Merck's integrase inhibitor raltegravir effectively decreases HIV viral loads after 24 weeks of use among HIV-positive people who have not responded to other treatments, according to a study published in the April 14 online edition of the journal Lancet, AFP/Yahoo! News reports (AFP/Yahoo! News, 4/13). Raltegravir, formerly known as MK-0158, works by blocking an HIV enzyme called integrase. Integrase is one of the three enzymes necessary for HIV to replicate in the body, and integrase inhibitors would stop HIV from inserting its genes into uninfected DNA. The other two enzymes necessary for viral replication -- reverse transcriptase and protease -- already are targeted by a variety of antiretrovirals (Kaiser Daily HIV/AIDS Report, 2/28). For the study, Beatriz Grinsztejn of Merck Research Laboratories in Westpoint, Pa., and colleagues divided 178 HIV-positive people into four groups. Participants in three groups received different doses of raltegravir, ranging from 200 milligrams to 600 milligrams, and the fourth group received a placebo. All four groups also took a basic "background treatment," according to AFP/Yahoo! News. The study found that after 24 weeks, HIV viral loads dropped below a measurable threshold of 50 copies per milliliter in 65% of the patients taking the drug, nearly five times as many as the placebo group. The study also found that immune system responses substantially improved. Pedro Cahn and Omar Sued of the Department of Clinical Research at the Fundación Huesped in Buenos Aires, Argentina, in an accompanying Lancet commentary wrote that raltegravir "showed unprecedented levels of virological efficiency," adding that the treatment "achieved virological suppression even in patients with limited options." According to Cahn and Sued, "If no long-term, unexpected side effects or resistance issues emerge, raltegravir will have a major role in salvage therapy, particularly in combination with another new drug" (AFP/Yahoo! News, 4/13). Merck has announced that it will apply for FDA approval in the second quarter of 2007 (Kaiser Daily HIV/AIDS Report, 2/28).
Friday, April 20, 2007
Tuesday, April 17, 2007
Isentress (raltegravir, Isentress): HIV Treatment Information
What is Isentress?
Isentress is an experimental integrase inhibitor being developed by Merck & Company.
After HIV's genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIV's DNA inside the cell's DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as Isentress, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA.
Isentress will need to be used in combination with other drugs. Clinical trials will evaluate its effect in combination with other drugs, including those currently approved for the treatment of HIV.
Merck has announced that it has initiated an expanded access program (EAP), called EARMRK, for Isentress. The program provides the drug, free of charge, to HIV-positive people with limited treatment options. This is defined as people who: 1) have HIV resistance to at least one drug in all three classes of oral HIV drugs, 2) are failing their current regimens, and 3) require a new drug to which their HIV may not be resistant. For more information on the EARMRK program, call 1-877-EARMRK1 or review Merck's EARMRK website.
What is already known about Isentress?
The Isentress dose being studied in phase III clinical trials is 400mg taken by mouth twice a day.
Isentress might interact with other medications, including those used to treat HIV. It is important that your personal physician and/or the research nurse or study investigator be aware of all drugs you are taking, including those you buy without a prescription.
Isentress holds promise for HIV-positive patients who have taken other anti-HIV drugs in the past. Because Isentress targets HIV differently than currently available drugs, chances are that most people living with the virus—regardless of their treatment history—will likely benefit from using Isentress.
What do we know from clinical trials of Isentress?
Results of a two-part phase II study have been presented. The first part of the study enrolled 35 HIV-infected patients who had not received other anti-HIV medications in the past. The patients received one of four doses of Isentress twice a day (100mg, 200mg, 400mg, or 600mg) or placebo without any other anti-HIV medications. After ten days of treatment, viral loads were reduced in all patients receiving Isentress by 1.7 to 2.2 log (approximately 98%).
The second part of the study enrolled 198 HIV-positive people, including 30 participants enrolled in part one of the study. The patients were to take one of the four doses of Isentress or Sustiva® (efavirenz). All patients in the study also received Viread® (tenofovir) and Epivir® (lamivudine). After 24 weeks of therapy, 85% to 95% of patients taking the Isentress regimen saw their viral loads reduced to less than 50, regardless of which dosing group they were in. In the Sustiva group, approximately 92% of patients experienced viral load reductions to less than 50. CD4 cell counts increased in all patients after 24 weeks or treatment. This study will follow patients for a total of 48 weeks.
A phase IIb study enrolled 178 HIV-positive participants, most of whom had evidence of resistance to drugs in three available classes (NRTIs, NNRTIs, and PIs). Patients were randomly assigned to one of three doses of Isentress (200, 400, or 600mg twice daily), or placebo, in combination with a regimen of currently approved anti-HIV drugs. After 24 weeks of treatment, up to 67% of the patients receiving Isentress (most notably those receiving 600mg twice daily) had viral loads below 50, compared to 14% of the patients who took placebo.
Phase III studies of Isentress have been started. An expanded access program (EAP) was initiated in September (see above and below).
What is known about side effects?
In the two phase II studies reported to date, Isentress therapy was generally well tolerated. The most common side effects included diarrhea, nausea, vomiting, fatigue, dizziness, headache, flushing, itching, and injection-site reactions (among patients taking Fuzeon®). However, these side effects were also seen in patients receiving placebo. The only possible treatment-related toxicity of concern was a patient in the two-part phase II study taking 600mg Isentress group. He was required to discontinue therapy due to significantly increased liver enzymes.
Additional data from studies evaluating the safety of Isentress are needed.
It is not known whether Isentress will harm an unborn baby. It is very important to treat HIV/AIDS during pregnancy to reduce the risk of infecting your baby. Talk to your doctor about your treatment options.
It is not known whether Isentress passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed.
Merck's Integrase Inhibitor Gets a Name: Raltegravir
Merck unveiled a new name for its integrase inhibitor, raltegravir, along with 16-week data on a pair of phase 3 clinical trials at the 14th Conference on Retroviruses and Opportunistic Infections.
The first-in-class compound is a small molecule that blocks an early stage in the HIV lifecycle, the integration of the virus into host cell DNA. The drug formally was known as MK-0518.
The Benchmrk 1 and 2 studies respectively enrolled 350 and 349 patients with triple-class drug failure defined as genotypic/phenotypic resistance to 1 or more drugs in each of the 3 classes and HIV RNA viral load of more than 1000 copies/mL. The typical patient was a man in his mid-40s, with a CD4+ cell count of about 150 cells/µL, and a viral load of 4.5 logs HIV-1 RNA, said David Cooper, MD, the Australia National HIV Center, who led the Benchmrk 1 study.
Background therapy was optimized and patients were randomized 2:1 to receive 400 mg of raltegravir twice daily or placebo. The 16-week interim analysis was built into the 48-week study at the request of European regulatory authorities.
Combined interim analysis of the 2 studies found that 79% of patients receiving raltegravir plus optimized background therapy (OBT) suppressed the virus below 400 copies/mL at week 16 compared with 43% of those receiving placebo plus OBT. "There were good CD4 count responses of around 100 cells, and a viral load response of 2 logs," said Dr. Cooper. Adverse effects were comparable between the 2 groups.
Dr. Cooper was particularly excited that the study allowed use of drugs that were still experimental at that time as part of OBT, in this instance, darunavir (subsequently approved), which was available through expanded access. Roughly 20% of patients in the slightly earlier study incorporated darunavir into their regimen and that increased to about 50% in the second study that started a bit later.
Benchmrk 2 lead investigator Roy Steigbigel, MD, from the University of Stony Brook in New York, said that 61% of patients with no active drug other than raltegravir achieved a viral load below 400 copies/mL. However, the drug requires the support of one or more active drugs to sustain viral suppression.
In the patients who added enfurvitide or darunavir for the first time as part of OBT, viral load dropped below 400 copies/mL in 90%, while 98% of those who received both drugs for the first time achieved a viral load less than 400 copies/mL, he said.
Resistance to raltegravir can develop along 2 different pathways, at positions 155 and 148 of the HIV integrase. They are associated with clusters of other mutations, Dr. Cooper said. "My understanding is that there is no cross resistance" with any of the approved classes of drugs. He cautioned against reading any clinical relevance into these findings because of the relatively small number of patients and short duration of use of the drug.
John Mellors, MD, vice chair of the conference scientific committee, was rhapsodic in declaring the significance of these data. He said at a CROI news conference that he moderated, "When HAART initially came out, the response [of <400>
Dr. Mellors was elated to see comparable rates of suppression of viral load below 400 copies/mL in this highly treatment-experienced population. He said, "This is really a remarkable development."
According to Daniel Kuritzkes, MD, "What clinicians need to be doing with their experienced patients is assessing patients' clinical status carefully and not leap to introduce any one of the new drugs until they are convinced they can put together a fully active regimen," Dr. Kuritzkes is director of AIDS research at Brigham and Women's Hospital in Boston, Massachusetts. He was not involved in the trial.
That may mean using an expanded access program or holding off until the drug becomes available. Dr. Kuritzkes said, "You really need to use these drugs in combination, whenever possible."
Merck is enrolling treatment-naive patients into phase 3 trials. The company anticipates submitting 24-week data on treatment-experienced patients to the US Food and Drug Administration later this year, with approval coming by the end of 2007.
The first-in-class compound is a small molecule that blocks an early stage in the HIV lifecycle, the integration of the virus into host cell DNA. The drug formally was known as MK-0518.
The Benchmrk 1 and 2 studies respectively enrolled 350 and 349 patients with triple-class drug failure defined as genotypic/phenotypic resistance to 1 or more drugs in each of the 3 classes and HIV RNA viral load of more than 1000 copies/mL. The typical patient was a man in his mid-40s, with a CD4+ cell count of about 150 cells/µL, and a viral load of 4.5 logs HIV-1 RNA, said David Cooper, MD, the Australia National HIV Center, who led the Benchmrk 1 study.
Background therapy was optimized and patients were randomized 2:1 to receive 400 mg of raltegravir twice daily or placebo. The 16-week interim analysis was built into the 48-week study at the request of European regulatory authorities.
Combined interim analysis of the 2 studies found that 79% of patients receiving raltegravir plus optimized background therapy (OBT) suppressed the virus below 400 copies/mL at week 16 compared with 43% of those receiving placebo plus OBT. "There were good CD4 count responses of around 100 cells, and a viral load response of 2 logs," said Dr. Cooper. Adverse effects were comparable between the 2 groups.
Dr. Cooper was particularly excited that the study allowed use of drugs that were still experimental at that time as part of OBT, in this instance, darunavir (subsequently approved), which was available through expanded access. Roughly 20% of patients in the slightly earlier study incorporated darunavir into their regimen and that increased to about 50% in the second study that started a bit later.
Benchmrk 2 lead investigator Roy Steigbigel, MD, from the University of Stony Brook in New York, said that 61% of patients with no active drug other than raltegravir achieved a viral load below 400 copies/mL. However, the drug requires the support of one or more active drugs to sustain viral suppression.
In the patients who added enfurvitide or darunavir for the first time as part of OBT, viral load dropped below 400 copies/mL in 90%, while 98% of those who received both drugs for the first time achieved a viral load less than 400 copies/mL, he said.
Resistance to raltegravir can develop along 2 different pathways, at positions 155 and 148 of the HIV integrase. They are associated with clusters of other mutations, Dr. Cooper said. "My understanding is that there is no cross resistance" with any of the approved classes of drugs. He cautioned against reading any clinical relevance into these findings because of the relatively small number of patients and short duration of use of the drug.
John Mellors, MD, vice chair of the conference scientific committee, was rhapsodic in declaring the significance of these data. He said at a CROI news conference that he moderated, "When HAART initially came out, the response [of <400>
Dr. Mellors was elated to see comparable rates of suppression of viral load below 400 copies/mL in this highly treatment-experienced population. He said, "This is really a remarkable development."
According to Daniel Kuritzkes, MD, "What clinicians need to be doing with their experienced patients is assessing patients' clinical status carefully and not leap to introduce any one of the new drugs until they are convinced they can put together a fully active regimen," Dr. Kuritzkes is director of AIDS research at Brigham and Women's Hospital in Boston, Massachusetts. He was not involved in the trial.
That may mean using an expanded access program or holding off until the drug becomes available. Dr. Kuritzkes said, "You really need to use these drugs in combination, whenever possible."
Merck is enrolling treatment-naive patients into phase 3 trials. The company anticipates submitting 24-week data on treatment-experienced patients to the US Food and Drug Administration later this year, with approval coming by the end of 2007.
Raltegravir - New HIV drug shows promise
A new drug called raltegravir shows promise in combating drug-resistant HIV, concludes an international study in The Lancet medical journal. HIV is the virus that causes Aids.
Raltegravir belongs to a new class of drugs called integrase-inhibitors, which block an enzyme essential for HIV to replicate itself, BBC News reported.
The study included 178 patients with advanced HIV who failed to respond to the antiretroviral drugs they'd been taking for about 10 years. The patients were assigned to take their usual drugs plus either raltegravir or a non-medicinal placebo.
After 24 weeks, patients taking raltegravir showed a 98 percent drop in the amount of HIV genetic material in their blood, compared to a 45 percent drop among the placebo group. Those taking raltegravir also showed a significant boost in the number of CD4 cells, an indication of immune response, BBC News reported.
"This drug has the potential to become an important component of combination treatment regimens...for patients failing current therapies with multidrug-resistant virus and limited treatment options," wrote the study's authors at Merck Research Laboratories in Pennsylvania. – (HealthDayNews)
Raltegravir belongs to a new class of drugs called integrase-inhibitors, which block an enzyme essential for HIV to replicate itself, BBC News reported.
The study included 178 patients with advanced HIV who failed to respond to the antiretroviral drugs they'd been taking for about 10 years. The patients were assigned to take their usual drugs plus either raltegravir or a non-medicinal placebo.
After 24 weeks, patients taking raltegravir showed a 98 percent drop in the amount of HIV genetic material in their blood, compared to a 45 percent drop among the placebo group. Those taking raltegravir also showed a significant boost in the number of CD4 cells, an indication of immune response, BBC News reported.
"This drug has the potential to become an important component of combination treatment regimens...for patients failing current therapies with multidrug-resistant virus and limited treatment options," wrote the study's authors at Merck Research Laboratories in Pennsylvania. – (HealthDayNews)
Sunday, April 15, 2007
New anti-AIDS drug aimed at the global market
Shanghai Target Drug Pharmaceutical Co., Ltd. and Australia's Avexa Limited have signed an agreement on international cooperation in Shanghai to promote follow-up studies of a new entry-inhibitor HIV drug, TD0232.
According to the agreement, China has the intellectual property rights to the drug, but will share the rights to any new intelligence that emerges during follow-up research and development. It also has full manufacturing and distribution rights to the drug in China, (including Hong Kong, Macao and Taiwan regions). Avexa is bearing the costs of the study, and has full rights to markets outside China.
In 2003, scientists discovered a number of drug molecules that they believed capable of fighting HIV and applied for an international patent. In June 2003, the Shanghai Institute for Biological Sciences under the Chinese Academy of Sciences and the Shanghai Institute of Organic Chemistry pooled their knowledge of the molecule. They entered an agreement with Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. to establish the Shanghai Target Drug Pharmaceutical Co., Ltd. to promote follow-up study of the new drug. Preclinical trials have revealed that the drug is equally as effective as other, similar types of drugs available.
According to the agreement, China has the intellectual property rights to the drug, but will share the rights to any new intelligence that emerges during follow-up research and development. It also has full manufacturing and distribution rights to the drug in China, (including Hong Kong, Macao and Taiwan regions). Avexa is bearing the costs of the study, and has full rights to markets outside China.
In 2003, scientists discovered a number of drug molecules that they believed capable of fighting HIV and applied for an international patent. In June 2003, the Shanghai Institute for Biological Sciences under the Chinese Academy of Sciences and the Shanghai Institute of Organic Chemistry pooled their knowledge of the molecule. They entered an agreement with Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. to establish the Shanghai Target Drug Pharmaceutical Co., Ltd. to promote follow-up study of the new drug. Preclinical trials have revealed that the drug is equally as effective as other, similar types of drugs available.
Friday, April 13, 2007
Raltegravir May Be Safe, Effective in Treating Multidrug-Resistant HIV
The HIV-1 integrase inhibitor raltegravir (MK-0518) is safe and effective in treatment-experienced patients with multidrug-resistant virus, according to the results of a phase 2, randomized controlled trial study reported in the April 14 issue of The Lancet.
"Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains, including those resistant to currently available antiretroviral drugs," write Beatriz Grinsztejn, from the Evandro Chagas Clinical Research Institute/Oswaldo Cruz Foundation in Rio de Janeiro, Brazil, and colleagues from the Protocol 005 Team. "The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients."
HIV-infected patients eligible for this multicenter, triple-blind, dose-ranging study had HIV-1 RNA viral load higher than 5000 copies/mL, CD4 cell counts greater than 50 cells/μL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one nonnucleoside reverse transcriptase inhibitor, and one protease inhibitor. The main outcome measures were change in viral load from baseline at week 24 and safety; analysis was by modified intention-to-treat.
Of 179 patients eligible for randomization, 44 patients were randomized to oral treatment twice daily with raltegravir 200 mg, 45 to raltegravir 400 mg, 45 to raltegravir 600 mg, and 45 to placebo. One patient in the 200-mg group did not receive treatment and was therefore excluded from analysis.
Median duration of previous antiretroviral treatment was 9.9 years (range, 0.4 - 17.3 years), and mean baseline viral load was 4.7 ± 0.5) log10 copies per mL. Of 4 patients who discontinued because of adverse events, 3 (2%) were in the raltegravir groups and 1 patient (2%) was in the placebo group.
Of 41 patients who discontinued because of lack of efficacy, 14 (11%) were in the raltegravir groups and 27 (60%) were in the placebo group. Mean change in viral load from baseline at week 24 was –1.80 (95% confidence interval [CI], –2.10 to –1.50) log10 copies/mL in the 200-mg group, –1.87 (95% CI, –2.16 to –1.58) log10 copies/mL in the 400-mg group, –1.84 (95% CI, –2.10 to –1.58) log10 copies/mL in the 600-mg group, and –0.35 (95% CI, –0.61 to –0.09) log10 copies/mL in the placebo group. At all doses, raltegravir had a safety profile similar to that of placebo, with no dose-related toxicities.
"In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen," the authors write. "The safety profile of raltegravir is comparable with that of placebo at all doses studied."
Raltegravir is manufactured by Merck & Co, which employs 4 of the authors. Some of the other authors report various financial relationships with Merck & Co, Abbott, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, Virgo, Boehringer Ingelheim, and/or Pfizer.
In an accompanying editorial, Pedro Cahn and Omar Sued, from the Fundación Huesped in Buenos Aires, Argentina, call these results "encouraging."
"Raltegravir showed a good safety profile and high potency in naive and experienced patients, achieving virological suppression even in patients with limited options," Drs. Cahn and Sued write. "If no long-term unexpected side-effects or resistance issues emerge, raltegravir will have a major role in salvage therapy, particularly in combination with another new drug. 48-week data for naive patients are eagerly expected. Should these data show similar efficacy to efavirenz-based regimens, raltegravir could be considered as a new option to build into initial regimens for highly active antiretroviral therapy."
"Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains, including those resistant to currently available antiretroviral drugs," write Beatriz Grinsztejn, from the Evandro Chagas Clinical Research Institute/Oswaldo Cruz Foundation in Rio de Janeiro, Brazil, and colleagues from the Protocol 005 Team. "The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients."
HIV-infected patients eligible for this multicenter, triple-blind, dose-ranging study had HIV-1 RNA viral load higher than 5000 copies/mL, CD4 cell counts greater than 50 cells/μL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one nonnucleoside reverse transcriptase inhibitor, and one protease inhibitor. The main outcome measures were change in viral load from baseline at week 24 and safety; analysis was by modified intention-to-treat.
Of 179 patients eligible for randomization, 44 patients were randomized to oral treatment twice daily with raltegravir 200 mg, 45 to raltegravir 400 mg, 45 to raltegravir 600 mg, and 45 to placebo. One patient in the 200-mg group did not receive treatment and was therefore excluded from analysis.
Median duration of previous antiretroviral treatment was 9.9 years (range, 0.4 - 17.3 years), and mean baseline viral load was 4.7 ± 0.5) log10 copies per mL. Of 4 patients who discontinued because of adverse events, 3 (2%) were in the raltegravir groups and 1 patient (2%) was in the placebo group.
Of 41 patients who discontinued because of lack of efficacy, 14 (11%) were in the raltegravir groups and 27 (60%) were in the placebo group. Mean change in viral load from baseline at week 24 was –1.80 (95% confidence interval [CI], –2.10 to –1.50) log10 copies/mL in the 200-mg group, –1.87 (95% CI, –2.16 to –1.58) log10 copies/mL in the 400-mg group, –1.84 (95% CI, –2.10 to –1.58) log10 copies/mL in the 600-mg group, and –0.35 (95% CI, –0.61 to –0.09) log10 copies/mL in the placebo group. At all doses, raltegravir had a safety profile similar to that of placebo, with no dose-related toxicities.
"In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen," the authors write. "The safety profile of raltegravir is comparable with that of placebo at all doses studied."
Raltegravir is manufactured by Merck & Co, which employs 4 of the authors. Some of the other authors report various financial relationships with Merck & Co, Abbott, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, Virgo, Boehringer Ingelheim, and/or Pfizer.
In an accompanying editorial, Pedro Cahn and Omar Sued, from the Fundación Huesped in Buenos Aires, Argentina, call these results "encouraging."
"Raltegravir showed a good safety profile and high potency in naive and experienced patients, achieving virological suppression even in patients with limited options," Drs. Cahn and Sued write. "If no long-term unexpected side-effects or resistance issues emerge, raltegravir will have a major role in salvage therapy, particularly in combination with another new drug. 48-week data for naive patients are eagerly expected. Should these data show similar efficacy to efavirenz-based regimens, raltegravir could be considered as a new option to build into initial regimens for highly active antiretroviral therapy."
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