The FDA's end-of-the-year approval of Janssen Therapeutics' Sirturo rang in a new year of hope for patients with multidrug-resistant pulmonary tuberculosis (MDR-TB). And it brought good cheer to other biopharma companies developing their own cocktails intended to make the deadly form of TB toast.

The agency's accelerated approval of Sirturo (bedaquiline), to be used in combination with other drugs, makes it the first drug specifically approved for MDR-TB and shapes a path forward for other TB candidates. It also shows that, when dealing with drugs that may respond to significant unmet needs, the FDA isn't always as risk-averse as rumor has it.

The approval, which was granted in six months, was based on two Phase II trials, only one of which was placebo-controlled, and a surrogate endpoint of the length of time for a patient's sputum to be free of TB, or sputum culture conversion (SCC).

In the first trial, subjects treated with Sirturo combination therapy achieved SCC in a median of 83 days, compared with 125 days for those treated with combination therapy including a placebo, according to the Titusville, N.J.-based Janssen. The median time to SCC in the ongoing second trial was 57 days.

While the trial results demonstrated the efficacy of Sirturo, which inhibits an enzyme needed for replication of Mycobacterium tuberculosis, they also raised safety concerns. Nine, or 11.4 percent, of the 79 subjects treated with the Sirturo combination died in the first trial, compared with two, or 2.5 percent, of the 81 subjects given the placebo combination.

Both deaths in the placebo group and five of those in the Sirturo group were related to the underlying disease, the FDA said, but no consistent reason has been identified for the other deaths.

Citing those deaths, a government watchdog group urged the FDA to deny accelerated approval to the drug. "It clearly is not possible to conclude that a surrogate endpoint is 'reasonably likely' to predict benefit for patients — as required by FDA regulations — when the clinical trial of a drug using that surrogate endpoint shows a significant increase in mortality," Public Citizen said in a letter to the FDA just days before the agency granted the approval.

"The only reasonable conclusion in such cases is that the selected surrogate endpoint is, in fact, not a useful or valid marker of clinical benefit," the letter continued.

Public Citizen also questioned the ethics of permitting ongoing trials, advising the FDA to ensure that all subjects in the trial be informed of the deaths and that consent forms be revised to clearly define the mortality risk.

In granting the approval, the FDA signaled that, contrary to the Public Citizen stance, SCC is a viable surrogate endpoint for new MDR-TB drugs and serious safety risks don't automatically outweigh benefits. The agency didn't ignore the risks, though, as it is requiring a boxed warning about the trial deaths and the possibility of QT prolongation, which could lead to an abnormal and potentially fatal heart rhythm. The labeling also stipulates that Sirturo should only be used when no other effective treatment is available.

Unmet Need

Despite the risks, FDA Commissioner Margaret Hamburg hailed the approval. "Having seen first-hand the threat to public health posed by [MDR TB], . . I'm pleased that another weapon has been added to the arsenal for fighting this deadly, contagious disease," she said in the agency's blog.

Hamburg also noted the need for more therapies to treat TB, which can become drug resistant due to the long, complex treatment regimens that generally involve a combination of drugs. "There is no question that we need more and better treatments for drug-resistant TB," she said. "And we'll continue to need new drugs as the disease mutates or changes."

While the U.S. reported fewer than 11,000 cases of TB in 2011, with 98 of those considered MDR-TB, the situation is much grimmer in the rest of the world. Nearly 9 million people worldwide contracted TB in 2011, and 1.4 million died, Hamburg said. Those statistics are expected to worsen, as the World Health Organization (WHO) estimated that more than 2 million people will develop MDR-TB between 2011 and 2015.

Even though its incidence of MDR-TB is relatively small, the U.S. represents one of the biggest markets for new TB drugs in terms of dollars spent per patient – along with Europe and Japan. How much Sirturo will impact the market numbers is unknown, as Janssen isn't announcing the price until it launches the new drug in the second quarter of 2013.

"We hope that this approval will encourage the introduction of other new therapies for MDR-TB and TB," Janssen spokeswoman Pamela Van Houten told BioWorld Today. To help address the global TB threat, Janssen is sharing its expertise and resources by working with such organizations as the WHO's Stop Tuberculosis Partnership. Under a 2009 agreement, Janssen granted the TB Alliance a royalty-free license for worldwide development and access to Sirturo to treat drug-susceptible TB.

Meanwhile, several other players – including Sequella Inc., Otsuka Pharmaceutical Development Co. Ltd., Pfizer Inc., GlaxoSmithKline plc, AstraZeneca plc and Sanofi SA – are developing their own new drugs to tackle TB. (See BioWorld Today, April 26, 2011.)