Summary Basis of Decision for Celsentri
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:
Celsentri
Maraviroc, 150 mg and 300 mg, Tablets, Oral
Pfizer Canada Inc.
Submission control no: 112435
Date issued: 2008-04-22
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), PrCELSENTRI, maraviroc, 150 mg et 300 mg, Pfizer Canada Inc., No de contrôle de la présentation 112435
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):
- 02299844 - 150mg
- 02299852 - 300mg
Therapeutic Classification:
Non-medicinal ingredients:
Film-coat: aluminum lake (FD&C blue #2), polyethylene glycol (macrogol 3350), polyvinyl alcohol, soya lecithin, talc, and titanium dioxide.
Submission type and control no:
Date of Submission:
Date of authorization:
* ™ CELSENTRI is a trademark of Pfizer Products Inc. / Pfizer Canada Inc., licensee
2 Notice of decision
On September 21, 2007, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product Celsentri.
Celsentri contains the medicinal ingredient maraviroc which is a CCR5 antagonist.
Celsentri in combination with other antiretroviral agents is indicated for treatment-experienced adult patients infected with CCR5-tropic HIV-1 who have evidence of resistance to multiple antiretroviral agents. Maraviroc selectively binds to the human chemokine receptor CCR5 and inhibits the interaction of the envelope glycoprotein (gp120) from CCR5-tropic HIV-1 strains with CCR5. Binding of gp120 to CCR5 is an essential step in the HIV-1 entry process for CCR5-tropic strains.
The market authorization was based on quality, non-clinical, and clinical information submitted. The clinical safety and efficacy of Celsentri were derived from analyses of 24-week data from two double-blind, placebo-controlled Phase 2b/3 studies in antiretroviral treatment-experienced adult patients infected with CCR5-tropic HIV-1. CCR5 tropism should be confirmed prior to initiation of Celsentri therapy. Celsentri is not recommended in patients infected with dual/mixed or CXCR4-tropic HIV-1; efficacy in this patient population was not demonstrated in a Phase 2b study.
Celsentri (150 mg and 300 mg, maraviroc) is presented in tablet form. Celsentri must be given in combination with other antiretroviral agents. The recommended dose is 300 mg twice daily but adjustments are recommended based on the patient's concomitant medications. Dosing guidelines are available in the Product Monograph.
Celsentri is contraindicated for patients with hypersensitivity to maraviroc or any component of this medication. Celsentri 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 Celsentri are described in the Product Monograph.
Priority Review status was granted for the evaluation of Celsentri as it appeared to provide an improved overall risk/benefit profile over existing therapies in a specific subset of patients for a disease or condition that is not adequately managed by a drug marketed in Canada.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Celsentri in combination with other antiretroviral agents is favourable for treatment-experienced adult patients infected with CCR5-tropic HIV-1 who have evidence of resistance to multiple antiretroviral agents.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Maraviroc, the medicinal ingredient of Celsentri is a CCR5 antagonist. Maraviroc selectively binds to the human chemokine receptor CCR5. The selective inhibition of the binding between human immunodeficiency virus-1 (HIV-1) and the CCR5 co-receptor has been shown to prevent entry of CCR5-tropic virus into CD4 cells.
Manufacturing Process and Process Controls
Maraviroc 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.
Characterization
The structure of maraviroc is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis and toxicological studies and are therefore considered acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of maraviroc.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that maraviroc is a stable compound when packaged as proposed over the proposed storage period.
3.1.2 Drug Product
Description and Composition
Celsentri (maraviroc) 150 and 300 mg tablets are blue, biconvex, oval, film-coated tablets debossed with "Pfizer" on one side and "MVC 150" or "MVC 300" on the other side. The tablets are packaged in high density polyethylene (HDPE) bottles and in polyvinyl chloride (PVC) blisters. The HDPE bottles have polypropylene child resistant closures and an aluminium foil/polyethylene heat induction seal containing 30, 60, 120, and 180 film-coated tablets for the 150 mg and 300 mg strengths. The PVC blisters have an aluminium foil backing and are in a carton containing 30, 60, 90, and 180 (2 x 90) film-coated tablets for the 150 mg and 300 mg strengths.
Celsentri tablets contain either 150 or 300 mg of maraviroc and the following inactive ingredients: dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film-coating contains aluminum lake (FD&C blue #2), polyethylene glycol (macrogol 3350), polyvinyl alcohol, soya lecithin, talc, and titanium dioxide.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of maraviroc with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Celsentri is tested to verify that the identity, appearance, content uniformity, levels of degradation products, microbiological impurities, and dissolution are within acceptance criteria. The proposed limits are considered adequately qualified (i.e. within ICH limits and/or qualified from toxicological studies). Control of the impurities and degradation products is therefore considered acceptable.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Celsentri.
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 stability data submitted, the proposed shelf-life of 24 months is considered acceptable for Celsentri tablets packaged in HDPE bottles or PVC blister packs stored between 15-30°C.
The compatibility of the drug product with the container closure systems was demonstrated through compendial testing and stability studies. The container closure systems met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. None of the components in the Celsentri tablets are of human or animal origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Celsentri 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
Maraviroc is a selective and reversible antagonist of the human chemokine receptor CCR5. In vitro studies showed that the binding of maraviroc to CCR5 inhibited the interaction of the envelope glycoprotein (gp120) from CCR5-tropic HIV strains. Maraviroc had no activity against CXCR4-tropic or dual-tropic viruses.
Numerous studies were conducted to assess whether or not the targeting of the human protein CCR5 would lead to unwanted secondary pharmacological effects. The potential for maraviroc to affect the host immune system was assessed in various in vitro models of human immune system. The experiments indicated that the selective binding and inhibition of CCR5 function was unlikely to affect immune processes as modelled in the in vitro immune function assays. Other in vitro studies demonstrated that maraviroc was active at the human cardiac HERG channel and has the potential to block the IKr current to affect cardiac repolarisation in vivo.
Postural hypotension was the dose-limiting adverse event in the Phase I studies. An in vitro study suggested a vasomotor role for CCR5 receptors in human vasculature. The effect of intravenously administered maraviroc on blood pressure and heart rate during postural change in the conscious dog was assessed. The results demonstrated that maraviroc produced a slight impairment of normal reflex control of blood pressure (BP) in the dog during the change to the upright position, however, once the upright position was established, BP control was maintained at a normal level. This was supported by the results of the dog toxicology studies in which maraviroc produced inconsistent reductions in blood pressure and no obvious postural hypotension.
3.2.2 Pharmacokinetics
Absorption
Following oral administration, maraviroc was rapidly absorbed. In all animal species studied, the time to reach maximum plasma concentration was ≤ 2 hours. In vitro and in vivo studies suggested that P-glycoprotein limits the absorption of maraviroc.
Distribution
Maraviroc showed moderate plasma protein binding in monkeys (~ 48%), rats (51%), mice (58%), dogs (64%), and rabbits (66%).
Following IV administration of radiolabelled maraviroc, distribution of radioactivity was rapid and extensive. Maraviroc and/or its metabolites were shown to have some affinity for melanin. Affinity for melanin is a common property of lipophilic bases and is not predictive of ocular toxicity. Results also demonstrated low brain penetration.
Metabolism
The major circulating component of maraviroc was unchanged drug, ranging from 40% in rabbits to 74% in mice. Unchanged drug was also the major drug component excreted in all of the species.
The identified metabolites were products of N-dealkylation and/or oxidation. There was a high degree of similarity observed across all species.
Maraviroc was shown to be a substrate for CYP3A4 in vitro. Therefore, the pharmacokinetics are likely to be affected by coadministration of inhibitors and inducers of this cytochrome P450 isoenzyme. Maraviroc did not inhibit the seven major cytochrome P450 isoenzymes and thus is unlikely to affect the metabolism of other coadministered P450 substrates at clinical doses.
Excretion
The major route of elimination was fecal (≥72% of the administered dose) in all species. Elimination was rapid and most of the radiolabelled drug was recovered within 48 hours.
3.2.3 Toxicology
Single-Dose Toxicity
No clinically significant toxicity was observed following a single oral dose of maraviroc to mice and rats at a dose of 2000 mg/kg.
Repeat-Dose Toxicity
The dose range studied in the repeat-dose toxicology studies provided plasma exposures of maraviroc many times higher than that found at the maximum therapeutic dose in humans, 300 mg twice daily (BID). The unbound maximum plasma concentration values (Cmax) and drug exposure values (AUC) represented exposure multiples of up to 45 and 68 in mice (750 mg/kg/day for 3 months); 30 and 51 in rats (900 mg/kg/day for 6 months); 23 and 28 in dogs (150 mg/kg/day for 1 month) and 35 and 37 in monkeys (400 mg/kg/day for 9 months), respectively.
Blood Pressure and Heart Rate:
Toxicology studies in monkeys demonstrated reductions in blood pressure at daily doses of 200 and 400 mg/kg/day, accompanied by lower heart rates at 400 mg/kg/day. The doses of 200 mg/kg/day (1-month study) and 400 mg/kg/day (9-month study) were associated with similar unbound plasma concentrations (1815 ng/mL and 1718 ng/mL, respectively) and were approximately 11-fold higher than that at the therapeutic dose, 300 mg BID. No effects on blood pressure or heart rate were observed at 120 mg/kg/day in the 9-month study, with a plasma concentration 5-fold that of the therapeutic dose in humans, 300 mg BID.
QTc Interval Prolongation:
Maraviroc increased QTc intervals in dogs at doses of ≥ 15 mg/kg/day and in monkeys at doses of ≥ 200 mg/kg/day. The unbound plasma concentrations at the lowest effect doses represented exposure multiples of 6- and 12-fold that observed in humans at the therapeutic dose of 300 mg BID, respectively. In these two species, doses of 5 mg/kg/day and 120 mg/kg/day, respectively, had no effect on QTc interval at plasma concentrations 2- and 5-fold the maximum therapeutic concentration. In addition, no evidence of cardiac arrhythmias was observed in dogs or monkeys at plasma concentrations 23- and 38-fold the maximum therapeutic concentration. Based on this data, maraviroc represents a low risk of serious arrhythmias to humans at the therapeutic dose. However, in the event of a significant overdose of maraviroc, changes to the QT interval may occur. The Product Monograph notes this in the overdose section.
Hepatic Findings:
Repeat-dose toxicology studies in mice, rats, dogs and monkeys identified the liver as a target organ in rats only. Bile duct hyperplasia was present from doses of 300 mg/kg/day (25-fold the human AUC exposure at 300 mg BID). At 900 mg/kg/day, additional findings included altered cell foci and multinucleated hepatocytes. At 1500 mg/kg/day (34-fold the human AUC exposure at 300 mg BID), there were increases in plasma transaminases, accompanied by hepatocellular necrosis in one animal.
Carcinogenicity
In the 24-month carcinogenicity study, an increased incidence of thyroid follicular cell adenoma was observed in both sexes of rats at plasma concentrations 21-fold the human exposure at 300 mg BID. A similar risk in man is not likely due to the close relationship that exists between the disruption of thyroid-pituitary homeostasis in rodents and the development of thyroid follicular cell adenomas. Two reports of a rare tumour, cholangiocarcinoma, were noted in the liver of two male rats at 900 mg/kg. The incidence, 2/60 (3.3%), was slightly higher than that observed in a large database of control male rats, 3/1850 (0.2%). Plasma drug exposure levels were again 21-fold the human exposure at 300 mg BID. Both of these findings are included in the Product Monograph.
Mutagenicity
Maraviroc was not mutagenic or clastogenic based on the results of the standard battery of tests for genotoxicity (ICH S2B Guidelines).
Reproductive and Developmental Toxicity
Maraviroc was found to have no adverse effects on fertility at AUC plasma exposures 39-fold higher than those found in humans at the maximum therapeutic dose.
In the rabbit embryo-fetal development study, there was an increased incidence of external anomalies in fetuses from the high dose group (200 mg/kg). The NOAEL was 75 mg/kg for pregnant females and fetuses (AUC exposure 7-fold higher than the therapeutic dose).
A study in lactating rats demonstrated that maraviroc was extensively secreted into milk.
Immunotoxicity
No adverse effects were detected on the immune system in monkeys at plasma exposures producing complete and continuous blockade of CCR5 receptors, and with an exposure 16-fold greater than that observed at the therapeutic dose 300 mg BID.
3.2.4 Conclusion
Pharmacodynamic studies have adequately demonstrated the high potency and selectivity of maraviroc as a CCR5 antagonist agent for the treatment of HIV-1 infection. Several safety concerns had been previously identified during the development of CCR5 co-receptor antagonists in general. To assess this, the non-clinical toxicity profile of maraviroc was characterized in an extensive battery of in vitro and in vivo studies including carcinogenicity studies in rats and mice. The results of these studies did not identify any increased risk for infections, lymphomas or heptotoxicity. There was a definite effect on QT interval prolongation. Effects on blood pressure and heart rate were demonstrated in dogs and monkeys; however, the mechanism was unable to be determined due to inconclusive results.
Overall, the non-clinical studies for Celsentri are considered acceptable. There are no non-clinical pharmacology or toxicology issues which would preclude the authorization of this new drug submission. Adequate statements are in place in the Product Monograph to address the identified safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Maraviroc was observed in vitro to bind with high affinity and high specificity to human CCR5 receptors. Maraviroc inhibited the attachment of the HIV-1 gp120 subunit to human CCR5 receptors.
In a randomized, double-blind, placebo-controlled study in asymptomatic HIV-infected patients, all doses of maraviroc [25 mg once daily (QD), 50 mg BID, 100 BID, and 300 mg BID] produced a viral load decrease that was statistically significantly superior to placebo. The 100 and 300 mg BID doses produced a large and similar decrease in viral load and 25 mg QD and 50 mg BID doses produced a sub-optimal decrease. Viral load took longer to return to baseline concentrations after 100 and 300 mg BID than after
25 mg QD and 50 mg BID. The time to return to baseline also took longer in patients that were treated with maraviroc (all doses) compared to placebo. There were no discontinuations, no dose-related adverse events and no clinically significant laboratory test result abnormalities after administration of maraviroc up to and including 300 mg BID.
In another pharmacodynamic study, two patients had changes in tropism from baseline. In both cases, there was evidence that patients had low levels of R5/X4 present prior to dosing with maraviroc. The recombinant entry assay showed that there were no apparent changes in susceptibility to maraviroc over time. There was a high degree of CCR5 saturation by four hours post-dose, and the mean CCR5 saturation was maintained above 80% throughout the 10-day dosing period for all maraviroc groups and was still >60% at Day 15.
3.3.2 Pharmacokinetics
Absorption
Peak maraviroc plasma concentrations were obtained 0.5-4 hours post dose following single oral doses ranging from 1-1200 mg when administered to healthy subjects. The pharmacokinetics of oral maraviroc were not dose proportional over the dose range. The absolute bioavailability of a 100 mg dose was 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the P-glycoprotein efflux transporter.
Distribution
Maraviroc was primarily bound (approximately 76%) to human plasma proteins, showing moderate affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc was approximately 194 L.
Metabolism
Maraviroc was primarily metabolized in the liver by the cytochrome P450 system. The major isoenzyme responsible was CYP3A4. The isoenzymes CYP2C9, CYP2D6 and CYP2C19 did not contribute significantly to the metabolism of maraviroc.
The major circulating component was unchanged drug. The major metabolite was formed by N-dealkylation and showed no significant pharmacological activity. The other metabolites were minor and were products of mono-oxidation.
Excretion
Maraviroc was primarily excreted in the feces. Approximately 96% of the radiolabelled dose was recovered, with 76% recovered in the feces and 20% recovered in the urine, over a period of 168 hours. Unchanged drug was the major drug component in the feces and urine.
Special Populations
A specific Phase I comparison between Asians and Caucasians did not indicate any differences in maraviroc pharmacokinetics (PK). The population PK analysis of the Phase III studies indicated that Asians had drug exposure levels (AUC) 26.5% higher than non-Asians. Based upon the findings, there is no recommendation to adjust the maraviroc dose in Asian HIV infected patients.
AUC values were 25% higher and 46% higher, respectively, for patients with mild hepatic impairment and moderate hepatic impairment compared to patients with normal hepatic function.
The effect of renal impairment on the exposure of maraviroc in subjects receiving CYP3A4/P-gp inhibitors was modelled using a computer simulation. The simulation of maraviroc concentration profiles with different degrees of renal impairment in combination with potent CYP3A4/P-gp inhibitors in the optimized background regimen led to a dose interval adjustment in the Product Monograph.
Drug Interactions
Drug interactions were studied with nucleoside reverse transcriptase inhibitors (didanosine EC, lamivudine, stavudine, tenofovir and zidovudine); non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine); protease inhibitors (atazanavir, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, ritonavir, saquinavir, saquinavir/ritonavir and tipranavir/ritonavir); and other drugs (midazolam, sulfamethoxazole/trimethoprim, ketoconazole, ethinyl estradiol-levonorgestrel and rifampacin). Of the three classes of antiretrovirals tested, all protease inhibitors (CYP3A4 inhibitors) with the exception of tipranavir/ritonavir significantly increased maraviroc exposure. This resulted in a proposed dosing recommendation of 150 mg BID instead of 300 mg BID when dosed in combination with a protease inhibitor or other CYP3A4 inhibitor, in part because of increased postural hypotension at higher exposure levels. Efavirenz and rifampicin, both CYP3A4 inducers, significantly decreased the exposure of maraviroc, which again resulted in a proposed dosing recommendation of 600 mg BID instead of 300 mg BID when dosed in combination with a CYP3A4 inducer.
Effect on QT Interval
With single oral doses of 100 mg, 300 mg, and 900 mg maraviroc, the placebo-adjusted mean maximum increases in QTc from baseline were -2.3, -0.6, and 1.0 msec, respectively. None of the subjects had increases in QTc of ≥60 msec from baseline and none of them experienced an interval exceeding the threshold of 500 msec.
Effect on Hemodynamics
Doses of 900 mg maraviroc decreased systemic vascular resistance and the stroke index, and increased the cardiac index and pulse rate. Maraviroc did not cause a clinically significant change in supine systolic or diastolic blood pressure. These effects were mostly sustained over the 4-hour post-dose measurement period.
The pharmacodynamic results with maraviroc are consistent with those expected of a mild vasodilator with a fully compensated hemodynamic response maintaining supine blood pressure. Three subjects experienced postural hypotension, implying that there was not always complete compensation for orthostatic changes.
3.3.3 Clinical Efficacy
The efficacy of maraviroc was evaluated at 24 weeks in two Phase III studies with treatment-experienced patients infected with CCR5-tropic virus and in one Phase IIb study in patients infected with dual/mixed-tropic HIV-1. The majority of the patients were Caucasian males with a median age of 46 years. In the Phase III studies, the patients received a 300 mg dose equivalent [150 mg twice daily (BID) or 150 mg once daily (QD) with optimized background therapy (OBT) containing at least one protease inhibitor (except tipranavir) and/or delavirdine; 300 mg QD or BID for all other OBT, including tipranavir]. Compared to patients treated with placebo and OBT, patients treated with maraviroc and OBT showed an additional mean change from baseline HIV-1 RNA of -0.97 log10 copies/mL as well as greater CD4+ cell count increases. The efficacy of maraviroc was statistically and clinically significant for the study population. In patients with low overall susceptibility scores (OSS) or CD4 cell counts <50 cells/µL, the twice-daily schedule of maraviroc dosing appeared to be more beneficial than the once-daily dosing for the achievement of viral load <50 copies/mL. The recommended twice-daily 300 mg dose equivalent is justified by the results of these studies as well as the results from the clinical pharmacology studies.
The determinants of virologic response to maraviroc treatment included HIV-1 tropism at baseline, development of resistance, and OSS. Maraviroc did not demonstrate statistically greater efficacy versus placebo in patients with dual/mixed-tropic virus in a Phase IIb study. In approximately 60% of the patients in Phase III studies who failed, treatment failure was due to the emergence of CXCR4- or dual/mixed-tropic HIV-1 variants undetected at screening by the tropism assay. The conclusion that co-receptor switching did not occur was based on an examination of 192 viral clones derived from 20 selected patients randomized to maraviroc (16) and placebo (4) arms. The possibility of co-receptor switching secondary to maraviroc treatment can not be ruled out in the general population. Analysis of viral isolates from patients who developed resistance to maraviroc treatment did not reveal any signature mutations. Maraviroc had greater efficacy than OBT alone over the range of OSS values, but a greater response compared to placebo was seen in patients with OSS <3 as compared to patients who were responding to OBT.
Since the efficacy of maraviroc was studied predominantly in male Caucasians, dose adjustments for women or other races cannot be recommended in the Product Monograph at this time. There was very limited evidence that maraviroc efficacy may be altered in Blacks, although the numbers were small. The efficacy of maraviroc was not specifically examined in geriatrics, pediatrics, patients with severe hepatic impairment or patients co-infected with Hepatitis B and/or Hepatitis C virus.
The efficacy results presented in the current submission support the sponsor's intended indication for treatment-experienced adult patients infected with CCR5-tropic HIV-1 who have evidence of resistance to multiple antiretroviral agents.
3.3.4 Clinical Safety
The safety of maraviroc was evaluated in two Phase III studies and one Phase IIb study. The number of patients with adverse drug events and serious drug events, as well as the number of patients discontinuing due to adverse events (AEs) were all similar across the treatment arms. There was no overall increase in mortality in maraviroc-treated patients as compared to those on placebo and the causes of death were typical for the target population.
The most frequently reported AEs in all treatment groups were diarrhea, nausea, headache and fatigue. The AEs that had a higher frequency rate in patients receiving maraviroc compared to placebo were cough, pyrexia, upper respiratory infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.
Cardiovascular AEs of myocardial ischemia and myocardial infarction were noted in the maraviroc arms but not in the placebo arm. Although most of the patients had underlying cardiac diseases and/or were at risk for cardiovascular disease, the imbalance in these events between the treatment and placebo arms indicates a potential safety concern.
More cases of postural hypotension [defined as standing systolic blood pressure <90 mmHg or a drop in blood pressure from supine to standing ≥10 mmHg (systolic) and ≥20 mmHg (diastolic)] were observed at 24 weeks in the maraviroc arms as compared to placebo. Postural hypotension was the dose-limiting toxicity observed at 600 mg maraviroc in the Phase I studies. The occurrence of postural hypotension and syncope at therapeutically relevant doses of maraviroc is a safety concern, especially in patients on concomitant CYP3A4 or phosphodiesterase type-5 (PDE-5) inhibitors. This safety concern as well as a warning about the use of maraviroc in patients on concomitant CYP3A4 or PDE-5 inhibitors were addressed in the Celesentri Product Monograph. There was no evidence that maraviroc is associated with prolongation of the QTc interval in patients enrolled in these studies.
The number of serious AEs that required intervention or treatment modifications were similar in patients that received maraviroc treatment compared to placebo. There was an increase in the incidence of herpes infection in maraviroc-treated patients as compared to placebo (4.3% in the QD arm and 6.8% in the BID arm as compared to 3.8% in the placebo arm). The incidence of respiratory tract infections was higher in maraviroc-treated patients as compared to those on placebo (20% versus 11.5%), with the exception of pneumonia where the reported rate was lower in patients receiving maraviroc as compared to those on placebo (2.1% versus 4.8%). There were no overall increases in malignancies in patients treated with maraviroc. A case of cholangiocarcinoma with a possible association to maraviroc treatment was reported in one of the Phase III studies. Rare cases of cholangiocarcinoma were also reported during the non-clinical studies with rats receiving maraviroc.
Hepatic AEs were observed in maraviroc-treated patients. Causality assessment was confounded by the presence of liver function abnormalities at baseline in many of these patients. Grade 3 and 4 liver function test abnormalities were similar across the treatment arms. One case of hepatotoxicity with allergic symptoms and a possible association to maraviroc treatment was reported in a healthy Phase I study volunteer, and is labelled in a black box warning in the Celsentri Product Monograph. There were insufficient numbers of Hepatitis B and/or Hepatitis C co-infected patients participating in the Phase II and III studies to adequately assess the effect of maraviroc on liver function in this subpopulation.
There was an increase in the overall percentage of treatment-emergent eye disorders (all causalities) in the maraviroc BID arm (~10%) as compared to the maraviroc QD arm (~8%) and the placebo arm (~8%).
Given that maraviroc interferes with a co-receptor involved in immune function, there are concerns about the impact of treatment on host immune surveillance. The assessment of long-term effects of maraviroc treatment was beyond the scope of the current submission. The sponsor made a commitment to do a 5-year follow-up of patients enrolled in the Phase III studies.
3.4 Benefit/Risk Assessment and Recommendation
Celsentri (maraviroc) interferes with one of the sequential steps required for entry of HIV-1 into CD4-expressing cells, thus preventing viral infection. Maraviroc, a selective and reversible antagonist of the CCR5 chemokine co-receptor, blocks the binding of HIV-1 glycoprotein 120 (gp120) to CCR5 by allosteric inhibition. The physiological function of CCR5 is thought to be the mediation of immune response. The rationale for the development of CCR5 antagonists is based on several earlier studies which showed that individuals with mutations that reduce or inactivate CCR5 activity have slower disease progression as compared to patients with the wild type gene. Priority Review status was granted for the evaluation of Celsentri as it appeared to provide an improved overall risk/benefit profile over existing therapies in a specific subset of patients (those with solely CCR5-tropic virus, as determined by tropism testing) for a disease or condition that is not adequately managed by a drug marketed in Canada.
The benefits of maraviroc treatment are as follows:
- A twice-daily regimen with no dietary restrictions that isassociated with good patient adherence and decreased likelihood of resistance due to discontinued treatment.
- Solid evidence of maraviroc efficacy at the proposed dose for the target population.
- No evidence of clinical QTc prolongation.
- No increased incidence of discontinuations due to adverse reactions or increased mortality.
The risks associated with maraviroc as a component of antiretroviral therapy are as follows:
- Emergence of mixed/dual-tropic virus (undetected at baseline by the tropism assay) in response to maraviroc treatment which may be associated with an increased risk of disease progression.
- Hepatoxicity.
- The risk for altered efficacy and/or safety (e.g. risk of hepatic adverse events) in Hepatitis B and/or Hepatitis C co-infected patients is unknown; however maraviroc levels are increased in patients with moderate hepatic impairment.
- Given that maraviroc-related cases of postural hypotension and syncope were reported during: 1) Phase 3 studies in HIV-infected patients at the recommended dose; 2) Phase 1 studies in healthy volunteers at dosing higher than the recommended dose, there is a need for caution in patients with a history of postural hypotension or on concomitant medications known to lower blood pressure.
- Increased risk of postural hypotension and syncope due to increased maraviroc exposure by concomitant PDE-5 or CY3A4 inhibitors.
- The possibility of maraviroc resistance due to decreased exposure.
- The potential risk of increased infection and/or malignancy due to impaired immune function as a result of the antagonistic action of maraviroc on the CCR5 receptor.
Labelling negotiations with the sponsor resulted in revisions to the Celsentri Product Monograph consistent with the risks and benefits associated with maraviroc therapy.
The sponsor made a commitment to carry out a 5-year follow-up of patients currently enrolled in the Phase III studies. This population will be monitored for increased incidence of liver failure, malignancy, myocardial ischemia or infarction, rhabdomyolysis, and infections. The sponsor has also undertaken a study in patients who are co-infected with hepatitis C and/or B, including some subjects with a Child-Pugh score of C.
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 Celsentri is favourable for the treatment of treatment-experienced adult patients infected with CCR5-tropic HIV-1 who have evidence of resistance to multiple antiretroviral agents. 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: Celsentri
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2007-01-24 |
| Request for priority status | |
| Filed | 2007-01-29 |
| Approval issued by Director, BGIVD | 2007-02-26 |
| Submission filed | 2007-03-01 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2007-03-28 |
| Review | |
| Biopharmaceutics Evaluation complete | 2007-08-22 |
| Quality Evaluation complete | 2007-09-17 |
| Clinical Evaluation complete | 2007-09-14 |
| Labelling Review complete | 2007-09-18 |
| NOC issued by Director General | 2007-09-21 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| CELSENTRI | 02299852 | VIIV HEALTHCARE ULC | MARAVIROC 300 MG |
| CELSENTRI | 02299844 | VIIV HEALTHCARE ULC | MARAVIROC 150 MG |