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Tipranavir submission takes fight to HIV mutations Boehringer
Ingelheim has submitted a new drug application to the FDA for the non-peptidic
protease inhibitor tipranavir. The drug could prove strategically vital to the
company, given its apparent efficacy in acting against resistant HIV mutations.
However positioning it in the treatment naive HIV market may prove more of a
challenge. As well as being submitted to the FDA, Boehringer Ingelheim (BI) has also applied to the European Medicines Agency for a European Marketing Authorization Application for tipranavir. Tipranavir is the first non-peptidic protease inhibitor (PI) under development for HIV therapy. In vitro, the drug showed the remarkable ability to inhibit up to 90% of HIV strains highly resistant to other widely used PIs, such as indinavir, nelfinavir, ritonavir and saquinavir. This unique feature is thought to be due to tipranavir's non-peptidic nature, which enables it to bind to the HIV protease more flexibly and therefore should account for its higher inhibitory potency and reduced susceptibility to resistance development. Experts estimate that up to 16 PI mutations are required to reduce HIV's susceptibility to tipranavir. Clinical
trials Although tipranavir's exact resistance profile has not been fully characterized, the results from the recent large-scale, phase III RESIST-1 and RESIST-2 trials strongly support the drug's use against resistant HIV mutations. The studies were restricted to triple-class experienced patients, although tipranavir is also being investigated in treatment-naive and pediatric patients. As with most other PIs, to maintain high levels of tipranavir in the blood, the drug needs to be boosted with low-dose ritonavir. Since the development of the first PIs in 1995, highly active antiretroviral therapy (HAART) has become the gold standard treatment for HIV. Usually consisting of a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone with either a PI or non-nucleoside reverse transcriptase inhibitor (NNRTI), HAART has succeeded in delaying the onset of AIDS in the majority of HIV patients, resulting in a lifespan equivalent to that of an uninfected individual. However, a key issue with HAART is the rapid development of resistant strains of the virus, rendering many combinations ineffective. Indeed, class resistance, where several drugs in each class may be affected, has become a serious concern for HIV patients and physicians alike. Additional
treatment options The launch of Roche's Fuzeon (enfuvirtide), the first in a new class of antiretrovirals known as the entry inhibitors (EIs), has provided a further option for treatment experienced, multi-drug resistant patients. However, as demonstrated by the significant HIV pipeline seen across the pharma industry, extensive R&D into more options for these patients is underway. Tipranavir offers a therapeutic option for patients that have developed PI resistance, and Datamonitor's key opinion leader research found that there may be a place for its use in combination with Fuzeon, and other late stage developmental drugs with activity against resistant strains of HIV. The prospective positioning of tipranavir into an increasingly crowded market poses a key strategic issue for BI. Should tipranavir prove effective in the treatment-naive population, such an indication would position it against the current recommended first-line therapy PI, Kaletra, a highly potent drug with an excellent resistance profile. Alternatively, tipranavir might be successfully positioned as a later line therapy in patients that have developed resistance against most other PIs and fail to respond or tolerate Kaletra, for example in combination with Roche's Fuzeon. Related
research:
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