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.
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