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By Claire Wingfield

After nearly 50 years, there is finally something to get excited about in tuberculosis (TB) drug development. Tibotec’s TMC207—the first compound from a novel class of TB drugs, the diarylquinolines—will likely be submitted to the U.S. Food and Drug Administration and the European Medicines Agency for accelerated or conditional approval sometime in 2012.

Between the 1940s and 1970s in the first wave of the antibiotic revolution, TB—previously incurable—was first conquered by the discovery of curative drugs and combination therapy containing three or four drugs taken for six months to two years. Since 1963, when the last new class of drugs to treat TB—the rifamycins—was discovered, and in sharp contrast to the accelerated pace of HIV treatment discovery and development in the past quarter century, research on new TB drugs virtually ground to a halt for nearly 40 years.

It is estimated that up to one-third of the world’s population—over two billion people—are infected with TB, and each one of them is a potential future case of TB disease. According to the WHO Global Tuberculosis Control Report 2010, TB remains the leading killer of people with HIV, accounting for at least a quarter of all HIV deaths in 2009. Despite being curable, TB claimed 4,700 lives each day—or the lives of 1.7 million people that same year.

Combination therapy for drug-susceptible TB can cure about 95% of all cases. Unfortunately, treatment for multidrugresistant TB (MDR-TB)—a form of TB disease that has developed resistance to the two most common and powerful TB drugs, isoniazid and rifampicin—cures only 50–70% of cases and requires 18–24 months of complicated, expensive, and often toxic combination therapy. This complex treatment regimen may include up to six different pills multiple times per day plus a painful injection that can cause a long list of side effects, not the least of which may include psychosis. Most drugs used in treating drug-resistant TB are not licensed for TB treatment, and therefore their recommended use is based on anecdotal experience rather than on a body of systematically collected evidence.

But there is hope. The TB treatment pipeline is the fullest it has been in decades, with six new drug compounds—four of which are from novel classes of drugs—being evaluated in clinical trials. Tibotec Pharmaceuticals’ diarylquinoline TMC207 and Otsuka Pharmaceuticals’ nitroimidazole OPC-67683 are in phase IIb clinical studies for treatment of drug resistant TB. The Global Alliance for TB Drug Development (aka the TB Alliance) has initiated phase II studies of PA824—also a nitroimidazole. Sequella’s SQ-109, which is a diamine, and Pfizer’s PNU-100480 and AstraZeneca’s AZ5847, both oxazolidinones, round out the list of drugs in human trials.

It is expected that Tibotec Pharmaceuticals, a subsidiary of Johnson & Johnson, will seek accelerated approval for TMC207 based on the results of its phase IIb trial and initiate an expanded access program—a first for TB treatment—in mid- to late 2011. At the 41st Union World Conference on Lung Health held in November 2010 in Berlin, Tibotec’s Dr. Dave McNeeley presented 24 week data from stage 2 of the phase IIb study showing that the addition of TMC207 to a standard background regimen resulted in faster time to culture conversion and higher conversion rate—both indicators of drug efficacy—than the control arm. Study volunteers with confirmed drug-resistant TB were given standard background therapy (later individualized based on drug susceptibility testing) with those in the experimental arm also receiving TMC207 for the first 8 weeks of treatment. The median time to convert from culture positive to culture negative in the TMC207 arm was 12 weeks, as compared to 18 weeks in the control arm. The shorter time to culture conversion has significant public health implications because conversion to culture negative indicates that a TB patient is no longer 
infectious and able to transmit the disease. Additionally, 79% of volunteers receiving TMC207 converted to culture negative at 24 weeks versus just 58% in the control arm. These early data demonstrate the potential impact that TMC207 may have on improving cure rates and decreasing the risk of transmission of drug-resistant TB in households and the community.

The second stage of this phase IIb study comparing 24 weeks of standard background regimen plus TMC207 versus standard background regimen plus placebo has completed dosing, and follow-up is ongoing. If the final data from stage 2 confirm the stage 1 results that TMC207 significantly improves cure rates for people with drug-resistant TB, Tibotec will most likely pursue accelerated approval for the compound while it conducts a phase III study. The company is planning to provide the drug through an expanded access program to those with a desperate need for treatment options who cannot participate in the phase III clinical trials. While there is a precedent for expanded access to experimental drugs for use in heavily pretreated or multidrug-resistant individuals in other diseases, the dispersed nature of the MDR-TB epidemic, the scarcity of well-functioning MDR-TB diagnostic and treatment programs, and the difficult, lengthy, and toxic nature of current treatment for the disease will likely pose challenges not encountered before.

The excitement about TMC207 is tempered by the concern that despite the drug’s promise, the pathway for worldwide regulatory approval is likely to be challenging. Depending on how quickly countries adapt their regulatory, diagnostic, and MDR-TB treatment programs, TMC207 may take years to roll out and become widely available to those living in high-burden, resource-limited settings. No TB drug has ever been made available through an expanded access program, making TMC207 a test case for how to ensure that a promising drug is made available as quickly as possible to those with limited or no treatment while making sure that it is used appropriately. There are lessons to be learned from HIV drug development about providing experimental drugs through expanded access.

But TB poses different challenges because pharmaceutical companies believe the target market to be small and poor. In most countries TB is treated with a public health approach that prioritizes the public good over individual patient needs. In the 1990s, during the highly active antiretroviral therapy (HAART) revolution, pharmaceutical companies took on the responsibility of providing expanded access to patients in need because it helped to generate pre-regulatory demand for the drug and taught health care providers—many of them private—how to use the drug. 

Because TB is a disease of the poor, many believe that there is limited potential for pharmaceutical companies to make substantial profits and that therefore they are less willing to bear the full cost and responsibility for expanded access programs—let alone the full costs of scaling up high-quality MDR-TB diagnosis, treatment, and supportive care.

There is also concern that if TMC207 is used inappropriately—with too few effective background drugs—new TB-
resistant strains could rapidly emerge, thus limiting the drug’s long-term impact on the TB pandemic.

Acknowledging these programmatic challenges and the urgent need and moral imperative to ensure access to promising TB drugs to people who are dying, TAG and others have been grappling with questions of how best to target the expanded access program for TMC207 in order to reach the individuals in greatest clinical need and to ensure that they receive care in high-quality programs without imposing unnecessary restrictions that would limit access. At the same time steps must be taken to ensure that the drug is given with appropriate active background TB therapy in the context of regular diagnostic and drug susceptibility testing to limit and monitor the emergence of drug resistance. TMC207 is farthest along in its development, so all eyes have been on Tibotec–it is encouraging that the company has taken the initiative to develop a plan for providing preapproval access to the compound. While in Berlin for the World Lung Conference, TAG met with Tibotec to review the company’s draft plan for an expanded access program and provided feedback on how to broaden its scope and make it easier for well-functioning programs to provide the compound to their patients.

Poor cure rates for drug-resistant TB and the limited understanding of how best to use current drugs make the need to establish an expanded access program for new treatments for drug-resistant TB more acute than for drug-susceptible TB,
and developers of these new drugs need to be prepared. Otsuka’s OPC-67683 is not far behind TMC207 in its development, thus Otsuka also needs to start planning for how it will roll out an expanded access program. TAG is working with researchers, providers, and activists to develop guidance on the type of mechanism that should be in place until the drugs are available to the general public; a document is expected to be completed in early 2011 and will include what worked in providing expanded access to antiretroviral drugs but will focus on addressing the specific challenges facing TB patients, health care providers, and national TB programs in accessing experimental treatments.

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