FDA Panel Endorses Novel Tuberculosis Drug
SILVER SPRING, Maryland — A federal advisory panel voted unanimously yesterday 18 to 0 for efficacy but split 11 to 7 on safety in support of accelerated approval of a novel drug to combat multidrug-resistant tuberculosis (MDR-TB).
The US Food and Drug Administration's (FDA's) Anti-Infective Drugs Advisory Committee agreed with Janssen Therapeutics, a division of Janssen Products, LP, that the manufacturer's drug bedaquiline could be approved on the basis of phase 2 data using the surrogate study endpoint of sputum culture conversion rather than clinical cure because of the unmet treatment need.
Bedaquiline works via a novel mechanism of action: inhibition of a mycobacterial enzyme that is essential to the bacteria's action. The proposed drug indication is a part of combination therapy for the treatment of pulmonary TB caused by MDR Mycobacterium tuberculosis in adults, to be administered under directly observed therapy.
If approved by the FDA, bedaquiline would be the first new TB drug since the introduction of rifampin in 1970.
Although the TB rate has dropped significantly in the United States during the last few decades, the proportion of cases caused by MDR strains has increased worldwide. Most US cases of MDR-TB happen in foreign-born individuals, said Kenneth G. Castro, MD, director of the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention, Atlanta, Georgia.
Current multidrug regimens are long and difficult, and only 54% of patients with MDR-TB worldwide are successfully treated, said Andreas Diacon, MD, PhD, from Janssen.
According to Dr. Castro, "US recovery from the devastating impact of MDR-TB must be sustained. The global situation constitutes a health threat. Achieving TB elimination in the US and marked improvements globally will require new tools and novel approaches."
Phase 2 Data
Janssen's new drug application for bedaquiline was based on efficacy and safety data from 2 phase 2 trials, with 1 of the trials consisting of 2 distinct stages. As a condition of submission under accelerated approval, the company is obligated to conduct a confirmatory phase 3 trial.
The 2 studies involved a total of 441 patients with MDR-TB, defined as TB resistant to at least rifampin and isoniazid. In the first trial, 47 newly diagnosed South African patients in stage 1 and 161 newly diagnosed patients from 7 countries in stage 2 were randomly assigned in a 1:1 ratio to receive bedaquiline or placebo for 8 weeks and 24 weeks, respectively, along with a background regimen of other anti-TB drugs. They were followed up for 104 and 120 weeks, respectively.
The other study was an open-label multicenter evaluation of 233 non–newly diagnosed patients, with a 2-year follow-up.
In all 3 evaluations, the primary endpoint was time to sputum culture conversion, defined as 2 consecutive negative cultures with negative intermediate cultures.
Results showed that bedaquiline resulted in 33% faster culture conversion within 24 weeks, with a P value of less than .001. At 24 weeks, 78.8% had converted with bedaquiline vs 57.6% with placebo ( P = .008). In the open-label trial, 79.5% of patients had culture conversion at week 24, according to Brian Danneman, MD, from Janssen.
Reviewers from the FDA generally agreed with the company's efficacy analysis.
Safety Concerns
Significant safety concerns reported by both Janssen and the FDA included signals for increased risks for QT interval prolongation, hepatotoxicity, and a greater number of deaths in the bedaquiline group compared with in the placebo group.
In stage 2 of the randomized trial, more patients in the bedaquiline group had corrected QT values of 450 to 480 ms (26.6% vs 8.6%), and more patients receiving bedaquiline developed a more than 60-ms increase from a reference values group (9.1% vs 2.5%).
Hepatobiliary disorders and elevated transaminases occurred in 7 patients receiving bedaquiline vs 1 patient receiving placebo in that study (8.9% vs 1.2%).
Also in the second stage of the randomized study, 10 (12.7%) deaths occurred with bedaquiline vs 2 (2.5%) deaths in the placebo group. In the open-label study, there were 16 (6.9%) deaths, with 12 occurring during the trial. Half of the deaths were related to TB itself, and the others did not appear to be related to the drug, but the difference was statistically significant.
Proposed labeling would include recommendations for EKG monitoring and precautions regarding use of the drug in patients with prolonged QTc intervals and those receiving other drugs that also prolong the interval, as well as monitoring for other safety concerns.
Committee Support
In voting unanimously for efficacy, all of the committee members expressed support for the need of a new drug to treat MDR-TB, although several said that the confirmatory phase 3 trial would need to use hard clinical endpoints rather than sputum conversion.
"This is a great drug, it appears, based on the data presented to date...but we need additional data," said committee chair Thomas A. Moore, MD, clinical professor in the Department of Medicine, University of Kansas School of Medicine in Wichita.
However, the safety signals worried some panel members. "I'm concerned about the mortality. Ten out of 79 is quite a high number," said Fred Gordin, MD, chief of infectious diseases at the Veterans Affairs Medical Center, Washington, DC.
Dr. Gordin, who voted no on the safety question, noted that the long half-life of the drug — about 5 months — is also worrisome because the potential for long-term organ damage is not known.
"I personally would still favor approval, with the caveat that we need much more safety data.... There's clearly a role for this drug, but in many patients who have other options, I think it has to be very clear to providers that there are long-term safety issues," Dr. Gordin said.
Janssen's phase 3 trial is planned for 2013. It is designed as a double-blind study comparing 9 months of treatment with bedaquiline with treatment with placebo, both with a background regimen.
Participants in FDA advisory committee meetings are vetted for conflicts of interest and waivers may be granted if necessary. No waivers were granted for this meeting.
Medscape Medical News © 2012 WebMD, LLC
沒有留言:
張貼留言