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October 13, 2011 7:00 am ET

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced results of new exploratory pre-specified analyses from the ongoing STARTMRK Phase III study of its integrase inhibitor ISENTRESS® (raltegravir) Tablets in combination therapy compared to efavirenz in combination therapy in previously untreated (treatment-naïve) adult HIV-1-infected patients. The analyses showed that the regimen containing ISENTRESS demonstrated better efficacy compared to the regimen containing efavirenz at 192 weeks of treatment, as measured by the percentage of patients maintaining undetectable virus levels (less than 50 copies/mL) [76.2 percent (n=214/281) vs. 67.0 percent (n=189/282); 95 percent confidence interval (CI) 1.6, 16.4]. The regimen containing ISENTRESS also showed a greater immunological effect as measured by mean increase from baseline in CD4-cell count at week 192 (360.7 vs. 300.9 cells/mm3; CI 24.1, 95.4) versus the efavirenz regimen.

“These results offer further insight into the virologic and immunologic response seen with ISENTRESS in combination therapy when compared to efavirenz at 192 weeks in treatment-naïve adult patients with HIV-1,” said Dr. Jürgen Rockstroh, University of Bonn, Bonn-Venusberg, Germany, who presented the data.

ISENTRESS is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients. The label for ISENTRESS is based on analyses of plasma HIV-1 RNA levels through 96 weeks in three double-blind controlled Phase III clinical studies of ISENTRESS. Two of these studies were conducted in clinically advanced, three-class ARV [non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)] treatment-experienced adults and one was conducted in treatment-naïve 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 pediatric patients.

Additionally, based on analyses of pre-specified demographics (age, gender, region, race and hepatitis co-infection) and baseline prognostic factors (viral load, CD4-cell count and HIV-1 subtypes), ISENTRESS in combination therapy demonstrated consistent virologic and immunologic efficacy relative to efavirenz in combination therapy at week 192. Data also showed that ISENTRESS in combination therapy resulted in fewer reported drug-related clinical adverse events (AEs) than combination therapy with efavirenz. These findings were presented for the first time today at the 13th European AIDS Conference (EACS 2011) in Belgrade, Serbia.

STARTMRK study design

In this ongoing multicenter, double-blind, randomized, active-controlled, Phase III non-inferiority study, 563 previously untreated HIV-1 infected adult patients received either 400 mg ISENTRESS orally twice-daily (n=281) or 600 mg efavirenz orally once-daily (n=282), each in combination with tenofovir/emtricitabine. The primary endpoint of the study was a reduction in HIV-1 viral load to less than 50 copies/mL. Secondary endpoints included ARV activity, as measured by the percentage of patients achieving HIV-1 viral load to less than 50 copies/mL, less than 400 copies/mL, and change from baseline in CD4-cell count at week 96, as well as tolerability and safety at week 96. The 192-week data reported at EACS 2011 represent results from a planned five-year monitoring of outcomes.

Patients who entered the study were required to have HIV-1 viral loads greater than 5,000 copies/mL and had no prior treatment with antiretroviral therapy. At baseline, the geometric mean HIV-1 viral load level for patients on the regimen containing ISENTRESS was 103,205 copies/mL (n=281) and for the regimen containing efavirenz was 106,215 copies/mL (n=282). Mean baseline CD4-cell counts were 218.9 cells/mm3 and 217.4 cells/mm3 for the groups receiving ISENTRESS and efavirenz, respectively.

ISENTRESS in combination therapy demonstrated better HIV-1 viral load suppression and an increased mean CD4-cell count at week 192 when compared to the efavirenz regimen in a pre-specified exploratory analysis

The STARTMRK trial in treatment-naïve HIV-1 adults is a non-inferiority study. However, according to the STARTMRK data analysis plan, the regimen containing ISENTRESS would be considered non-inferior to the regimen containing efavirenz if the lower bound of the 95 percent confidence interval (CI) for the difference in percent response was above -12 percent, and superior to the regimen containing efavirenz if the lower bound exceeded 0.

Using this criteria, at week 192, the regimen containing ISENTRESS demonstrated better suppression of HIV-1 viral levels to below 50 copies/mL, 76.2 percent of patients (n=214/281) compared to 67.0 percent of patients (n=189/282) for the regimen containing efavirenz [treatment difference of 9.0 percent of patients; 95 percent CI 1.6, 16.4; Non-Completer=Failure (NC=F) analysis]. The regimen containing ISENTRESS demonstrated non-inferiority in suppressing HIV-1 viral levels to below 50 copies/mL to the regimen containing efavirenz at the 48-week, 96-week and 156-week pre-specified time points, respectively: 48 weeks = 86.1 percent (n=241/280) vs. 81.9 percent (n=230/281), treatment difference 4.2 percent (CI -1.9, 10.3); 96 weeks = 81.1 percent (n=228/281) vs. 78.7 percent (n=222/282), treatment difference 2.4 percent (CI -4.3, 9.0); and 156 weeks = 75.4 percent (n=212/281) vs. 68.8 percent (n=194/282), treatment difference 6.6 percent (CI -0.8, 14.0).

Observed-failure (OF) analysis at week 192 showed that patients receiving ISENTRESS in combination therapy experienced a greater increase from baseline in mean CD4-cell count than those on the regimen containing efavirenz, 360.7 cells/mm3 vs. 300.9 cells/mm3 (treatment difference 59.8 percent; 95 percent CI 24.1, 95.4), respectively.

Consistent results seen across patient subgroups at week 192

For both treatment regimens, an exploratory analysis showed generally consistent virologic and immunologic effects at week 192 across patient subgroups, based on analyses of demographic and prognostic factors at baseline.

Virologic Response Rates (vRNA <50 c/mL) at Week 192 Using Observed-Failure Analysis

Overall Efficacy Rate

Raltegravir Group n/N %

Efavirenz Group n/N %

Difference in Response Rates [95% CL]

214/235

91.1

189/222

85.1

6.0 [0.1, 12.2]

Baseline Variable

Raltegravir Group n/N %

Efavirenz Group n/N %

Difference in Response Rates [95% CI]

Gender

Female

41/44

93

32/37

86

7 [-7, 22]

Male

173/191

91

157/185

85

6 [-1, 13]

Age

≤median†

109/122

89

105/129

81

8 [-1, 17]

>median†

105/113

93

84/93

90

3 [-5, 11]

Race/Ethnicity

Black

21/24

88

17/22

77

10 [-13, 34]

White

86/93

92

75/83

90

2 [-7, 11]

Hispanic

47/53

89

44/57

77

11 [-3, 26]

Asian

31/34

91

25/28

89

2 [-14, 20]

Native American

1/1

100

—-

—-

Multi-racial

28/30

93

28/32

88

6 [-11, 23]

Plasma vRNA level [c/mL]

≤100,000

98/105

93

86/106

81

12 [3, 22]

>100,000

116/130

89

103/116

89

0 [-8, 9]

CD4-count [cells/mm3]

≤50

17/22

77

25/29

86

-9 [-32, 13]

>50 to ≤200

84/88

95

71/85

84

12 [3, 22]

>200

113/125

90

93/108

86

4 [-4, 13]

HIV subtype¶

Clade B

164/181

91

149/177

84

6 [0, 14]

Non-clade B

47/51

92

35/40

88

5 [-8, 19]

Hepatitis co-infection

B and/or C

11/12

92

12/13

92

-1 [-30, 27]

Neither B or C

203/223

91

177/209

85

6 [0, 13]

n, the number of responders in the specified subgroup; N, the total number of treated patients evaluable at week 192 in the specified subgroup using an observed-failure approach; CI, confidence interval.

† Median ages at entry were 37 yrs for the RAL group & 36 yrs for the EFV group.

¶ The viral subtype was missing in 3 RAL recipients & 5 EFV recipients, all of whom responded.

Tolerability profile of ISENTRESS at week 192

At week 192, the overall incidence of drug-related clinical AEs was lower for patients on the regimen containing ISENTRESS compared to the regimen containing efavirenz (50.2 percent vs. 80.1 percent, respectively; p<0.001). There were few treatment discontinuations due to clinical AEs for either regimen, 5.0 percent for patients on the regimen containing ISENTRESS versus 8.2 percent for patients on the regimen containing efavirenz. The rate of serious clinical AEs seen in this study was similar (17.8 percent vs. 18.4 percent, in the groups with ISENTRESS and efavirenz, respectively). Between week 156 and week 192, there were 14 new serious clinical AEs (n=7 and n=7 for the regimens, respectively). Although not considered drug-related, there were five deaths in the treatment group containing ISENTRESS and two in the treatment group containing efavirenz.

About ISENTRESS

ISENTRESS is Merck’s integrase inhibitor for the treatment of HIV-1 infection in treatment-naïve and treatment-experienced adult patients as part of combination therapy. ISENTRESS is currently the only approved integrase inhibitor for the treatment of HIV-1. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase – but ISENTRESS is the only approved drug that inhibits the integrase enzyme. ISENTRESS is now approved in combination therapy in more than 45 countries for use in treatment-naïve adult patients with HIV-1 and in more than 90 countries for use in treatment-experienced adult patients with HIV-1. Merck is continuing to move forward with filings in additional countries around the world.

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 during the initial phase of treatment immune reconstitution syndrome can occur, which may necessitate further evaluation and treatment. Monitor for immune reconstitution syndrome.

The most common adverse reactions of moderate to severe intensity greater than or equal to two percent that occurred at a higher rate than the comparator were insomnia in treatment-naïve patients and headache in treatment-experienced patients. Intensities were defined as follows: Moderate (discomfort enough to cause interference with usual activity); or Severe (incapacitating with inability to work or do usual activity).

Grade 2-4 creatine kinase laboratory abnormalities were observed in patients treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS and darunavir/ritonavir compared to patients receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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.

Dosing and administration

For the treatment of adult patients with HIV-1 infection, the dosage of ISENTRESS is 400 mg administered orally, twice daily with or without food, in combination therapy. During coadministration with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily with or without food.

Drug interactions

Coadministration of ISENTRESS with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may result in reduced plasma concentrations of raltegravir. Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS should be increased during coadministration with rifampin. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown.

In drug interaction studies, ISENTRESS did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, methadone, lamivudine, tenofovir, etravirine and darunavir/ritonavir. Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of ISENTRESS.

About Merck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2010 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see accompanying prescribing information for ISENTRESS® (raltegravir) Tablets at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf, and patient information for ISENTRESS® (raltegravir) Tablets at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.

ISENTRESS® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA

 

 

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