Issue Date: September 24, 2007
Taking Down TB
FOR CENTURIES, tuberculosis took a terrible toll until the advent of effective medicines. The world then grew complacent and let its guard down, allowing research, product development, and vigilance against the disease to wane. The belief was that a medical armamentarium, consisting of a diagnostic test from the 1880s, a vaccine from the 1920s, and antibiotics from the 1940s, had stemmed the spread of TB. A few newer drugs still were added, but incidence of the disease unexpectedly shot up in the 1980s, propelled in part by the emerging HIV pandemic. By 1993, with an alarming rise in drug-resistant TB, the World Health Organization (WHO) designated TB a global health emergency.
Although the rate at which people are developing TB has declined, the number of cases continues to increase slowly, according to WHO figures. Hardest hit areas are in the developing world, where poverty, other diseases, and inadequate health care are factors. Killing about 1.6 million people annually, TB is the second leading infectious cause of death worldwide, after HIV/AIDS, and the leading cause in people infected with HIV. An estimated one-third of 40 million people with HIV are infected with TB.
HIV-infected people have a high risk for developing TB. But most people, if not HIV-infected, don't get TB when exposed to it. Of those who do, just a few percent develop active disease, while about 90% develop asymptomatic, noncontagious latent TB infections. Carried by nearly 2 billion people worldwide, latent TB infections can reactivate decades later, for instance when the immune system is suppressed. TB often manifests as pulmonary disease, but disseminated forms can affect almost all the body's organs.
The existing vaccine helps protect young children from developing serious disseminated forms of TB, but it is unreliable in preventing pulmonary TB in adolescents and adults (see page 34). TB is curable when diagnosed adequately and treated appropriately, but this remains difficult (see page 39). WHO recommends a treatment regimen for active, drug-susceptible TB consisting of four antibiotics—isoniazid, rifampicin (also called rifampin), ethambutol, and pyrazinamide—taken for two months, followed by isoniazid and rifampicin for another four. Latent TB infections often are treated with isoniazid alone for nine months.
Using multiple drugs with different modes of action prevents Mycobacterium tuberculosis (Mtb), the disease-causing agent, from developing resistance to any one drug. The extent of treatment is designed to purge a resilient and persistent bacterium adept at hiding from the immune system and lying dormant in the body for decades. Current HIV and TB therapies can be incompatible and thus are given separately or under strict monitoring.
In the most basic cases, patient compliance with the complicated, lengthy, and unpleasant drug treatment is a significant problem. Many patients stay with therapy for only a few months, and failure to complete it risks not only relapse but also the creation of drug-resistant Mtb. And TB resistant to the first-line drugs isoniazid and rifampicin, called multi-drug-resistant (MDR) TB, has been increasing, particularly in China, India, and the former Soviet Union countries.
While difficult and expensive to treat, MDR-TB can be combated— albeit sometimes less than 60% of the time—by taking one or more of a group of second-line drugs, some with serious side effects, for up to two years. Much more lethal because of the limited treatment options is extensively drug-resistant (XDR) TB. This form is also resistant to second-line fluoroquinoline drugs and one of three injectables—amikacin, capreomycin, or kanamycin.
Controlling TB and preventing the development of MDR-TB and XDR-TB will require more effective drugs and treatment plans. Programs are under way to better employ existing therapies and make them more accessible. Meanwhile, R&D on TB has reemerged in the past decade—trying to make up for lost time—and drug developers are moving new candidates into clinical testing. Looking further ahead, the R&D community, including a few large companies, is motivated to better understand the bacterium and the disease, along with conducting targeted screening and drug discovery.
To control TB with existing drugs, WHO relies on the Directly Observed Therapy Short-course (DOTS) program, which includes having independent observers make sure patients swallow their pills. The DOTS program, WHO reports, is now in 187 countries, has treated 26 million people since 1995, and can offer a 95% success rate. The Stop TB Partnership, a network of more than 500 public and private organizations, helps supply the DOTS program through the Global Drug Facility (GDF).
Most TB drugs are no longer patented and are produced by generics firms and a few major pharmaceutical companies. Four Indian drug firms have signed long-term contracts to supply the GDF: Svizera, Lupin Pharmaceuticals, Cadila Pharmaceuticals, and Strides Arcolab. Strides is working with Sandoz, the generic drug business of Novartis, a producer of rifampicin.
Pharmaceutical companies are also helping to make drugs accessible. For example, Sandoz manufactures fixed-dose combinations of TB drugs in India, and the Novartis Foundation for Sustainable Development has donated enough to the GDF over five years to treat 500,000 people. Likewise, Sanofi-Aventis, which makes rifampicin and TB drug combinations, has decided to produce all its TB drugs at its plant in South Africa, where it has been supporting the TB Free program for five years. And Eli Lilly & Co. supplies subsidized antibiotics for treating MDR-TB to DOTS programs.
SINCE 2003, Lilly has committed $120 million to a partnership with WHO to increase the affordable supply and proper use of the second-line drugs capreomycin and cycloserine. The wide-ranging initiative also includes the Centers for Disease Control & Prevention (CDC), and 12 other organizations, and it trains health care workers, develops disease surveillance systems, and runs outreach programs. On the supply side, Lilly has transferred antibiotic production technology to four companies: South Africa's Aspen Pharmacare, Hisun Pharmaceutical in China, Shasun Chemical & Drugs in India, and Russia's SIA.
The manufacturing processes are fairly complex, explains Patrizia Carlevaro, head of Lilly's international aid unit and team leader of the MDR-TB partnership. To ensure that high-quality drugs are produced at reasonable costs, Lilly has invested in its partners' plants and sent manufacturing and quality-control teams to assist in setting up production, she explains. Lilly also supplies dossier materials for regulatory approval and even allows the use of its trademark.
"We wanted to create a multisource supply environment and make sure these producers can be viable long-term," Carlevaro says. "Not only can these four companies produce for their own countries, which are among those with the highest MDR-TB burden, but they also are strategically placed to supply larger regions." In May, the Chao Center for Industrial Pharmacy & Contract Manufacturing, an affiliate of Purdue University, in Indiana, agreed to become the sole U.S. supplier of Lilly's capreomycin.
ALONGSIDE expanding drug supply and treatment programs are increased efforts in TB research to meet Stop TB goals by 2015. These goals are better diagnostics, more effective vaccines, and oral drugs with limited side effects that can shorten treatment, combat resistant strains, work with HIV drugs, and treat latent infection. Having better diagnostics and more efficacious and tolerable drugs, the TB community believes, will improve patient compliance, increase cure rates, and ease burdens on public health systems. Resources could then be used to reach more patients, leading ultimately to declines in infection, resistance, and death.
To achieve these ends, a number of organizations have been putting money into TB-related R&D. According to a report from the Treatment Action Group (TAG), an AIDS advocacy group, 40 that were willing to report figures spent a combined $393 million in 2005—69% came from public sources, 20% from philanthropies, and 11% from six companies. Accounting for industry contributions in particular is incomplete, since many drug companies clearly involved—such as GlaxoSmithKline, Bayer, and Sanofi-Aventis—did not disclose their spending.
The National Institute of Allergy & Infectious Diseases (NIAID) was the main source of funds, spending $120 million in 2005, while other parts of the National Institutes of Health spent a combined $37 million. The Bill & Melinda Gates Foundation was second at $57.4 million, followed by the U.K. Medical Research Council, CDC, Wellcome Trust, and the European Commission (EC).
"Spending has increased steadily over the past 10 years but has started to level off," says Christine F. Sizemore, chief of the TB and other mycobacterial diseases section in NIAID's Division of Microbiology & Infectious Diseases. In 1991, NIAID spent just $3.5 million on TB-related research, but that jumped to more than $30 million by 1995. In fiscal-year 2006, NIAID spent about $120 million to support 319 projects: about 42% went to 156 basic or clinical research projects, 35% for 100 in drug discovery and development, and the rest to vaccine and diagnostic work. In comparison, this amount represents just about 4% of what NIH spends annually on HIV-related research.
For a few decades up until the 1990s, TB research and product development was pretty much at a standstill, Sizemore says. "The goals set now are ambitious, and they may be achievable, but what is certain is that the community is learning immeasurable things about how to actually do drug and vaccine development." To advance the process, she says, NIAID's job is to help create a knowledge base that will inform these efforts and move basic findings into tangible applications.
NIAID supports several large programs designed to meet the R&D community's need for research tools and facilities. Among these is the TB Antimicrobial Acquisition & Coordinating Facility (TAACF), which involves the Southern Research Institute in Birmingham, Ala.; Colorado State University; and Johns Hopkins University. Drug developers can submit antimicrobial agents for screening to, or obtain materials from, TAACF. Another program is the Tuberculosis Animal Research & Gene Evaluation Taskforce (TARGET) at Johns Hopkins, which is developing animal models and testing Mtb mutants. Also, at Case Western Reserve University, the TB Research Unit is trying to identify markers of infection and immunity and of disease progression and drug efficacy that are needed for clinical trials. Meanwhile, a program at Research Triangle Institute International, in North Carolina, hopes to bring in pharmaceutical industry partners for drug development and commercialization.
IN THE PAST five years, the TB drug pipeline has shifted from nearly empty to having about 30 compounds under investigation; several are in early clinical testing. Stop TB estimates, however, that through 2015, it will take about $2.4 billion for further discovery and early-stage development work and another $2.4 billion for clinical trials. Current resources are believed to total about $600 million, leaving a substantial funding gap. For now, several small and large drug companies are supporting work on their own, while consortia and public-private partnerships have formed to coordinate efforts.
Since 2000, the not-for-profit Global Alliance for TB Drug Development (TB Alliance) has received nearly $130 million in Gates money and $53 million from the Rockefeller Foundation and from Dutch, U.S., Irish, and U.K. agencies. TB Alliance doesn't have its own labs or plants but instead commissions work and brings together collaborators from academia, industry, and government, explains R&D Director Melvin Spigelman. It takes a business-based approach to drug development and manages the largest portfolio of TB drug candidates. Its goal is to have a new drug on the market by 2010.
GlaxoSmithKline, Bayer, Novartis, and Cumbre Pharmaceuticals are among TB Alliance's industrial partners, and AstraZeneca and Sanofi-Aventis are discussing strategies that might involve working with the group. "Some of the major pharmaceutical companies have stepped up to the plate and have devoted resources and efforts, and that's been extremely welcomed," Spigelman says. "We have adopted a variety of different models to work with partners, and part of TB Alliance's strength lies in its flexibility." Each relationship has the understanding that resulting products will be made affordable in developing countries, he adds.
In 2005, TB Alliance joined with GlaxoSmithKline to direct and support 25 full-time researchers at the company's Tres Cantos, Spain, drug discovery facility that focuses on diseases of the developing world. There, GlaxoSmithKline also supports a like number of researchers and pays overhead costs. According to the company, the project has screened about 1.5 million compounds, and four preclinical programs are under way.
Between 1993 and 2003, GlaxoSmithKline invested more than $30 million to run the Action TB initiative, which brought together research groups from the U.K., U.S., and Africa to identify and validate targets for therapeutic intervention. This effort has helped fuel the company's in-house work and its academic collaborations.
ALSO IN 2005, Bayer and TB Alliance launched Phase II trials of moxifloxacin that just recently showed faster treatment. Bayer donates the drug to trials being run by clinical investigators who are looking at substituting it for either ethambutol or isoniazid. They soon expect to start what Spigelman says may be the largest Phase III TB drug study ever conducted.
Clinical testing generally involves substituting a new drug into the existing regimen and looking for an increase in efficacy. Researchers hope a new combination might initially shorten treatment by at least two months. The ultimate goal is a total treatment time of two months or less, and ideally just a few weeks. To advance in development, compounds should be active against MDR-TB, researchers tell C&EN, although most studies planned so far are in patients with active, drug-susceptible TB.
OFLOTUB, an EC-supported consortium of public and private partners, including Lupin, has started Phase III studies of the generic drug gatifloxacin in place of ethambutol. The drug has been found, however, to cause severe side effects. Lupin also has its own pyrrole compound, LL3858, in Phase I studies. It has shown rapid bacterial kill rates in preclinical tests when combined with other TB drugs, but its mechanism of action is unknown.
Moxifloxacin and gatifloxacin are fluoroquinolones that inhibit DNA gyrase, an enzyme needed for bacterial survival. To their benefit, they have little interaction with the liver's cytochrome P450 enzyme system, which metabolizes some antiretroviral HIV drugs. Drug-drug interactions are a serious complicating factor in finding treatments for people coinfected with TB and HIV. For example, rifampicin, which inhibits RNA polymerase, interacts with P450 and causes some HIV drugs to be cleared too quickly.
Rifampicin has been considered a cornerstone of TB therapy for more than 30 years. Adding it shortened treatment to the current six months, Spigelman says. Pfizer has been studying the related drug rifabutin, which has comparable effectiveness but less interference with antiretrovirals. And Sanofi-Aventis continues work on rifapentine, another related drug approved in 1998.
In 2002, TB Alliance licensed PA-824 from Chiron (now part of Novartis). It is from a class of nitroimidazole agents believed to offer a novel mode of action related to inhibiting bacterial protein production and cell-wall synthesis. In mice, PA-824 was found to have potent bactericidal activity and showed no significant P450 interaction. TB Alliance has just moved it into proof-of-concept Phase II testing to observe its antibacterial activity in humans.
Japan's Otsuka Pharmaceutical has been working on its own nitrodihydroimidazo-oxazole derivative (OPC-67683). "Otsuka has been screening TB compounds for about 25 years, and OPC-67683 has been in clinical development for about three years," says Lawrence Geiter, senior director of the TB products unit at Otsuka Pharmaceutical Development & Commercialization, one of three Otsuka companies in the U.S. The compound, which has shown extremely potent and rapid antibacterial activity and no P450 issues, is in Phase II clinical testing as an add-on to the treatment of MDR-TB.
Although its mechanism of action is not clearly defined, Geiter says, OPC-67683 probably interferes with the production of two key mycolic acids that are in Mtb's thick, waxy cell wall. The compound may be able to kill Mtb in both aerobic environments, as present during active pulmonary infections, and anaerobic environments, such as in tubercles (nodules) in which Mtb lies dormant for decades. But Geiter says it's much too early to know whether it will work against latent TB infections.
Otsuka has been building its development team: Geiter, who helped set up CDC's TB Trials Consortium, joined in April, and Charles D. Wells, former chief of CDC's international research branch, joined in May. "Otsuka wants to ensure the drug gets developed as quickly and optimally as possible and is putting the resources into developing it itself, including investing in clinical trial capacity," Geiter says. Otsuka spent $12.3 million in 2005 on TB R&D, ranking 10th in the TAG report.
Similarly independent, Johnson & Johnson affiliate Tibotec Inc. has been developing a diarylquinoline compound, TMC207. The compound is specifically active against the adenosine triphosphate (ATP) synthase enzyme of mycobacteria but not the ATP synthases of other bacteria or species, says David F. McNeeley, director of global clinical development at Tibotec.
Early animal studies have shown that TMC207 may be able to halve treatment time when substituted for rifampicin or isoniazid, and its long half-life promises the potential for intermittent, rather than daily, dosing. Potent against both drug-sensitive and resistant strains, it is currently in a Phase II trial in MDR-TB patients, McNeeley says.
Because existing therapies against drug-susceptible TB can be highly effective and trials to prove the efficacy of new drugs are expected to be large and lengthy, it made sense to explore the potential of TMC207 against MDR-TB, McNeeley says. In addition, since available MDR-TB therapies have lower cure rates and longer treatment times, showing an improved effect should be more straightforward.
Another factor in favor of testing against MDR-TB is the strict control over TB therapies. "To have your drug used in a brand-new regimen will require a very convincing story that what you offer is enough to make hundreds of countries change their TB programs," he explains. "If we can address an immediate need in MDR-TB, then subsequently we can work with other stakeholders toward that bigger paradigm shift."
Like Tibotec, FASgen, a 1999 spin-off from Johns Hopkins, intends to first test 3-sulfonyltridecanamide, or FAS20013, against MDR-TB to help expedite approval. The compound interferes with cell-wall Mtb's synthesis and its energy-generating pathways. The firm has reported that FAS20013 is more potent than existing TB drugs and may be one of the first effective against latent TB infections since it appears to be active against bacteria that are not dividing.
Further along in development is Sequella, in Rockville, Md., which recently completed Phase I safety studies of SQ109, a 1,2-ethylenediamine discovered by the company and NIAID collaborators in a high-throughput screen of about 64,000 compounds. Although it primarily inhibits cell-wall synthesis, SQ109 differs from ethambutol, another diamine, in up- and down-regulating different Mtb genes. In mice, SQ109 has shown synergistic effects with rifampicin and isoniazid that enhance activity and shorten treatment by 25%, says Carol A. Nacy, Sequella's chief executive officer.
SQ109 is effective against MDR-TB and may have activity against latent TB infections, Nacy adds. Sequella is working with NIH to continue clinical testing and is seeking a larger pharmaceutical partner for development and commercialization. "Our push internally is to file regulatory approval documents by 2009," she says. The company also has a dipiperidine, SQ609, in preclinical studies and has licensed natural-product-derived inhibitors of translocase I, an enzyme involved in cell-wall synthesis, from the Japanese drug company Sankyo.
ALTHOUGH results so far sound promising, TB researchers admit it's easier to kill Mtb in a petri dish than in humans, where testing is only now beginning. The microbe's ability to hide in immune-system cells makes it hard to attack, and treating latent Mtb is critical to long-term control efforts. In fact, except for rifampicin and pyrazinamide, today's TB drugs are effective only against actively growing bacteria. And most have been discovered through whole-cell screens, by simply seeing what kills Mtb.
Many compounds under study are from existing classes or target similar cellular processes, according to an analysis by Doctors Without Borders, the medical humanitarian group. New drug entities with different known modes of action will not only help avoid resistance but also, it is hoped, target diverse mechanisms during the bacterium's life cycle: killing it during active replication, preventing the transition into latency, attacking it while latent, or stopping reactivation. To create the required breadth, many more compounds need to be fed into the pipeline.
To address this problem, the Gates Foundation will invest $40 million in a new TB Drug Accelerator program. Its goal is rational drug discovery through projects aimed at understanding how existing TB drugs work, reducing the uncertainty in knowledge about the biology of TB and how it persists in human tissues, developing adequate screening methods, and creating other needed tools. The foundation has been consulting with academic and industrial researchers and reviewing proposals for funding.
Lilly has seen a similar gap and responded recently by forming a public-private partnership for early-phase TB drug discovery based in Seattle. The company has contributed $9 million in lab space and equipment, along with $6 million in cash to catalyze work over five years. Lilly will give the partnership access to a library of more than 500,000 compounds, while Merck will provide its natural-product libraries.
Initial staff includes three former scientists from Icos, a biopharmaceutical firm Lilly acquired this year, who founded the not-for-profit Afya World Medicines. Other partners include the Indian company Jubilant Biosys, the Infectious Disease Research Institute in Seattle, the Seattle Biomedical Research Institute, the University of Washington's department of global health, and NIAID. In five years, the partnership hopes to grow to 25 full-time researchers and eventually become self-sustaining.
"No single entity has enough resources on its own, and we realize it is going to take the best efforts on all our parts to be successful," says Gail H. Cassell, Lilly's vice president for scientific affairs, who will lead the partnership. "We also will be working hand in hand with the TB Alliance to try to enhance their efforts, certainly not to compete with them." The partnership plans to reach out to researchers, particularly in academic institutions, who have expressed a need for screening against validated targets, access to medicinal chemistry, and help in developing clinical leads, she says.
"A major goal is to stay very focused, avoid fragmented efforts, and instead try to coordinate some of the work that is ongoing, particularly by individual investigators," Cassell says. "One of the first things this new entity will do is a very systematic global inventory of what research is under way to characterize, prioritize, and optimize what we have in the discovery portfolio."
DOZENS OF discovery efforts are now exploiting Mtb genomic information to identify targets and test new compounds. The EC-backed New Medicines for Tuberculosis (NM4TB) program is a consortium for TB drug discovery and enabling tools. Stewart T. Cole of the Pasteur Institute, who led the team that deciphered the genome of Mtb in 1998, directs the program. Started in 2006 with about $15 million in funding over five years, NM4TB involves 15 academic and institute participants, a few small companies, and AstraZeneca.
AstraZeneca is one of a few major companies that has turned its attention to diseases in the developing world and is conducting discovery programs aimed at adding to the TB drug pipeline. In 2003, the company opened a $10 million facility in Bangalore, India, devoted to finding new TB treatments, and committed $30 million over five years for equipment and operating costs.
"We have been looking at targets in the Mtb genome to design assays and move through the drug discovery process," explains Tanjore S. Balganesh, head of research at the site. "The entire focus so far has been to build a stable portfolio of projects running in lead identification and optimization and have this in place by 2008." While it is too early to talk about specific programs, he says, efforts are moving toward testing in animal models. The company had hoped to have a candidate in human studies by 2008 but recently pushed the timeline out to 2010.
Despite progress in understanding the disease and the underlying bacterium, a remaining challenge is deciphering and identifying targets related to persistence, Balganesh and others say. Another significant breakthrough, Balganesh says, would be a biomarker indicative of effective treatment that would simplify clinical trials. As it stands, because current therapies are 95% successful, huge trials are required to see statistically significant results and reaching a typical endpoint of no disease relapse can take 18 months.
Nevertheless, TB researchers emphasize the need to start testing compounds in humans as part of a learning process that will feed confirming data back into discovery work and help validate animal models. Although useful models for testing drugs against active pulmonary disease are available, they say, no suitable ones exist for latent infections, and none allows scientists to predict whether a drug will shorten treatment. "Not being able to predict from animal models what will happen in humans is a major problem," says Paul L. Herrling, head of corporate research at Novartis. "So we are putting together a consortium to systematically try different models."
DISCOVERY EFFORTS at the Novartis Institute for Tropical Diseases, in Singapore, should also help boost the TB pipeline. NITD's approach is directed toward understanding the bacterium's biology, finding drugs against MDR-TB, and identifying Mtb targets in the latent state, Herrling explains. Along with the Wellcome Trust and researchers at Imperial College London, Novartis is part of a $20 million project under the Gates Grand Challenges in Global Health Initiative attempting to understand the biology of latency and to develop drugs against latent TB infections.
There's a lot of catching up to do. TB R&D has been neglected not only by pharmaceutical companies but also by granting agencies, Herrling points out. "Thus, the stock of basic knowledge we can build on to select our targets and understand the biology of the disease is very much less than in other areas, such as cancer, where we can count on the work of thousands. So we must work with partners in academia to catch up," he says. "We would like to be able to deliver at least one new drug to the TB area by 2012."
Toward that goal, NITD began a clinical research program with Eijkman Institute and Hasanuddin University, both in Indonesia, this year. "A key reason for putting our research station in the tropics was trying to understand the disease better," Herrling says. "It's essential that you understand not only the molecular biology of a disease but also the patients' environment, their culture, the way the doctors treat the disease, and the conditions under which the treatment is being given."
As Herrling implies, drug discovery and development encompasses just a few of the many hurdles the TB research community faces. Significant funding will be required to sustain development work and to move drugs into late-stage clinical trials. But clinical trial capacity in developing countries, where trials will have to be conducted, is limited and needs to be built to meet international standards. Groups such as the European & Developing Countries Clinical Trials Partnership, CDC, and universities have been striving to build that infrastructure. And TB Alliance has been assessing clinical sites.
STOP TB envisions that sustained development through 2015 could lead to entirely new drug regimens. But evaluating novel combinations and each of the drugs in the combination sequentially is expected to be extremely time-consuming. To address this problem, TB Alliance hopes to create a new paradigm for more efficiently identifying the best combinations using animal models. It recently selected two partners to begin a comprehensive survey of combinations of existing and new drug candidates.
TB Alliance has talked with other drug sponsors about making compounds available for this work and has initiated discussions with regulatory agencies. But like all the other involved parties, regulators today have limited experience when it comes to handling new TB drug candidates or being able to offer specific guidance. Still, they have been open and engaged, Spigelman says, and European regulators are even in the process of developing guidelines.
If new TB drugs do emerge, they still must be manufactured, marketed, and distributed. Commercial incentives may be limited, since the drugs will have to be made affordable in high-burden developing countries, and markets in high-income areas, while present, are small. Yet clear opportunities should exist for new drugs that can shorten treatment or that can treat MDR-TB or latent TB infections. The combined global market for all first-line TB drugs is estimated to be about $315 million annually, according to TB Alliance's May 2007 "Pathway to Patients" study. When new drugs do emerge, health care systems worldwide then must contend with the immense complexities that, as the study describes, will arise as they adopt new therapies that could eventually reach millions, if not billions, of people.
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