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U.S. FDA Approves New Anti-HIV Drug Aptivus For Use In Combination Therapy

RIDGEFIELD,CT -- June 23, 2005 -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Aptivus (tipranavir) capsules.

Accelerated approval is a regulatory process that expedites the approval of therapies for serious or life-threatening illnesses that provide meaningful benefit to patients over existing treatments.

This approval is based on 24-week data from ongoing studies. Longer-term data will be needed before FDA can consider traditional approval for Aptivus. There are no study results demonstrating the effect of Aptivus on clinical progression of HIV-1.

The approved dose of Aptivus is 500 mg taken with 200 mg of ritonavir (Aptivus/r), twice daily. Aptivus must be co-administered with ritonavir to boost the therapeutic levels of Aptivus; otherwise, levels of Aptivus will be insufficient to inhibit HIV replication. Aptivus/r must be taken in combination with other anti-HIV medications. Aptivus 250 mg soft gel capsules will begin to be available in pharmacies nationwide within two weeks of FDA approval.

Aptivus is a non-peptidic protease inhibitor that works by inhibiting 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 protease inhibitors (PI).

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.

"The prevalence of drug resistant HIV underscores the need for new treatments," said Dr. Daniel Kuritzkes, Associate Professor of Medicine, Harvard Medical School, Director of AIDS Research, Brigham and Women's Hospital. "Aptivus offers an important new treatment option to highly treatment-experienced patients or those with multiple protease inhibitor resistant virus."

Aptivus (tipranavir), co-administered with 200 mg of ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of Aptivus of 24 weeks duration. Both studies were conducted in clinically advanced, 3-class antiretroviral treatment-experienced adults with evidence of HIV 1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with Aptivus/ritonavir:
1. The use of other active agents with Aptivus/ritonavir is associated with a greater likelihood of treatment response.
2. Genotypic or phenotypic testing and/or treatment history should guide the use of Aptivus/ritonavir. The number of baseline primary protease inhibitor mutations affects the virologic response to Aptivus/ritonavir.
3. Liver function testing should be performed at initiation of therapy with Aptivus/ritonavir and monitored frequently throughout the duration of treatment. Use caution when prescribing Aptivus/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or other underlying hepatic impairment.
4. The extensive drug-drug interaction potential of Aptivus/ritonavir when co-administered with multiple classes of drugs must be considered prior to and during Aptivus/ritonavir use.
5. The risk-benefit of Aptivus/ritonavir has not been established in treatment-naïve adult patients or pediatric patients.

Pivotal Data
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. These trials examined the treatment response at 24 weeks of Aptivus/r 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. 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 in these trials were highly treatment-experienced and the majority were at least possibly resistant to the comparator PI chosen. The median baseline viral load and CD4+ count were 4.82 log10 copies/mL and 155 cells/mm3, respectively.

The results of the RESIST studies showed that a statistically significant greater percentage of HIV-positive patients taking Aptivus/r 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. At 24 weeks, 34% of patients in the Aptivus/r group and 16% of patients in the boosted comparator group achieved a viral load of less than 400 copies/mL, and 23% vs. 9% achieved less than 50 copies/mL.

Patients treated with Aptivus/r also experienced greater increases in their immune cells than those treated with a ritonavir-boosted comparator PI. The median change from baseline in CD4+ cell count at week 24 was +34 cells/mm3 in patients receiving Aptivus/r (n=582) versus +4 cells/mm3 in the comparator group of ritonavir-boosted PIs (n=577).

"The approval of Aptivus marks an important milestone in Boehringer Ingelheim's long-standing commitment to the HIV community," said Burkhard Blank, MD, Senior Vice President, Medical and Drug Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "Our HIV research and development program is dedicated to bringing innovative HIV therapies to patients and their healthcare providers."

Safety Information
Aptivus co-administered with 200 mg ritonavir 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. All patients should be followed closely with clinical and laboratory monitoring. Liver function tests should be performed prior to initiating therapy with Aptivus/r and frequently throughout the duration of treatment. Patients who develop symptoms of liver problems, such as fatigue, loss of appetite, yellowing of the eyes or skin, or liver tenderness, should stop taking Aptivus/r treatment. Patients with moderate to severe hepatic insufficiency should not take Aptivus/r.

Aptivus/r has an effect on the way some medications are eliminated by the body, and if these medications are combined with Aptivus/r, an elevation of their level may occur, which can lead to serious and/or life-threatening side effects. This concern is due to the extensive drug-drug interaction potential of Aptivus/r. Some medications from the following drug classes must not be taken with Aptivus/r: antiarrhythmics, antihistamines, ergot derivatives, GI motility agents, neuroleptics and sedatives/hypnotics.

Other medications taken with Aptivus/r may require a dose adjustment or additional monitoring, including those in the following classes: reverse transcriptase inhibitors, protease inhibitors, antifungals, antimycobacterials, calcium channel blockers, antidepressants, HMG-CoA reductase inhibitors, hypoglycemics, immunosuppressants, narcotic analgesics, estrogens, PDE5 inhibitors, anticoagulants, antibiotics, and drugs to treat alcohol dependence. Patients should discuss the potential for drug interactions with their healthcare provider.

Aptivus, a sulfa-containing drug, should be used with caution in patients with a known sulfa allergy. Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in subjects receiving Aptivus/r. In Phase 2 and 3 trials rash was observed in 14% of females and in 8-10% of males receiving Aptivus/r. Additionally, in one drug interaction trial in healthy female volunteers who were administered a single dose of ethinyl estradiol followed by Aptivus/r, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized itching has been reported in both men and women receiving Aptivus/r. Women taking estrogen-containing medications with Aptivus/r have an increased risk of developing a rash.

Like other protease inhibitors, Aptivus/r may be associated with the development or worsening of diabetes, elevations in cholesterol and triglycerides, abnormal distribution of body fat, immune-related inflammatory response to infections and increased bleeding in hemophiliacs.

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. There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. Aptivus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The long-term effects of Aptivus are unknown at this time.

The most commonly (>/= 2%) reported side effects of at least moderate intensity in patients enrolled in the RESIST studies taking Aptivus/r are gastrointestinal, including diarrhea (10.9%), nausea (6.7%), vomiting (3.4%), and abdominal pain (2.8%). Fever (4.6%), fatigue (4%), headache (3.1%), bronchitis (2.9%), depression (2%), and rash (2%) also occurred. The most common (>/= 2%) moderate to severe laboratory abnormalities in patients enrolled in the RESIST studies taking Aptivus/r are elevated triglycerides (45.1%), elevated liver enzymes (17.5%), elevated cholesterol (14.6%), decreased white blood cell count (3.6%), and elevated amylase (2.9%).

Ongoing Clinical Trials
Boehringer Ingelheim is committed to further understanding the clinical utility of Aptivus for the treatment of HIV. Ongoing studies will continue to evaluate the safety and efficacy of Aptivus. The safety and efficacy of Aptivus in pediatric patients or in treatment-naïve adults have not been established. Phase 2 and 3 studies in these populations are fully enrolled and ongoing. In addition, Boehringer Ingelheim will continue to study Aptivus in women and hepatitis co-infected patients, and conduct further pharmacokinetic interaction studies of the drug.


SOURCE: Boehringer Ingelheim Pharmaceuticals, Inc.

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