, 29% were M204V, and 23% were mixed M204 mutants. Due to the fact that the majority of treatment-emergent resistance in both groups was based on the M204I mutant, the possibility of conferred resistance cannot be eliminated. Telbivudine appeared to be less susceptible to resistance development as there were fewer subjects who experienced treatment-emergent resistance in the telbivudine group than in the lamivudine group (62/81 breakthrough subjects were in the lamivudine group and 19/81 were in the telbivudine group).
When comparing the telbivudine vs. lamivudine therapy, telbivudine therapy appeared to completely eliminate the M204V resistance category, remove most of the M204 mixed mutant population, and modestly shrink the M204I-based resistance. However, it is important to note that there were fewer incidents of treatment resistance in the telbivudine group, and of the ones that did develop resistance, 94% of them were of the M204I genotype. The more appropriate conclusion is not that telbivudine shrinks the occurrence of the M204V mutations, more that it is simply prone to resistance from the M204I mutation. It was further noted that the M204V variant seen in lamivudine resistance was clearly associated (100%) with a second mutation, L180M. The mutation was previously documented as a compensatory mutation that improves the replication of the 204I mutant HBV. Since lamivudine resistance is based on both the M204V/L180M mutation and the M2041 mutation, it appears very possible that lamivudine-resistant mutations could confer considerable telbivudine resistance as 94% of breakthrough resistance on telbivudine was associated with M2041. When considering clinical use of the drug, this would suggest that telbivudine would only be useful as a first-line therapy and could possibly leave the patient lamivudine-resistant if telbivudine therapy failed. It is important to note though, that in the lamivudine-resistant patients, the L180M mutation was only found in two M204I resistant lamivudine patients. This suggests a lack of contribution of the L180M mutation to M204I resistance, however this is difficult to interpret conclusively.
Another study, Study IDIX-04-189, examined the activity of telbivudine in vitro against lamivudine-resistant mutants of HBV. This study showed that the M204V and M204I mutants typically appeared 4 to 8 weeks prior to the emergence of the highly resistant L180M/M204V double mutant. The L180M/M204V double mutant accounts for 60-70% of all lamivudine resistance in hepatitis B patients. Telbivudine failed to exhibit antiviral activity against the M204I, L180M, and M204V mutants (changes to wild-type were >1360±363 fold) and demonstrated only marginal activity against the L180M/M204I double mutant (change of >1049±226 fold). Against the M204V virus alone however, telbivudine retained almost full activity (changes of 1.2 and 2.1 fold, respectively). The data from this in vitro study combined with the data from the single clinical study suggest that telbivudine would only be effective in treating patients who have no resistance, or patients who have lamivudine resistance based only on a M204V mutation. No subjects in the NV-02B-007 registration trial developed lamivudine resistance based solely on the M204V mutation; it was 100% accompanied by the L180M mutation. This data suggests that telbivudine would have limited clinical benefit.
Mutations at codon 80 appeared to play a significant role in M204I resistance overall with L80I or L80V seen in 68% of lamivudine M204I-resistant subjects. The sponsor notes that outside of codons 80 and 180, the more frequent secondary mutations associated with specific resistance patterns were codons 91, 135, and 207 for M204I telbivudine resistance; codons 91, 269, 106, 221 and 238 for M204I lamivudine resistance, and 124 for M204V lamivudine resistance. Codon 91 is associated with resistance to both drugs and shows a very high variability both between and within genotypes so its impact on overall resistance to either drug is difficult to interpret. It is possible that codons 80, 180, and 204 played the most significant role in virologic breakthrough as they were the most frequently mutated with 39, 27, and 69 change from baseline.
In the genotypic resistance vs. wild-type breakthrough analysis it was found that two of the 19 telbivudine-resistant subjects were pure wild-type and had failed therapy without resistance. Of the 62 lamivudine-resistant subjects, ten were pure wild-type or had genotypic changes that were not linked to resistance. This resulted in 89.5% of telbivudine breakthrough subjects being due to genotypic resistance, and 83.9% of lamivudine breakthrough subjects being due to genotypic resistance (no statistically significant difference). Therefore, telbivudine therapy shows no advantage over lamivudine therapy with respect to genotypic resistance.
3.3.3 Clinical Safety
CK elevations and Muscle Toxicity Associated with Telbivudine
The risk of musculoskeletal toxicity associated with telbivudine is a safety concern. Based on the available safety data thus far, there have been 17 patients who discontinued or who had their dose interrupted due to creatine kinase (CK) elevations associated with musculoskeletal adverse events (AEs) due to telbivudine treatment compared to one case due to lamivudine treatment. The majority of these cases were in the large pivotal trial, Study 007. The other cases were reported in ongoing studies not included in this submission.
Some of the patients (3) who experienced CK elevations and musculoskeletal events had muscle biopsies performed. One muscle biopsy reported partial rhabdomyolysis. Another confirmed muscle damage with myofibrillary degeneration. The third muscle biopsy was normal. The majority of these cases developed after several months of treatment with telbivudine. Most did not have urinary or serum myoglobin levels measured. Of the one case that did, serum myogloblin was slightly elevated. Additionally, in Study 003, a patient with numbness in the toes at Day 222 of drug treatment and a possible drug induced neuropathy diagnosis was reported. This patient also had accompanying CK elevation.
These results indicate that telbivudine is toxic to muscle. It needs to be kept in mind that muscle toxicity has a clinical spectrum ranging from mild, annoying symptoms to moderate physical impairment to rhabdomyolysis, a potentially life-threatening condition. Although there have not been cases of rhabdomyolysis reported with telbivudine, other than the case of partial rhabdomyolysis seen on muscle biopsy, the safety database may not be large enough to detect all serious AEs. The population receiving telbivudine in the clinical drug development program was not large, approximately 1500 patients. In addition, the large number of discontinuations or dose interruptions of telbivudine compared to lamivudine due to CK elevations associated with musculoskeletal AEs indicates that the tolerability of telbivudine may not be acceptable to a subset of patients. Whether a dose interruption or a study drug discontinuation occurs, either outcome can potentially lead to a post-treatment ALT flare, a potentially severe consequence of discontinuing a nucleoside (such as telbivudine) used to treat chronic Hep B infection. A warning has been included in the Product Monograph regarding the potential for these musculoskeletal events.
Nucleoside Analogue Class Effects
Lactic acidosis is a potential AE with the use of any nucleoside analogue. Lactic acidosis is a serious and potentially life-threatening event.
Risk of ALT Flare After Discontinuation of Anti-Hep B Therapy
There is a risk of hepatic flare after discontinuation of telbivudine. This can be a serious event and potentially life-threatening.
Effects on Other Organs
Telbivudine does not appear to be hepatotoxic. There were no reported cases of liver dysfunction in compensated patients. No data was provided however, for patients with existing hepatic dysfunction.
Telbivudine dose not appear to cause renal toxicity. However, since telbivudine is excreted in the urine, dose adjustments should be made in patients with renal impairment and caution should be used in patients who are taking concomitant medications which may affect renal function.
Telbivudine does not appear to cause QT prolongation and cutaneous effects were minimal (occasional cases of rash).
Adverse Events
Common non-serious AEs included fatigue, headache and dizziness, nausea, and diarrhea.
Comparative data past 52 weeks is limited. Long-term safety data from patients with greater than 1 or 2 years of exposure, though limited, suggest that there is a cumulative increase in AEs, with no change in AE pattern. The incidence of musculoskeletal AEs associated with CK elevations occurred in association with telbivudine use after 52 weeks. All of these led to either telbivudine discontinuation or dose interruption.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/risk assessment
Based on a novel primary efficacy endpoint in a single pivotal trial, telbivudine was demonstrated to be as effective as lamivudine in achieving a Therapeutic Response after 52 weeks of treatment with 600 mg telbivudine. Telbivudine was also demonstrated to be as effective as lamivudine after 52 weeks of treatment based on histology data.
Musculoskeletal toxicity was the most notable safety issue related to telbivudine. There is a clear signal that telbivudine has the potential to be toxic to muscle. This is based on 17 telbivudine-associated case reports of myositis, polymyositis, muscle weakness, and myalgia associated with telbivudine-related CK elevations. These cases were reported in the pivotal trial, Study 007 (13 to date compared to 1 in the lamivudine arm); in Study 015, an ongoing trial in China (3 narratives all in telbivudine-treated patients); and in one patient enrolled in the ongoing Study 018. All of these cases required telbivudine discontinuation or dose interruption.
Although some cases did lead to muscle weakness and impairment of activity for periods of several months in some individuals, in other individuals the muscular adverse event was milder and did not include functional impairment. It was therefore decided that this safety concern should not preclude approval of the drug. However, a warning has been included in the Product Monograph regarding the potential for these musculoskeletal events.
The other safety concerns associated with telbivudine were more straight-forward (although not less serious) than the issues of muscular toxicity. These included safety issues associated with the nucleoside class of drugs of which telbivudine is a member. These potentially life-threatening events include the risk of lactic acidosis with nucleoside use and the risk of hepatic flares after nucleosides are discontinued. These concerns are both contained within the black box warning in the Product Monograph.
Overall, the benefits of the use of Sebivo* (telbivudine) in the treatment of HBV in treatment-naïve adult patients with compensated liver disease with evidence of viral replication and active liver inflammation outweigh the risks.
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 Sebivo* is favourable for the treatment of chronic HBV in adults 16 years and older with compensated liver disease and evidence of viral replication and active liver inflammation. 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: Sebivo
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed | 2006-03-06 |
| Approval issued by Director, BGIVD | 2006-04-07 |
| Submission filed | 2006-03-06 |
| Submission filed | |
| Screening Acceptance Letter issued | 2006-04-07 |
| Review | |
| Biopharmaceutics Evaluation complete | 2006-11-07 |
| Quality Evaluation complete | 2006-09-14 |
| Clinical Evaluation complete | 2006-11-09 |
| Labelling Review complete | 2006-11-17 |
| NOC issued by Director General | 2006-11-28 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SEBIVO | 02288389 | NOVARTIS PHARMACEUTICALS CANADA INC | TELBIVUDINE 600 MG |