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Bedaquiline: Drug-Resistant Tuberculosis Drug Backed By FDA Panel
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(2 Briefing documents attached)

By Ransdell Pierson

Nov 28 (Reuters) - An advisory panel to the U.S. Food and Drug Administration on Wednesday voted that an experimental Johnson & Johnson drug for multidrug-resistant tuberculosis appears to be safe and effective, but highlighted potential heart and liver-safety issues.

The medicine, called bedaquiline, targets adenosine triphosphate synthase, an enzyme the tuberculosis bacterium needs to generate its energy. If approved, J&J said it would be the first drug in 40 years with a new mechanism of action against tuberculosis.

J&J said the panel of outside medical experts, in a vote of 18 to 0, found that trial data provide "substantial evidence" of efficacy and safety for bedaquiline in adults, taken in combination with standard treatments. It backed the drug's safety, by a vote of 11 to 7.

The FDA usually follows the advice of its advisory panels when deciding whether to approve new medicines.

In September, the FDA granted priority review of the drug, based on data from two mid-stage trials that tested it among patients with tuberculosis that is resistant to standard drugs.

J&J's Janssen drug subsidiary is hoping the agency will grant accelerated approval of its drug, on the basis of favorable data from mid-stage trials. The company plans to begin a larger Phase 3 study early next year.

In a pair of completed Phase 2 trials, two doses of the medicine were tested for 24 weeks, in combination with standard treatments, followed by continuation of standard therapy for a year to 18 months.

In one of the trials, 10 deaths were seen among 79 people taking bedaquiline and standard drugs, compared with only 2 deaths among 81 patients taking only standard drugs.

Some members of the FDA advisory panel expressed concern about that "mortality imbalance," as well as elevated liver enzymes -- a potential sign of liver toxicity -- among patients taking the J&J drug.

Patients taking bedaquiline also had increases in the so-called QT interval -- suggesting a possible electrical irregularity in the heart -- than those not taking the medicine.

But Wim Parys, Janssen's head of development for infectious disease medicines, said in an interview that the drug's superiority to standard medicines in the mid-stage trials held sway with the advisory panel.

He said 21 percent fewer patients taking the J&J drug still had signs of the TB bacterium in their sputum after one of the mid-stage studies, than those taking just standard drugs.

"This is a new mechanism of action to treat TB, particularly (bacteria) that have become resistant to first-line treatments," Parys said.

Cowen and Co has forecast peak annual sales of $300 million for bedaquiline, which would make it a fairly modest product for the diversified healthcare company.

Parys acknowledged the drug's limited sales potential, given that it would be used mainly in poorer developing countries. But he said J&J approved development of the medicine due to a compelling medical need.

The planned larger trial will involve nine months of treatment with bedaquiline, in combination with standard drugs, compared with standard drugs alone for the same period. The total nine-month treatment period would be far shorter than the current 18- to 24-month treatment period for multidrug-resistant tuberculosis drugs recommended by the World Health Organization, J&J said.

Multidrug-resistant tuberculosis is caused by strains of the bacterium that have become resistant to at least isoniazid and rifampin, the two most potent drugs for TB.

Resistance to anti-TB drugs can occur when they are misused or mismanaged, for instance when patients don't complete their full course of treatment or when doctors prescribe the wrong treatment, wrong dose or length of time taking the drugs.

An estimated 8.7 million people in 2011 fell ill with tuberculosis - which is spread by coughing and sneezing -- while 1.4 million died from the disease, according to the World Health Organization. About 310,000 cases of multidrug-resistant TB were reported the same year, the organization said, with almost 60 percent in India, China and Russia. (Reporting by Ransdell Pierson; Editing by Jan Paschal and Carol Bishopric)


Group Calls on FDA to Reject MDR-TB Drug

By David Pittman, Washington Correspondent, MedPage Today

Published: December 28, 2012

WASHINGTON -- The FDA should not grant accelerated approval to a treatment for multi-drug resistant tuberculosis (MDR-TB) due to a seemingly higher mortality rate with the drug compared with placebo, urged consumer watchdog Public Citizen.

A phase II, randomized trial of bedaquiline (Sirturo) showed a mortality rate five times higher in patients taking the drug plus a standard regimen compared with those taking the standard regimen with a placebo, the group pointed out in a letter addressed to Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, and others.

While patients in the study group did show improvement in the surrogate endpoint of sputum culture conversion, "it is not possible to conclude that a surrogate endpoint is 'reasonably likely' to predict benefit for patients -- as required by FDA regulations -- when the same clinical trial of a drug using that surrogate endpoint shows a significant increase in mortality, regardless of the drug's effects on the surrogate marker," the Dec. 21 letter stated.

The only reasonable conclusion is that the surrogate endpoint in this case is not a valid marker of clinical benefit, Public Citizen said.

The FDA was scheduled to render its decision on bedaquiline today. Last month, the agency's Anti-Infective Drugs Advisory Committee voted 11-7 in support of the safety of bedaquiline and unanimously deemed it effective.

Many panelists voted no because of the way the FDA phrased the question, asking if the product had "substantial" rather than "sufficient" evidence of safety, Myriam Haxaire-Theeuwes, Janssen's compound development team leader, told MedPage Today after the meeting. "For all the people who voted 'No,' it was not their intent to block an accelerated approval."

Janssen, bedaquiline's manufacturer, is a Johnson & Johnson subsidiary based in Titusville, N.J.

The FDA can grant accelerated approval based on a surrogate, rather than clinical endpoint if the agent treats a serious or life-threatening illness as is the case with bedaquiline. The drug was studied in two phase II trials and a phase III trial is ongoing.

Public Citizen highlighted one phase II study of 160 patients in which 10 patients on the regimen with bedaquiline died compared with two given standard treatment and placebo. However, the study investigators concluded that deaths in nine patients were unrelated to the drug and cast doubt that the other deaths were drug-related.

Nevertheless, the watchdog group pointed out that three bedaquiline-treated subjects had relapsed and died from multi-drug resistant TB, while two never had sputum conversion and also died from MDR-TB.

"Both the FDA and the sponsor attempted to discount the mortality data from stage 2 of study C208 by trying to exclude bedaquiline as a cause of the subject's death and suggesting that the imbalance in deaths was due to chance," the Public Citizen letter stated. "It is certainly plausible that these deaths were due to failure of the TB drug regimen that included bedaquiline, even if the mechanism for this poorer outcome is not understood."

Bedaquiline inhibits the production of energy in mycobacterial cells, and no other anti-mycobacterial agents have the same mechanism of action. Because of that, it's seen as a prospect in offsetting the drug-resistant strain.

Public Citizen suggested there is some unmeasured toxicity in the new class of TB drug.

However, the advisory committee saw no problems with the drug's efficacy, voting 18-0 that bedaquiline was efficacious.

In the first stage of the 8-week C208 trial, more than 47% of 21 patients receiving bedaquiline met the study's endpoint of acceptable sputum culture conversion compared with just over 8% on placebo (P=0.004). That significance remained for nearly 2 years, the FDA said. The culture is a measure of the growth of mycobacterial cells.

In the ongoing second stage of the C208 trial, 81% of bedaquiline patients had acceptable cultures compared with 65% of patients on placebo (P=0.293) after 24 weeks.

Bedaquiline is an immediate-release tablet taken orally. The drug is taken at 400 mg once a day for 3 weeks followed by 22 weeks of 200 mg three times a week.

TB has grown resistant to first-line treatments isoniazid and rifampin, the backbone of a standard 6-month course of treatment. The disease also has developed resistance to second-line drug classes aminoglycoside and fluoroquinolone. No new TB drug has been approved in the U.S. since 1970.

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