Summary Basis of Decision for Prezista

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:

Drug

Contact: Bureau of Gastroenterology Infection and Viral Diseases

Prezista

Darunavir, 300 mg, Tablet, Oral

Janssen-Ortho Inc.

Submission control no: 103324

Date issued: 2007-05-22

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), ^PrPrezista*, darunavir, 300 mg, comprimés, Janssen-Ortho Inc., No de contrôle de la présentation 103324

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:

Prezista

Manufacturer/sponsor:

Janssen-Ortho Inc.

Medicinal ingredient:

Darunavir

International non-proprietary Name:

Darunavir

Strength:

300 mg

Dosage form:

Tablet

Route of administration:

Oral

Drug identification number(DIN):

02284057

Therapeutic Classification:

HIV Protease Inhibitor

Non-medicinal ingredients:

Colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose.
Film coating: polyethylene glycol, polyvinyl alcohol - partially hydrolyzed, sunset yellow FCF aluminum lake, talc, and titanium dioxide.

Submission type and control no:

New Drug Submission,
Control No. 103324

Date of Submission:

2005-12-23

Date of authorization:

2006-07-28

* All trademark rights used under license
© 2006 JANSSEN-ORTHO Inc.

2 Notice of decision

On July 28, 2006, Health Canada issued a Notice of Compliance with Conditions (NOC/c) to Janssen-Ortho Inc. for the drug product Prezista*. The product was authorized under the NOC/c Policy on the basis of the promising nature of the clinical evidence and the need for confirmatory studies to verify the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

Prezista* contains the medicinal ingredient darunavir which is a human immunodeficiency virus (HIV) protease inhibitor.

Prezista* co-administered with 100 mg ritonavir (RTV) and with other antiretroviral agents is indicated for the treatment of HIV infection in treatment-experienced adult patients who have failed prior antiretroviral therapy. Darunavir selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, thereby preventing the formation of mature infectious virus particles.

The market authorization with conditions was based on submitted data from quality control studies, pre-clinical and clinical studies. The evidence of clinical efficacy and safety was based on the analysis of 24-week data from 255 antiretroviral treatment-experienced HIV-1-infected adult patients from two ongoing, randomized controlled studies. The results of the two studies show evidence of clinical effectiveness, and an acceptable safety profile. Additional data on the safety of Prezista*/RTV 600/100 mg twice daily (b.i.d.) was obtained from 327 treatment-experienced patients participating in non-randomized trials which support the safety profile observed in the two randomized controlled studies.

Prezista* (300 mg, darunavir) is presented in tablet form. Prezista* must always be given with 100 mg ritonavir (pharmacokinetic enhancer), and in combination with other antiretroviral medicinal products. The prescribing information of ritonavir must, therefore, be consulted prior to initiation of therapy with Prezista*/RTV. The recommended oral dose of Prezista* tablets is 600 mg (two 300 mg tablets) b.i.d. taken with ritonavir 100 mg b.i.d. and with food. The type of food does not affect exposure to darunavir. Dosing guidelines are available in the Prezista* Product Monograph.

Prezista* is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Co-administration of Prezista*/RTV is contraindicated with drugs that are highly dependent on the cytochrome P450 system (CYP3A4) for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in the Product Monograph.

Prezista* 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 Prezista* 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 Prezista* co-administered with 100 mg ritonavir and with other antiretroviral agents is favourable for the treatment of HIV infection in treatment-experienced adult patients who have failed prior antiretroviral therapy.

3 Scientific and Regulatory Basis for Decision

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)

Manufacturing Process and Process Controls

The drug substance, darunavir, is synthetically derived. Materials used in the manufacture of darunavir are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Characterisation

The structure of darunavir is considered to be adequately elucidated. The representative spectra have been provided.

Darunavir is poorly soluble and has several potential polymorphic forms. Under synthesis conditions darunavir appears as an ethanolate solvate pseudopolymorph, however a hydrate and an amorphous non-solvated form are also possible depending on the environmental conditions. Bioavailability studies have been conducted demonstrating the equivalence of the hydrated and solvated forms of the drug substance. The sponsor has agreed to conduct further studies on the amorphous form which may be present under conditions of low humidity.

Impurities arising from manufacturing and/or storage were reported and characterized. The proposed limits for these impurities were within ICH established limits or were qualified through toxicology studies and therefore considered to be acceptable.

Control of Drug Substance

The analytical methods and validation reports are considered satisfactory for all analytical procedures used for release and stability testing of darunavir. The specifications are considered acceptable for the drug substance.

Batch analysis results were reviewed and are within the proposed acceptance criteria.

The drug substance packaging is considered to be acceptable.

Stability

Based on the long-term and accelerated stability data submitted, the proposed retest period, storage, and shipping conditions for the drug substance were supported and considered to be satisfactory.

3.1.2 Drug Product

Description and Composition

Prezista tablets are orange, oval-shaped, and film-coated. Each tablet contains 300 mg of darunavir (corresponding to 325.23 mg of darunavir ethanolate). The tablets are debossed with "300MG" on one side and "TMC114" on the other side. The container-closure system is a white, opaque, high-density polyethylene (HDPE) bottle with a child-resistant polypropylene cap lined with a foil induction seal. Each bottle holds 120 tablets.

The tablets are formulated for oral administration. Each tablet contains the inactive ingredients microcrystalline cellulose, colloidal silicon dioxide, crospovidone, and magnesium stearate. The tablet film-coating contains polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, sunset yellow FCF aluminum lake, talc, and titanium dioxide.

All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The tablet and film-coating ingredients are standard pharmaceutical components, and the tablets are packaged using customary pharmaceutical packaging materials.

Pharmaceutical Development

The description of the formulation development is acceptable. Changes to the manufacturing process and formulation made throughout the development are also considered acceptable.

Manufacturing Process and Process Controls

The tablets are manufactured according to conventional pharmaceutical processes; the testing and specifications are typical for oral tablets. The process is considered adequately controlled within justified limits.

Control of Drug Product

Prezista tablets are tested to verify that their identity, appearance, weight, dissolution, and levels of degradation products are within acceptance criteria. The test specifications are considered acceptable to control the drug product.

Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing.

Batch analysis results for the 300 mg formulation were within the proposed specification limits for all lots tested.

The proposed limits for degradation products were considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies). All analyzed batches complied with the proposed specifications at release testing and during stability testing.

Stability

Based on the long-term and accelerated stability data submitted, the proposed shelf life of 24 months is considered acceptable when the product is packaged in the commercial container/closure system and stored at controlled room temperature (15-30°C).

3.1.3 Facilities and Equipment

The design, operations, and controls of the facility and equipment are considered suitable for the activities and products manufactured at the site. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.

3.1.4 Adventitious Agents Safety Evaluation

N/A

3.1.5 Summary and Conclusion

The Chemistry and Manufacturing information submitted for Prezista 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

The non-clinical pharmacodynamic studies consisted primarily of safety pharmacology studies. No primary or secondary non-clinical pharmacodynamic studies were included with this submission.

The safety pharmacology studies assessed the effects of darunavir on QT prolongation. The studies were in accordance with the ICH Guidelines on the non-clinical evaluation of the potential for delayed ventricular repolarization and included: in vitro effects on HERG currents from transfected HEK293 cells, in vivo cardiovascular effects in conscious telemetered beagle dogs, and various in vitro assays in animal tissues.

Overall, darunavir appeared to have little significant effect on cardiac parameters or anti-arrhythmic activity. RR interval prolongation and statistically significant increases in QTcF interval were noted at 60 mg/kg and 120 mg/kg doses, respectively, but the sponsor did not perceive them as related to the study drug. The RR interval prolongation could be explained by a corresponding decrease in heart rate, and the increase in QTcF interval had no corresponding change in QTcQ. Statistically significant negative chronotropic activity in the guinea pig right atria was noted at 30 µM. The clinical studies should further investigate the possible effects of darunavir on QT intervals despite the little apparent effect in the non-clinical studies.

No evidence of a delay in gastrointestinal transit time or effects of respiratory parameters (at doses of 10, 200, and 2000 mg/kg) were noted. The only neuro-behavioural effects that were statistically significant were the decreases in motor activity after six hours with the 2000 mg/kg dose, a dose well above the human exposure level.

3.2.2 Pharmacokinetics

Absorption

Exposure to darunavir appeared to increase in a dose-dependent manner over the lower dose range (150-1000 mg/kg/day) tested in many of the studies, but was not dose-dependent over the higher dose range (1000-5000 mg/kg/day). Generally, the time to reach maximum plasma concentration (Tmax) was 0.5-1 hour after dosing and the half-life was 1.7-4.3 hours. Exposure in rodents tended to decrease after repeated dosing, however co-administration with ritonavir appeared to help maintain and boost exposure levels. The animal studies found that the overall systemic exposure was best with 500 mg/kg/day darunavir and 75 mg/kg/day ritonavir, in rats.

Distribution

Darunavir was well distributed. Concentrations were highest in the adrenal gland, and liver (10-16 times higher than blood), and in the pancreas, kidney, and lacrimal gland (2-3 times higher than blood). Concentrations in the spleen, salivary gland, heart, brown fat, lung, and muscle were equal to or 2-fold higher than blood. Concentrations in white fat were equal to that in blood. In the procreative tissues, the highest levels were found in uterine epithelium (8-fold that of blood), ovary, vagina, placenta, mammary gland and uterine lumen (2-fold that of blood). The lowest levels were found in the brain at the limit of quantitation after co-administration with ritonavir. Without ritonavir co-administration, levels in the brain were below quantitation.

Metabolism

The major metabolic pathways of darunavir were aliphatic, aromatic, alicyclic hydroxylation, and carbamate hydrolysis. Other noted metabolic pathyways of darunavir were glucuronidation, oxidative N-dealkylation, and N-acetylation. Darunavir metabolism to the six primary metabolites was catalyzed primarily by the CYP3A4 enzyme in the cytochrome P450 system. Metabolite m²9 was also formed by interactions with the CYP2C19 and CYP2D6 enzymes.

Delavirdine, ritonavir, indinavir and nelfinavir are expected to strongly inhibit darunavir metabolism in vivo. Ritonavir is predicted to completely inhibit darunavir metabolism.

Excretion

In rats, radiolabelled darunavir was primarily excreted in the faeces with approximately 92.6% excreted after 96 hours when darunavir was administered alone, and 94.8% excreted after 96 hours when boosted with ritonavir. Darunavir was excreted fairly rapidly with approximately 83.9% excreted in the faeces and 3.8% excreted in the urine during the time period 0-24 hours post-dose.

Potential Toxicity

The only potential toxicity issues that arose from the pharmacokinetic studies were a small but statistically significant increase in hepatic microsomal protein content (116% of control) at 30 mg/kg/day. Additionally, darunavir appeared to be a statistically significant inducer of hepatic microsomal thyroxine UDP-glucuronosyltransferase which can stimulate thyroid tumour formation. This effect was noted at 100 and 500 mg/kg/day in rats.

3.2.3 Toxicology

Acute Toxicity

Darunavir was moderately well tolerated in the single-dose toxicity studies. In dogs (the best model of human metabolism for this drug), darunavir was well tolerated up to a single oral dose of 80 mg/kg. Clinical effects at higher oral doses included salivation, vomiting, abnormal posture, reduced food consumption, and weight loss. In mice, drug exposure as high as 360 µg·h/mL resulted in 1 death and gastrointestinal distention and lethargy.

Long-Term Toxicity

In repeat-dose toxicity studies in dogs, high systemic exposures were observed (80 µg ·h/ml for a 120 mg/kg dose). The highest exposure level that produced no observable significant increases in adverse effects (NOAEL) was considered to be 120 mg/kg/day. In the repeat dosing, the most common clinical effects were lower heart rates; and decreases in total leukocytes, mean corpuscular hemoglobin, hemoglobin, hematocrit, and mean corpuscular values. Decreases in chloride levels, believed to be drug-related, also occurred. No major toxicity findings or key target organ changes were observed in the dog. However, after 12 months of dosing, limited changes in the liver did occur (increases in liver weight, hepatocellular vacuolation and pigmentation).

In rats at very high exposure levels, similar clinical effects were noted. Findings included disturbances of hematological parameters, high platelet counts and changes in activated partial thromboplastin times. The significant changes in laboratory parameters included high creatinine values; lower triglyceride, aspartate aminotransferase, and alkaline phosphatase values; higher cholesterol and phospholipid values; and high protein and calcium values. Increases in excretion of sodium and chloride were also noted. The NOAEL in rats was determined to be 20 mg/kg/day.

When darunavir was co-administered with ritonavir in rats, the overall exposure of darunavir was increased and the systemic exposure of ritonavir was decreased. Toxicity was generally increased with the co-administration of darunavir and ritonavir, as toxicity was noted in all dose groups.

Carcinogenicity

Carcinogenicity studies have not yet been submitted. Hepatocellular hypertrophy and thyroid effects should also be examined.

Genotoxic/Mutagenic Toxicity

Darunavir showed no genotoxic/mutagenic potential.

Reproductive and Development Toxicity

Drug exposure levels in the reproductive and developmental toxicity studies were below the recommended clinical dose in humans and therefore administration of darunavir to pregnant or nursing mothers is not recommended.

In studies investigating fertility and early embryonic development the most notable effects were a significant weight reduction at 1000 mg/kg that may have impacted the number of ovulated eggs and live fetuses. The exposure levels were below the recommended clinical dose in humans. The NOAEL for maternal and developmental toxicity of darunavir during embryo-fetal development was 1000 mg/kg/day.

Significant clinical effects were noted on the pups when the mothers were given darunavir during lactation at doses of 200 and 1000 mg/kg/day. Pup survival and mean body weight gain were reduced during lactation which resulted in a delay in the acquisition of developmental milestones of pinna detachment and eye opening. No post-weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats directly dosed with darunavir between day 12 and 25 of age (equivalent to less than 2 years old in humans), toxicity and deaths were seen at 40 mg/kg/day and above, and were believed to be related to undeveloped liver enzymes which resulted in higher darunavir exposure.

3.2.4 Summary and Conclusion

The non-clinical studies for this drug submission are considered acceptable. The non-clinical pharmacology and toxicology program for Prezista (darunavir) demonstrated that the compound is relatively safe for humans. 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

The antiretroviral activity of darunavir along with the pharmacokinetics, safety and tolerability of darunavir were assessed in a Phase IIa study with 34 HIV-1 infected patients. The patients were randomized to receive one of the following dosing regimens of darunavir: 400 mg twice a day, 800 mg twice a day, 800 mg three times a day, or 1200 mg three times a day for 13 days, followed by a single dose on day 14. The control group consisted of HIV-1 infected patients that continued their current therapy.

In general, better response was associated with higher exposure to darunavir, which is supported by pharmacokinetic/pharmacodynamic relationships. Treatment with darunavir 800 mg twice a day, 800 mg three times a day, and 1200 mg three times a day for 13 days followed by a single intake on day 14 resulted in a significant reduction of viral load when compared to the control group. Under treatment with 400 mg twice a day, the reduction in viral load was smaller but still statistically significant compared to the control group at treatment endpoint. No conclusions could be drawn for CD4+ cell count due to the high variability of the data and the short duration of the trial.

The darunavir treatment regimens were generally safe and well tolerated. The most common adverse events (AEs) during the treatment period were diarrhea, headache, flatulence, hot flush, fatigue, dyspepsia, nausea, and dizziness. The safety and tolerability profile of darunavir was similar for all four dose groups.

The efficacy, safety and tolerability of Prezista co-administered with low-dose ritonavir was assessed in an open-label, Phase IIa, controlled, randomized trial in multi-protease inhibitor-experienced patients. The patients were randomized to receive dose levels of 300 mg b.i.d., 600 mg b.i.d. and 900 mg b.i.d., co-administered with 100 mg ritonavir, for 14 days. Patients randomized to the control group continued on their current therapy until the end of the treatment period.

Exposure was highest in the 900 mg Prezista, 100 mg ritonavir dose group. Prezista, in combination with ritonavir showed efficacy over the control group. The 600 mg Prezista, 100 mg ritonavir b.i.d., dose group showed the best results in mean averaged changes from baseline plasma HIV-1 RNA, followed by the 900 mg Prezista, 100 mg ritonavir b.i.d. dose group. Due to the short duration of the trial, no noticeable changes in CD4 cell count were noted.

The Prezista/ritonavir treatment regimens were generally well tolerated. The most commonly reported AEs with treatment were gastrointestinal (diarrhea, flatulence, abdominal pain, nausea), fatigue and central nervous system (headache, and dizziness (excluding vertigo)) disorders. These AEs were more commonly reported in the Prezista/ritonavir dose groups than in the control group and were more common in the 900 mg/100 mg dose group than in the other dose groups.

3.3.2 Pharmacokinetics

Absorption

The pharmacokinetic test parameter results of Prezista (darunavir) co-administered with ritonavir revealed a rapid up-take of darunavir after its oral administration, reaching a maximum plasma concentration between 2.5-4.0 hours. The absolute oral bioavailability of a single dose of Prezista (600 mg) was estimated at about 37%, a value which increased to 82% in the presence of ritonavir (100 mg b.i.d.).

Distribution

In the plasma, 95% of darunavir was bound to plasma proteins, primarily alpha-1-acid glycoprotein.

Metabolism

Darunavir is primarily metabolized by the liver through the cytochrome P450 3A4 (CYP3A4) isozyme. The systemic exposure of a single dose Prezista (600 mg) increased 14-fold in the presence of a low dose of ritonavir (100 mg b.i.d.). This increase in exposure was likely due in large part to CYP3A4 inhibition. Higher doses of ritonavir had no significant exposure effects on Prezista.

Elimination

Metabolic studies of ¹⁴C-darunavir/ritonavir showed about 79.5% and 13.9% of the administered ¹⁴C-label dose was present in the faeces and urine, respectively. The portion of administered darunavir that remained unchanged was about 41.2% and approximately 7.7% in the faeces and urine, respectively. The terminal elimination half-life of darunavir was about 15 hours when co-administered with ritonavir. The intravenous clearance of darunavir in the presence and absence of low-dose ritonavir was 32.8 L/h and 5.9 L/h, respectively.

Drug-Drug Interactions

The drug interaction studies, between Prezista/ritonavir and other pharmaceutical products, provided evidence of exposure kinetics for drugs which are not recommended to be co-administered with Prezista, drugs which require dose adjustments upon co-administration, and drugs which are considered safe upon co-administration with Prezista. The pharmacokinetic results of these drug interaction studies have been summarized in the Product Monograph. The Product Monograph also contains information on drug interactions (e.g. Prezista/ritonavir and methadone) predicted solely on the basis of drug effects on the same metabolic enzyme(s) (e.g. CYP 3A4).

Special Populations

Patients with hepatic impairment are expected to have increased plasma concentrations of darunavir and ritonavir since both drugs are primarily metabolized and eliminated by the liver through the CYP3A4 isozyme. Adequate warnings are in place in the Product Monograph.

The safety and efficacy of darunavir in pediatric patients have not yet been established. There are insufficient data at this time to recommend a dose.

3.3.3 Clinical Efficacy

The submission contained two pivotal Phase IIb trials, as well as two supporting trials. The two pivotal trials, TMC114-C213 and TMC114-C202, will hereafter be known by their acronyms, POWER 1 and POWER 2 trials, respectively. The supporting trials were TMC114-C208 and TMC114-C215, and will hereafter be known as the POWER 3 trial as the analysis was based on pooled data from these two trials.

The POWER 1 and POWER 2 trials provided efficacy and safety data from the 24-week mark, and are being continued in order to provide 96-week data. In addition to this, 48-week data from a Phase III study is expected soon. This treatment-experienced Phase III study will be submitted as part of the Letter of Undertaking. The commitment to provide the additional information is consistent with the Notice of Compliance with Conditions (NOC/c) Policy.

The POWER 1 and POWER 2 trials were randomized, controlled Phase IIb studies consisting of two parts: an initially partially-blinded dose-finding phase, and a second long-term phase in which all patients randomized to Prezista/ritonavir received the recommended 600/100 b.i.d. dose. The POWER 1 trial had 319 patients, and the POWER 2 trial had 318 patients, each with 5 arms (400/100 q.d., 800/100 q.d., 400/100 b.i.d., 600/100 b.i.d. and a control arm) so there were 131 patients who received the proposed 600/100 b.i.d dose, and 124 in the control arm. It is considered that these studies both have adequate population sizes for a submission considered under the NOC/c Policy.

The trials were open-label, multicentre studies in HIV-positive, triple-class experienced patients, evaluating treatment with Prezista, co-administered with low-dose ritonavir, plus an optimized background drug regimen (OBR). The OBR which did not include a non-nucleoside reverse transcriptase inhibitor (NNRTI) was individually defined for each patient based on genotypic resistance testing and patient history. The comparator regimen included the best protease inhibitor (PI) or PI options (mainly boosted PI), also individually defined plus an OBR not including an NNRTI. All patients had previously received at least two PI-based antiretroviral regimens and all were failing a PI-based regimen at the time of study entry. At least one primary protease gene mutation had to be present at baseline.

The 131 patients in the 600/100 b.i.d. arm had a median age of 43.9 years, were 89% male, and 81% Caucasian. They had a mean duration of infection of 12.0 years. Similarly, the 124 patients in the comparator arm had a median age of 44.4 years; 88% male, and 73% Caucasian. They had a mean duration of infection of 12.9 years.

In the 600/100 b.i.d and comparator arms, the median baseline CD4 cell counts were 153 and 162.5 cells/mm³, respectively, and the median baseline plasma HIV-1 RNA values were 4.61 and 4.49 log₁₀ copies/mL, respectively.

The primary efficacy endpoint was the proportion of patients with a treatment response (a decrease in viral load of ≥ 1 log₁₀ vs. baseline) at 24 weeks.

Secondary efficacy endpoints included the following:

Proportion of patients with a decrease in plasma viral load >1.0 log₁₀ vs. baseline at all time points other than the 24-week mark, and the time to achieve this.
Proportion of patients with a decrease in plasma viral load >0.5 log₁₀ vs. baseline at each time point, and the time to achieve this.
Proportion of patients with plasma HIV-1 RNA levels <50 copies/mL at each time point, and the time to achieve this.
Proportion of patients with plasma HIV-1 RNA levels <400 copies/mL at each time point, and the time to achieve this.
Time to virologic failure for each of the four definitions of virologic response over the 96-week treatment period.
Change in log₁₀ plasma viral load at all time points.
DAVG (time averaged difference) of log₁₀ plasma viral load over 24 weeks.
Dose response (the dose-finding period of the study).
Change in CD4 cell count (absolute and %).

Data from the two pivotal trials demonstrated that Prezista was superior to the comparator treatment regimens for all dose regimens, with the 600/100 b.i.d. dose regimen producing the best results. The 400/100 q.d. dose produced a 60.0% virologic response (a drop in viral load of ≥1 log₁₀ vs. baseline) at 24 weeks, while the 600/100 b.i.d. dose produced a 70.7% virologic response. The comparator arm produced a 20.6% virologic response.

Additionally, 62.6% of the patients in the 600/100 b.i.d. arm had a viral load <400 copies/mL and 45.0% had a viral load <50 copies/mL. In contrast, only 18.5% and 12.1% of patients in the comparator arm had viral loads of <400 and <50 copies/mL, respectively. The 600/100 b.i.d. arm also resulted in a mean increase of 92.4 CD4+ cells/µL versus baseline, compared to only 17.3 cells/µL in the control arm, thus showing that Prezista produces both a virologic and an immunologic response.

Supportive data on the efficacy of the 600/100 b.i.d dose of Prezista was obtained from the Power 3 analysis that included two open-label trials, where 246 treatment-experienced patients had completed 24 weeks of treatment. The baseline characteristics of the patients were comparable to the patients in the POWER 1 and 2 trials. In the week-24 analysis, 65% had a virologic response (a drop in viral load of ≥ 1 log₁₀ vs. baseline), 57% had a viral load <400 copies/mL and 40% of the patients reached <50 copies/mL. Additionally, the patients showed a mean increase of 80 CD4+ cells/µL vs. baseline after 20 weeks, thereby showing that Prezista produced both a virologic and an immunologic response. The pharmacokinetic/pharmacodynamic analysis failed to show a relationship between the pharmacokinetics of darunavir/ritonavir at the recommended dose of 600/100 mg b.i.d. and antiviral activity or virologic response.

3.3.4 Clinical Safety

Two pivotal trials (POWER 1 and POWER 2) and two supporting trials (POWER 3) were submitted to evaluate the safety of Prezista. The trials are described in section 3.3.3 Clinical Efficacy. In keeping with the provisions outlined in the NOC/c Policy, the sponsor is committed to provide additional safety results at 96 weeks for the pivotal trials, as well as results at 48 weeks for a Phase III clinical trial conducted in treatment-experienced HIV-1 infected patients.

The safety endpoints for the two pivotal trials included the following:

Proportion of patients with treatment-emergent adverse events.
Proportion of patients with serious adverse events.
Proportion of patients reporting adverse events by severity.
Proportion of patients with laboratory test abnormalities.
Laboratory test changes over time.
Discontinuations due to adverse events.

An examination of the safety results from the pivotal trials (N=131) and other supporting studies, including two long-term rollover safety studies [POWER 3 analysis (N = 327)] as well as safety data published in peer-reviewed journals and conference abstracts indicate that Prezista is well tolerated in treatment-experienced patients. The most common adverse events, with the exception of injection site reactions (caused by the use of enfurtivide) included headache, nausea, diarrhea, and nasopharyngitis.

Serious adverse events (SAEs) were seen in approximately 15% of Prezista-treated patients, with 1.7% of patients with a SAE considered at least possibly related to Prezista. The most common SAE was pneumonia (1%). Trial discontinuation due to SAEs was infrequent.

It was noted that during their Phase III trial in treatment-naive patients (not submitted with this submission), a case of Stevens-Johnson syndrome occurred, and as a result, the sponsor added an additional warning in the Product Monograph for severe rash.

The clinical evaluation of the effect of Prezista on QT prolongation was detailed, and meets current ICH standards. Prezista/ritonavir was found not to have an effect on QT prolongation.

3.3.5 Issues Outstanding

Under the NOC/c Policy, the sponsor commits to submitting the results of the following confirmatory studies:

Phase IIb Study TMC114-C213: A Phase II randomized, controlled, partially blinded trial (POWER 1) to investigate dose-response of Prezista/ritonavir in 3-class-experienced HIV-1 infected patients, followed by an open-label period on the recommended dose of Prezista/ritonavir (at 96 weeks).
Phase IIb Study TMC114-C202: A Phase II randomized, controlled, partially blinded trial (POWER 2) to investigate dose response of Prezista/ritonavir in 3-class-experienced HIV-1 infected patients, followed by an open-label period on the recommended dose of Prezista/ritonavir (at 96 weeks).
Phase III Study TMC114-C214: A randomized, controlled, open-label trial to compare the efficacy, safety and tolerability of Prezista/ritonavir vs. lopinavir/ritonavir in treatment-experienced HIV-1 infected subjects (at 48 weeks).

The sponsor will include monitoring and follow-up of adverse events from these studies as well as events noted in post-marketing data and any other major safety concerns identified.

The sponsor agrees to submit to Health Canada Periodic Safety Update Reports semi-annually (the first report covering the period of June 23 through December 22, 2006) until the conditions have been fulfilled and removed from the NOC/c by Health Canada. In addition, the sponsor will commit to post-marketing surveillance and reporting of adverse drug reactions.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Prezista has shown promising evidence of clinical effectiveness, and an acceptable safety profile. The efficacy and safety of Prezista were evaluated from two ongoing pivotal Phase IIb clinical trials (POWER 1 and POWER 2) as well as two supporting trials. The two pivotal trials provided data from the 24-week mark, and are being continued in order to provide further data at the 96-week mark. These additional results along with others will be submitted to verify the clinical benefit. In keeping with the provisions outlined in the NOC/c Policy, the additional information is required to complete the assessment.

The efficacy results from the 24-week mark demonstrated a clear clinical benefit of the recommended dose of Prezista/ritonavir (600/100 mg b.i.d.) in treatment-experienced HIV-1-infected patients with limited or no treatment options. The antiretroviral efficacy was superior when compared with the control group. The results for the primary efficacy parameter (decreases in viral load versus baseline of ≥ 1.0 log₁₀) were supported by those of the secondary parameters (other virologic responses and increases in CD4 cell counts). The responses were greater in the Prezista/ritonavir group compared to control at all time points and were sustained. The differences were statistically significant at the primary endpoint at Week 24.

The evaluation of the safety data indicated that Prezista/ritonavir 600/100 mg b.i.d. treatment was generally safe and well tolerated. Apart from injection site reactions, the most common treatment-emergent adverse events were headache, nausea, diarrhea, and nasopharyngitis. The majority of the adverse events were grade 1 to 2 in severity. Most graded laboratory abnormalities were grade 1 or 2 in severity. Overall, the incidence of adverse events related to laboratory parameters was low. These events were rarely reported as serious adverse events and seldom led to discontinuation.

Therefore, based on the efficacy results and the safety profile, the risk/benefit ratio is acceptable for Prezista. The benefit associated with the use of the 600/100 b.i.d regimen for Prezista/ritonavir for the proposed treatment group outweighs the potential risk.

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 Prezista co-administered with 100 mg ritonavir and with other antiretroviral agents is favourable for the treatment of HIV infection in treatment-experienced adult patients who have failed prior antiretroviral therapy.

This New Drug Submission (NDS) qualifies for authorization under the NOC/c Policy. The NDS 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.

Consistent with the NOC/c Policy, the sponsor has committed to submitting the results of the following confirmatory studies:

Phase IIb Study TMC114-C213: A Phase II randomized, controlled, partially blinded trial to investigate dose-response of Prezista/ritonavir in 3-class-experienced HIV-1 infected patients, followed by an open-label period on the recommended dose of Prezista/ritonavir (at 96 weeks).
Phase IIb Study TMC114-C202: A Phase II randomized, controlled, partially blinded trial to investigate dose response of Prezista/ritonavir in 3-class-experienced HIV-1 infected patients, followed by an open-label period on the recommended dose of Prezista/ritonavir (at 96 weeks).
Phase III Study TMC114-C214: A randomized, controlled, open-label trial to compare the efficacy, safety and tolerability of Prezista/ritonavir vs. lopinavir/ritonavir in treatment-experienced HIV-1 infected subjects (at 48 weeks).