ISENTRESS (Page 7 of 9)

14.2 Treatment-Naïve Adult Subjects

STARTMRK (ISENTRESS 400 mg twice daily)

STARTMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of ISENTRESS 400 mg twice daily versus efavirenz 600 mg at bedtime both with emtricitabine (+) tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; or >50,000 copies/mL) and by hepatitis status. In STARTMRK, 563 subjects were randomized and received at least 1 dose of either raltegravir 400 mg twice daily or efavirenz 600 mg at bedtime, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 563 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 37 years (range: 19-71), 19% female, 58% non-white, 6% had hepatitis B and/or C virus co-infection, 20% were CDC Class C (AIDS), 53% had HIV-1 RNA greater than 100,000 copies per mL, and 47% had CD4+ cell count less than 200 cells per mm3 ; the frequencies of these baseline characteristics were similar between treatment groups.

ONCEMRK (ISENTRESS HD 1200 mg [2 × 600 mg] once daily)

ONCEMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of ISENTRESS HD 1200 mg (2 × 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-1-infected subjects with HIV-1 RNA ≥1000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤100,000 or >100,000 copies/mL) and by hepatitis B and C infection status.

In ONCEMRK, 797 subjects were randomized and received at least 1 dose of either raltegravir 1200 mg once daily or raltegravir 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 797 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years (range: 18-84), 15% female, 41% non-white, 3% had hepatitis B and/or C virus co-infection, 13% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, and 13% had CD4+ cell count less than 200 cells per mm3 ; the frequencies of these baseline characteristics were similar between treatment groups.

Table 19 shows the virologic outcomes in both studies. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up.

Table 19: Virologic Outcomes of Randomized Treatment in STARTMRK and ONCEMRK (Snapshot Algorithm) in HIV Treatment-Naïve Adults
STARTMRK Week 240 ONCEMRK Week 96
ISENTRESS 400 mg Twice Daily (N=281) Efavirenz 600 mg At Bedtime (N=282) ISENTRESS HD 1200 mg Once Daily (N=531) ISENTRESS 400 mg Twice Daily (N=266)
Notes: ISENTRESS BID, ISENTRESS HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate
*
Lower Limit of Quantitation: STARTMRK <50 copies/mL; ONCEMRK < 40 copies/mL.
Includes subjects who discontinued because of adverse event (AE) or death at any time point from day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
Other Reasons includes: lost to follow-up, moved, non-compliance with study drug, physician decision, pregnancy, withdrawal by subject.

HIV RNA < Lower Limit of Quantitation *

66%

60%

82%

80%

Treatment Difference

6.6% (95% CI: -1.4%, 14.5%)

1.4% (95% CI: -4.4%, 7.3%)

HIV RNA ≥ Lower Limit of Quantitation

8%

15%

9%

8%

No Virologic Data at Analysis Timepoint

26%

26%

9%

12%

Reasons

Discontinued trial due to AE or Death

5%

10%

1%

3%

Discontinued trial for Other Reasons

15%

14%

7%

8%

On trial but missing data at timepoint

6%

2%

1%

2%

In the ONCEMRK trial, ISENTRESS HD 1200 mg (2 × 600 mg) once daily demonstrated consistent virologic and immunologic efficacy relative to ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, across demographic and baseline prognostic factors, including: baseline HIV RNA levels >100,000 copies/mL and demographic groups (including age, gender, race, ethnicity and region), concomitant proton pump inhibitors/H2 blockers use and viral subtypes (comparing non-clade B as a group to clade B).

Consistent efficacy in subjects receiving ISENTRESS HD 1200 mg (2 × 600 mg) once daily was observed across HIV subtypes with 80.6% (270/335) and 83.5% (162/194) of subjects with B and non-B subtypes respectively, achieving HIV RNA <40 copies/mL at week 96 (Snapshot approach).

14.3 Treatment-Experienced Adult Subjects

BENCHMRK 1 and BENCHMRK 2 are Phase 3 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-1-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. >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 20 shows the demographic characteristics of subjects in the group receiving ISENTRESS 400 mg twice daily and subjects in the placebo group.

Table 20: Trials BENCHMRK 1 and BENCHMRK 2 Baseline Characteristics
Randomized Studies BENCHMRK 1 and BENCHMRK 2 ISENTRESS 400 mg Twice Daily + OBT (N = 462) Placebo + OBT (N = 237)
*
Hepatitis B virus surface antigen positive or hepatitis C virus antibody positive.

Gender

Male

88%

89%

Female

12%

11%

Race

White

65%

73%

Black

14%

11%

Asian

3%

3%

Hispanic

11%

8%

Others

6%

5%

Age (years)

Median (min, max)

45 (16 to 74)

45 (17 to 70)

CD4+ Cell Count

Median (min, max), cells/mm3

119 (1 to 792)

123 (0 to 759)

≤50 cells/mm3

32%

33%

>50 and ≤200 cells/mm3

37%

36%

Plasma HIV-1 RNA

Median (min, max), log10 copies/mL

4.8 (2 to 6)

4.7 (2 to 6)

>100,000 copies/mL

36%

33%

History of AIDS

Yes

92%

91%

Prior Use of ART, Median (1st Quartile, 3rd Quartile)

Years of ART Use

10 (7 to 12)

10 (8 to 12)

Number of ART

12 (9 to 15)

12 (9 to 14)

Hepatitis Co-infection *

No Hepatitis B or C virus

83%

84%

Hepatitis B virus only

8%

3%

Hepatitis C virus only

8%

12%

Co-infection of Hepatitis B and C virus

1%

1%

Stratum

Enfuvirtide in OBT

38%

38%

Resistant to ≥2 PI

97%

95%

Table 21 compares the characteristics of optimized background therapy at baseline in the group receiving ISENTRESS 400 mg twice daily and subjects in the control group.

Table 21: Trials BENCHMRK 1 and BENCHMRK 2 Characteristics of Optimized Background Therapy at Baseline
Randomized Studies BENCHMRK 1 and BENCHMRK 2 ISENTRESS 400 mg Twice Daily + OBT (N = 462) Placebo + OBT (N = 237)
*
Darunavir use in OBT in darunavir-naïve 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-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.

Number of ARTs in OBT

Median (min, max)

4 (1 to 7)

4 (2 to 7)

Number of Active PI in OBT by Phenotypic Resistance Test *

0

36%

41%

1 or more

60%

58%

Phenotypic Sensitivity Score (PSS)

0

15%

18%

1

31%

30%

2

31%

28%

3 or more

18%

20%

Genotypic Sensitivity Score (GSS)

0

25%

27%

1

38%

40%

2

24%

21%

3 or more

11%

10%

Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of ISENTRESS 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 22.

Table 22: Virologic Outcomes of Randomized Treatment of BENCHMRK 1 and BENCHMRK 2 Trials at 96 Weeks (Pooled Analysis)
ISENTRESS 400 mg Twice Daily + OBT (N = 462) Placebo + OBT (N = 237)
*
Includes subjects who switched to open-label raltegravir after Week 16 due to the protocol-defined virologic failure, subjects who discontinued prior to Week 96 for lack of efficacy, subjects changed OBT due to lack of efficacy prior to Week 96, or subjects who were ≥50 copies in the 96 week window.
Includes subjects who discontinued due to AE or death at any time point from day 1 through the Week 96 window if this resulted in no virologic data on treatment during the Week 96 window.
Other includes: withdrew consent, loss to follow-up, moved etc., if the viral load at the time of discontinuation was <50 copies/mL.

Subjects with HIV-1 RNA less than 50 copies/mL

55%

27%

Virologic Failure *

35%

66%

No virologic data at Week 96 Window

Reasons

Discontinued study due to AE or death

3%

3%

Discontinued study for other reasons

4%

4%

Missing data during window but on study

4%

<1%

The mean changes in CD4 count from baseline were 118 cells/mm3 in the group receiving ISENTRESS 400 mg twice daily and 47 cells/mm3 for the control group.

Treatment-emergent CDC Category C events occurred in 4% of the group receiving ISENTRESS 400 mg twice daily and 5% of the control group.

Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 23.

Table 23: Virologic Response at 96 Week Window by Baseline Genotypic/Phenotypic Sensitivity Score
Percent with HIV-1 RNA <50 copies/mL At Week 96
n ISENTRESS 400 mg Twice Daily + OBT (N = 462) n Placebo + OBT (N = 237)
*
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-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.

Phenotypic Sensitivity Score (PSS) *

0

67

43

43

5

1

144

58

71

23

2

142

61

66

32

3 or more

85

48

48

42

Genotypic Sensitivity Score (GSS) *

0

116

39

65

5

1

177

62

95

26

2

111

61

49

53

3 or more

51

49

23

35

Switch of Suppressed Subjects from Lopinavir (+) Ritonavir to Raltegravir

The SWITCHMRK 1 & 2 Phase 3 studies evaluated HIV-1 infected subjects receiving suppressive therapy (HIV-1 RNA <50 copies/mL on a stable regimen of lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors for >3 months) and randomized them 1:1 to either continue lopinavir (+) ritonavir (n=174 and n=178, SWITCHMRK 1 & 2, respectively) or replace lopinavir (+) ritonavir with ISENTRESS 400 mg twice daily (n=174 and n=176, respectively). The primary virology endpoint was the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24 with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks.

Subjects with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.

These studies were terminated after the primary efficacy analysis at Week 24 because they each failed to demonstrate non-inferiority of switching to ISENTRESS versus continuing on lopinavir (+) ritonavir. In the combined analysis of these studies at Week 24, suppression of HIV-1 RNA to less than 50 copies/mL was maintained in 82.3% of the ISENTRESS group versus 90.3% of the lopinavir (+) ritonavir group. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups.

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