In a new Phase III study that compared Merck & Co., Inc.’s HIV integrase inhibitor ISENTRESS(R) (raltegravir) to efavirenz (one of the leading antiretrovirals prescribed for previously untreated (treatment-naive) HIV-infected patients), ISENTRESS reduced HIV viral load to undetectable levels (less than 50 copies/mL) in 86 percent of patients compared to 82 percent of patients treated with efavirenz in previously untreated HIV patients at Week 48. Both medicines were taken in combination with tenofovir/emtricitabine. Patients taking ISENTRESS had a greater increase in CD4 cell counts, an average increase of 189 cells/mm(3), compared to patients taking efavirenz who had an average increase of 163 cells/mm(3 )at Week 48. In addition, drug-related adverse events of any severity occurred in fewer patients (44 percent vs. 77 percent; p less than 0.001) treated with ISENTRESS. The use of ISENTRESS in treatment-naive patients is investigational. These 48 week findings were presented today at the late-breaker session of the joint 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/Infectious Diseases Society of America (IDSA) 46th Annual Meeting in Washington, D.C.
“This study showed that when paired with other anti-HIV medicines, ISENTRESS lowered the amount of virus in the blood to below detectable (less than 50 copies/mL) levels in over 8 out of 10 treatment-naive patients and had fewer side effects than the standard of care,” said Daniel S. Berger, M.D., clinical associate professor, College of Medicine University of Illinois at Chicago and medical director of NorthStar Medical Center. “These results further demonstrate that, if approved for such use, ISENTRESS may be another important option for patients when first initiating HIV therapy.”
ISENTRESS is the first integrase inhibitor approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents. This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, three-class antiretroviral (nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)) treatment-experienced adults. In these studies the use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naive adult or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.
ISENTRESS studied in more than 500 previously untreated HIV patients in Phase III trial
These findings presented today are from an ongoing multi-center, double-blind, randomized, active-controlled Phase III trial of previously untreated HIV-infected patients called STARTMRK. In this study, 563 treatment-naive, HIV-infected patients received either 400 mg ISENTRESS administered orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz dosed orally once daily in combination with the same agents. The primary endpoints were reductions in HIV RNA to less than 50 copies/mL and an evaluation of safety and tolerability at Week 48. Secondary endpoints included antiretroviral activity as measured by the proportion of patients achieving HIV RNA less than 400 copies/mL and change from baseline in CD4 cell counts at Week 48. An additional secondary safety endpoint was the proportion of patients experiencing nervous system symptoms through week eight.
Suppression of viral load and increase in CD4 cell counts maintained through 48 weeks
At baseline, geometric mean HIV RNA levels for patients on the regimen including ISENTRESS was 103,205 copies/mL (n=281) and for the efavirenz regimen was 106,215 copies/mL (n=282). Mean baseline CD4 cell counts were 219 and 217 cells/mm(3) for the groups receiving ISENTRESS and efavirenz, respectively.
After 48 weeks of treatment, 86 percent of patients receiving the regimen with ISENTRESS achieved reductions in HIV RNA levels below 50 copies/mL. Results were comparable for patients taking the efavirenz regimen, with 82 percent of patients achieving reductions in HIV RNA levels below 50 copies/mL in the same time period. Similarly, 90 percent of patients receiving the regimen containing ISENTRESS maintained reductions in HIV RNA levels to below 400 copies/mL compared to 86 percent of patients taking the regimen containing efavirenz. Time to virologic response was significantly shorter for patients taking ISENTRESS compared to those taking the efavirenz regimen, confirming the rapid viral load reductions demonstrated by ISENTRESS in previous trials. At week eight, 74 percent of patients receiving the regimen with ISENTRESS achieved HIV RNA levels below 50 copies/mL compared to 38 percent of patients receiving the regimen with efavirenz.
Patients receiving the regimen with ISENTRESS had greater immunologic response as measured by change from baseline in CD4 cell count. At Week 48 the mean increase from baseline in CD4 cell count was 189 cells/mm(3 )for patients receiving ISENTRESS and 163 cells/mm(3 )for patients receiving efavirenz.
Tolerability profile of ISENTRESS in STARTMRK study
The most commonly (greater than or equal to 2.0 percent in either treatment group) reported drug-related clinical adverse experiences of moderate or severe intensity in patients receiving ISENTRESS and efavirenz, respectively, were headache (3.9 percent vs. 4.6 percent), nausea (2.8 percent vs. 3.5 percent), dizziness (1.4 percent vs. 6.4 percent), insomnia (3.6 percent vs. 3.2 percent), diarrhea (1.1 percent vs. 2.8 percent), fatigue (1.4 percent vs. 2.8 percent), rash (0.0 percent vs. 2.8 percent), and maculo-papular rash (0.0 percent vs. 2.5 percent). Central nervous system symptoms were reported significantly less frequently with the group receiving ISENTRESS compared to the group receiving efavirenz through week eight (20.3 percent vs. 52.1 percent). Cancer occurred in one patient taking the regimen with ISENTRESS and nine patients taking the regimen with efavirenz.
Researchers also assessed lipid levels based upon the profile observed with ISENTRESS and efavirenz in an earlier Phase II trial in a similar population. Results from the STARTMRK study showed that ISENTRESS had minimal effect on lipid levels. The mean changes from baseline at Week 48 for ISENTRESS and efavirenz, respectively, were 10 mg/dL and 32.7 mg/dL (p less than 0.001) for total cholesterol; 5.9 mg/dL and 16.1 mg/dL (p less than 0.001) for LDL cholesterol; 4.2 mg/dL and 10.0 mg/dL (p less than 0.001) for HDL cholesterol; and -2.8 mg/dL and 37.4 mg/dL (p less than 0.001) for triglycerides.
“These findings reinforce the efficacy and safety data seen with ISENTRESS in Phase II trials in treatment-naive patients, and are consistent with efficacy already established in treatment-experienced patients for whom it is currently approved,” said Robin Isaacs, M.D., executive director, Infectious Disease/Vaccines Clinical Research, Merck Research Laboratories. “Viral load reductions and CD4 cell count increases were sustained through 48 weeks in this study.”
Important safety information about ISENTRESS
ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.
Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.
In the clinical trials involving treatment-experienced patients, the most commonly reported adverse experiences of any severity (mild, moderate or severe) for ISENTRESS plus optimized background therapy (OBT) versus placebo plus OBT, respectively, regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4.9 percent vs. 10.3 percent).
In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively. Results from pooled safety analyses from three separate studies (BENCHMRK-1, BENCHMRK-2 and a Phase II dose ranging study) in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT.
Drug interactions
Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes. Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of ISENTRESS. Preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes.
About ISENTRESS
ISENTRESS is the first medicine to be approved in a class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase – but ISENTRESS is the only drug approved that inhibits the integrase enzyme.
In October 2007, the U.S. Food and Drug Administration granted ISENTRESS accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.
Merck HIV Research
Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases – including HIV. Merck’s efforts to develop investigational treatments for HIV and AIDS have been under way for more than 20 years and continue today. Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.
Prevalence of HIV and AIDS
In 2006, more than one million Americans were living with HIV and AIDS, and it is estimated that approximately more than 56,000 new cases of HIV and AIDS are diagnosed each year in the United States.
Worldwide, an estimated 33 million people are infected with HIV and AIDS, and more than two million new infections occurred in 2007.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-looking statement
This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management’s current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck’s business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck’s Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company’s periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.
Prescribing information and patient prescribing information for ISENTRESS(R) is attached.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ISENTRESS safely and effectively. See full prescribing information for ISENTRESS.
ISENTRESS (raltegravir) Tablets
Initial U.S. Approval: 2007
INDICATIONS AND USAGE
ISENTRESS(TM) is a human immunodeficiency virus integrase strand transfer inhibitor (HIV-1 INSTI) indicated:
— In combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents (1).
The safety and efficacy of ISENTRESS have not been established in treatment-naive adult patients or pediatric patients (1).
DOSAGE AND ADMINISTRATION
— 400 mg administered orally, twice daily with or without food (2.1).
DOSAGE FORMS AND STRENGTHS
Tablets: 400 mg (3).
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Monitor for Immune Reconstitution Syndrome (5.1)
Drug Interactions
— Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of raltegravir (5.2).
ADVERSE REACTIONS
— The most common adverse reactions (greater than 10%) of all intensities, reported in subjects in either the ISENTRESS or the placebo treatment group, regardless of causality were: nausea, headache, diarrhea and pyrexia (6.1).
— Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pregnancy:
— ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Physicians are encouraged to register pregnant women exposed to ISENTRESS by calling 1-800-258-4263 so that Merck can monitor maternal and fetal outcomes (8.1).
Nursing Mothers:
— Breast-feeding is not recommended while taking ISENTRESS (8.3).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 05/2008
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Immune Reconstitution Syndrome
5.2 Drug Interactions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents
7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Use in Patients with Hepatic Impairment
8.7 Use in Patients with Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the Full Prescribing Information are not listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
ISENTRESS(1) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.
This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults.
The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response (see Clinical Studies (14)).
The safety and efficacy of ISENTRESS have not been established in treatment-naive adult patients or pediatric patients.
There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
For the treatment of patients with HIV-1 infection, the dosage of ISENTRESS is 400 mg administered orally, twice daily with or without food.
3 DOSAGE FORMS AND STRENGTHS
400 mg pink, oval-shaped, film-coated tablets with “227” on one side.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Immune Reconstitution Syndrome
During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.
5.2 Drug Interactions
Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of raltegravir (see Drug Interactions (7)).
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Treatment-Experienced Studies
The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), and the randomized, double-blind, placebo-controlled, dose-ranging trial (Protocol 005) in antiretroviral treatment-experienced HIV-1 infected adult subjects reported using the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) in 507 subjects, in comparison to 282 subjects taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 332.2 patient-years in the ISENTRESS 400 mg twice daily group and 150.2 patient-years in the placebo group.
The most commonly (greater than 10%) reported adverse reactions, of all intensities, regardless of causality in subjects treated with ISENTRESS and OBT versus placebo and OBT are presented in Table 1.
Table 1: Percentage of Subjects with the Most Commonly Reported (greater than 10%) Adverse Reactions of All Intensities* and Regardless of Causality Occurring in
Treatment-Experienced Adult Subjects
System Organ Class, Adverse Randomized Studies P005, P018 and Reactions P019 ------------------------------------- ISENTRESS 400 mg Placebo + OBT twice daily + OBT (n=282)+ (n=507)+ % % ---------------------------------------------------------------------- Gastrointestinal Disorders ---------------------------------------------------------------------- Diarrhea 16.6 19.5 ---------------------------------------------------------------------- Nausea 9.9 14.2 ---------------------------------------------------------------------- Nervous System Disorders ---------------------------------------------------------------------- Headache 9.7 11.7 ---------------------------------------------------------------------- General Disorders and Administration Site Conditions ---------------------------------------------------------------------- Pyrexia 4.9 10.3 ---------------------------------------------------------------------- *Intensities are defined as follows: Mild (awareness of sign or symptom, but easily tolerated); Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). +n=total number of subjects per treatment group.
The clinical adverse reactions listed below were considered by investigators to be of moderate to severe intensity and causally related to any drug in the combination regimen (ISENTRESS/placebo alone or in combination with OBT, or OBT alone):
Common Adverse Reactions
Drug-related clinical adverse reactions of moderate to severe intensity occurring in =>2% of subjects treated with ISENTRESS + OBT are presented in Table 2.
Table 2: Percentage of Subjects with Drug-Related* Adverse Reactions of Moderate to Severe Intensity+ Occurring in =>2% of Treatment-Experienced Adult Subjects
System Organ Class, Randomized Studies P005, P018 and P019 Adverse Reactions ------------------------------------------- ISENTRESS 400 mg Twice Daily Placebo + OBT + OBT (n = 282)++ (n = 507)++ % % ---------------------------------------------------------------------- Gastrointestinal Disorders ---------------------------------------------------------------------- Diarrhea 3.7 4.6 ---------------------------------------------------------------------- Nausea 2.2 3.2 ---------------------------------------------------------------------- Nervous System Disorders ---------------------------------------------------------------------- Headache 2.4 1.4 ---------------------------------------------------------------------- *Includes adverse reactions at least possibly, probably, or very likely related to the drug. +Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). ++n=total number of subjects per treatment group.
Less Common Adverse Reactions
Drug-related adverse reactions occurring in at least 1% but less than 2% of treatment-experienced subjects (n=507) receiving ISENTRESS + OBT and of moderate (discomfort enough to cause interference with usual activity) to severe (incapacitating with inability to work or do usual activity) intensity are listed below by system organ class:
Gastrointestinal Disorders: abdominal pain, vomiting
General Disorders and Administration Site Conditions: asthenia, fatigue
Nervous System Disorders: dizziness
Skin and Subcutaneous Tissue Disorders: lipodystrophy acquired
Discontinuations
In the pooled analyses for studies P005, P018 and P019, the rates of discontinuation of therapy due to adverse reactions were 2.0% in subjects receiving ISENTRESS + OBT and 1.4% in subjects receiving placebo + OBT.
Serious Events
Drug Related
The following serious drug-related reactions were reported in the clinical studies, P005, P018 and P019: hypersensitivity (hypersensitivity was seen in 2 subjects with ISENTRESS; therapy was interrupted and upon rechallenge the subjects were able to resume drug), anemia, neutropenia, myocardial infarction, gastritis, hepatitis, herpes simplex, toxic nephropathy, renal failure, chronic renal failure and renal tubular necrosis.
Regardless of Drug Relationship
Cancers were reported in treatment-experienced subjects who initiated ISENTRESS with OBT; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ cell counts below 50 cells/mm3 and most had prior AIDS diagnoses). The cancers included Kaposi’s sarcoma, lymphoma, squamous cell carcinoma, hepatocellular carcinoma and anal cancer. Most subjects had other risk factors for cancer including tobacco use, papillomavirus and active hepatitis B virus infection. It is unknown if these cancer diagnoses were related to ISENTRESS use.
Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 3). Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.
Patients with Co-existing Conditions
Patients Co-infected with Hepatitis B and/or Hepatitis C Virus
In the clinical studies, P018 and P019, subjects with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection (N = 113/699 or 16.2%) were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). The rates of AST and ALT abnormalities were somewhat higher in the subgroup of subjects with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to subjects without hepatitis B and/or hepatitis C virus co-infection. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 26%, 27% and 12%, respectively, of raltegravir-treated coinfected subjects as compared to 9%, 8% and 7% of all other raltegravir-treated subjects.
Laboratory Abnormalities
The percentages of adult subjects treated with ISENTRESS 400 mg twice daily in P005, P018 and P019 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening from baseline are presented in Table 3.
Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects
Randomized Studies P005, P018 and P019 Laboratory Parameter Preferred Limit ISENTRESS 400 mg Placebo Term (Unit) Twice Daily + + OBT OBT (N = 507) (N = 282) ---------------------------------------------------------------------- Hematology ---------------------------------------------------------------------- Absolute neutrophil count (103/(mu)L) Grade 2 0.75 - 0.999 3.7% 7.4% Grade 3 0.50 - 0.749 2.4% 2.5% Grade 4 500 0.0% 0.0% ---------------------------------------------------------------------- Total serum bilirubin Grade 2 1.6 - 2.5 x ULN 5.3% 6.7% Grade 3 2.6 - 5.0 x ULN 3.2% 2.5% Grade 4 >5.0 x ULN 0.8% 0.0% ---------------------------------------------------------------------- Serum aspartate aminotransferase Grade 2 2.6 - 5.0 x ULN 9.1% 5.7% Grade 3 5.1 - 10.0 x ULN 2.2% 2.1% Grade 4 >10.0 x ULN 0.4% 0.7% ---------------------------------------------------------------------- Serum alanine aminotransferase Grade 2 2.6 - 5.0 x ULN 6.9% 7.8% Grade 3 5.1 - 10.0 x ULN 3.0% 1.4% Grade 4 >10.0 x ULN 0.6% 1.1% ---------------------------------------------------------------------- Serum alkaline phosphatase Grade 2 2.6 - 5.0 x ULN 2.0% 0.4% Grade 3 5.1 - 10.0 x ULN 0.4% 1.1% Grade 4 >10.0 x ULN 0.4% 0.4% ---------------------------------------------------------------------- Serum pancreatic amylase test Grade 2 1.6 - 2.0 x ULN 1.4% 0.7% Grade 3 2.1 - 5.0 x ULN 3.6% 2.1% Grade 4 >5.0 x ULN 0.2% 0.0% ---------------------------------------------------------------------- Serum lipase test Grade 2 1.6 - 3.0 x ULN 3.4% 1.8% Grade 3 3.1 - 5.0 x ULN 0.6% 0.4% Grade 4 >5.0 x ULN 0.2% 0.0% ---------------------------------------------------------------------- Serum creatine kinase Grade 2 6.0 - 9.9 x ULN 2.2% 1.4% Grade 3 10.0 - 19.9 x ULN 2.4% 1.8% Grade 4 =>20.0 x ULN 2.2% 0.7% ---------------------------------------------------------------------- ULN = Upper limit of normal range
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders: rash, Stevens-Johnson syndrome
7 DRUG INTERACTIONS
7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents
Raltegravir does not inhibit (IC50 greater than 100 uM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC50 greater than 50 uM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, methadone, opioid analgesics, statins, azole antifungals, proton pump inhibitors, oral contraceptives, and anti-erectile dysfunction agents).
In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: lamivudine, tenofovir.
7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir
Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, caution should be used when coadministering ISENTRESS with rifampin or other strong inducers of UGT1A1 (see Warnings and Precautions (5.2)). The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Other less strong inducers (e.g., efavirenz, nevirapine, rifabutin, St. John’s wort) may be used with the recommended dose of ISENTRESS.
Similar to rifampin, tipranavir/ritonavir reduces plasma concentrations of ISENTRESS. However, approximately 100 subjects received raltegravir in combination with tipranavir/ritonavir in Protocols 018 and 019. Comparable efficacy was observed in this subgroup relative to subjects not receiving tipranavir/ritonavir. Based on these data, tipranavir/ritonavir may be coadministered with ISENTRESS without dose adjustment of ISENTRESS.
Atazanavir, a strong inhibitor of UGT1A1, and atazanavir/ritonavir increase plasma concentrations of raltegravir. However, concomitant use of ISENTRESS and atazanavir/ritonavir did not result in a unique safety signal in Protocol 005 and Protocols 018 and 019. Based on these data, atazanavir/ritonavir may be coadministered with ISENTRESS without dose adjustment of ISENTRESS.
Coadministration of ISENTRESS with other drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women. In addition, there have been no pharmacokinetic studies conducted in pregnant patients.
Developmental toxicity studies were performed in rabbits (at oral doses up to 1000 mg/kg/day) and rats (at oral doses up to 600 mg/kg/day). The reproductive toxicity study in rats was performed with pre-, peri-, and postnatal evaluation. The highest doses in these studies produced systemic exposures in these species approximately 3- to 4-fold the exposure at the recommended human dose. In both rabbits and rats, no treatment-related effects on embryonic/fetal survival or fetal weights were observed. In addition, no treatment-related external, visceral, or skeletal changes were observed in rabbits. However, treatment-related increases over controls in the incidence of supernumerary ribs were seen in rats at 600 mg/kg/day (exposures 3-fold the exposure at the recommended human dose).
Placenta transfer of drug was demonstrated in both rats and rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug concentrations in fetal plasma were approximately 1.5- to 2.5-fold greater than in maternal plasma at 1 hour and 24 hours postdose, respectively. Mean drug concentrations in fetal plasma were approximately 2% of the mean maternal concentration at both 1 and 24 hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
8.3 Nursing Mothers
Breast-feeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. Mean drug concentrations in milk were approximately 3-fold greater than those in maternal plasma at a maternal dose of 600 mg/kg/day in rats. There were no effects in rat offspring attributable to exposure of ISENTRESS through the milk.
8.4 Pediatric Use
Safety and effectiveness of ISENTRESS in pediatric patients less than 16 years of age have not been established.
8.5 Geriatric Use
Clinical studies of ISENTRESS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Use in Patients with Hepatic Impairment
No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied (see Clinical Pharmacology (12.3)).
8.7 Use in Patients with Renal Impairment
No clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects were observed. No dosage adjustment is necessary (see Clinical Pharmacology (12.3)).
10 OVERDOSAGE
No specific information is available on the treatment of overdosage with ISENTRESS. Doses as high as 1600-mg single dose and 800-mg twice-daily multiple doses were studied in healthy volunteers without evidence of toxicity. Occasional doses of up to 1800 mg per day were taken in the P005/P018 & P019 studies without evidence of toxicity.
In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. The extent to which ISENTRESS may be dialyzable is unknown.
11 DESCRIPTION
ISENTRESS contains raltegravir potassium, a human immunodeficiency virus integrase strand transfer inhibitor. The chemical name for raltegravir potassium is N-((4-Fluorophenyl)methyl)-1,6-dihydro-5-hydroxy-1-methyl-2-(1-methyl -1-(((5-methyl-1,3,4-oxadiazol-2-yl)carbonyl)amino)ethyl)-6-oxo-4- pyrimidinecarboxamide monopotassium salt.
The empirical formula is C20H20FKN6O5 and the molecular weight is 482.51. The structural formula is:
(GRAPHIC OMITTED)
Raltegravir potassium is a white to off-white powder. It is soluble in water, slightly soluble in methanol, very slightly soluble in ethanol and acetonitrile and insoluble in isopropanol.
Each film-coated tablet of ISENTRESS for oral administration contains 434.4 mg of raltegravir potassium (as salt), equivalent to 400 mg of raltegravir (free phenol) and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Raltegravir is an HIV-1 antiviral drug (see Clinical Pharmacology (12.4)).
12.2 Pharmacodynamics
In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log10 copies/mL by Day 10.
In Protocol 005 and Protocols 018 and 019, antiviral responses were similar among subjects regardless of dose.
Effects on Electrocardiogram
In a randomized, placebo-controlled, crossover study, 31 healthy subjects were administered a single oral supratherapeutic dose of raltegravir 1600 mg and placebo. Peak raltegravir plasma concentrations were approximately 4-fold higher than the peak concentrations following a 400 mg dose. ISENTRESS did not appear to prolong the QTc interval for 12 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided 95% upper Cl: 3.1 msec).
12.3 Pharmacokinetics
Absorption
Raltegravir is absorbed with a Tmax of approximately 3 hours postdose in the fasted state. Raltegravir AUC and Cmax increase dose proportionally over the dose range 100 mg to 1600 mg. Raltegravir C12hr increases dose proportionally over the dose range of 100 to 800 mg and increases slightly less than dose proportionally over the dose range 100 mg to 1600 mg. With twice-daily dosing, pharmacokinetic steady state is achieved within approximately the first 2 days of dosing. There is little to no accumulation in AUC and Cmax. The average accumulation ratio for C12hr ranged from approximately 1.2 to 1.6.
The absolute bioavailability of raltegravir has not been established.
In subjects who received 400 mg twice daily alone, raltegravir drug exposures were characterized by a geometric mean AUC0-12hr of 14.3 (mu)M●hr and C12hr of 142 nM.
Considerable variability was observed in the pharmacokinetics of raltegravir. For observed C12hr in Protocols 018 and 019, the coefficient of variation (CV) for inter-subject variability = 212% and the CV for intra-subject variability = 122%.
Effect of Food on Oral Absorption
ISENTRESS may be administered without regard to food. Administration of raltegravir following a high-fat meal increased raltegravir AUC by approximately 19%. A high-fat meal slowed the rate of absorption resulting in an approximately 34% decrease in Cmax, an 8.5-fold increase in C12hr, and a delay in Tmax following a single 400 mg dose. The effect of consumption of a range of food types on steady-state pharmacokinetics is not known. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-1 positive subjects.
Distribution
Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 uM.
Metabolism and Excretion
The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter (alpha)-phase half-life (tilde1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. Studies using isoform-selective chemical inhibitors and cDNA-expressed UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme responsible for the formation of raltegravir-glucuronide. Thus, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.
Special Populations
Pediatric
The pharmacokinetics of raltegravir in pediatric patients has not been established.
Age
The effect of age on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.
Race
The effect of race on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.
Gender
A study of the pharmacokinetics of raltegravir was performed in young healthy males and females. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV-1 infected subjects receiving raltegravir monotherapy with fasted administration. No dosage adjustment is necessary.
Hepatic Impairment
Raltegravir is eliminated primarily by glucuronidation in the liver. A study of the pharmacokinetics of raltegravir was performed in subjects with moderate hepatic impairment. Additionally, hepatic impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.
Renal Impairment
Renal clearance of unchanged drug is a minor pathway of elimination. A study of the pharmacokinetics of raltegravir was performed in subjects with severe renal impairment. Additionally, renal impairment was evaluated in the composite pharmacokinetic analysis. There were no clinically important pharmacokinetic differences between subjects with severe renal impairment and healthy subjects. No dosage adjustment is necessary. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided.
UGT1A1 Polymorphism
Data currently available are not sufficient to determine the impact of UGT1A1 polymorphism on raltegravir pharmacokinetics.
Drug Interactions (see Drug Interactions (7)).
Table 4: Effect of Other Agents on the Pharmacokinetics of Raltegravir
Ratio (90% Confidence Interval) of Raltegravir Pharmacokinetic Parameters with/without Coadministered Drug; Coadministered Raltegravir No Effect = 1.00 Coadministered Drug Dose/ Dose/ --------------------------- Drug Schedule Schedule n Cmax AUC Cmin ---------------------------------------------------------------------- atazanavir 400 mg daily 100 mg 10 single 1.53 1.72 1.95 dose (1.11, (1.47, (1.30, 2.12) 2.02) 2.92) ---------------------------------------------------------------------- atazanavir/ 300 mg/100 mg 400 mg 10 1.24 1.41 1.77 ritonavir daily twice (0.87, (1.12, (1.39, daily 1.77) 1.78) 2.25) ---------------------------------------------------------------------- efavirenz 600 mg daily 400 mg 9 0.64 0.64 0.79 single (0.41, (0.52, (0.49, dose 0.98) 0.80) 1.28) ---------------------------------------------------------------------- rifampin 600 mg daily 400 mg 9 0.62 0.60 0.39 single (0.37, (0.39, (0.30, dose 1.04) 0.91) 0.51) ---------------------------------------------------------------------- ritonavir 100 mg twice 400 mg 10 0.76 0.84 0.99 daily single (0.55, (0.70, (0.70, dose 1.04) 1.01) 1.40) ---------------------------------------------------------------------- tenofovir 300 mg daily 400 mg 9 1.64 1.49 1.03 twice (1.16, (1.15, (0.73, daily 2.32) 1.94) 1.45) ---------------------------------------------------------------------- tipranavir/ 500 mg/200 mg 400 mg 15 ritonavir twice daily twice (14 0.82 0.76 0.45 daily for (0.46, (0.49, (0.31, Cmin) 1.46) 1.19) 0.66) ----------------------------------------------------------------------
12.4 Microbiology
Mechanism of Action
Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases (alpha), (beta), and (gamma).
Antiviral Activity in Cell Culture
Raltegravir at concentrations of 31 +/- 20 nM resulted in 95% inhibition (EC95) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir at concentrations of 6 to 50 nM resulted in 95% inhibition of viral spread in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide.
Resistance
The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M/R, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226D/F/H, S230R and D232N). Amino acid substitution at Y143C/H/R is another pathway to raltegravir resistance.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term (2-year) carcinogenicity studies of raltegravir in rodents are ongoing.
No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage and in vitro and in vivo chromosomal aberration studies.
No effect on fertility was seen in male and female rats at doses up to 600 mg/kg/day which resulted in a 3-fold exposure above the exposure at the recommended human dose.
14 CLINICAL STUDIES
Description of Clinical Studies
The evidence of efficacy of ISENTRESS is based on the analyses of 24-week data from 2 ongoing, randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), in antiretroviral treatment-experienced HIV-1 infected adult subjects. These efficacy results were supported by the 48-week analysis of a randomized, double-blind, controlled, dose-ranging trial, Protocol 005, in antiretroviral treatment-experienced HIV-1 infected adult subjects.
Treatment-Experienced Subjects
BENCHMRK 1 and BENCHMRK 2 are Phase III studies to evaluate the safety and antiretroviral activity of ISENTRESS 400 mg twice daily in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-infected subjects, 16 years or older, with documented resistance to at least 1 drug in each of 3 Classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. greater than 1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.
Table 5 shows the demographic characteristics of subjects in the ISENTRESS 400 mg twice daily arm and subjects in the placebo arm.
Table 5: Baseline Characteristics
ISENTRESS 400 mg Twice Daily Placebo BENCHMRK 1 and 2 Pooled + OBT + OBT (N = 462) (N = 237) ---------------------------------------------------------------------- Gender n (%) ---------------------------------------------------------------------- Male 405 (87.7) 210 (88.6) Female 57 (12.3) 27 (11.4) ---------------------------------------------------------------------- Race n (%) ---------------------------------------------------------------------- White 301 (65.2) 173 (73.0) Black 66 (14.3) 26 (11.0) Asian 16 (3.5) 6 (2.5) Hispanic 53 (11.5) 19 (8.0) Others 26 (5.6) 13 (5.5) ---------------------------------------------------------------------- Age (years) ---------------------------------------------------------------------- Median (min, max) 45.0 (16 to 74) 45.0 (17 to 70) ---------------------------------------------------------------------- CD4+ Cell Count ---------------------------------------------------------------------- Median (min, max), cells/mm3 119 (1 to 792) 123 (0 to 759) 50 and 100,000 copies/mL, n (%) 164 (35.5) 78 (32.9) ---------------------------------------------------------------------- History of AIDS n (%) ---------------------------------------------------------------------- Yes 426 (92.2) 216 (91.1) ---------------------------------------------------------------------- Prior Use of ART, Median (1st Quartile, 3rd Quartile) ---------------------------------------------------------------------- Years of ART Use 10.1 (7.4 to 12.1) 10.2 (7.9 to 12.4) Number of ART 12.0 (9 to 15) 12.0 (9 to 14) ---------------------------------------------------------------------- Hepatitis Co-infection* n (%) ---------------------------------------------------------------------- No Hepatitis B or C virus 385 (83.3) 201 (84.8) Hepatitis B virus only 36 (7.8) 7 (3.0) Hepatitis C virus only 37 (8.0) 27 (11.4) Co-infection of Hepatitis B and C virus 4 (0.9) 2 (0.8) ---------------------------------------------------------------------- Stratum n (%) ---------------------------------------------------------------------- Enfuvirtide in OBT 175 (37.9) 89 (37.6) Resistant to =>2 PI 447 (96.8) 226 (95.4) ---------------------------------------------------------------------- *Hepatitis B virus surface antigen positive or hepatitis C virus antibody positive.
Table 6 compares the characteristics of optimized background therapy at baseline in the ISENTRESS 400 mg twice daily arm and subjects in the control arm.
Table 6: Characteristics of Optimized Background Therapy at Baseline
ISENTRESS 400 mg Twice Daily Placebo BENCHMRK 1 and 2 Pooled + OBT + OBT (N = 462) (N = 237) ---------------------------------------------------------------------- Number of ARTs in OBT ---------------------------------------------------------------------- Median (min, max) 4.0 (1 to 7) 4.0 (2 to 7) ---------------------------------------------------------------------- Number of Active PI in OBT by Phenotypic Resistance Test* ---------------------------------------------------------------------- 0 166 (35.9) 97 (40.9) 1 or more 278 (60.2) 137 (57.8) ---------------------------------------------------------------------- Phenotypic Sensitivity Score (PSS)+ ---------------------------------------------------------------------- 0 67 (14.5) 44 (18.6) 1 145 (31.4) 71 (30.0) 2 142 (30.7) 66 (27.8) 3 or more 85 (18.4) 48 (20.3) ---------------------------------------------------------------------- Genotypic Sensitivity Score (GSS)+ ---------------------------------------------------------------------- 0 115 (24.9) 65 (27.4) 1 178 (38.5) 96 (40.5) 2 111 (24.0) 49 (20.7) 3 or more 51 (11.0) 23 (9.7) ---------------------------------------------------------------------- *Darunavir use in OBT in darunavir naive subjects was counted as one active PI. +The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject's viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-naive subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naive subjects was counted as one active drug in OBT.
Week 24 outcomes for subjects on the recommended dose of ISENTRESS 400 mg twice daily from the pooled studies BENCHMRK 1 and 2 are shown in Table 7. The efficacy responses were evaluated based upon the 436 subjects from the pooled studies BENCHMRK 1 and 2 who had completed 24 weeks of treatment or discontinued earlier. All other outcomes were based upon the total 699 subjects who were randomized and treated.
Table 7: Outcomes by Treatment Group through Week 24
ISENTRESS 400 mg Twice Daily Placebo BENCHMRK 1 and 2 Pooled + OBT + OBT n (%) (N = 462) (N = 237) ---------------------------------------------------------------------- Outcome at Week 24 n (%) n (%) ---------------------------------------------------------------------- Subjects with Week 24 data 286 150 Subjects with HIV-1 RNA less than 400 copies/mL* 216 (75.5) 59 (39.3) Subjects with HIV-1 RNA less than 50 copies/mL* 179 (62.6) 50 (33.3) ---------------------------------------------------------------------- Virologic Failure (confirmed)+,++ 74 (16.0) 121 (51.1) Non-responder+,++ 13 (2.8) 78 (32.9) Rebound+,++ 61 (13.2) 43 (18.1) ---------------------------------------------------------------------- Death++,ss. 6 (1.3) 3 (1.3) Discontinuation due to adverse experiences++,ss. 9 (1.9) 5 (2.1) Discontinuation due to other reasons++,ss.,6 (1.3) 1 (0.4) ---------------------------------------------------------------------- *Based upon the 436 subjects with Week 24 data +Virologic failure: defined as non-responders who did not achieve >1.0 log10 HIV-1 RNA reduction and 400 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response with HIV-1 RNA 1.0 log10 increase in HIV-1 RNA above nadir level (on 2 consecutive measurements at least 1 week apart). ++Based upon the total 699 subjects randomized and treated, not all subjects complete to Week 24 ss.Includes available data beyond Week 24
Includes loss to follow-up, subjects withdrew consent, noncompliance, protocol violation and other reasons.
The mean changes in plasma HIV-1 RNA from baseline were -1.85 log10 copies/mL in the ISENTRESS 400 mg twice daily arm and -0.84 log10 copies/mL for the control arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving ISENTRESS 400 mg twice daily (89 cells/mm3) than in the control arm (35 cells/mm3).
Virologic responses at Week 24 by baseline genotypic and phenotypic sensitivity score are shown in Table 8.
Table 8: Virologic Response at Week 24 by Baseline Genotypic/Phenotypic Sensitivity Score
BENCHMRK 1 and Percent with HIV RNA Percent with HIV RNA 2 Pooled16 HOW SUPPLIED/STORAGE AND HANDLING
ISENTRESS tablets 400 mg are pink, oval-shaped, film-coated tablets with "227"
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