PRESS RELEASE: Boehringer Ingelheim Corporation's Aptivu Capsules Granted Full Approval by the U.S. FDA

Boehringer Ingelheim Corporation's Aptivu Capsules Granted Full Approval by the U.S. FDA

RIDGEFIELD, Conn., Oct. 5 -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) granted full (traditional) approval of Aptivus® (tipranavir) capsules. The FDA granted accelerated approval to APTIVUS in June 2005; accelerated approval is a regulatory process that expedites the approval of therapies for serious or life-threatening illnesses. The full approval of APTIVUS is based largely on 48-week analyses of the Phase 3 pivotal clinical studies known as the RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir) trials. These trials comprise one of the largest study programs conducted in treatment-experienced HIV patients.

"Data show that APTIVUS/r may provide treatment-experienced HIV patients with an effective treatment option through nearly one year of therapy. Furthermore, longer-term safety data are now available for physician and patient consideration," said Dr. Daniel Kuritzkes, associate professor of medicine, Harvard Medical School; director of AIDS research, Brigham and Women's Hospital, Boston, MA.

APTIVUS, a protease inhibitor, co-administered with 200 mg of ritonavir (APTIVUS/r), is indicated for combination antiretroviral treatment of HIV-1 infected adult patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor.

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/r of 48 weeks duration. Both studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with APTIVUS/r:

-- The use of APTIVUS/r in treatment-naïve patients is not recommended.

-- The use of other active agents with APTIVUS/r is associated with a greater likelihood of treatment response.

-- Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/r. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/r.

-- Use caution when prescribing APTIVUS/r to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment.

-- Liver function tests should be performed at initiation of therapy with APTIVUS/r and monitored frequently throughout the duration of treatment.

-- The drug-drug interaction potential of APTIVUS/r when co-administered with other drugs must be considered prior to and during APTIVUS/r use.

-- Use caution when prescribing APTIVUS/r in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding.

-- The risk-benefit of APTIVUS/r has not been established in pediatric patients.

There are no study results demonstrating the effect of APTIVUS/r on clinical progression of HIV-1.

APTIVUS/r does not cure HIV or help prevent passing HIV to others.

About RESIST

The RESIST clinical trial program consists of two ongoing Phase 3 pivotal trials, RESIST-1 and RESIST-2. Comprising one of the largest study programs conducted in treatment-experienced HIV patients, RESIST-1 includes 620 patients in the U.S., Canada and Australia, and RESIST-2 includes 863 patients in Europe and Latin America. The trial design and baseline patient characteristics are similar across studies. Patients enrolled in the RESIST studies were failing their current PI-based regimen, had received at least two previous PI-based regimens, had received prior treatment from at least three classes of antiretroviral agents and had documented PI resistance.

At the time of full approval, the studies examined treatment response, defined as a confirmed 1 log10 or greater decrease in the amount of HIV in the blood, or viral load, at 48 weeks versus a comparator group in which patients received one of several marketed ritonavir-boosted PIs. Investigators selected a comparator PI (CPI/r) that offered patients the best opportunity for treatment response based on resistance testing. The comparator PIs were lopinavir, indinavir, saquinavir and amprenavir. In addition, patients in both arms received an optimized background regimen of other antiretroviral drugs. Patients were treatment-experienced and the majority (85.1%) were at least possibly resistant to the comparator PI chosen.

Analysis of the primary endpoint at week 48 demonstrated that more than twice the percentage of patients (33.8%) treated with APTIVUS/r achieved a treatment response compared to those patients treated with a CPI/r (14.9%). The median change from baseline in HIV-1 viral load at the last measurement up to week 48 was -0.64 log10 copies/mL in APTIVUS/r patients versus -0.22 log10 copies/mL in CPI/r patients.

Secondary endpoints included reduction in viral load to less than 400 copies/mL or 50 copies/mL and increase in CD4+ cell count. Through 48 weeks of treatment, more than twice the percentage of patients in the APTIVUS/r arm achieved a viral load of less than 400 copies/mL (30.3%) compared to the CPI/r arm (13.6%). Regarding a viral load of less than 50 copies/mL, 22.7% of APTIVUS/r patients achieved this level compared to 10.2% of CPI/r patients. The median change from baseline in CD4+ cell count at the last measurement up to week 48 was +23 cells/mm3 in APTIVUS/r patients (n=740) versus +4 cells/mm3 in CPI/r patients (n=727).

According to HIV treatment guidelines, achieving and maintaining an undetectable viral load -- less than 50 copies/mL of blood -- is the goal of HIV therapy.(1)

The APTIVUS labeling includes boxed warnings for reports of: -- Clinical hepatitis and hepatic decompensation including 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 hepatotoxicity. -- Both fatal and non-fatal intracranial hemorrhage (ICH).

The most commonly reported adverse events in patients taking APTIVUS/r are diarrhea, nausea, fever, vomiting, fatigue, headache and abdominal pain. The most common laboratory abnormalities are elevated liver enzymes (AST/ALT) and triglycerides.

"For more than a decade, Boehringer Ingelheim has been at the forefront of developing innovative therapies for HIV patients. The full approval of APTIVUS further demonstrates our commitment to HIV/AIDS," said Dr. Thor Voigt, Senior Vice President, Medicine and Drug Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We have developed a robust clinical trial program around APTIVUS. In addition to RESIST, clinical trials for treating HIV are in progress in racially, ethnically and gender diverse patients and hepatitis co-infected patients. A trial comparing the efficacy and safety of APTIVUS/r versus darunavir/r, both as part of combination antiretroviral therapy, is also planned."

Important Safety Information for APTIVUS -- APTIVUS/r has been associated with reports of clinical hepatitis and hepatic decompensation, including 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 hepatotoxicity. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/r treatment and seek medical evaluation. -- APTIVUS/r has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). -- All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co- infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/r, and frequently throughout the duration of treatment. -- Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In the RESIST trials, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) of patients receiving APTIVUS/r through week 48. In a study of treatment-naïve patients, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/r through week 48. -- APTIVUS/r is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. -- The drug-drug interaction potential of APTIVUS/r when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/r use. -- APTIVUS/r is contraindicated with amiodarone, bepridil, flecainide, propafenone, quinidine, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's wort, lovastatin, simvastatin, pimozide, midazolam and triazolam due to the potential for serious and/or life-threatening events or loss of efficacy. -- A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures. Concomitant use of APTIVUS/r and fluticasone propionate may produce systemic corticosteroid side effects, including Cushing's syndrome and adrenal suppression. APTIVUS/r should not be taken with fluticasone propionate, inhaled or intranasally administered, unless the potential benefit to the patient outweighs the risk. -- Caution should be used when prescribing sildenafil, tadalafil, and vardenafil with APTIVUS/r because concentrations of these drugs may increase. -- Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentrations. -- Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentrations. -- Use caution when prescribing APTIVUS/r in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E. In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/r. In rats, co-administration with vitamin E increased the bleeding effects of tipranavir. -- Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in patients receiving APTIVUS/r. In some, rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled clinical trials, rash (all grades, all causality) was observed in 10% of females and in 8% of males receiving APTIVUS/r through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5%. In an uncontrolled compassionate use program (n=3,920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. Discontinue and initiate appropriate treatment if severe skin rash develops. -- APTIVUS should be used with caution in patients with a known sulfonamide allergy. -- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia and increased bleeding (in patients with hemophilia) have been reported in patients taking protease inhibitors. A causal relationship between protease inhibitors and these events has not been established. -- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including APTIVUS/r. -- Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy. A causal relationship has not been established. -- Treatment with APTIVUS/r has resulted in large increases in total cholesterol and triglycerides, which should be monitored prior to and during APTIVUS/r therapy. -- Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in APTIVUS/r-treated patients, it is unknown what effect therapy with APTIVUS will have on the activity of subsequently administered protease inhibitors. -- APTIVUS must be co-administered with 200 mg of ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions. -- Please refer to the complete ritonavir prescribing information for a description of ritonavir contraindications and additional information on precautionary measures. -- In clinical trials, the most frequently reported adverse events associated with APTIVUS/r were diarrhea, nausea, fever, vomiting, fatigue, headache and abdominal pain.

Please see full Prescribing Information (PI), including boxed WARNINGS, for APTIVUS at www.APTIVUS.com [1]. The PI is in the new Physicians Labeling Rule (PLR) format required by the U.S. FDA.

Additional Information about APTIVUS

APTIVUS, a non-peptidic protease inhibitor, works by inhibiting protease, an enzyme needed to complete the HIV replication process. The approved dose of APTIVUS is 500 mg taken with 200 mg of ritonavir, twice daily.

APTIVUS is also approved in Argentina, Australia, Canada, Switzerland, Mexico, Iceland, Taiwan and the European Union.

Boehringer Ingelheim is actively conducting a clinical trial program to further evaluate APTIVUS for the treatment of HIV-1 infection. The program is comprised of ongoing and planned studies in more than 1,000 HIV-infected patients.

About Boehringer Ingelheim

Boehringer Ingelheim is committed to improving HIV therapy by providing physicians and patients with innovative antiretroviral agents.

For more information on Boehringer Ingelheim Pharmaceuticals, Inc., please visit http://us.boehringer-ingelheim.com [2]. (1) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents, October 10, 2006; Treatment for Adult HIV Infection. 2006 Recommendations of the International AIDS Society - - USA Panel. JAMA. 296(7): 837. August 16, 2006.