ISENTRESS (raltegravir) in Combination Therapy Demonstrated Long-Term Efficacy, Safety and Tolerability in Previously Untreated Adult Patients with HIV-1 for up to 240 Weeks

WASHINGTON--(BUSINESS WIRE)--Jul 22, 2012 - Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced final results from the STARTMRK study – the longest double-blind Phase III non-inferiority study evaluating an integrase inhibitor in treatment-naïve adults with HIV-1. In this pre-specified exploratory analysis of ISENTRESS® (raltegravir) 400 mg Film-coated Tablets in combination therapy in previously untreated (treatment-naïve) adult HIV-1 patients, virologic efficacy was better than the efavirenz-based regimen at 240 weeks. At all pre-specified time points, the regimen containing ISENTRESS had fewer drug-related adverse events versus the comparator. The 240-week analysis showed that the regimen containing ISENTRESS demonstrated long-term viral suppression and a greater immunologic response, as well as a proven safety and tolerability profile.

These results were presented as a late-breaker [LBPE19] at the 19th International AIDS Conference (AIDS 2012) in Washington, D.C.

ISENTRESS is an integrase inhibitor indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels in three double-blind controlled 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 adult patients through 96 weeks and one was conducted in treatment-naïve adults through 156 weeks.

The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

Severe, potentially life-threatening and fatal skin reactions have been reported with ISENTRESS (raltegravir). Additionally, during the initial phase of treatment, immune reconstitution syndrome may occur. (See Important Selected Safety Information below.)

“These new data provide additional perspective on the safety and efficacy of the integrase inhibitor ISENTRESS,” said Dr. Jürgen Rockstroh, University of Bonn, Bonn-Venusberg, Germany. “Long-term data with antiretrovirals is increasingly important for today's HIV patient.”

“Our continued study of ISENTRESS is an example of Merck's longstanding commitment to HIV,” said Dr. Daria Hazuda, worldwide head of Antiviral Basic Research at Merck, and lead scientist for ISENTRESS. “After more than 25 years of leadership in HIV research, we remain dedicated to conducting comprehensive research to help address the real-world needs of people living with HIV.”

STARTMRK study design

STARTMRK is a multi-center, double-blind, randomized, active-controlled, Phase III non-inferiority 240-week study in which 563 previously untreated HIV-1 infected adult patients with HIV-1 RNA greater than 5000 copies/mL 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 at week 48. Secondary endpoints included ARV activity, as measured by the proportion of patients achieving HIV-1 viral load to less than 50 copies/mL at 96 weeks, as well as achieving viral load less than 400 copies/mL, and change from baseline in CD4 cell count, both measured at 48 and 96 weeks. Safety was evaluated throughout the study period. Merck previously reported on results from exploratory analyses at weeks 156 and 192. These 240-week data, reported at AIDS 2012, represent final results from STARTMRK.

The STARTMRK trial in treatment-naïve HIV-1 adults is a non-inferiority study. However, according to the STARTMRK data analysis plan, for virologic efficacy (<50 HIV-1 vRNA copies/mL), 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.

ISENTRESS (raltegravir) combination therapy demonstrated better HIV-1 viral load suppression when compared to the efavirenz regimen in exploratory analyses at weeks 192 and 240

In the STARTMRK trial, the regimen containing ISENTRESS was better than the regimen containing efavirenz at reducing HIV-1 viral load to undetectable levels (less than 50 copies/mL) at follow-up at weeks 192 and 240 in these pre-specified exploratory analyses. At the study entry, the geometric mean baseline plasma HIV-1 RNA for patients was over 100,000 copies/mL (103,205 copies/mL for those on a regimen containing ISENTRESS and 106,215 copies/mL for patients on a regimen containing efavirenz).

 
Virologic Response Rates (HIV-1 vRNA <50 copies/mL) at Pre-specified Time Points

 

     
Study
Week

 

  % (n/N) of Patients with vRNA <50 copies/mL2

 

 

  RAL (N=281)   EFV (N=282)

 

  RAL – EFV
48   86.1 (241/280)   81.9 (230/281)   4.2 (-1.9, 10.3)*
96   81.1 (228/281)   78.7 (222/282)   2.4 (-4.3, 9.0)*
156   75.4 (212/281)   68.8 (194/282)   6.6 (-0.8, 14.0)*
192   76.2 (214/281)   67.0 (189/282)   9.0 (1.6, 16.4)*°
240   71.0 (198/279)   61.3 (171/279)   9.5 (1.7, 17.3)*°
n/N, number of pts with vRNA <50 c/mL over Number of evaluable pts at each time point.
2 Non-Completer=Failure (NC=F): Pts who discontinued for any reason were considered as failures thereafter.

 

1 Difference calculated as RAL minus EFV (95% CI). A positive value favors RAL over EFV. The treatment difference & 95% CIs were weighted proportionally by the size of screening HIV RNA stratum (> or ‰¤50,000 c/mL).

 

§ RAL would be considered non-inferior to EFV if the lower bound of the 95% CI for the difference in response rates was above -12%, & superior to EFV if the entire 95% CI was >0.
* P-value for non-inferiority <0.001.
° Met criteria for superiority.
 
At weeks 48, 96, and 156, the non-inferiority criteria were satisfied, but the lower bound did not exceed 0 and, therefore, did not satisfy the superiority criteria.

Results at the 240-week exploratory analysis showed viral suppression for patients on a regimen containing ISENTRESS (raltegravir) of 71.0 percent compared to 61.3 percent for the regimen containing efavirenz [treatment difference of 9.5 percent of patients with 95 percent CI: [1.7 percent, 17.3 percent]. As in the 192-week analysis, the lower bound exceeded 0, meeting the criteria for superiority at the 240-week time point.

The regimen containing ISENTRESS also demonstrated greater immunologic response than the regimen containing efavirenz at 240 weeks using the observed-failure approach. At study entry, patients on the regimen containing ISENTRESS had a mean baseline CD4 cell count of 219 cells/mm3, and at 240 weeks experienced a mean change of 374 cells/mm3. Patients on the regimen containing efavirenz had a mean baseline CD4 cell count of 217 cells/mm3, and experienced a mean change of 312 cells/mm3 at 240 weeks. Patients on the regimen containing ISENTRESS had a treatment difference in the mean baseline CD4 cell count of 62 cells/mm3 versus the regimen containing efavirenz, with 95 percent CI: 22, 102.

     
Baseline CD4 Cell Count Change (cells/mm3) at Pre-specified Time Points

 

     
Study
Week

 

  Change (cells/mm3) from BL CD4 Count
  RAL (N=281)

 

  EFV (N=282)

 

  RAL – EFV11

 

48   189   163   26 (4, 47)
96   240   225   15 (-12, 43)
156   331   295   36 (3, 68)
192   361   301   60 (24, 95)
240   374   312   62 (22, 102)
Observed Failure (OF): Pts who discontinued for lack of efficacy were considered as virologic failures thereafter, & BL CD4 values were carried forward.

 

11 Difference calculated as RAL minus EFV (95% CI). A positive value favors RAL over EFV. The 95% CIs were calculated based on a t-distribution.

 

 
Safety and Tolerability Profile of ISENTRESS (raltegravir) in treatment-naïve adult patients with HIV-1 at 240 weeks

At week 240, the overall incidence of drug-related adverse experiences was lower for patients on the regimen containing ISENTRESS compared to the regimen containing efavirenz (52 percent versus 80 percent, respectively). There were few treatment discontinuations due to drug-related adverse experiences for either regimen, with discontinuation rates at 5 percent for patients on the regimen containing ISENTRESS versus 8.9 percent for patients on the regimen containing efavirenz. The most common drug-related clinical adverse events with an incidence ‰¥10 percent in either treatment group were dizziness (7.8 percent versus 35.1 percent, respectively), headache (9.3 percent versus 14.2 percent, respectively), abnormal dreams (6.8 percent versus 13.1 percent, respectively), nausea (8.9 percent versus 10.3 percent, respectively) and diarrhea (5.0 percent versus 9.6 percent, respectively).

ISENTRESS in combination therapy also had less effect on lipids [total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol] and triglycerides fasting serum lipids at week 240, shown in the table below.

 
Lipid Values, Mean Change from Baseline at Week 240

 

         
Laboratory
Parameter
Preferred
Term

 

  ISENTRESS (raltegravir) 400 mg
Twice Daily + Emtricitabine (+)
Tenofovir
N = 281

 

  Efavirenz 600 mg
At Bedtime + Emtricitabine (+)
Tenofovir
N = 282

 

    Change from Baseline at Week 240   Change from Baseline at Week 240
  Baseline Mean

(mg/dL)

 

  Mean Change (mg/dL)

 

  Baseline Mean

(mg/dL)

 

  Mean Change (mg/dL)

 

LDL-
Cholesterol*

 

  96.19   9.92   92.54   25.38
HDL-
Cholesterol*

 

  37.85   5.68   38.37   12.62
Total
Cholesterol*

 

  158.80   16.01   157.10   44.01
Triglycerides*

 

  128.30   1.53   140.60   37.26
*Fasting (non-random) laboratory tests at week 240.
N = Number of subjects in the treatment group. The analysis is based on all available data.
 
Important Selected Safety Information

ISENTRESS (raltegravir) does not cure HIV-1 infection or AIDS.

Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS and other suspect agents if severe hypersensitivity, severe rash, or rash with systematic symptoms or liver aminotransferase elevations develop and monitor clinical status, including liver aminotransferases closely.

Health care 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.

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 for adults should be increased to 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age.

The most commonly reported (‰¥2%) drug-related clinical adverse reactions of moderate to severe intensity in treatment-naïve adult patients receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%), headache (4% vs 5%), nausea (3% vs 4%), and fatigue (2% vs 3%), respectively. 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 to 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 subjects receiving regimens containing ISENTRESS plus darunavir/ritonavir, compared to subjects 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.

Additional data presentations on ISENTRESS (raltegravir) at AIDS 2012:

Oral Abstract Presentation:

 

  • IMPAACT P1066: Raltegravir (RAL) Safety and Efficacy in HIV Infected (+) Youth 2 to 18 Years Through Week 48 (TUAB0205)

Poster Exhibition Presentation:

 

  • Final 5-Year Results of the BENCHMRK Studies: Sustained Antiretroviral Effect of Raltegravir, and Exploratory Analysis of Late Outcomes based on Early Virologic Response (TUPE025)

About ISENTRESS (raltegravir)

ISENTRESS is Merck's integrase inhibitor for the treatment of HIV-1 infection in adult patients as part of combination HIV therapy. ISENTRESS is currently the first and 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.

To assist patients taking ISENTRESS (raltegravir), Merck offers the SUPPORT™ program, which provides personal support and patient advocacy regarding individual reimbursement issues. For more information about the SUPPORT™ program, please visit www.merckhelps.com or call 1-800-850-3430.

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 http://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 all of 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 in the United States and internationally; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; 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 2011 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 Prescribing Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf and Patient Information for ISENTRESS 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

INFC-1036337-0012

Contact: Merck
Media:
Pam Eisele, 908-423-5042
Tracy Ogden, 215-370-5597
or
Investor:
Carol Ferguson, 908-423-4465

 

Posted: July 2012

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