FDA advisory committee gives nod to old drug with new therapy potential

More study needed to determine proper use of drug

Rifapentine, the long-neglected cousin of rifampin, is one step away from becoming the first anti-tuberculosis drug approved by the Food and Drug Administration in more than 25 years. The drug holds the promise of once-weekly therapy, but more study is needed before guidelines can be set, say officials at the Centers for Disease Control and Prevention in Atlanta.

"The data presented indicate that it does have activity, would be effective, and certainly the safety data are good," says Rick O'Brien, MD, chief of the research and evaluation branch of the CDC's Division of TB Elimination. "What we don't know yet is how to best use it."

The advisory committee voted for FDA-accelerated approval of rifapentine for treatment of HIV-negative patients with pulmonary TB. However, it expressed reservations over a higher relapse rate shown in the rifapentine arm of one of two studies presented at the meeting. Although the FDA is expected to follow the committee's recommendation, it still is working out how the drug would be labeled, says Julie O'Dell, spokeswoman for the drug's manufacturer, Hoechst Marion Roussel of Kansas City, MO. "The labeling is not finalized. Right now the indication is for pulmonary TB," she says, adding that the company hopes to launch the drug this fall.

Rifapentine was developed as a compound around the same time rifampin was developed in the 1960s. Unlike rifampin, Marion Merrell Dow, now Hoechst Marion Roussel, never undertook the studies required to market the compound. It was taken off the shelf and put into human trials only in the last decade, when TB resurged and the possibility arose that it could be used against Mycobacterium avium in AIDS treatment as well. Recent mouse studies have shown its long half-life may enable the use of once-weekly treatment during the maintenance phase of therapy.

The FDA advisory committee met May 5 to consider the new drug application for rifapentine. This followed an earlier agreement to consider it for accelerated approval for the treatment of TB based on six-month follow-up data from a single clinical trial known as Protocol 8. That study is a randomized trial conducted at 29 sites in South Africa, five in the United States, and five in Canada. Data presented at the meeting had been collected from 96% of patients who had completed six months of follow-up and 68% of whom had reached 12 months of follow-up.

The committee also reviewed data from a CDC-sponsored trial, Study 22, which has nearly completed enrolling 1,000 patients in sites in the United States and Canada. Preliminary endpoint data from that study, a randomized, open-label trial comparing once-weekly rifampin plus isoniazid to twice-weekly rifampin during the 16-week continuation phase of treatment, were presented behind close doors so the study remains blind, O'Brien says. The only result made public was the recent announcement that a significantly high rate of HIV-positive patients relapsed with rifampin-resistant strains. Consequently, HIV-positive patients were taken off the study. (See TB Monitor, January 1998, p. 3.)

Patients in Protocol 8 were randomized to receive two months of either daily rifampin or twice-weekly rifapentine, together with daily isoniazid, pyrazinamide, and ethambutol. After the induction phase, patients on the rifapentine arm received once-weekly rifapentine and isoniazid, while those in the rifampin arm were given twice-weekly isoniazid and rifampin.

A total of 722 patients were enrolled and equally divided into the two arms. Those with negative pretreatment cultures and drug resistance were excluded. There were few adverse events and no life-threatening toxicity, O'Brien notes, adding there was an increased incidence of hyperuricemia in the rifapentine arm.

Although the FDA panel expressed some concern about the higher relapse rate in the rifapentine arm - 8.7% compared with 3.9% in the rifampin arm - there was little discussion about the higher failure rate in the rifampin arm - 2.8% compared with 0.3% for the rifapentine arm. An analysis of relapse showed male gender, baseline severity of disease, delayed sputum culture conversion, and noncompliance with the three other drugs during the induction phase were associated significantly with relapse and found more frequently in the rifapentine arm, O'Brien says.

Both the company's and the FDA's intent-to-treat analyses of Protocol 8 indicate compliant patients taking rifapentine who were "early converters" showed a low rate of relapse compared with patients in the rifampin arm. The panel's statisticians, however, expressed reservations about those post hoc findings, he says.

China data omitted

Researchers in China have been studying rifapentine for several years. However, data from a completed Hong Kong study, which also showed a higher-than-expected relapse rate, were not presented at the meeting because Hoechst Marion Roussel insists the drug used in the study is manufactured in China and differs from its product. The Hong Kong researchers have reported the batches of the drug used in that study had suboptimal bioavailability. The Hong Kong study results were published in the June issue of the American Journal of Respiratory Care and Critical Medicine.

Because of the limited human data on rifapentine, the FDA panel approved rifapentine pending final review of Protocol 8 study after patients reach 24 months of follow-up, which would be more than a year from now. The company also has committed to developing additional studies that could better define how it should be used, O'Brien says.

The committee suggested the need for several follow-up studies, including an evaluation of higher doses of intermittent rifapentine, other intermittent regimens, modified induction regimens, and rifapentine use in HIV-positive patients and children. Toward that end, the CDC, the World Health Organization, and the International Union Against Tuberculosis and Lung Disease (IUATLD) are developing a protocol for a collaborative international trial of rifapentine as a follow-up to Study 22. As part of designing the study, the CDC will review new animal data on rifapentine this summer and meet with collaborators just before the IUATLD meeting in Bangkok this fall, O'Brien tells TB Monitor. One study of rifapentine in mice, published in the May issue of the American Journal of Respiratory Care and Critical Medicine, looked at the efficacy of the drug for once-weekly regimens, says O'Brien, one of the study's authors. A follow-up study, conducted by researchers in Paris, is evaluating rifapentine use in a shortened phase of daily treatment, possibly as short as two weeks, followed by once-weekly dosing during the continuation phase, he adds.

Ongoing studies will continue to evaluate why HIV-positive patients on rifapentine were at risk for relapse with rifampin-resistant TB in Study 22. However, because rifapentine, like rifampin, is an enzyme inducer, the drug probably would not be suitable for patients taking protease inhibitors, O'Brien adds.