A clinical trial of three new tuberculosis drugs, along with one that is used in standard therapy, exemplifies FDA's evolving approach to studies that combine more than one investigational drug.

The Global Alliance for TB Drug Development, a non-profit virtual R&D organization, is sponsoring the Phase II study, dubbed New Combination 1 or NC001.

The TB Alliance has been working with FDA and others in the field through the Critical Path to TB Drug Regimens, a new initiative started by the Gates Foundation, Critical Path Institute, and the TB Alliance, to tackle many of the problems facing TB drug development, including the emerging science of combination drug testing.

"But we have to maintain a wall," Raymond Woosley, the Critical Path Institute's president and chairman of the board, said in an interview. "We're not sponsoring the trial and have not even seen the protocol, though we are urging them to use the most modern methods. We don't sponsor trials. We work on the process, not the product."

The implications of early-phase studies of combination regimens extend far beyond TB, and could even benefit development of products for an area such as AIDS, where the "cocktail" approach for antiretroviral therapies is already well established.

"TB drug development will create new regulatory pathways," Woosley said. FDA has been working on guidance on developing investigational drugs in combination, with significant implications for noninfectious diseases such as cancer and Alzheimer's disease as well. The agency just released a draft general guidance on the topic and is planning more targeted guidances for specific diseases (Also see "FDA Draft Co-Development Guidance Emphasizes Phase II Studies" - Pink Sheet, 20 December, 2010.).

A Factorial Approach To Trial Design

The most logical pivotal trial design using a combination of investigational drugs, and the one the agency likely would be looking for, would contain four arms, Jeff Allen, executive director of the Friends of Cancer Research, said earlier this year. These arms would be the standard of care, drug A, drug B, and drugs A + B. The factorial design is daunting in scope and complexity, but other approaches are possible, and that is the kind of information the agency is collecting.

The design of the current Phase II TB trial appears to be in harmony with this approach. The new drugs being studied are:

Moxifloxacin, marketed by Bayer as Avelox for severe bacterial infections and by Alcon as Vigamox for ophthalmic indications, which has been in Phase III trials for TB;
PA-824, a compound developed by Chiron (now Novartis) and licensed by the TB Alliance that has been in Phase II trials; and
TMC-207, another Phase II compound sponsored by Johnson & Johnson subsidiary Tibotec and the TB Alliance.

The trial is testing moxifloxacin and PA-824 with pyrazinamide, which is commonly used in TB treatment. Based on pre-clinical data, this three-drug combination may be able to shorten treatment time for virtually all tuberculosis patients from up to two years for the multi drug-resistant form of the disease to less than six months, while harmonizing the treatment of drug-sensitive TB and multi-drug resistant-TB, the TB Alliance said in a statement.

The same study is also examining two two-drug combinations: PA-824 with pyrazinamide and TMC-207 with pyrazinamide. These combinations "may prove to be the building blocks of future regimens," the TB Alliance says. "Regimen development may become the new gold standard in TB research and offer lessons for other diseases requiring combination treatment, such as cancer, hepatitis C and malaria."

All the new drugs being tested are from different classes – moxifloxacin is a fluoroquinolone, PA-824 is a nitroimidazole, and TMC-207 is a diarylquinoline. They are among the nine TB drugs currently in development (see chart, " Also see "Going Solo: Non-Combination TB Drugs In Development" - Pink Sheet, 13 December, 2010. ").

A longer-range goal Woosley cited is to have a combination regimen ready for Phase III testing within four to five years.

Unique Drug Combinations

A clinical trial that brings together these different classes of drugs to fight TB is unprecedented, Ann Ginsberg, chief medical officer of the TB Alliance, said in an interview. "To the best of my knowledge, it’s the first time these classes of drugs have been used together," she said. PA-824 in particular is in a novel class and is itself a new chemical entity, she said.

The trial is enrolling 68 participants at two sites in South Africa, the University of Stellenbosch and the University of Cape Town. Each patient is receiving two weeks of treatment and three months of follow-up to evaluate effectiveness, safety and tolerability. Funding comes from the U.S. Agency for International Development, the Bill and Melinda Gates Foundation and the UK Department for International Development.

"A Truly Novel Combination" To Fight Resistance

If the data from NC001 are promising, the next stage is a two-month Phase IIb trial, and if that in turn is promising and funding is available, a pivotal Phase III trial would be next, Ginsberg said.

"This is the first time a truly novel combination is being tested for TB," Ginsberg said. The standard of care for TB involves combinations of pyrazinamide and three other drugs that have been available for decades: rifampacin, isoniazid and ethambutol.

In the trial, "pyrazinamide is important, because it synergizes with lots of compounds," Ginsberg said. "Fluoroquinolones are not registered for TB, though many of the older fluoroquinolones are used now for treating multi-drug resistant TB – but that's an off-label use. Drug-sensitive TB trials have substituted moxifloxacin for isoniazid or ethambutol."

The hope is that the combinations being tested in NC001 will be able to treat both DS-TB and MDR-TB, and that the regimen developed will take only about four months to treat DS-TB, compared with six to nine months for the standard of care. The reduction in treatment time could be even more dramatic for MDR-TB. Currently, patients with this form of the disease have to stay on drug therapy for 18 to 24 months or even longer, Ginsberg said. Another advantage would be that the new drugs are oral, while the standard of care is injectable, which makes compliance more difficult, especially in the developing world.

The TB Alliance and Bayer are also conducting a separate three-arm Phase III trial called REMoxTB. In one arm, moxifloxacin is substituted for isoniazid; in the second arm, it is substituted for ethambutol; and the third arm is the control arm. Each group includes about 600 patients. "This is the way TB drug development has been done," the TB Alliance explained. "The difference is with the new three-drug combination, we are testing several new drugs together at once, instead of one new drug at a time. This can allow us to dramatically speed the time it takes to develop a novel regimen."

On The Path To TB Treatment

The Critical Path Institute is deeply involved with these efforts. The Critical Path to TB Drug Regimens started with a meeting on the Critical Path program in Washington, D.C. in September 2008, sponsored by the Drug Information Association and FDA. At the meeting, Jan Gheuens of the Gates Foundation asked CDER Director Janet Woodcock why there wasn't a Critical Path project for TB.

The result was the foundation of CPTR. The Critical Path Institute is doing overall project management, using funding from the Science Foundation Arizona, while the Gates Foundation and the TB Alliance are using their own resources to fund their efforts in the program. Industry makes in-kind donations of staff and drugs only.

Meanwhile, FDA put out a request for applications for studies of TB and various tropical diseases that closed Aug. 11. FDA announced Oct. 4 that it had awarded $2.9 million in grants, divided among six research projects (see chart, " Also see "FDA TB Research Grantees" - Pink Sheet, 20 December, 2010. ").

"I trained in a TB ward and was shocked to learn that nothing has changed in 35 years except for the emergence of drug resistance."

The grant awards "emphasized FDA's interest in new rapid diagnostic tests, biomarkers for use in clinical trials for TB, biomarkers for vaccine efficacy and strategies to move products from the discovery phase to the point where they were ready for use in clinical trials," the agency said. "We believe that the program will advance the development of drugs for drug sensitive and drug resistant TB, facilitate the development of vaccines, and encourage scientific and commercial interest in TB."

Woosley emphasized the woeful state of product development. "I trained in a TB ward and was shocked to learn that nothing has changed in 35 years except for the emergence of drug resistance," he said.

There are four drugs used as the standard of care for TB – rifampacin, isoniazod, pyramidizide and ethambutol – all of which are generics that have been in use for decades. Patients have to take this combined regimen for at least six months, which often leads to compliance problems in the developing world settings where the disease is rampant. Therefore, Woosley said he told FDA Commissioner Margaret Hamburg that "we need to develop two or three new drugs."

That's a tall order, because the drug industry was not initially enthusiastic," Woosley maintained. "The Gates Foundation spent $800 million to encourage companies to develop drugs for TB. Nine were ready to go into clinical trials, but [the sponsors] didn't want to go into a decades-long process. They won't make money on it," he said.

That's because there are a limited number of TB cases in the U.S. – 12,904 in 2008, the last year for which the Centers for Disease Control and Prevention has figures, and representing a slow but steady decline for 2000, when 16,310 cases were reported. Many of the U.S. cases are HIV patients, although the numbers are much higher in the developing world. But that doesn't mean an outbreak in the U.S. couldn't have serious – and expensive – consequences. When Hamburg was New York City Health Commissioner in the 1990s, there was a drug-resistant TB outbreak that "could have cost $1 billion if they hadn't shut it down quickly," Woosley said.

Still, FDA says, "drug development for TB invariably will rely on studies in other countries since the prevalence of TB in the U.S. is thankfully too low to support clinical therapeutic trials here."

FDA's Anti-Infective Drugs Advisory Committee discussed endpoints that can support accelerated approval of drugs to treat pulmonary multi-drug resistant TB in a June 2009 meeting ("FDA Panel To Discuss Endpoints For Accelerated Approval Of Multi-Drug Resistant TB," "The Pink Sheet" DAILY, June 3, 2009).

The panel was part of a process the agency is engaged in of developing clinical trial guidance for all types of TB (Also see "Conspicuous Consumption: TB Therapies Are A Priority At FDA" - Pink Sheet, 1 June, 2009.).

A Cooperative Approach

To move the ball forward in the fight against this difficult disease, the Critical Path to TB Drug Regimens was set up with three arms: the "Coalition," which brings sponsors together to discuss how to advance the most promising combinations of TB drugs, under the aegis of the TB Alliance; the "Consortium," which brings together FDA, European Medicines Agency and other stakeholders to discuss regulatory science issues, under the aegis of the Critical Path Institute; and a research resources arm to grapple with ways to get the actual clinical trials under way, which is the responsibility of the Gates Foundation.

This strategy has succeeded in bringing on board Johnson & Johnson, Bayer, Sanofi-Aventis, Pfizer, AstraZeneca, GlaxoSmithKline, Otsuka, Novartis, Sequella and Anacor Pharmaceuticals. The World Health Organization and NIH's National Institute of Allergy and Infectious Diseases also are involved.

According to a statement issued at the founding of CPTR, the partners agreed to a number of steps, including:

Information sharing and collaboration;
Developing new regulatory approaches to support TB research;
Working together to test TB drug candidates in combination regimens beginning early in the development process;
Finding funding for developing novel combination TB therapies;
Encouraging use of existing clinical trial sites for TB while building additional clinical trial site capacity for late-stage combination TB drug trials; and
Supporting relevant organizations in accelerating procurement of and access to new TB drug therapies for patients in need.

"We've recruited outstanding people and have held test meetings to see if the global TB community is ready to work together. What do we do to bring together expertise to new testing approaches for TB?" Woosley said.

A number of technical problems confront developers of TB drugs. First of all, "we need clinics capable of developing biomarkers," Woosley said. The traditional bacillus stain test is still used, but it takes time to get results and is only 85% accurate.

Cepheid's new Xpert MTB/RIF automated nucleic acid-amplification tuberculosis and rifampin-resistance test provides results in two hours and can be used by relatively unskilled health care workers in the field, according to a study and editorial in the Sept. 1 New England Journal of Medicine (Also see "Field-Ready, Automated Cepheid TB Test Shows Promise In Developing World" - Medtech Insight, 6 September, 2010.). But Woosley noted that this still leaves unsolved the questions of how to test for TB in HIV patients and children who can't do the sputum test.

The disease itself is challenging to treat even without the problem of drug-resistant strains. "TB has … rapid and slow-growing phases, and it grows differently in different parts of the body," Woosley said. "We need treatments that will hit the disease at multiple stages while avoiding the terrible drug interactions seen with current treatments, as well as rapid diagnostics that can be used in the field."

[Editor's note: This article has been corrected to remove several errors. The Global Alliance for TB Drug Development is the sole sponsor of the NC001 study; Bayer's Avelox (moxifloxacin) is being tested, but the firm is only supplying the drug and is not sponsoring the trial. FDA is not part of the TB Alliance. The TB Alliance licensed PA-824, one of the drugs being studied in NC001, from Chiron (now Novartis); it was not developed jointly. The budget of the Critical Path to TB Drug Regimens includes the Critical Path Institute's funding from the Science Foundation Arizona; FDA is not funding the effort, and the Gates Foundation and the TB Alliance are using their own resources and industry makes in-kind donations of staff and drugs only. CPTR's three arms – the "Coalition," the "Consortium" and research resources – are run respectively under the aegis of the TB Alliance, the Critical Path Institute and the Gates Foundation. There were 12,904 TB cases in the U.S. in 2008, the last year for which figures are available; the article had incorrectly stated that there were 1,500 cases per year. Jan Gheuens' name was originally misspelled.]

By Martin Berman-Gorvine

TB Study Lights Pathway Toward Combination Drug Trial Guidance

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