Tipranavir: PNU 140690, tipranivir

Tipranavir [PNU 140690, tipranivir, Aptivus] is a second-generation HIV dihydropyrone (a sulphonamide derivative), nonpeptidic protease inhibitor (NPPI) discovered by Pharmacia & Upjohn (now Pfizer) in the US. The compound is in development with Boehringer Ingelheim. Tipranavir has potent in vitro activity against a variety of HIV-1 laboratory strains and clinical isolates, including those resistant to ritonavir, as well as HIV-2. Tipranavir has been shown to act synergistically with other antiretroviral agents. The limited bioavailability of the hard gel (and first available) formulation of tipranavir led to the development of a soft capsule formulation that has better oral bioavailability. Pharmacia Corporation (now Pfizer) considers that the resistance profile of tipranavir may be sufficiently unique for it to be effective against protease inhibitor resistant virus. On 16 April 2003, Pharmacia Corporation was acquired by, and merged into, Pfizer. In February 2000, Boehringer Ingelheim acquired exclusive worldwide rights to tipranavir. Tipranavir was launched in the US in mid-2005. In June 2005, the US FDA granted accelerated approval to tipranavir capsules for use in combination treatment, based on 24-week data from ongoing clinical trials. The approved dose is Aptivus 500 mg taken with ritonavir 200 mg, twice daily. Aptivus 250 mg soft gel capsules are expected to be available in the second half of 2005. A submission was made to the FDA in October 2004 seeking accelerated approval. In May 2005, the Antiviral Drugs Advisory Committee of the FDA recommended the approval of tipranavir. The positive recommendation is based on data from the RESIST-1 and RESIST-2 studies. Also in October 2004, Boehringer Ingelheim submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMEA) for tipranavir for the treatment of HIV-1 infection in combination with other antiretroviral agents in patients who are protease inhibitor experienced. In July 2005, the Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for tipranavir in the European Union. If approved, the drug will be marketed in Europe too under the name Aptivus. Marketing authorisation under exceptional circumstances (accelerated approval) is expected before the end of 2005.A phase III clinical programme (RESIST- Randomised Evaluation of Strategic Intervention in Multi-drug ReSistant Patients with Tipranavir) was launched by Boehringer Ingelheim in February 2003. The RESIST programme consists of two phase III pivotal trials (RESIST 1 and RESIST 2) and two companion trials (study 1182.51 and RESIST 3) available at some sites for even more advanced patients. The trials are designed to further study the efficacy and safety of tipranavir (500 mg) boosted with low-dose (200 mg) ritonavir, taken twice daily, versus a low-dose ritonavir boosted comparator protease inhibitor that is chosen by the patient's physician on the basis of the treatment history and baseline resistance testing. Each patient will also receive an individualised background regimen. Study participants will all be highly treatment-experienced HIV-positive adults. RESIST 1 study enrolled 620 patients in the US, Canada and Australia and RESIST 2 enrolled more than 863 patients in Europe and South America. These trials are now fully recruited. The clinical endpoint for RESIST 1 is at 24 weeks and for RESIST 2, the endpoints are at 16 and 24 weeks. Interim data from RESIST 1 (1182.12) were presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington, DC, USA, in October 2004. Results from this study show that tipranavir is a viable treatment option for patients who have failed other protease inhibitors. In June 2004, Boehringer Ingelheim announced the expansion of enrolment criteria in the international Compassionate Use Programme to allow broader access to tipranavir for HIV patients in need of new treatment options. All countries participating in the tipranavir phase III programme are eligible to take part in the Compassionate Use programme, which is enrolling patients over the age of 18 years, who are triple-antiretroviral class-experienced with at least two PI-based regimens. In November 2004, Boehringer Ingelheim opened the tipranavir Expanded Access Program (EAP) in the US, following a review of the protocol by the FDA. The programme will provide access to tipranavir for HIV-infected patients (> or =18 years old) who are not enrolled in the ongoing tipranavir clinical studies and who are triple-antiretroviral class-experienced with at least two previous PI-based regimens, and have documented PI-resistance and need tipranavir to construct a viable treatment regimen. Eligibility is not dependent upon viral load or CD4+ cell count. Tiparanvir is also being evaluated in phase II studies for use in paediatric and treatment-naive patient populations. Phase II trials completed in the US have established the clinical activity of tiprananvir in both antiretroviral-naive and -experienced patients with HIV infection. The studies have also shown that tipranavir can be combined with ritonavir for maximal clinical benefit. In its 2003 Annual Report, Boehringer Ingelheim stated that the process- and paediatric- formulation development of tipranavir had been completed.