European Commission grants full approval of HIV protease inhibitor, tipranavir (Aptivus®)

Boehringer IngelheimBoehringer Ingelheim announced that the European Commission has given the full marketing authorisation to its HIV protease inhibitor (PI), Aptivus® (tipranavir). The Commission has fully approved Aptivus ® for the suppression of HIV in highly treatment experienced patients who have developed resistance to other protease inhibitors.

Resistance to HIV therapies is a considerable problem, with an increasing number of people developing strains of HIV that are resistant to protease inhibitors. For example, in one study in the UK 27% of treatment-experienced patients demonstrated resistance against protease inhibitors [1] and in Spain, 43% of patients treated for more than eight years carry more than five protease resistance mutations.[2]

Dr Andreas Barner, Member of the Board of Boehringer Ingelheim and responsible for Research, Development and Medicine said: "We welcome this decision by the EU Commission to grant full marketing authorisation for Aptivus®. This full approval demonstrates the confidence that the authorities have in the benefit of Aptivus® for patients with resistant virus."

Aptivus®, the first non-peptidic protease inhibitor, shows good antiviral activity against viruses that have shown decreased susceptibility to other currently marketed PIs.[3]

The decision to grant full marketing authorisation was taken on the evidence of two large multicentre pivotal trials (RESIST I and II) demonstrating Aptivus® superiority across several efficacy measures to a group of comparator PIs boosted with ritonavir. Treatment response rates over 156 weeks were almost three times higher in the Aptivus® arm compared to the comparator arm (20.9% vs. 7.5%) and were markedly higher for those patients who also started a new class of HIV therapy.[3]

With over 1,400 participants [4] the RESIST trials are one of the largest studies ever of treatment-experienced patients. The data demonstrate that Aptivus® enables treatment-experienced patients to achieve and sustain undetectable viral loads, one of the most important goals of therapy. This efficacy, alongside the acceptable safety profile of Aptivus®, as seen in more than 20.000 patient years of use of Aptivus®, prompted European authorities to remove the 'exceptional circumstances' restriction on the marketing authorisation, previously granted in 2005.

Holger P., a patient from Frankfurt, Germany, who has been treated with nearly all the 22 currently available HIV drugs, said: “This full approval is good news for treatment experienced patients like me. It gives us the confidence that our therapies have passed the rigorous tests demanded of them. With drugs like tipranavir available to us, we can, regardless of our treatment experience, aim for an undetectable viral load."

Attaining an undetectable viral load has been shown in several studies to prolong survival and reduce the risk of AIDS or death by more than 80% in people with HIV that have become resistant to multiple therapies and classes of therapies.[5,6]

About Aptivus®
Aptivus® is a non-peptidic protease inhibitor which works by inhibiting the viral protease, an enzyme needed to complete the HIV replication process. It is approved for combination antiretroviral treatment of HIV-1 infected adults that are highly pre-treated with virus resistant to multiple protease inhibitors.

Based on available clinical and in vitro data, Aptivus® is active against most strains of HIV-1 that are resistant to commercially available protease inhibitors.

Currently, phase II and III studies in paediatric and other populations are fully enrolled and ongoing.

The most commonly reported side effects of at least moderate intensity in patients enrolled in the RESIST studies taking Aptivus® are gastrointestinal, including diarrhoea, nausea, vomiting and abdominal pain. Fever, fatigue, headache, bronchitis, depression and rash also occurred. Elevated transaminase, cholesterol and triglycerides were more frequent in the Aptivus®/r arm than in the ritonavir boosted comparator group but only in a minority of cases treatment discontinuation was necessary.

Aptivus® boosted with low-dose ritonavir has been associated with reports of hepatic adverse events, which have included some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of liver toxicity. The most common moderate to severe laboratory abnormalities were elevated liver enzymes and elevated lipid levels. Most laboratory abnormalities were asymptomatic and most patients were successfully treated without discontinuation.

Aptivus®-containing HAART regimens have been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH) in some highly treatment-experienced patients. Caution should be used when prescribing Aptivus®/r in patients who may be at risk of increased bleeding or who are receiving medications known to increase the risk of bleeding.

Aptivus ® does not cure HIV infection/AIDS or prevent the transmission of HIV to others. Patients may continue to develop opportunistic infections and other complications associated with HIV disease.

Apart from the EU, Aptivus® received U.S. marketing authorization by the FDA and was launched there in June 2005. On Oct 4th, 2007, the FDA granted traditional approval for Aptivus®. Additional marketing authorizations from different countries have been received or are expected.

About Boehringer Ingelheim HIV Clinical Trials
Boehringer Ingelheim is actively conducting clinical trial programs to further evaluate Aptivus® and the non-nucleoside-reverse transcriptase inhibitor (NNRTI) Viramune® for the treatment of HIV-1 infection.

POTENT is a trial comparing the efficacy and safety of Aptivus® (tipranavir) versus darunavir, both with ritonavir as part of combination antiretroviral therapy. POTENT will include 800 treatment-experienced patients in 15 countries. The primary endpoint is time to virologic failure, with a secondary endpoint of virologic response at 48 weeks of treatment.

SPRING study will be one of the largest racially and gender diverse international studies of highly treatment-experienced HIV-1 infected patients. The trial will examine the safety, efficacy and pharmacokinetics of Aptivus® (tipranavir) in a racially diverse group of 200 female and 200 male treatment-experienced patients across eight countries in three continents.

RESIST I, II –two large-scale clinical studies on tipranavir involving more than 1,400 patients (RESIST-I and RESIST-II) formed the foundation of the marketing authorization approval by the EMEA. The RESIST clinical trial program is one of the largest study programs undertaken with an investigational antiretroviral agent in patients previously treated with multiple combinations of antiretroviral drug regimens.

The Viramune® clinical trial program includes the ArTEN trial, which aims to compare the efficacy and safety of Viramune dosed once or twice daily versus atazanavir boosted with ritonavir in HIV-positive antiretroviral-naïve patients.

About Boehringer Ingelheim
Boehringer Ingelheim is committed to the research and development of novel antiretroviral agents. Apart from Aptivus® (tipranavir), Viramune® (nevirapine) is a product of original research done at Boehringer Ingelheim. Viramune® was the first member of the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of anti-HIV drugs on the market. The company is involved in basic research in that area and is committed to improving HIV therapy by providing physicians and patients with innovative antiretroviral treatment options.

References:
[1] Pillay D, Green H on behalf of the UK Collaborative Group on HIV Drug Resistance and the UK Register of HIV Seroconverters, 12th International HIV Drug Resistance Workshop
[2] Rodes B, Garcia F, Gutierrez C, Martinez-Picado J, Aguilera A, Saumoy M, Vallejo A, Domingo P, Dalmau D, Riera M, Blanco JL, Pedreira J, de Mendoza C, Perez-Elias MJ, Vidal F, Leal M, Soriano V. Prevalence of cross-resistance genotypes in treatment-experienced patients. Int Conf AIDS. 2004 Jul 11-16; 15: abstract no. B12107.
[3] Hicks et al. Tipranavir/r (TPV/r) maintains long term virological suppression - Three year follow-up of RESIST; 11th annual European AIDS Conference (EACS); 24-27 October 2007, Madrid, Spain. Abstract number P4.3/70.
[4] Hicks CB, Cahn P, Cooper DA, et al on behalf of RESIST investigator group. Durable efficacy of tripanavir-ritonavir in combination with an optimised background regimen of antiretrovital drugs for treatment experienced HIV-1 infected patients at 48 weeks. Lancet 2006;368:466-475
[5] Zaccarelli M, Tozzi V, Forbici F, et al. Achieving undetectable HIV viral load after genotypic resistance test dramatically decreases HIV progression and survival even in more advanced patients. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 93.
[6] Bracciale L, Colafigli M, Di Giambenedetto S, et al. Reaching undetectable HIV RNA levels is an independent predictor of AIDS-free survival in patients with 3-class resistant HIV-1. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 90.

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