New Protease Inhibitor Approved for Treatment-experienced Patients

By Liz Highleyman

On June 23, the Food and Drug Administration (FDA) announced the accelerated approval of darunavir, formerly known as TMC114, Tibotec's new non-peptide protease inhibitor (PI); the drug will be marketed under the brand name Prezista.

Darunavir was approved for treatment-experienced HIV positive adults who are not responding to their current antiretroviral regimens. To achieve adequate concentrations in the body, darunavir must be coadministered with a boosting dose of ritonavir (Norvir). The recommended dose is 600 mg darunavir (two 300 mg tablets) plus 100 mg ritonavir twice daily with food.

Model of TMC-114 in the active site of HIV-1 protease

"One of the greatest challenges in HIV care is finding therapies for treatment-experienced patients," said Michael Saag, MD, director of the University of Alabama at Birmingham's 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."

Approval was based on 24-week data from two randomized, controlled Phase IIb trials showing that boosted darunavir produced superior virological suppression and greater CD4 cell recovery compared with other boosted PIs. POWER 1 (conducted in Europe, Australia, Brazil, and Canada) and POWER 2 (conducted in the United States) together included nearly 600 participants. Longer-term data will be required for full traditional approval.

At the 13th Conference on Retroviruses and Opportunistic Infections this past February, researchers reported that, in the two studies combined, 70% of heavily treatment-experienced patients with evidence of PI-resistance mutations experienced at least a 1 log (90%) reduction in HIV RNA after taking darunavir for 24 weeks, compared with 21% of patients taking other boosted PIs. Further, 45% of patients in the darunavir arm achieved HIV viral loads below 50 copies/mL, compared with 12% of those taking other PIs; CD4 cell count increases were 92 cells/mm3 vs 17 cells/mm3, respectively. The studies also showed that darunavir worked best when combined with T-20 (enfuvirtide, Fuzeon). In an additional non-randomized, open-label study (POWER 3), 65% of subjects achieved at least a 1 log reduction in HIV RNA and 40% achieved undetectable viral load after 24 weeks.

The most common side effects observed in patients taking darunavir were headache, diarrhea, abdominal pain, constipation, and vomiting (all reported by fewer than 5%). In additions, about 7% developed skin rashes of varying severity, including a few cases of erythema multiforme and Stevens-Johnson Syndrome; individuals with a known allergy to sulfa drugs should not take darunavir. Some patients also had elevated liver enzymes. It is too soon to know whether darunavir will cause the same types of long-term metabolic complications (e.g., blood lipid elevations, body shape changes, diabetes) seen in individuals taking other PIs.

Darunavir should not be used with a variety of other medications (including certain antihistamines, anticonvulsants, sedatives, statins, and the herb St. John's wort), and should be used cautiously with other inhibitors or inducers of the CYP3A enzyme, due to the potential for drug interactions.

The safety and efficacy of darunavir as first-line therapy for treatment-naïve individuals has not yet been established. As a condition of approval, Tibotec must conduct post-marketing trials to assess how well darunavir works in children and in people with pre-existing liver impairment, as well as further drug interaction studies.

Darunavir is the first approved antiretroviral agent developed by Tibotec Pharmaceuticals, an Irish company that was acquired by Johnson & Johnson in 2002 and is a now a division of Ortho Biotech Products. The company also has an investigational non-nucleoside reverse transcriptase inhibitor, etravirine (TMC125), in advanced clinical trials.

"This approval offers new hope to HIV patients who too often urgently need new therapies in order to maintain their health," said Acting Commissioner of Food and Drugs Andrew von Eschenbach, MD. "This drug is not a cure, but when combined with other standard therapies, it presents one more major step in our effort to help patients combat the effects of the disease."

6/23/06

Sources

Food and Drug Administration. FDA Approves New HIV Treatment for Patients Who Do Not Respond to Existing Drugs. Press release. June 23, 2006.

Tibotec Pharmaceuticals. Prezista Receives U.S. FDA Approval as Part of HIV Combination Therapy. Press release. June 23, 2006.