Boehringer Ingelheim

Long-Term Data Show Aptivus(R) (tipranavir) Continues to Outperform Group of Protease Inhibitors in RESIST Trials

Glasgow, Scotland, November 15 (ots/PRNewswire) - - New Sub-analyses Provide Insight into Treatment Benefits New data from the combined RESIST studies (RESIST-1 and RESIST-2) show that Aptivus(R) (tipranavir), used with ritonavir (tipranavir/r) as part of combination antiretroviral therapy, continued to provide a superior and durable treatment response in highly treatment-experienced patients versus a comparator group of protease inhibitors (p<0.001).(1) Further, a sub-analysis shows that tipranavir/r scored higher in quality of life measures compared to other protease inhibitors.(2) These data were presented at the 8th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland. "The RESIST trial continues to provide insight into how to maximize treatment response with APTIVUS/r," said Professor Brian Gazzard, M.A., M.D., FRCP, consultant physician and research director, Department of HIV/GU Medicine, Chelsea Westminster Hospital, London, England. "Data show that APTIVUS provides a durable treatment option through nearly two years of therapy. This is important for this patient population who have limited treatment options." Tipranavir and Long-Term Durability At 96 weeks, tipranavir/r continues to outperform a group of ritonavir-boosted comparator protease inhibitors that include lopinavir/r (Kaletra(R)), amprenavir/r (Agenerase(R)), saquinavir/r (Invirase(R)) and indinavir/r (Crixivan(R)).(1) In the RESIST studies, treatment response was defined as a confirmed 1 log10 or greater decrease in viral load from baseline.(1) When compared to these protease inhibitors: - More than twice the percentage of patients in the tipranavir/r arm responded to treatment: 26.9% vs. 10.9% achieved a viral load below 400 copies/mL; 20.4% vs. 9.1% achieved a viral load of less than 50 copies/mL, p<0.001.(1) - The virologic benefits of a tipranavir-based regimen were enhanced by co-administration of an antiretroviral agent from a new class, in this case enfuvirtide: 34.7% vs. 14.4% of patients taking tipranavir/r combined with first-time enfuvirtide use achieved an undetectable viral load of less than 50 copies/mL, p=0.0002.(1) - Patients taking tipranavir/r combined with first-time enfuvirtide use achieved a greater mean change from baseline (-2.00 log10 copies/mL vs. 0.95 log10 copies/mL)(1) and a larger mean CD4+ cell count increase (102 cells/mm^3 vs. 44 cells/mm^3) than comparator ritonavir-boosted protease inhibitors.(1) Tipranavir/r-Containing Therapy and Quality of Life A 48-week sub-analysis within the RESIST patient population shows that patients treated with tipranavir/r experienced stable or greater improvements in health-related quality of life (HRQOL) in comparison to treatment with lopinavir/r, amprenavir/r, saquinavir/r or indinavir/r.(2) When compared to these protease inhibitors: - Patients receiving tipranavir/r showed positive between group changes for Mental Health Summary (MHS) (+1.47 points; p<0.05), Physician Health Summary (PHS) (+0.99) and ten subscale scores: cognitive Functioning (+1.04), energy/fatigue (+2.43; p<0.05), general health perceptions (+3.53; p<0.05), health distress (+2.93; p<0.05), mental health (+2.78; p<0.05), overall QOL (+2.72; p<0.05), pain (+2.19), physical functioning (+1.89), role functioning (+2.83) and social functioning scores (+1.68).(2) - Patients receiving tipranavir/r reported these health-related quality of life scores despite a higher frequency of treatment-related adverse events (75.0 vs. 56.6 per 100 patient-exposure years).(2) Patients in the tipranavir/r arm experienced a lower rate of non treatment-related adverse events (514.4 vs. 562.8 per patient-exposure years).(2) HRQOL was measured by the Medical Outcomes Study HIV (MOS-HIV) Health Survey, which consists of 35 questions which assess 10 dimensions of health-related quality of life.(3) Susceptibility to Tipranavir/r-Containing Therapy Compared to Lopinavir/r Another 48-week sub-analysis of isolates from patients in the RESIST studies found that a numerically higher percentage of patients who were genotypically lopinavir-sensitive, but had three or more lopinavir score mutations, taking a tipranavir/r-containing regimen achieved undetectable viral loads (less than 50 copies/mL) compared to patients who stayed on a lopinavir/r-containing regimen.(4) All patients had previously been treated with two or more PIs.(4) Results show: - A higher percentage of patients receiving tipranavir/r experienced a decrease in viral load to less than 50 copies/mL vs. patients receiving lopinavir/r (44% vs. 27% in patients with 4-5 lopinavir mutations, p=0.0739;(4) 26% vs. 13% in patients with 6-7 lopinavir mutations, p=0.0603.(4) These findings demonstrate that treatment regimens containing tipranavir/r as part of combination therapy may prevent persistent low-level viraemia (51-100 copies/mL) in genotypically lopinavir-sensitive patients with four or more lopinavir score mutations.(4) Persistent low-level viraemia has been associated with virological failure.(5) "These analyses demonstrate again that an APTIVUS-based regimen can be used to address the critical therapeutic needs of the highly treatment-experienced HIV-positive patient population," said Dr. Andreas Barner, Vice-Chairman, Board of Managing Directors and Head of Corporate Board Division Pharma Research, Development and Medicine, Boehringer Ingelheim. "APTIVUS has already been studied in more than 6,800 patients, and Boehringer Ingelheim remains committed to defining the full clinical utility of APTIVUS in ongoing and planned clinical studies." The tolerability profile of tipranavir/r was similar to that of other ritonavir-boosted protease inhibitors. Gastrointestinal symptom disorders and elevated transaminase, cholesterol and triglyceride levels were more frequent in the tipranavir/r arm than in the comparator-ritonavir arm but necessitated discontinuation of treatment in a minority of cases. Rates of leucopoenia and increased lipase concentrations were more frequent in the comparator ritonavir-boosted protease inhibitor arm. Tipranavir Clinical Trial Programme Boehringer Ingelheim is actively conducting a clinical trial programme to further evaluate tipranavir for the treatment of HIV-1 infection. The tipranavir clinical trial programme is comprised of ongoing and planned studies in more than 1,400 treatment-experienced patients, including paediatric, racially and gender diverse, or hepatitis co-infected patients. About RESIST The RESIST trials are randomised, controlled, open-label, Phase III trials designed to study tipranavir combined with ritonavir versus a group of ritonavir-boosted comparator protease inhibitors. The RESIST clinical trial programme is one of the largest study programs undertaken with an investigational antiretroviral agent in patients previously treated with three classes of antiretrovirals, with Phase II and III data from more than 1,400 patients taking the 500 mg/200 mg dose of tipranavir/r. About Tipranavir Tipranavir is a new 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, tipranavir 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. In studies to date, tipranavir/r 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 tipranavir/r are gastrointestinal, including diarrhoea, nausea, vomiting and abdominal pain. Fever, fatigue, headache, bronchitis, depression and rash also occurred. Gastrointestinal symptom disorders and elevated transaminase, cholesterol and triglycerides were more frequent in the tipranavir/r arm than in the comparator-ritonavir group but necessitated discontinuation of treatment in a minority of cases. Rates of leucopenia and increased lipase concentrations were more frequent in the comparator-ritonavir arm. Gastrointestinal symptom disorders and elevated transaminase, cholesterol and triglycerides were more frequent in the tipranavir/r arm than in the comparator-ritonavir group but necessitated discontinuation of treatment in the minority of cases. Rates of leucopenia and increased lipase concentrations were more frequent in the comparator-ritonavir arm. Tipranavir 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. Tipranavir boosted with low-dose ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Caution should be used when prescribing tipranavir/r in patients who may be at risk of increased bleeding or who are receiving medications known to increase the risk of bleeding. Tipranavir 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, tipranavir has received U.S. marketing authorization by the FDA and was launched there in June 2005. Additional marketing authorizations from different countries have been received or are expected. Boehringer Ingelheim Boehringer Ingelheim is committed to the research and development of novel antiretroviral agents. Apart from Aptivus(R) (tipranavir), Viramune(R) (nevirapine) is a product of original research done at Boehringer Ingelheim. nevirapine 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. For more information on Boehringer Ingelheim HIV Franchise, please see http://www.boehringer-ingelheim.com/hiv. References: (1) Gazzard et al. Combined analysis of RESIST 96-week data: durability and efficacy of tipranavir/r in treatment-experienced patients; 8th International Congress on Drug Therapy in HIV Infection; 12-16 November 2006, Glasgow, UK. Poster P23. (2) Wu et al. Health-related quality of life and tolerability of patients treated in RESIST; 8th International Congress on Drug Therapy in HIV Infection; 12-16 November 2006, Glasgow, UK. Poster P25. (3) Wu A Mos-HIV Health Survey Users Manual 1999. (4) Walmsley et al. Better Treatment Response To Tipranavir/r Compared to Lopinavir/r in Patients with Higher Lopinavir Mutation Scores; 8th International Congress on Drug Therapy in HIV Infection; 12-16 November 2006, Glasgow, UK. Poster P197. (5) Sungkanuparph S, Groger RK, Overton ET, Fraser VJ, Powderly WG. Persistent low-level viraemia and virological failure in HIV-1- infected patients treated with highly active antiretroviral therapy. HIV Medicine 2006; 7: 437-441. Prescribing Information (UK) APTIVUS Capsules containing 250mg tipranavir. Action: non-peptidic protease inhibitor. Indication: co-administered with low dose ritonavir, for combination antiretroviral treatment of HIV-1 infection in highly pre-treated patients with virus resistant to multiple protease inhibitors. Dose & administration: Adults only. 500mg co-administered with 200mg ritonavir twice daily with food. Contra-indications: Hypersensitivity to any component. Moderate or severe hepatic impairment. Co-administration with rifampicin, St John's wort, active substances highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g. amiodarone, flecainide, propafenone, quinidine, astemizole, terfenidine, ergometrine, ergotamine, cisapride, pimozide, triazolam, simvastatin, lovastatin). Warnings & precautions: The elderly- limited data available. Monitor liver function before initiation, after 2, 4, and 8 weeks, and then every 8-12 weeks. For patients with elevated AST or ALT, mild hepatic impairment, chronic hepatitis B or C, or other underlying liver disease, monitor every 2 weeks during the first 3 months and then monthly. Do not initiate if AST or ALT > 5x ULN. Discontinue permanently if AST or ALT > 10 x ULN, or patient develops signs or symptoms of clinical hepatitis. Haemophiliac patients should be warned of the possibility of increased bleeding. Use with caution in patients at an increased risk of bleeding. Monitor triglyceride and cholesterol before and during therapy. Clinical examination should include evaluation for physical signs of fat redistribution. An inflammatory reaction to asymptomatic or residual opportunistic infections may arise on initiation of CART. Interactions: see SPC. The interaction profile of Aptivus with low-dose ritonavir is complex and includes interaction with other antiretroviral agents. Pregnancy and lactation: No relevant data available. Undesirable effects: Serious reactions include hepatitis (uncommon) and, rarely, hepatic failure (including fatal outcome). Increased risk of bleeding. Cases of ICH reported, some cases fatal. Common/ very common: hypertriglyceridaemia, hyperlipidaemia, anorexia; headache; diarrhoea, nausea, vomiting, flatulence, abdominal distension, abdominal pain, loose stools, dyspepsia; rash, pruritus; fatigue. Uncommon/rare reactions include anaemia, neutropenia, thrombocytopenia; hypersensitivity; metabolism & nutrition disorders (e.g. diabetes mellitus, hypercholesterolaemia, facial wasting); insomnia, sleep disorder; dizziness, peripheral neuropathy, somnolence; dyspnoea; gastrooesophageal reflux disease, pancreatitis; exanthema, lipoatrophy, acquired lipodystrophy, lipohypertrophy; muscle cramp, myalgia; renal insufficiency; influenza like illness, malaise, pyrexia. See SPCs for other undesirable effects. Pack sizes and NHS price: 120 capsules 490.00 pounds Sterling. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, 55216 Ingelheim am Rhein, Germany. MA number: EU/1/05/315/001. For full prescribing information please see Summary of Product Characteristics for Aptivus and for ritonavir. Prepared in October 2006. Adverse events should be reported to Boehringer Ingelheim Drug Safety on 0800-328-1627 (freephone). Information about adverse event reporting can be found at http://www.yellowcard.gov.uk SPC ref: A2/UK/SPC/3 ots Originaltext: Boehringer Ingelheim Im Internet recherchierbar: http://www.presseportal.ch Contact: Judith von Gordon, CD Communications, Boehringer Ingelheim GmbH, +49-6132-773582, Fax: +49-6132-776601

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