First approval for new tuberculosis drugs paves the way for better combinations of new and old agents.
The US Food and Drug Administration (FDA)'s approval of Janssen's bedaquiline for multidrug-resistant tuberculosis (MDR-TB) in December ended a four-decade-long lull in the hunt for a new tuberculosis (TB) therapy with a novel mechanism of action. It also earned Janssen the second-ever priority review voucher, which rewards developers of therapies for tropical diseases by allowing them to expedite the review of another drug of their choosing.
“This a major step forward, and the beginning of what should be a dramatic improvement in TB therapy that I hope we're going to see over the next 5–10 years,” say Mel Spigelman, President and CEO of the Global Alliance for TB Drug Development.
Although uncommon in developed countries, the World Health Organization (WHO) reports that TB caused more than 8 million cases of illness and 1.4 million deaths globally in 2011. In 1993, when the WHO declared TB a global emergency, most strains were susceptible to a quadruple-drug, 6-month regimen of isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB) and rifampicin (RMP), says Alimuddin Zumla of University College London Medical School, UK.
But the past two decades have seen the emergence of MDR-TB (TB that is resistant to the first-line therapies INH and RMP) and, more recently, extensively drug-resistant TB (XDR-TB, or MDR-TB that is also resistant to the quinolones and at least one other second-line therapy). MDR-TB now accounts for around 10% of global TB mortality. Regimens comprising second-line therapies can be used to treat MDR-TB, but they must be taken for 18 months or longer and include chemotherapies associated with unpleasant side effects, leading many patients to discontinue treatment.
“Globally, cure rates for MDR-TB vary, but average around 50%,” says Salmaan Keshavjee of Harvard Medical School, Boston, Massachusetts, USA, and a member of the Stop TB Partnership's MDR-TB Working Group and Core Group. And when MDR-TB therapy fails, it's a disaster for patients. “In a study we carried out in Tomsk, Russia, on patients whose therapy for MDR-TB had failed, 100% were dead within 3 years — this is the context in which we have to look at the approval of bedaquiline.”
The good news also comes at a time when the search for TB vaccines has yet again faltered. The bacille Calmette–Guérin (BCG) vaccine was approved for the prevention of TB in the 1920s, but has low protective efficacy. The lead candidate in the vaccine space, Emergent's MVA85A, designed to boost the efficacy of the BCG vaccine, failed last month in a Phase II trial in infants (Lancet, 4 February 2013; doi: 10.1016/S0140-6736(13)60177-4).
Bedaquiline breaks through
Bedaquiline is the first member of the new class of diarylquinoline compounds and works by inhibiting Mycobaterium tuberculosis ATP synthase, depriving the bacterium of energy and causing it to die. By contrast, INH and EMB disrupt the formation of the cell wall, although via different mechanisms; PZA is hydrolysed into pyrazinoic acid, which may affect bacterial fatty acid synthesis or protein synthesis; and RMP inhibits RNA synthesis.
The approval of bedaquiline, under the FDA's accelerated approval programme, was based on two Phase II trials, one of which was placebo-controlled, in a total of 440 patients with MDR-TB who received the drug for 24 weeks along with a background regimen of other currently used anti-TB agents. In both trials, the efficacy of bedaquiline was assessed by sputum conversion, the time taken for M. tuberculosis to clear from the sputum. In a placebo-controlled trial, patients on bedaquiline showed 33% faster median conversion than the placebo group (83 days versus 125 days), and in the non-placebo trial median sputum conversion was 57 days.
Despite a clear efficacy signal (panellists voted unanimously in favour of approval at an FDA advisory meeting last year), safety concerns persist. Bedaquiline carries a black box warning about QT prolongation. The warning also notes an imbalance in deaths between patients receiving bedaquiline (nine deaths, only five of which were attributable to TB) and placebo (two deaths, both attributable to TB). “There are long-term safety issues that need monitoring, as rare toxicities can only be evaluated after widespread usage in various geographical settings and in combination with a range of existing TB drugs,” says Zumla.
Further safety data should be available in the future, with a confirmatory Phase III trial in the works. The 5-year trial will enrol 600 patients with MDR-TB and will compare bedaquiline plus background therapy versus background therapy alone for 9 months. The primary end point is favourable treatment outcomes 6 months after treatment stops, and the trial will also look at mortality 2 years after treatment stops. “This will be the largest randomized controlled trial that we've done to date,” says Myriam Haxaire, Compound Development Team Leader at Janssen Research & Development in Belgium.
The Phase III trial will include a subset of patients with MDR-TB who are HIV-positive and on antiretroviral therapy. HIV-positive patients have an increased susceptibility to TB, says Liz Corbett of the London School of Hygiene and Tropical Medicine, UK, and TB is the leading cause of death among people living with HIV. Often this is due to the activation of latent TB. “For people without HIV the risk that latent TB will become activated is low, at around 5–10% over the lifetime,” says Corbett. “For an HIV-positive patient with latent TB, the risk is more like 10% per year.”
Corbett expects that bedaquiline will soon find its way into TB regimens for HIV-positive patients with MDR-TB. The simultaneous treatment of HIV and TB, however, raises the possibility of drug–drug interactions, says Keshavjee. “The question is whether HIV therapies like lopinavir increase or decrease the amount of available bedaquiline in the body, and that needs to be tested.”
New regimens needed
The approval of bedaquiline is being seen as a starting point for a new era of TB therapy, not the end of the road (see Table). “Ultimately, we need to develop new TB regimens that combine drugs, all of which have a novel mechanism of action,” says Spigelman. “The approval of bedaquiline paves the first step along that path.”
Although the goal of getting all-new drug regimens to patients is some way off, the TB Alliance is currently coordinating the development of regimens that combine old and repurposed drugs with new agents such as bedaquiline.
The TB Alliance is developing PA-824, a nitroimidazole antibiotic that inhibits cell wall biosynthesis. In a series of Phase II MDR-TB trials, PA-824 is being combined with: bedaquiline and PZA; bedaquiline and the antimycobacterial agent clofazimine; and moxifloxacin (a repurposed antibacterial agent that inhibits DNA gyrase and is not approved for TB) and PZA. The PA-824 plus moxifloxacin plus PZA regimen cured mice with TB in 3–4 months, and Spigelman hopes it will be useful for MDR-TB as well. Results from the clinical trial of this regimen are expected by the end of the year.
Other compounds are closer to the clinic. Otsuka's delamanid, a nitro-dihydro-imidazooxazole derivative that inhibits mycolic acid synthesis, has entered Phase III MDR-TB testing and has been filed for approval. Last year, Phase II MDR-TB trial results showed that 45.4% of patients receiving delamanid plus standard of care had clear sputum after 2 months of treatment, compared with 29.6% of patients receiving the standard regimen plus placebo (N. Engl. J. Med. 366, 2151–2160; 2012).
In time, the TB Alliance also plans to run trials of triple therapies comprising agents from the nitroimidazole, oxazolidinone and diarylquinoline classes of drugs — but at first only in patients with XDR-TB. “Although these regimens will carry more risk as they are entirely new, the potential benefits for patients who really have no alternative is so much higher,” says Spigelman.
Designing new treatment regimens for drug-resistant TB, and getting them to patients quickly, remains difficult. Some of the challenges revolve around regulatory questions — for example, whether new TB agents need to be developed and approved separately before they can be combined with other experimental agents, or whether development programmes can be run together. “This is one of the key issues we've been discussing with regulators,” says Spigelman, who notes that agencies such as the FDA and European Medicines Agency (EMA) have been helpful so far.
Another obstacle arises from the fact that different companies are developing the various agents, and so need to be co-opted to work together. “Consensus needs to be achieved between industry and trial networks so that they can to work together to move efficiently towards new regimens for TB,” says Zumla.
To this end, the Critical Path to TB Drug Regimens (CPTR) launched in March 2010, through a partnership between the TB Alliance, the Bill & Melinda Gates Foundation and the Critical Path Institute. The CPTR is working to devise new guidelines for the clinical testing of TB drug combinations and coordinating a hunt for biomarkers that could enable treatment success to be detected faster. It is also developing the infrastructure required to carry out trials in regions where TB is more common, which typically means developing or poor nations.
“These efforts must be supported by donors and governments,” says Zumla. “Wealthy nations cannot ignore the ominous rise of MDR- and XDR-TB, because it does not respect international borders.”
Source: Nature Reviews Drug Discovery