Biotech Values

[DewDiligence]

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.]

http://biz.yahoo.com/bw/081026/20081026005061.html

›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.”‹


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