Boehringer Ingelheim Announces 48-week Results from Tipranavir RESIST Studies

The US Food and Drug Administration (FDA) approved the HIV protease inhibitor (PI) Aptivus (tipranavir) in June 2005 for use in combination with the PI ritonavir (Norvir) among adult HIV patients who have active HIV replication, have used other anti-HIV medications or who show evidence of HIV strains that are resistant to multiple protease inhibitors. Tipranavir/ritonavir in combination should be used in combination with other active anti-HIV agents to produce a greater likelihood of a robust treatment response.

New data on tipranavir from a 48-week combined analysis of the RESIST-1 and RESIST-2 studies were presented recently at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, CO (February 5-8, 2006).

The RESIST trials are randomized, controlled, open-label Phase 3 trials designed to study APTIVUS combined with ritonavir (APTIVUS/r) versus a group of ritonavir-boosted comparator protease inhibitors (CPI/r) in patients previously treated with all three classes of antiretroviral agents.  Patients enrolled in the RESIST studies had received at least two previous PI-based regimens and were failing a PI-based regimen at the time of study entry.

APTIVUS/r and the ritonavir-boosted comparator PIs were taken in conjunction with other anti-HIV agents as part of combination antiretroviral therapy.  CPIs included lopinavir, saquinavir (Invirase), amprenavir (Agenerase) and indinavir (Crixivan).  All patients had

baseline genotypic resistance testing prior to randomization to aid investigators in the selection of the CPI/r.  Of these highly treatment-experienced patients in the RESIST trials, the majority (86%) were at least possibly resistant to the CPI/r chosen.

In this 48-week combined analysis of RESIST-1 and RESIST-2, 33.6% of patients taking APTIVUS/r achieved a treatment response vs. 15.3% of patients in the CPI/r group (p<0.0001). 

In the RESIST studies, treatment response was defined as a confirmed 1 log10 or greater decrease in viral load from baseline.  With regard to viral load, 30.4% of patients in the APTIVUS/r arm were able to reduce the amount of HIV present in their blood (viral load) to <400 copies/mL versus 13.8 % in the CPI/r group (p<0.0001). 

Treatment with APTIVUS/r also increased the mean amount of immune (CD4+ cells by 45 cells/mm3 compared to 21 cells/mm3 in the CPI/r group.  The median time to treatment failure was 113 days in the APTIVUS/r arm and 0 days in the CPI/r group (p<0.0001).

Data from this combined analysis were stratified by baseline CD4+ cell count and baseline viral load:

Treatment response stratified by baseline CD4+ cell count

Treatment response stratified by baseline viral load

“A challenge for treatment of HIV is to find compounds that can affect virologic and immunologic response in patients with virus that is resistant to multiple protease inhibitors,” said Christine Katlama, M.D., Hôpital Pitié-Salpêtrière, Paris, France.  “The 48-week results from the Aptivus combined analysis are encouraging.  Ongoing analyses of the combined studies are designed to confirm these initial results.”

The most commonly reported adverse events in patients taking APTIVUS/r are gastrointestinal-related and include diarrhea, nausea, fatigue, headache and vomiting.  The most common laboratory abnormalities are elevated liver enzymes (AST/ALT) and triglycerides.  The APTIVUS label includes a boxed warning for hepatic events.

About RESIST

The RESIST clinical trial program consists of two Phase 3 pivotal trials, RESIST-1 and RESIST-2.  Comprising one of the largest study programs conducted in highly treatment-experienced HIV patients, RESIST-1 was conducted in 620 patients in the U.S., Canada and Australia, and RESIST-2 was conducted in 863 patients in Europe and Latin America. 

The trial design and baseline patient characteristics were 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.

The studies examined the treatment response at 48 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 (Kaletra), indinavir, saquinavir and amprenavir.  In addition, patients in both arms received an optimied background regimen of other antiretroviral drugs.  Patients in these trials were highly treatment-experienced and the majority (86%) were at least possibly resistant to the comparator PI chosen.

More about Aptivis (tipranavir)

APTIVUS, a non-peptidic protease inhibitor, works by inhibiting protease, an enzyme needed to complete the HIV replication process.  The U.S. Food and Drug Administration (FDA) granted accelerated approval of APTIVUS (tipranavir) capsules on June 22, 2005.  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 using surrogate endpoints.  The long-term effects of APTIVUS/r therapy are not confirmed at this time. 

Longer term data will be needed before FDA can consider traditional approval for APTIVUS.

APTIVUS is also approved in Canada, Switzerland, Mexico, Iceland and the European Union.  The European Commission granted marketing authorization for APTIVUS on October 25, 2005.

APTIVUS Indications and Usage

APTIVUS, 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/r of 24 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 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.

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

·         Use caution when prescribing APTIVUS/r to patients with elevated transaminases, coinfection with HIV-HBV or HIV-HCV co-infection or other underlying hepatic impairment.

·         The extensive 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.

·         The risk-benefit of APTIVUS/r has not been established in treatment-naïve adult patients or pediatric patients.

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

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

Important Safety Information for APTIVUS

APTIVUS must be taken with 200 mg of ritonavir and always at the same time as ritonavir, to have a therapeutic effect.  Please refer to the complete ritonavir (Norvir) prescribing Information for additional information on precautionary measures.

·         Patients taking APTIVUS, together with 200 mg of ritonavir, may develop severe liver disease that can cause death; some fatalities have occurred. 

·         Patients with chronic hepatitis B or C co-infection have an increased chance of developing liver problems.  These patients require close clinical monitoring and should have their healthcare providers check their blood more often.

·         Patients who are allergic to any of the ingredients of APTIVUS should not take the drug.

·         APTIVUS/r should not be taken by patients with moderately or severely reduced liver function.

·         APTIVUS/r must not be taken with amiodarone, bepridil, flecainide, propafenone, quinidine, astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, or triazolam, due to the potential for serious and/or life-threatening events.  Caution should be used when taking APTIVUS/r with drugs to treat impotence, including sildenafil, tadalafil or vardenafil because blood levels of these drugs may increase.  Taking APTIVUS/r with rifampin, St. John’s wort, lovastatin, or simvastatin is not recommended.  This list of medications is not complete.

·         A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures.  Concomitant use of APTIVUS/ritonavir and fluticasone propionate may produce systemic corticosteroid side effects, including Cushing's syndrome and adrenal suppression.  APTIVUS/ritonavir should not be taken with fluticasone propionate, inhaled or intranasally administered, unless the potential benefit to the patient outweighs the risk. 

·         Failure to take APTIVUS with and at the same time as ritonavir will result in reduced blood levels of tipranavir.  Reduced levels of tipranavir will not be able to achieve the desired anti-HIV effect and will alter some interactions with other drugs.

·         Patients’ health should be monitored closely by their healthcare professionals when taking APTIVUS/r, especially those with chronic hepatitis B or C co-infection.  Patients with elevated liver enzyme levels are also at increased risk for developing serious liver problems.  Patients should have their healthcare professional check their liver function prior to initiating and frequently throughout therapy with APTIVUS/r.

·         If any of the following symptoms of liver problems develop, patients should stop taking APTIVUS/r treatment and call their healthcare professional right away: tiredness, general ill feeling or “flu-like” symptoms, loss of appetite, nausea, yellowing of the skin or whites of the eyes, dark urine, pale stools, or pain, ache, or sensitivity on the right side below the ribs.

·         APTIVUS and many other medicines can interact.  Patients should discuss all medications they are taking or plan to take with their healthcare professional or pharmacist prior to and during APTIVUS/r use.

·         New onset or the worsening of existing diabetes and high blood sugar have occurred in patients taking protease inhibitors.  Some patients with hemophilia have experienced increased bleeding when treated with protease inhibitors.  A cause and effect relationship between protease inhibitors and these events has not been established.

·         Patients with an allergy to sulfa drugs should use APTIVUS with caution.

·         Mild to moderate rashes, sometimes with other symptoms, and possible sun allergy have occurred in patients 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.  Women using estrogens may have an increased risk of rash.  In one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by APTIVUS/r, 33% of subjects developed a rash.

·         Patients taking APTIVUS/r have experienced large increases in total cholesterol and triglyceride levels, which should be monitored prior to and during APTIVUS/r therapy.

·         Changes in body fat have been seen in patients taking HIV therapy.  A cause and effect relationship between HIV treatment and body fat changes has not been established.

·         Patients have experienced an inflammatory reaction upon taking HIV therapy, including APTIVUS/r, as their immune system begins to improve.  These reactions may necessitate further evaluation and treatment.

·         In clinical trials, the most frequently reported adverse reactions associated with APTIVUS/r were diarrhea, nausea, fatigue, vomiting, and headache.

For full prescribing information, including boxed WARNING for APTIVUS, please visit www.APTIVUS.com.

Boehringer Ingelheim

For more information on Boehringer Ingelheim Pharmaceuticals, Inc.

02/10/06

Source
Boehringer Ingelheim. Boehringer Ingelheim Announces 48-week Results from Aptivus^® (tipranavir) RESIST Studies. Press Release. February 9, 2006.