Tuberculosis treatment pipeline

1 July 2010. Related: Special reports, TB coinfection.

Claire Wingfield

Introduction: a robust pipeline, but uncertain support

Over the past several years we have seen a level of activity in tuberculosis (TB) drug research that hasn’t been witnessed since the heady days of the 1950s and ’60s when the introduction of combination therapy and the regulatory approval of rifampin revolutionized TB treatment. Indeed, the advent of combination curative chemotherapy for tuberculosis predated the anti-HIV combination antiretroviral therapy (ART) revolution of 1996 by over forty years. The current TB drug pipeline is the fullest and most promising it has been in 50 years, with 10 drug candidates currently in clinical trials—a level unprecedented since the 1960s. Not all of these drugs are new to TB treatment, as some have been used off-label to treat TB. Yet there are still insufficient data to best guide their use. Other drug candidates consist of new molecules with novel, unique ways of inhibiting or killing the TB bacteria and second-generation drugs with better activity and hopefully better safety profiles than their predecessors.

The enthusiasm inspired by this recent progress must be balanced with a realistic acknowledgment that even with ten drugs in the pipeline—six of them novel—it is not robust enough to achieve the World Health Organization’s (WHO’s) goal of halving global TB incidence from 1990 levels by 2015, nor the Stop TB Partnership’s target of having six new TB drugs approved by then. There are an estimated 2 billion people infected with TB around the world, compared with approximately 33 million infected with HIV (UNAIDS 2009; World Health Organization 2009). Over the past 23 years the U.S. Food and Drug Administration (FDA) has approved 24 new compounds to treat HIV infection. During that same time, the FDA approved just one new drug—rifapentine—to treat TB from an existing class of drugs, the rifamycins.

TB is most common in poor countries and communities; despite over nine million new cases each year, the vast majority of patients are unable to pay for the drugs. Because TB is an airborne infectious bacterium, curing TB disease is a public health responsibility yet governments have not allocated the necessary resources to cover the cost of TB diagnosis and treatment. A major rationale for the 50-year drought in TB drug development—aside from complacency of the fact that the disease was curable with existing, off-patent drugs—was the belief that new TB drugs would never command the blockbuster sales so beloved of pharmaceutical marketing and planning departments when compared with chronic diseases of the developed world such as cancer, diabetes, or heart disease. Thus, pharmaceutical companies felt limited incentive to invest in developing new treatments for TB, despite the emergence in the early 1990s around the world of deadlier, harder-to-cure forms of drug-resistant TB. But companies may be underestimating the potential for profits from superior new drugs and treatment regimens that could improve cure rates and shorten treatment duration, potentially making TB cures accessible to the world’s poorest people even in cases of drug-resistant disease.

If TB is curable why are new drugs needed?

Despite the fact that first-line treatment is able to cure 95% of all drug-susceptible TB, almost two million people died of TB in 2008; of these, 500,000 were HIV positive (World Health Organization 2009). Of the nine million people newly diagnosed with TB in 2008, only 61% were notified of their status (World Health Organization 2009) meaning that the status of a whopping 39% was not recorded and that many of these people likely were never diagnosed or treated properly. The majority of these cases occurred where TB services are underresourced within poorly functioning health systems. TB control programs put the onus on the person with symptoms to seek out diagnosis. Even when someone—particularly young children and people with HIV—appears for diagnosis at a microscopy center, they may remain undiagnosed because the most commonly used tool, smear microscopy, misses extrapulmonary and smear-negative TB. In many treatment programs, properly diagnosed patients are required to travel to health centers every day to pick up their medications for the entire duration of six to eight months of first-line treatment. This burden can make accessing treatment untenable for many patients and costs time and resources for the patient and the health system. It would be difficult to try to improve on the 95% cure rate for drug-susceptible disease, but a substantially shorter treatment regimen—perhaps ten days to cure (similar to that of other bacterial infections), or even two months—would vastly improve treatment adherence and significantly ease burdens on TB patients and health systems.

The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) and the rise of TB/HIV coinfection have further complicated clinical management of TB and the delivery of primary health services. Health care providers lack reliable information about which drugs to use and for how long to treat and cure drug-resistant TB. As a result, cure rates only reach 70% for MDR-TB patients in the best-run health systems, and drop to 30% for XDR-TB patients who are HIV negative. For many drug-resistant patients, treatment regimens are based on drug availability, many of them unlicensed for TB. Meanwhile, in some parts of sub-Saharan Africa up to 70% of TB patients are coinfected with HIV (World Health Organization 2009). One of the most powerful first-line TB drugs, rifampin, interacts with some antiretrovirals (ARVs), specifically nevirapine, the most common component of first-line therapy globally, and boosted protease inhibitors—the backbone of second-line ART. The appropriate substitute TB drug, rifabutin, is not available in most parts of the world, and where it is, it is far too expensive.

Despite the fact that people with HIV, infants, and young children bear an undue burden of TB morbidity and mortality, they are often excluded from many clinical trials (Burman. 2008; Ma 2010; Marais 2010). As a result there is a dearth of age-specific data on the correct dosing of TB drugs in children, or how best to dose TB drugs and ARVs concurrently. TB treatment researchers have begun to grapple with how to include these “special” populations in clinical studies safely and effectively. One solution has been for different research consortia to work together to increase the enrollment of young children and people with HIV in clinical trials. However, most trials exclude anyone with smear-negative or extrapulmonary TB, ruling out most children and most people with HIV up front. In a sign of progress, however, at least one developer—Tibotec—of a novel TB drug, has submitted a plan to evaluate its compound TMC207 in children.

Pregnant women are also consistently excluded from participation in TB clinical trials despite their high risk for TB morbidity and mortality. Women bear the greatest burden of both TB and HIV during their childbearing years. In fact, TB kills more women in this age group than all maternal cause mortality—maternal death during and shortly after pregnancy—combined: it is estimated that 15% of maternal deaths are among women coinfected with TB and HIV (Gupta 2009; Marais 2010; Mofenson and Laughton 2007). These dire facts demand a fundamental shift in trial designs to include pregnant women and women who may become pregnant in drug trials.

Accelerating research

Despite these challenges there have been some promising developments within the TB treatment research field over the past year that have the potential to increase research capacity, speed up the development of new treatment strategies and accelerate approval of new regimens:

• The Tuberculosis Trials Consortium (TBTC), a research network funded by the U.S. Centers for Disease Control and Prevention (CDC) has been conducting TB drug trials for over 20 years. The consortium was recently reconfigured to include more international sites with increased capacity to conduct treatment trials for drug-resistant TB and enroll more HIV-positive volunteers and children into studies. The shift to evenly distributing its study sites between U.S.-based and international research institutions and a broader research agenda demonstrates the TBTC’s commitment to filling important gaps in our knowledge of the best ways to treat and cure both active TB and latent infection.
• In 2009, Dr. Anthony Fauci, the head of U.S. National Institute of Allergies and Infectious Diseases (NIAID)—the largest public funder of TB research in the world—announced that TB would be integrated as one of the focal areas of its reconfigured HIV clinical trials network system, including the AIDS Clinical Trials Group, the HIV Vaccine Trials Network, and other sites (Fauci 2009). By broadening the scope of the NIAID-supported clinical trials infrastructure to include studies evaluating TB drugs for both monoinfection and HIV coinfection, the TB treatment research field will in short order almost double its capacity to conduct clinical trials in high- and medium-TB-burden settings among geographically and demographically diverse groups.
• In March 2010, the Critical Path to TB Drug Regimens (CPTR) Initiative was launched to accelerate the evaluation and regulatory approval of novel TB treatment regimens. The initiative is a collaborative effort of public- and private-sector stakeholders—including the FDA, the Critical Path Institute, the Alliance for Global TB Drug Development (TB Alliance), the Bill and Melinda Gates Foundation, and several pharmaceutical companies including Anacor, AstraZeneca, Bayer, Novartis, Otsuka, Pfizer, Sanofi-Aventis, Sequella, and Tibotec/Johnson & Johnson—to identify more efficient ways to study TB drugs in combination to expedite regimen change rather than introducing TB drugs sequentially. The move to regimen development is a paradigm shift for the field and will require regulatory agencies, research institutions, funders, policy makers, and advocates to alter their strategies to work collaboratively to ensure that the efficient testing and approval of new regimens is safe and maximizes resources.

Getting back to basics

A great number of unanswered questions about TB pathogenesis make up some of the biggest challenges to discovering new and better TB treatments. Researchers are unable to explain why only some people progress from latent infection to active disease or why most immunocompetent people remain healthy despite infection. We do not yet fully understand what happens to the TB bacterium when it goes into latency and what—at the molecular or cellular levels—triggers reactivation. These knowledge gaps hamper the development of new TB treatments and highlight our lack of understanding of how the current drugs work alone and in combination to inhibit and kill the bacteria. The spectrum of TB disease needs to be better characterized to identify which drugs or combinations of drugs are potent enough to halt and/or cure each phase of the bacterial life cycle. This knowledge could also lead to the development of better surrogate markers—biological measures that might indicate a treatment effect and predict clinical outcomes—to predict the efficacy of TB drugs in individual patients or in clinical trials.

Starting in the early 1990s, the FDA began to approve HIV drugs based on their effect on surrogate markers such as, at first, changes in CD4 cell levels and finally, after the development of quantitative real-time polymerase chain reaction tests, changes in HIV RNA levels (viral load). These changes allowed for an unprecedented acceleration of clinical trials, paving the way for the combination ART revolution of 1996. However, most approved TB drugs came to market in an era when such techniques did not exist. Reading the earliest randomized clinical trial in humans, of the antibiotic streptomycin for monotherapy of TB in the 1940s, one would think the measures used—including chest X-ray and solid bacterial culture, as well as clinical improvement and relapse—were somewhat primitive, except that now in 2010, some 60 years later, virtually the same tools are used to measure TB drug activity. With TB, there is no way to measure drug activity in real time. Unfortunately for TB patients and researchers, at this time the TB field lacks a test that can predict whether a drug or regimen will result in a stable cure for a patient.

The Pipeline

The TB Treatment Pipeline—Drugs in Clinical Trials, July 2010

Notes: *Indicates novel drug candidates; LTBI = Latent TB infection; DS-TB = drug-susceptible TB; DR-TB = drug-resistant TB; MDR-TB = multidrug-resistant TB: XDR-TB = extensively drug-resistant TB.

So what’s new?

There are six novel compounds being evaluated in clinical trials. Two of these new compounds could be considered for regulatory approval within the next two years; they are Tibotec Pharmaceuticals’ diarylquinolone TMC207 and Otsuka Pharmaceuticals’ nitroimidoxazole OPC-67683. Both companies have indicated that they will pursue accelerated regulatory approval based on favorable results in ongoing phase II studies taking place in patients with MDR-TB.

In June 2008, Tibotec (a subsidiary of Johnson & Johnson) published preliminary data from stage 1 of a phase II placebo-controlled, randomized trial showing faster time to culture conversion and a higher number of culture conversions after eight weeks of standard background regimen plus TMC207 in patients with MDR-TB (Diacon 2009). A second stage of the phase II study is comparing six months of placebo or TMC207 plus standard background regimen. Stage 2 patients have recently completed their last dose. There is still follow-up being done with stage 2 patients while they complete their background regimen. An interim analysis of both stages will take place in summer 2010. There is some evidence to suggest that TMC207 may affect ARV levels, so Tibotec has initiated drug-to-drug interaction studies with its compound and boosted protease inhibitors nevirapine and efavirenz. Tibotec is recruiting at multiple sites in Europe, Asia, and Africa for an open-label trial of TMC207 for adults who have smear-positive, confirmed MDR- or XDR-TB, including people with HIV. Tibotec is the only drug developer that has submitted a pediatric development plan to regulatory authorities to guide future clinical studies of TMC207 in children to establish safe and effective dosing based on age and development (McNeeley 2010).

Otsuka has completed enrollment of a phase II, double-blind, randomized controlled study comparing twice-daily doses of 100 mg and 200 mg of OPC-67683 plus optimized background therapy (OBT) to placebo plus OBT in volunteers with confirmed MDR-TB at sites in Europe, Asia, South America, Egypt, and the United States. Volunteers must stay in the hospital for the 56-day treatment period, and then be followed in the community for an additional 28 days after treatment. All patients who complete the double-blind portion will then be eligible to enroll in an open-label study of OPC-67683 for six months. Otsuka is also enrolling a study of patients in Latvia who did not have a meaningful clinical response after being treated for nine months or more with second-line drugs. Otsuka has completed ARV drug-to-drug interaction studies of OPC-67683 with tenofovir and lopinavir/ritonavir; results are not yet public. A study looking at OPC-67683 with efavirenz was recently initiated (Geiter 2010).

Both companies are in early discussions about phase III studies for their drugs, but no definitive decisions will be made until data from phase II are available. However, if the results from the second stage of the TMC207 trial confirm the stage I interim analysis, it is very likely that Tibotec will apply to the FDA and the European Medicines Agency (EMA) for early regulatory approval. The approval would be conditional and would require Tibotec to continue to collect confirmatory post-marketing safety and efficacy data. If conditional approval is granted, TMC207 may be brought to market in 2011. Otsuka may also seek regulatory approval for OPC-67683 after its phase II studies are complete. Many ARVs have been granted accelerated approval, but this has never been done for a TB drug before. There may be unanticipated hurdles for drug sponsors, researchers, activists, and regulatory authorities. The FDA and EMA have been working with sponsors to establish the regulatory requirements to ensure that there are sufficient data to determine the safety and efficacy of new TB drugs after phase II/III clinical studies are complete. There is significant concern whether or not regulators in countries with a high burden of MDR-TB will have the resources to grant accelerated approval or if they will be willing to follow the recommendations of the FDA and the EMA.

PA-824 is a novel compound—a nitroimidazole like Otsuka’s OPC-67683—that was licensed by the TB Alliance from the former biotechnology company Chiron. The compound hit a snag last year when the FDA put it on a clinical hold due to preclinical reports of cataracts in animals; however, in July 2009, the FDA released the clinical hold and the next month the TB Alliance initiated a planned, second 14-day early bactericidal activity (EBA) study—a clinical trial assessing the ability of varying doses of a drug to rapidly kill metabolically active TB bacilli. The study evaluated doses of 50, 100, 150 and 200 mg per day over a 14-day period. PA-824 continues to appear safe and well tolerated, with no evidence that the drug causes cataracts in humans. Once the final data of the second EBA study are complete and analyzed, these results will form the basis for choosing a dose of PA-824 to take into later stage clinical trials. The TB Alliance is planning to evaluate PA-824 in novel regimens for both drug-susceptible and drug-resistant TB, if funding allows. The first EBA study of a novel PA-824-containing three-drug combination is being planned for initiation in the second half of 2011 (Seidel 2010).

Following the June 2009 announcement of an agreement between the TB Alliance and Tibotec/Johnson & Johnson granting the TB Alliance rights to develop Tibotec’s TMC207 for drug-susceptible TB, the TB Alliance conducted a phase I drug-to-drug interaction study further examining the interaction between this drug and rifamycins (specifically, rifampicin and rifapentine). Results are expected by August 2010. The TB Alliance is also conducting a 14-day EBA study of TMC207 in order to explore the potential for lowering the dose for future clinical trials. Further, the TB Alliance is planning to initiate a 14-day EBA study of a novel drug combination containing TMC207 in the second half of 2010. Finally, Tibotec and the TB Alliance are collaborating on a drug discovery program to identify second-generation diarylquinolines—the same drug class as TMC207. Under the terms of the agreement, the TB Alliance will own the rights to any new compound through a royalty-free license to facilitate lower pricing (Seidel 2010).

Second-generation compounds

SQ 109 is a distant cousin of ethambutol—a drug used in first-line treatment to prevent the development of isoniazid-resistant TB—that has and is undergoing multiple EBA studies to determine optimal dosing. The drug’s sponsor Sequella is working the Pan African Consortium for Evaluating Anti-tuberculosis Agents (PanACEA) to evaluate SQ 109 for drug-susceptible TB. Phase II/III studies are expected to begin enrollment in 2011. In parallel, Sequella intends to evaluate SQ 109 in drug-resistant TB (Horwith 2010).

Pfizer is nearly finished with a multidose study of its second-generation oxazolidinone PNU-100480 in healthy volunteers. Mouse studies have shown PNU-100480 to have superior activity over linezolid, an earlier oxazolidinone, at lower doses. Pfizer is planning the first study of PNU-100480 in TB patients and intends to study the compound for drug-resistant TB (Wallis 2010).

AstraZeneca Pharmaceuticals also has a second-generation oxazolididnone, AZT5847, that is currently in phase I safety, tolerability, and PK dose-escalation studies in healthy volunteers. Results are expected later in 2010.

Latent TB infection

Each person who is latently infected with TB is a potential future case of TB disease. Therefore it is vital for TB control efforts to prevent the progression of latent TB infection to active disease. Treatment for latent infection remains a conundrum for most national TB programs. The current strategy is to give 6–9 months of isoniazid preventive therapy (IPT). Study after study has shown IPT to be a valuable intervention in reducing the incidence of TB disease but its implementation presents multiple challenges for underresourced programs. IPT is, by its very nature, a therapy for healthy people, thus making the long duration of treatment, side effects, and uncertainty of durability an adherence challenge. But many policy makers and clinicians in high-TB-burden countries have been reluctant to implement IPT as an intervention for fear of missing a diagnosis of active disease and putting people on isoniazid monotherapy. Because young children who are contacts of adult TB cases and people with HIV who are latently infected with TB are at increased risk for TB disease progression and death, failure to implement this intervention can be deadly. A few operational studies and clinical trials are underway to evaluate strategies to make preventive therapy easier to operationalize.

The CDC, in collaboration with the Botswana Ministry of Health, conducted the BOTUSA trial, which compared 36 months of daily IPT to a standard six-month regimen of IPT in people with HIV for the treatment of latent TB infection. The study demonstrated that continuous IPT significantly reduced the risk of developing TB disease in HIV-positive persons who tested positive for exposure to TB using a tuberculin skin test (TST). In both the 6- and 36-month arms the protective effect of IPT waned 6 months after treatment completion (Samandari 2010)—likely due, in part, to reinfection.

The Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) is made up of research institutions based in the United States, Brazil, South Africa, and Zambia that are conducting IPT and intensified case finding studies in high-HIV-prevalence settings. Two of the three studies, THRio and Thibela, are evaluating the provision of IPT to people with HIV in urban clinics in Brazil and to gold mine workers (of any HIV status) in South Africa.

As part of the THRio study, health care workers in 29 HIV clinics in Rio de Janeiro received training to use a TST to detect TB among—and to provide IPT to—people who are accessing HIV care and treatment. Over 18,000 HIV-positive clients have been included in the study, and of these over 1,300 received IPT and more than 80% completed therapy (Eldred 2010). Although the primary outcome data of TB incidence are pending, a baseline study conducted in these clinics revealed that combined ART and IPT is more effective in reducing TB incidence than either used individually (Golub 2007).

In the Thibela study, over 27,000 miners have been screened for TB and more than 24,000 have begun IPT. Trial results are due later this year. In implementing IPT, researchers identified more cases of active TB than had been diagnosed through regular gold mine clinical care. This highlights the benefits of intensified case finding before initiating IPT, and could address some of the concerns raised by policy makers about misdiagnosing active TB disease as latent infection. Adverse events and adherence data will be released in fall 2010 (Eldred 2010).

The TBTC is expecting to complete data analysis this fall on Study 26, which is evaluating a 12-week, once-weekly rifapentine/isoniazid regimen versus 9 months of daily isoniazid. If the study demonstrates that the shorter regimen is superior or at least equivalent to 9 months of IPT, it has the potential to simplify adherence. Two substudies of TBTC Study 26 looked at liver toxicity (hepatoxicity) and pharmacokinetics—how a drug is absorbed, distributed, metabolized, and eliminated by the body—in children. Pediatric dosing is not always studied as it should be—many sponsors simply extrapolate from adult data, which can be misleading—so the TBTC pediatric pharmacokinetic substudy can be a model of how to include children in TB drug studies.

Drug-susceptible TB

In light of the fact that first-line TB treatment has a cure rate of 95%, the cost and logistics required to recruit thousands of volunteers and establish hundreds of clinical trial sites to demonstrate statistical improvement from the current standard of care appears unlikely. So how can treatment for drug-susceptible TB be improved upon? Rather than showing superiority over current treatment standards, the aim of current research is to identify a new drug regimen or regimens that will improve treatment success by shortening treatment duration, simplifying dosing schedules, and improving side-effect profiles as well as improving treatment outcomes in pediatric TB and TB/HIV coinfection.

Fluoroquinolones—a class of broad-spectrum antibiotics used to treat a variety of bacterial infections—have been used in the treatment of drug-resistant TB since the 1990s, but are also being evaluated as part of a shortened first-line treatment regimen. There are two phase III studies looking at fluoroquinolones to shorten treatment for drug-susceptible TB from six months to four months.

The REMox TB trial is being conducted by a collaborative of research institutions including the TB Alliance, Bayer HealthCare, and University College London. Moxifloxacin—a newer flouroquinolone—is being evaluated to replace either ethambutol or isoniazid as part of a treatment-shortening regimen. The last patient visit will be in the second half of 2012 (Seidel 2010).

The OFLOTUB consortium—a partnership of researchers based in Africa and Europe and the WHO’s Special Programme for Research and Training in Tropical Diseases (TDR)—completed follow-up of all volunteers from its study evaluating gatifloxacin as part of a treatment-shortening first-line regimen. Safety and efficacy results are expected to be released by the end of 2010 (Lienhardt 2010).

Several other drug-susceptible studies are comparing rifapentine to rifampin as part of the backbone of first-line treatment. The two drugs are from the same class of drugs, rifamyacins, and have good penetration and sterilizing ability—meaning that they are able to kill active and slowly reproducing TB bacteria—but both are contraindicated for use with certain commonly used ARVs such as nevirapine and boosted protease inhibitors. Rifampin has been one of the most powerful and widely used TB drugs since the 1970s (Fox 1999). Some preliminary data suggest that rifapentine may be more bactericidal—able to kill TB bacteria—then rifampin at lower doses and is better tolerated at higher doses. Several phase II studies are evaluating the use of rifapentine to shorten first-line treatment.

The TBTC has almost fully enrolled Study 29, which is a phase IIb trial comparing rifapentine to rifampin during the intensive phase—the first two months—of treatment for drug-susceptible TB. The Johns Hopkins University, the University of Cape Town, and the the University of Cape Town Lung Institute began enrolling a safety and efficacy study of two doses of rifapentine during the intensive phase of first-line treatment in TB/HIV coinfected adults with CD4 counts above 200 as compared to standard of care (Efron 2010). The Johns Hopkins University in collaboration with the Federal University of Rio de Janiero is conducting a second rifapentine study evaluating the safety and efficacy of rifapentine/moxifloxacin in place of rifampicin/ethambutol during the intensive phase of first-line treatment. Study completion is expected in late 2011 (Efron 2010).

A four-month regimen might become a reality within the next five years, but the challenge will be to get national TB programs to adopt the new shorter regimen(s), train health care workers to implement new treatment guidelines, and build patients’ TB treatment literacy to increase demand. Operational and implementation research needs to be scaled up by national programs to expedite and support the adoption of successful strategies where they are needed most.

Rethinking last-chance drugs

The TBTC recently completed enrollment in the LiMiT study (also known as TBTC Study 30), which is evaluating the safety and tolerability of low-dose linezolid in volunteers with confirmed MDR-and XDR-TB. Linezolid is an oxazolidinone antibiotic that has been used since the 1990s to treat drug-resistant TB; occasionally it has been used as a last resort for XDR-TB regimens, as it has a nasty side-effect profile including irreversible peripheral neuropathy. The TBTC study is using a lower dose of the drug in hopes that it will be safer and more tolerable.

By May 2010 NIAID enrolled 24 of a target of 40 chronic XDR-TB patients in a study evaluating two doses of linezolid (600 mg and 300 mg). In the study, volunteers failing all treatment for the previous six months are enrolled into two arms—one that starts linezolid immediately and one that delays starting the drug for two months. An interim data analysis for sputum conversion is expected to occur sometime in summer 2010 to determine if it is still ethical to continue the delayed arm (Barry 2010).

NIAID is evaluating a broad-spectrum antibiotic, metronidazole, which has been used but never formally indicated for drug-resistant TB. The Data Safety Monitoring Board (DSMB)—an independent committee that reviews ongoing studies to ensure that study volunteers are not exposed to undue harm—officially recommended closing new enrollment into the study after an excess of adverse events, including peripheral neuropathies and seizures, in volunteers receiving the study drug. Only half the projected enrollment was achieved, and it is uncertain whether there will be enough data to support going forward with a new trial using a lower dose. Data analysis is ongoing, and patients enrolled prior to the DSMB closure will continue to be followed up per protocol (Barry 2010).

Where Is Lupin?

For the past few years, Treatment Action Group’s TB drug pipeline has included Lupin Pharmaceutical’s LL-3858. According to the Stop TB Partnership’s working group on new TB drugs’ website, Lupin is set to begin phase II clinical studies of the compound. No representatives from Lupin have attended any of the numerous TB research meetings to present recent data on the compound. Thus, the future of LL-3858 remains unknown. Considering that the field is moving toward novel regimens that will require greater collaboration between drug developers and research institutions, Lupin seems to be still waiting on the platform while the train has already left the station.

Recommendations

Relative to the past 50 years, TB treatment research is making significant progress, but not enough is being done to eliminate TB as a public health threat by 2050.

Pregnant women, children, and people with HIV must be included in clinical trials of new TB drugs and regimens. These groups bear a higher risk for TB death, thus underscoring the need for research that will lead to appropriate treatment and dosing. Their inclusion in clinical trials should be planned from the beginning of the development process and not as add-ons once phase III studies are being initiated.

Investment to build the capacity of activists to understand and advocate for research on new drugs and the uptake of these new tools is critical. The achievements of HIV research activists demonstrate the value and influence patients and affected communities can bring to innovation in research and regulatory processes. Research institutions and local trial sites need to engage community members through community advisory boards and educational workshops, and to develop research and TB literacy materials to increase awareness and acceptance of TB research.

TB and TB/HIV activists need to pay attention to research taking place in their communities and make contact with researchers. Activists need to understand the research process and the potential impact of research findings on clinical care and advocate for the uptake of promising interventions by national programs.

Policy makers must think more innovatively about their national TB guidelines and be unafraid to challenge the status quo. Many TB control programs and protocols rely on evidence dating back decades and do not take into account new data. Ministries of Finance need to ensure that national TB programs are adequately resourced and Ministries of Health must adopt new evidence-based treatment strategies quickly and consistently.

Otsuka and Tibotec have shown that it is possible to conduct drug registration trials in areas where drug-resistant TB is being treated; however, a great deal of additional capacity is needed to navigate the regulatory bodies and sustain local research infrastructure. Because there is limited (or no) experience conducting studies in compliance with the regulatory standards of the International Conference on Harmonisation and the WHO’s Good Clinical Practice in many of these countries, sponsors of studies will need to commit sizable resources to strengthen the research infrastructure. This capacity development is not just for researchers but also for regulatory authorities. Therefore, the governments of high- and medium-TB-burden countries need to adequately resource these regulatory bodies so that they are able to respond to trial sponsors and provide timely feedback.

TB treatment research consistently receives the most funding of any area within TB research—$174 million in 2008, representing 35% of all monies spent on TB research—yet it is still wholly insufficient to address the gaps to support even current efforts (Treatment Action Group 2010). The field needs more funders to invest in TB research including basic science, which is the foundation for the development of all new tools. More funds are necessary to ensure that there are sufficient resources to conduct phase III and IV studies of the compounds already in the pipeline and support the development of those in discovery and preclinical studies. Likewise, operational research needs to be prioritized by national programs to prepare for the quick adoption of promising new interventions.

The great news is that there are ten compounds, six of which are new drugs, in clinical trials. The bad news is that funding for phase III and IV studies is not guaranteed and the capacity to conduct studies in line with regulatory requirements is limited. Initiatives like the CPTR and the expansion of trial networks are fostering greater collaboration among research institutions. As part of these efforts, building capacity of researchers in high- and medium-TB-burden countries to conduct registration trials and supporting national programs to conduct operational research must be a priority. The research priorities and activities should be driven by the realities on the ground. More than anything, radical change is required from all stakeholders to ensure that TB control is equipped with the necessary tools to prevent, diagnose, and cure TB in all populations.

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