ISENTRESS raltegravir, Merck's First in Class Integrase Inhibitor, Reduced HIV Viral Load and Increased CD4 Cell Counts Through 96 Weeks in Treatment-Naive HIV-Infected Patients When Taken With Other Anti-HIV Medicines
2008 AUG 20 - (NewsRx.com) -- ISENTRESS (raltegravir), Merck & Co., Inc.s first-in-class integrase inhibitor, in combination with two other anti-HIV medicines, reduced HIV viral load to undetectable levels (less than 50 copies/mL) in 83 percent of previously untreated (treatment-naive) HIV-infected patients which was comparable to that seen with efavirenz (Sustiva/STOCRIN)*, which reduced HIV viral load to undetectable levels in 84 percent of treatment-naive HIV-infected patients when also combined with the same anti-HIV medicines in patients through 96 weeks of treatment. Patients taking ISENTRESS experienced a mean increase in CD4 cell counts of 221 cells/mm3 without adverse impact on total or low-density lipoprotein (LDL) cholesterol, or triglycerides (exploratory endpoints). Results from this ongoing Phase II study were presented today at the 17th International AIDS Conference (AIDS 2008) in Mexico City, Mexico. The use of ISENTRESS in treatment-naive patients is investigational. ISENTRESS is approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. 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. 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 patients or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection. These findings are consistent with the efficacy and safety data seen with ISENTRESS in treatment-experienced patients, said Martin Markowitz, M.D., study investigator and clinical director of the Aaron Diamond AIDS Research Center in New York. Viral load reductions were sustained through 96 weeks in this study, the longest conducted to date with ISENTRESS." ISENTRESS studied in nearly 200 previously untreated patients These findings are from an ongoing multi-center, dose-ranging, double-blind, randomized trial of previously untreated HIV-infected patients. In this study, 198 treatment-naive, HIV-infected patients received either ISENTRESS administered orally twice daily in combination with tenofovir (Viread ) and lamivudine (Epivir) or 600 mg efavirenz dosed orally once daily in combination with the same agents. During the first 48 weeks of the study, four dose regimens of ISENTRESS (100, 200, 400 and 600 mg twice daily) were studied. After 48 weeks, all ISENTRESS groups received 400 mg dosed twice daily. The primary endpoints were reductions in HIV RNA less than 400 copies/mL and the evaluation of safety at 96 weeks. The evaluation of total cholesterol, LDL cholesterol and triglycerides were exploratory endpoints. Reduction in viral load and increase in CD4 cell counts maintained through 96 weeks of treatment with ISENTRESS At baseline, geometric mean HIV RNA for patients on the combined regimen including ISENTRESS was approximately 55,000 copies/mL (n=160) and for the efavirenz regimen was approximately 68,000 copies/mL (n=38). Mean baseline CD4 cell counts were 305 and 280 cells/mm3 for the groups receiving ISENTRESS and efavirenz, respectively. After 96 weeks of therapy, 83 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 regimen containing efavirenz, with 84 percent of patients achieving reductions in HIV RNA levels below 50 copies/mL in the same time period. Similarly, 84 percent of patients receiving the regimen containing ISENTRESS maintained reductions in HIV RNA levels to below 400 copies/mL compared to 84 percent of patients taking the regimen containing efavirenz. Patients on both treatment regimens experienced increases in CD4 cell counts. At 96 weeks of treatment, the mean increase from baseline in CD4 cell count was 221 cells/mm3 for patients taking ISENTRESS and 232 cells/mm3 for patients taking efavirenz. Tolerability profile and effect on lipid levels The most commonly reported adverse experiences in patients receiving ISENTRESS and efavirenz, respectively, were diarrhea (6.9 percent versus 10.5 percent), nausea (12.5 versus 13.2 percent), dizziness (8.8 versus 28.9 percent), headache (8.8 percent versus 23.7 percent), abnormal dreams (6.3 percent versus 18.4 percent), insomnia (8.1 percent versus 10.5 percent) and nightmares (0 percent versus 10.5 percent). Neuropsychiatric adverse events, which included abnormal dreams, depression, nightmare and suicidal thoughts, were reported less frequently with the ISENTRESS group compared to the efavirenz group, occurring respectively in 16 versus 32 percent of patients through Week 96; most of these had occurred earlier in the study by Week 48. ISENTRESS had neutral effect on total and LDL cholesterol, or triglycerides. The mean changes from baseline at Week 96 for ISENTRESS and efavirenz, respectively, were +1.1 mg/dL and +24.0 mg/dL (p=0.002) for total cholesterol; -5.8 mg/dL and +4.4 mg/dL (p=0.045) for LDL cholesterol; +7.4 mg/dL and +13.0 mg/dL (p=0.017) for HDL cholesterol; -10.8 mg/dL and +13.4 mg/dL (p=0.145) for triglycerides; and -0.7 mg/dL and -0.7 mg/dL (P=0.689) for total: HDL ratio. Important safety information about ISENTRESS ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment. 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). 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. 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. 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. 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. About ISENTRESS ISENTRESS is the first medicine to be approved in a new 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. Merck's commitment to providing access to treatment Merck is committed to ensuring access to our antiretroviral medicines (ARVs) through a differential pricing policy that provides our ARVs at dramatically lower prices-at which Merck does not profit-to people living in the world's least developed countries and those hardest hit by the pandemic, as defined by various United Nations indices. Also, Merck is committed to seeking additional ways to reduce the cost of its ARVs for people living in the world's poorest countries and those hardest hit by the pandemic, including through partnering with external manufacturers and suppliers to achieve incremental efficiencies and cost savings. In the United States, Merck is freezing the price for AIDS Drug Assistance Programs (ADAP) of ISENTRESS at its launch price until December 31, 2010. ADAP is a unique fixed-funding program with a flat federal budget whose cost burden and patient load continues to grow. In freezing the price of ISENTRESS, Merck will help mitigate the funding challenges of these programs. Since 2006, when Merck established a worldwide expanded access program with ISENTRESS for HIV patients with limited or no treatment options, more than 9,000 patients have enrolled in early access programs for ISENTRESS globally. 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. ISENTRESS is a registered trademark of Merck & Co., Inc. Whitehouse Station, NJ USA. * Bristol-Myers Squibb has exclusive marketing rights to efavirenz in the United States (including territories and possessions), Canada, United Kingdom, Republic of Ireland, France (continental only), Spain, Italy and Germany, and markets efavirenz under its trademark Sustiva. Through its subsidiaries and marketing partners, Merck has exclusive marketing rights in all other countries worldwide, and markets efavirenz under the trademark STOCRIN. All other brands are trademarks of their respective owners and are not trademarks of Merck & Co., Inc. Full prescribing information and patient product information for ISENTRESS 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 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 (>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 ISENTRESS1 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, BENCHMRK1 and BENCHMRK2 (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 (>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 (>10%) Adverse Reactions of All Intensities* and Regardless of Causality Occurring in Treatment-Experienced Adult Subjects System Organ Class, Adverse Reactions Randomized Studies P005, P018 and P019 ISENTRESS 400 mg twice daily + OBT (n=507) % Placebo + OBT (n=282) % 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, Adverse Reactions Randomized Studies P005, P018 and P019 ISENTRESS 400 mg Twice Daily + OBT (n = 507) % Placebo + OBT (n = 282) % 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 (see also Merck & Co., Inc.).
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 50cells/mm3 and most had prior AIDS diagnoses). The cancers included Kaposis sarcoma, lymphoma, squamous cell carcinoma, hepatocellular carcinoma and anal cancer. Most subjects had other risk factors for cancer including tobacco use, papillomavirus and active hepatitisB 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 hepatitisB and/or hepatitisC 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 hepatitisB and/or hepatitisC virus co-infection was similar to subjects without hepatitisB and/or hepatitisC 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 Term (Unit) Limit ISENTRESS 400 mg Twice Daily + OBT (N = 507) Placebo + OBT (N = 282) Hematology Absolute neutrophil count (103/L) Grade 2 0.75 - 0.999 3.7% 7.4% Grade 3 0.50 - 0.749 2.4% 2.5% Grade 4 <0.50 1.0% 1.1% Hemoglobin (gm/dL) Grade 2 7.5 - 8.4 1.0% 2.8% Grade 3 6.5 - 7.4 1.0% 0.4% Grade 4 <6.5 0.0% 0.0% Platelet count (103/L) Grade 2 50 - 99.999 3.7% 5.7% Grade 3 25 - 49.999 0.4% 0.4% Grade 4 <25 0.8% 0.4% Blood chemistry Fasting (non-random) serum glucose test (mg/dL) Grade 2 126 - 250 9.3% 6.8% Grade 3 251 - 500 1.4% 1.4% 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>100 M) 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>50 M) 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 subjectsregardless 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 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 M. Metabolism and Excretion The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter a-phase half-life (~1 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 Coadministered Drug Coadministered Drug Dose/ Schedule Raltegravir Dose/ Schedule Ratio (90% Confidence Interval) of Raltegravir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 n Cmax AUC Cmin atazanavir 400 mg daily 100 mg single dose 10 1.53 (1.11, 2.12) 1.72 (1.47, 2.02) 1.95 (1.30, 2.92) atazanavir/ ritonavir 300 mg/100 mg daily 400 mg twice daily 10 1.24 (0.87, 1.77) 1.41 (1.12, 1.78) 1.77 (1.39, 2.25) efavirenz 600 mg daily 400 mg single dose 9 0.64 (0.41, 0.98) 0.64 (0.52, 0.80) 0.79 (0.49, 1.28) rifampin 600 mg daily 400 mg single dose 9 0.62 (0.37, 1.04) 0.60 (0.39, 0.91) 0.39 (0.30, 0.51) ritonavir 100 mg twice daily 400 mg single dose 10 0.76 (0.55, 1.04) 0.84 (0.70, 1.01) 0.99
Isentress Comparable to Sustiva in Efficacy and Superior on Secondary Endpoints
[These results confirm the results seen in a sister phase-3 study (#msg-31357056); the difference between is in the backbone treatment to which Isentress and Sustiva were added: Truvada in the new study and Viread + Lamivudine (a lesser-used combination) in the prior study. In both studies, Isentress was comparable to Sustiva in efficacy and clearly superior to Sustiva in its effects on the lipid profile. Isentress also had statsig fewer total AE’s.
Isentress from MRK is currently approved for treatment-experienced patients only; these data will presumably support a label expansion into the first-line setting.]
›New Phase III Study in Previously Untreated HIV Patients Showed Merck's ISENTRESS(R) (raltegravir) Reduced HIV Viral Load to Undetectable Levels, Comparable to Efavirenz, When Taken in Combination with Other Medicines
Sunday October 26, 10:30 am ET
Study Showed ISENTRESS Increased CD4 Cells More Than Efavirenz, with Significantly Fewer Side Effects
WASHINGTON--(BUSINESS WIRE)--In a new Phase III study that compared Merck & Co., Inc.'s HIV integrase inhibitor ISENTRESS® (raltegravir) to efavirenz [one of the leading antiretrovirals prescribed for previously untreated (treatment-naïve) 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/mm3, compared to patients taking efavirenz who had an average increase of 163 cells/mm3 at Week 48. In addition, drug-related adverse events of any severity occurred in fewer patients (44 percent vs. 77 percent; p<0.001) treated with ISENTRESS.
The use of ISENTRESS in treatment-naïve 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-naïve 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-naïve 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-naïve, 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 <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/mm3 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/mm3 for patients receiving ISENTRESS and 163 cells/mm3 for patients receiving efavirenz.
Tolerability profile of ISENTRESS in STARTMRK study
The most commonly (≥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<0.001) for total cholesterol; 5.9 mg/dL and 16.1 mg/dL (p<0.001) for LDL cholesterol; 4.2 mg/dL and 10.0 mg/dL (p<0.001) for HDL cholesterol; and -2.8 mg/dL and 37.4 mg/dL (p<0.001) for triglycerides.
“These findings reinforce the efficacy and safety data seen with ISENTRESS in Phase II trials in treatment-naïve 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.”‹
<font size=3><font color=red> “The efficient-market hypothesis may be the foremost piece of B.S. ever promulgated in any area of human knowledge!”
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