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EU Commission Approves Aptivus (Tipranavir) for Treatment of HIV

New drug shown to be effective in treating multi-drug resistant HIV patients

INGELHEIM, GERMANY -- October 26, 2005 -- Boehringer Ingelheim today announced that it has received authorization from the European Commission to market Aptivus(R) (tipranavir) for the treatment of HIV in combination with other antiretroviral agents.

Aptivus, a non-peptidic protease inhibitor, co-administered with low-dose ritonavir is indicated for combination antiretroviral treatment of HIV-1 infection in highly pre-treated adult patients with virus resistant to multiple protease inhibitors (PIs). This authorization was based on exceptional circumstances given that HIV/AIDS is a life threatening illness with a need for rapid access to new treatment options.

The approved dose of Aptivus is 500 mg taken with 200 mg of ritonavir, twice daily. Co-administration with ritonavir is required and "boosts" the therapeutic levels of Aptivus. Aptivus 250 mg soft gel capsules will become available in the various countries of the European Union as soon as the necessary pricing and reimbursement approvals have been achieved. Aptivus was approved for use in the U.S. on 22 June 2005, in Mexico on 19 July 2005, and in Switzerland on 26 August 2005, and is currently under review by further regulatory agencies.

Aptivus works by blocking protease, an enzyme needed to complete the HIV replication process. Aptivus is able to enter infected immune cells and inhibit HIV replication for many strains of HIV that are resistant to other commercially available PIs.

In two large-scale clinical trials, Aptivus was shown to be effective in treating HIV patients whose virus has developed resistance to other therapies. These studies showed that Aptivus was more effective in treating drug resistant HIV than other commonly used ritonavir-boosted PIs, including Kaletra(R) (lopinavir/r), Invirase(R) (saquinavir), Agenerase(R) (amprenavir) and Crixivan(R) (indinavir).1

"With the advent of drugs to treat HIV, patients are living longer. However, they continue to face challenging health issues, such as the development of resistance to available anti-HIV drugs," said Dr. Andreas Barner, member of the Board of Managing Directors of Boehringer Ingelheim and responsible for Research, Development and Medicine. "The research and development of innovative new therapies such as Aptivus is imperative for the successful treatment of HIV and we are proud that Aptivus is a significant breakthrough for the many patients who need an effective new treatment option to help manage their disease."

Drug resistance is one of the major challenges that patients and physicians face in the treatment of HIV. Resistance develops when the virus mutates and is no longer suppressed by drugs that were once effective. A recent 6-year study demonstrated a high prevalence of drug-resistant virus in a European cohort of patients under treatment for HIV-1 infection.2 Additionally, U.K. data indicate that transmission of drug-resistant virus is on the rise.3

Pivotal Data
Data from two large-scale clinical studies on tipranavir involving more than 1,400 patients (RESIST-1 and RESIST-2) formed the foundation of the marketing authorization approval by the EMEA. These trials examined the treatment response of Aptivus boosted with ritonavir versus a comparator group in which patients received one of several marketed ritonavir-boosted PIs. Investigators selected a comparator PI that offered patients the best opportunity for treatment response based on resistance testing and their prior treatment history. The comparator PIs were lopinavir, indinavir, saquinavir and amprenavir. In addition, patients in both arms received an optimized background regimen of other antiretroviral drugs.

The results of the RESIST studies demonstrated that a statistically significant greater percentage of HIV-positive patients taking Aptivus boosted with ritonavir achieved a treatment response versus the comparator group (40% vs. 18%). Treatment response was defined as a confirmed 1 log10 or greater decrease in viral load from baseline.

In addition, a significantly greater proportion of patients receiving regimens that contain boosted Aptivus were able to reduce the amount of HIV in their blood to undetectable levels than in the boosted comparator group (<400 copies/ml: 34% vs. 15%). Patients treated with Aptivus boosted with ritonavir also experienced greater increases in their immune cells than those treated with a ritonavir-boosted comparator PI (34 cells vs. 4).

Aptivus(R)
Aptivus, a new non-peptidic protease inhibitor, works by inhibiting protease, an enzyme needed to complete the HIV replication process. 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. The safety and efficacy of Aptivus in paediatric patients or in adult patients who have not previously taken anti-HIV medications have not been established. Phase 2 and 3 studies in these populations are fully enrolled and ongoing.

In studies to date, Aptivus has been well tolerated by most patients and has a safety profile similar to other PIs. The most commonly reported side effects of at least moderate intensity in patients enrolled in the RESIST studies taking Aptivus/r are gastrointestinal, including diarrhoea, nausea, vomiting and abdominal pain. Fever, fatigue, headache, bronchitis, depression and rash also occurred.

Aptivus boosted with low-dose ritonavir has been associated with reports of hepatic adverse events, which have included some fatalities. 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 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.

REFERENCES:
1. Kaletra, Invirase, Agenerase and Crixivan are registered trademarks of Abbott Laboratories, Hoffmann-La Roche Inc., GlaxoSmithKline and Merck & Co, respectively.
2. Tamalet, C, Fantini, J, Tourres C, Yahi N. Resistance of HIV-1 to multiple antiretroviral drugs in France: a 6-year survey (1997-2002) based on an analysis of over 7000 genotypes. AIDS 2003; 17(16): 2383-8.
3. Commun. Dis Rep. CDR Weekly online 2004; 14.


SOURCE: Boehringer Ingelheim GmbH

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