Innovative TB Drug Trials Set the Stage for a Revolutionary Development Model -- UPDATE

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Brazil , China , India , Latin America , Malaysia , Republic of South Africa , Sub-Saharan Africa , Topic: Discovery/Development

[NOTE: This is an UPDATE to a case study initially published in 2009. Read the original case study for appropriate context.]

It was a breakthrough in tuberculosis research in 2005 when the Global Alliance for TB Drug Development (TB Alliance) and German pharmaceutical company Bayer HealthCare (Bayer) agreed to work together to develop a pre-existing antibiotic, moxifloxacin, as a possible treatment for tuberculosis. REMox TB, a global Phase III clinical trial, was launched in 2008. A successful trial could lead to the first new drug approved to treat drug-sensitive tuberculosis (TB) in more than 40 years.

The joint effort was an innovative model of partnership between a non-profit organization and a major pharmaceutical corporation (along with supporting academic and public organizations) to develop a new medicine that would be accessible to developing countries.

Beyond this, the capacity and commitment built by partnerships like the TB Alliance/Bayer program has helped enable a conceptual revolution in TB drug development—the establishment of the Critical Path to TB Drug Regimens (CPTR) by the TB Alliance, the Bill & Melinda Gates Foundation and the Critical Path Institute. The new model is intended to bring multiple partners together, change the approach to TB drug research and speed up development of new drug combinations. Trials for the first new combination of “novel” drugs, the NC001 trial, or New Combination 1, have already been undertaken. “Novel” describes drugs not previously approved for TB treatment.

In REMox TB (“Rapid Evaluation of Moxifloxacin in Tuberculosis”) and other traditional TB clinical trials, one new drug at a time is tested as part of the otherwise standard TB drug regimen. However, since TB must be treated with combinations of drugs, this approach means that the development of new treatments proceeds slowly, through sequential substitutions in multiple trials over the course of decades. “Novel” TB regimens—those that use multiple new drugs—show promise to treat both drug-sensitive and drug-resistant TB, and have potential to transform the epidemic by greatly simplifying and enabling the scale-up of treatment. The NC001 trial was the first in which multiple new drugs are developed simultaneously and tested in combination. This new clinical approach could reduce the time needed to develop novel regimens by as much as 75 percent.

“The intent is to study combinations of two or more novel drugs together and speed up the process of finding dramatically improved new treatments,” says Mel Spigelman, M.D., the TB Alliance’s president and chief executive officer.  “We all recognize the urgent need to find impactful new TB therapies, and to do so in the shortest time possible.”

A Worldwide Scourge Requiring Lengthy Treatment

The World Health Organization estimates that one-third of the world’s population is infected with Mycobacterium tuberculosis (M.tb.), the bacterium that causes TB. Most people are protected by healthy immune systems and carry the infection, inactive and symptom-free, as “latent TB.” But about nine million people develop new cases of active tuberculosis annually. Some 1.4 million people die from the disease each year.

TB is particularly prevalent in countries like India and China, whose populations account for 35 percent of all cases, and in sub-Saharan Africa, where rates of TB incidence are highest. But the disease is present in every country in the world. Since HIV weakens the immune system, people with HIV are 20 times more likely to develop or contract tuberculosis. In South Africa, more than 60 percent of TB sufferers are co-infected with HIV.

Additionally, M.tb. is known to quickly develop resistance to antibiotics unless they are used in combination with each other. To overcome this, traditional therapy for active “drug-sensitive” TB relies on a four-drug, daily treatment regimen administered over the course of six months. This makes adherence quite difficult, especially in resource-poor settings. Poor compliance leads to development of drug-resistant TB. Treatment of drug-resistant TB, which can take as long as 24 months, is extremely expensive and complex, and is only successful in approximately 60 percent of treated patients.

REMox TB Offers Hope for Improved Treatment

Moxifloxacin is a registered antibiotic used to treat respiratory tract infections. The REMox TB study combines it with three established TB drugs and was conducted in sites around the world. Previous research suggests that a moxifloxacin-containing treatment could shorten treatment from six months to four months, improving health outcomes through increased compliance, and slowing the development of new drug resistance.

The REMox TB trial completed enrollment of its 1,900 patients in early 2012. Since patients must be observed for one year after completion of therapy to document cure, final analysis of results will not occur until at least late 2012.

“It’s a collaboration of unprecedented magnitude—a large, complex study in multiple endemic countries, from South Africa to Mexico to Malaysia and China,” notes Martin Springsklee, M.D., Bayer HealthCare’s vice president of global medical affairs. “Its challenges have included getting all the parts in place in so many developing countries—issues like training everyone in conducting trials.”

The Critical Path to TB Drug Regimens

The REMox TB trial and the development of a TB drug pipeline have helped set the stage for re-imagining the TB drug development process, with a focus on speeding new regimens to patients. The new clinical model employed in the NC001 trial shows how this is feasible. To catalyze the global effort needed to achieve this goal, in 2010 the TB Alliance joined with the Bill & Melinda Gates Foundation and the Critical Path Institute to establish Critical Path to TB Drug Regimens (CPTR) as a cross-sector initiative that would champion this model and bring drug developers and others together to tackle the scientific, regulatory, and other challenges associated with TB regimen development.

Today, CPTR includes many of the world’s leading pharmaceutical companies and has garnered participation from the U.S. Food and Drug Administration, the World Health Organization and other regulatory agencies. CPTR’s regimen development efforts are informed by a preclinical testing program operated by the TB Alliance in partnership with Johns Hopkins University.

“In CPTR, each partner brings its strengths to the effort,” Spigelman notes. “Some will be more interested in participating in the early parts of research, some in drug development, some in clinical trials. Each story is different. Once potentially useful drug combinations are identified, the groups are free to devise models for pursuing them.”

Agreements Reached, Trials Initiated

NC-001, the first trial of a new, three-drug combination, has already been completed by the TB Alliance, with the support of the CPTR initiative. The novel regimen tested in the trial includes moxifloxacin, another new drug called PA-824 and pyrazinamide, an existing TB medication. This treatment (PaMZ) is being tested for its potential to shorten treatment and treat both drug-sensitive TB and multidrug-resistant TB in a single combination. “PaMZ” shows promise to shorten drug-resistant TB treatment from two years to as little as four months. Additional trials testing PaMZ, as well as those testing other new combinations are expected by the end of 2012.

And REMox TB? “It’s still an important trial of a promising drug,” Springsklee says. “Furthermore, while the REMox TB trial took time to get established, the infrastructure and capacity it created enabled further innovation in the field and has helped to build a blueprint for modern TB clinical research.”

By Ralph Fuller

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