PREZISTA Receives U.S. FDA Approval As Part Of HIV Combination Therapy

Bridgewater, NJ - The U.S. Food and Drug Administration (FDA) has granted accelerated approval to the anti-HIV medication PREZISTA™ (darunavir) tablets. PREZISTA, a protease inhibitor previously known as TMC114, was developed by Tibotec Pharmaceuticals Ltd. and will be marketed in the U.S. by Tibotec Therapeutics, a division of Ortho Biotech Products, L.P.

FDA accelerated approval procedures allow for earlier approval of drugs that provide a meaningful therapeutic advantage over existing treatment for serious or life-threatening diseases. This approval is based on the 24-week analysis of HIV viral load and CD4+ cell counts from the pooled analysis of the TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2) studies. Longer-term data will be required before the FDA can consider traditional approval for PREZISTA.

"One of the greatest challenges in HIV care is finding therapies for treatment-experienced patients," said Michael S. Saag, M.D., director of the AIDS Outpatient Clinic and the University of Alabama at Birmingham Center for AIDS Research. "This is an important new option for the thousands of people with HIV in the United States who are resistant to more than one protease inhibitor."

PREZISTA, co-administered with 100 mg ritonavir (PREZISTA/rtv) and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.

This indication is based on Week 24 analyses of plasma HIV RNA levels and CD4+ cell counts from two controlled trials of PREZISTA/rtv in combination with other antiretroviral drugs. Both studies were conducted in clinically advanced, treatment-experienced (NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with PREZISTA/rtv:

• Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/rtv.
  
• The use of other active agents with PREZISTA/rtv is associated with a greater likelihood of treatment response.

• The risks and benefits of PREZISTA/rtv have not been established in treatment-naïve adult patients or pediatric patients.

"The Fair Pricing Coalition believes that Tibotec Therapeutics has priced PREZISTA responsibly. This is a particularly thoughtful move on the company's part since it recognizes the crisis in funding faced by payers in and out of government," said Martin Delaney, on behalf of the Fair Pricing Coalition and Founding Director, Project Inform. (Actual prices paid by individual payers may vary.)

"PREZISTA is an important new medicine in HIV and Tibotec Therapeutics and Tibotec R&D have demonstrated a true commitment to putting the needs of patients first. We applaud them for their efforts to make this product available and accessible to people living with HIV in the United States," said Howard Grossman, M.D., Executive Director, American Academy of HIV Medicine.

POWER 1 and 2 Efficacy and Design

The regulatory filing included a pooled analysis of 24-week data from the POWER 1 and 2 studies in treatment-experienced adult patients. Participants were randomized to receive PREZISTA/rtv (600mg/100mg) twice daily plus an individualized combination of anti-HIV drugs called an optimized background regimen (OBR) (131 patients) or commercially available investigator-selected protease inhibitors boosted with ritonavir plus OBR (124 patients). The results showed that at 24 weeks patients in the PREZISTA/rtv arm were significantly more likely to achieve a virologic response, achieve undetectable viral load and have an increase in CD4+ cell counts from baseline compared to the patients in the control arm:

• 69.5 percent vs. 21 percent achieved a virologic response defined as ³ 1.0 log10 reduction (90 percent reduction) in viral load from baseline

• 45 percent vs. 12.1 percent achieved undetectable viral load (<50 copies/mL)

• CD4+ cell mean increase of 92 cells/mm3 vs.17 cells/mm3 from baseline

Patients with HIV-1 who were eligible for POWER 1 and POWER 2 studies had previously been treated with at least one protease inhibitor, one non-nucleoside reverse transcriptase inhibitor (NNRTI) and one nucleoside reverse transcriptase inhibitor (NRTI), had one or more primary protease inhibitor mutations, and were failing a PI-based regimen. Investigator selected OBR and control protease inhibitors were based on resistance testing and prior treatment history. The OBR consisted of at least two NRTIs with or without enfuvirtide.

POWER 3 Results

The regulatory filing included supportive data from the TMC114-C215/C208 (POWER 3) analysis, a non-randomized, open-label analysis of treatment-experienced patients. Data from this cohort (n=246) showed that:

• 65 percent of patients achieved a ³ 1.0 log10 reduction in viral load from baseline at 24 weeks

• 40 percent of patients reached undetectable virus levels (<50 HIV RNA copies/mL) at 24 weeks

• CD4+ cell mean increase of 80 cells/mm3 from baseline at week 20

"The approval of PREZISTA reflects our ongoing commitment to delivering therapeutic approaches that help people with HIV who have unmet needs," said Glenn Mattes, President, Tibotec Therapeutics. "This is the first in what we hope will be a series of treatment advances Tibotec Therapeutics will offer during the next five years."

Important Safety Information

PREZISTA does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

PREZISTA is contraindicated in patients with known hypersensitivity to any of its ingredients.

PREZISTA/rtv is contraindicated with astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, and triazolam. Coadministration is not recommended with carbamazepine, phenobarbital, phenytoin, rifampin, lopinavir/ritonavir, saquinavir, lovastatin, pravastatin, simvastatin, or products containing St. John's wort (Hypericum perforatum).

Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A in patients receiving PREZISTA/rtv. This list of potential drug interactions is not complete.

PREZISTA must be co-administered with 100 mg ritonavir and food to exert its therapeutic effect. Please refer to ritonavir prescribing information for additional information on precautionary measures.

Severe skin rash, including erythema muliforme and Stevens-Johnson Syndrome, has been reported in subjects receiving PREZISTA during the clinical development program. In some cases, fever and elevations of transminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in seven percent of subjects treated with PREZISTA; discontinuation due to rash was 0.3 percent. Rashes were generally mild-to-moderate, self-limiting and maculopapular. PREZISTA should be discontinued if severe rash develops.

PREZISTA should be used with caution in patients with known sulfonamide allergy.

New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.

PREZISTA should be used with caution in patients with hepatic impairment. There are no data regarding the use of PREZISTA in patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made.

Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.

Immune reconstitution syndrome has been reported in patients treated with ARV therapy.

The potential for HIV-cross-resistance among protease inhibitors has not been fully explored in PREZISTA/rtv treated patients.

In the pooled analysis of POWER 1 and 2 studies, the most frequently reported drug-related adverse events of at least moderate to severe intensity in patients receiving PREZISTA/rtv-containing regimen were headache (3.8%), diarrhea (2.3%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%).

SOURCE: Tibotec Therapeutics