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European Commission Approves Raltegravir (Isentress) and Once-daily Lopinavir/ritonavir (Kaletra) for First-Line HIV Therapy

The European Commission, which plays a regulatory role similar to that of the U.S. Food and Drug Administration (FDA) for the countries of the European Union, this week announced expanded approvals for 2 HIV drugs for first line therapy. The integrase inhibitor raltegravir (Isentress) is now approved for both treatment-naive and treatment-experienced HIV patients. The boosted protease inhibitor lopinavir/ritonavir (Kaletra) for once-daily as well as twice-daily dosing. Both new indications are already approved in the U.S.

Below is an excerpt from a press release from Merck about the raltegravir expanded approval.

A press release from Abbott regarding the lopinavir/ritonavir approval is available online.

European Union Commission Approves Expanded
Use of Isentress (Raltegravir), from MSD, in
Adult Patients with HIV-1 Infection

Isentress (Raltegravir)

Whitehouse Station, NJ -- September 15, 2009 -- Merck Sharp & Dohme Limited (MSD) announced today that ISENTRESS (raltegravir) has been granted an expanded licence from the European Union Commission (Commission) for use in combination with other antiretroviral (ARV) medicinal products for the treatment of HIV-1 infection in adult patients, including adult patients starting HIV-1 therapy for the first time (treatment-naive), as well as treatment-experienced adult patients. The safety and efficacy of ISENTRESS has not been established in patients below 16 years of age. The Commission's decision is applicable to the 27 Member States of the European Union (EU), including France, Germany, Italy, Spain and the United Kingdom as well as to Iceland and Norway.

The Commission`s decision, reflecting the positive opinion of the Committee for Medicinal Products for Human Use (CHMP), was based on data from three double-blind controlled Phase III studies. Two of these studies were conducted in clinically advanced, three-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults and one was conducted in treatment-naive adults. In the study with treatment-naive patients (STARTMRK), raltegravir was found to be as effective as efavirenz (one of the standard antiretrovirals prescribed for treatment-naive patients) at suppressing viral load and restoring immune system function through 48 weeks in treatment-naïve patients. Both medicines were administered in combination with tenofovir and emtricitabine.

"Having a therapeutic option like raltegravir, with an efficacy and safety profile established through clinical studies, provides adult patients treated for the first time with a new way of targeting the virus," said Dr. Adriano Lazzarin, professor of Infectious Illnesses, University Vita-Salute San Raffaele, Milan, Italy. "New treatment options in the EU may help physicians to better individualise treatment regimens, which is important due to the complexity of HIV and increasingly diverse patient needs."

Despite the availability of drugs to treat HIV and AIDS, the pandemic continues. In the EU, nearly 270,000 cases of HIV have been reported since 2002, according to the European Centre for the Epidemiological Monitoring of HIV and AIDS. Worldwide, an estimated 33 million people are infected with HIV and AIDS, and about 2.7 million new infections occurred worldwide in 2007.

"Merck Sharp & Dohme is committed to bringing innovative therapies to patients who need them most, and we are pleased that raltegravir will now be available to a broader spectrum of adult HIV patients. The expanded licence is important because it gives adult patients starting HIV therapy for the first time an additional treatment option," said Patrick Bergstedt, senior vice president and general manager of Infectious Diseases at Merck and Co., Inc.

Treatment-naive indication supported by a double-blind, controlled study of raltegravir

The treatment-naïve indication for raltegravir in combination therapy was based on analyses of 563 treatment-naïve, HIV-1-infected patients through 48 weeks in an ongoing, multi-centre, double-blind, randomised, active-controlled, Phase III study called STARTMRK. Patients in the study received either 400 mg raltegravir (n=281) administered orally twice daily or 600 mg efavirenz (n=282), one of the leading ARVs prescribed for treatment-naïve patients, dosed orally once daily. Raltegravir and efavirenz were administered in combination with tenofovir/emtricitabine.

Suppression of viral load and increase in CD4 cell counts durable through 48 weeks

In the STARTMRK trial, the regimen including raltegravir reduced HIV-1 viral load to undetectable levels (less than 50 copies/mL) at a rate comparable to the regimen containing efavirenz (86 percent of patients treated with raltegravir versus 82 percent of patients treated with efavirenz, both in combination therapy); the difference in viral load reduction between the two treatment groups was 4.2 percent (95 percent CI; -1.92, 10.3) through 48 weeks. There were greater average increases in CD4 cell counts for raltegravir in combination therapy (189 cells/mm3) versus efavirenz in combination therapy (163 cells/mm3); the difference in mean CD4 cell count change from baseline between the two treatment groups was 25.8 (95 percent CI; 4.4, 47.2) through 48 weeks. This difference though was not statistically significant.

These efficacy results were supported by the 96-week analysis of a randomised, double-blind, controlled, dose-ranging trial, Protocol 004, in ARV treatment-naïve HIV-1-infected adult subjects comparing raltegravir to efavirenz, both in combination with tenofovir and lamivudine.

About raltegravir

Raltegravir works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated early antiviral activity. 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 raltegravir is the only drug approved that inhibits the integrase enzyme. Raltegravir is a single 400 mg tablet taken twice daily without regard to food. Raltegravir does not require boosting with ritonavir. A doubling of raltegravir dose to 800 mg twice daily can be considered during coadministration with rifampicin.

Global filing status of raltegravir

Since 2007, raltegravir has received regulatory approval in more than 80 countries across six continents for use in combination with other ARV agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of HIV-1 replication despite ongoing ARV therapy. MSD is continuing to move forward with filings in additional countries around the world. In July, 2009 the U.S. Food and Drug Administration (FDA) approved an expanded indication for raltegravir in combination with other ARV medicines to include use in treatment of adult patients starting HIV-1 therapy for the first time (treatment-naive), as well as in treatment-experienced adult patients.

About MSD

Merck & Co., Inc., Whitehouse Station, N.J., U.S.A., which operates in many countries as MSD (Merck Sharp & Dohme), is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, MSD 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 MSD medicines but help deliver them to the people who need them. MSD also publishes unbiased health information as a not-for-profit service.



Merck Sharp & Dohme. European Union Commission Approves Expanded Use of Isentress (Raltegravir), from MSD, in Adult Patients with HIV-1 Infection. Press release. September 15, 2009.

Abbott. Abbott Receives European Approval for Once-Daily Dosing of Kaletra (lopinavir/ritonavir) Tablet New Approval Expands Dosing Options for Adult HIV-Infected Patients New to Antiretroviral Therapy. Press release. September 14, 2009.