Taking aim at tuberculosis

TB Alliance announces four drug discovery collaborations to stock TB pipeline

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WASHINGTON—Thwarting the spread of tuberculosis is the focus of the Global Alliance for TB Drug Development (TB Alliance), and the not-for-profit development partnership is taking the wraps off four drug discovery collaborations aimed at boosting that effort.

All four projects, announced in June, have the potential to generate compounds active against drug-resistant tuberculosis and show promise to advance the science of TB drug development.

According to Dr. Mel Spigelman, CEO of the TB Alliance, the partnerships are indicative of the organization's efforts to aggressively increase the depth and strength of its portfolio to ensure that promising new TB drug candidates continue moving toward the clinic.

"Tuberculosis is responsible for the death of one person approximately every 20 seconds—and there is a significant need for novel medications to combat growing bacterial resistance to current drugs and to reduce the duration and complexity of therapy," he says.

In one partnership program, TB Alliance will work with Anacor Pharmaceuticals Inc., a biopharmaceutical company developing small-molecule therapeutics derived from its boron chemistry platform, to explore a novel anti-bacterial drug target for use in tuberculosis therapy. Under the agreement, Anacor will provide the TB Alliance with a non-exclusive, royalty-free worldwide license for any compounds ultimately registered for a TB indication. Compounds that attack novel targets have the potential to be effective against drug-resistant disease.

David Perry, CEO of Anacor, says funds from public-private partnerships like the TB Alliance and DNDi make it possible to both meet his company's responsibilities to its shareholders and help reduce the burden of neglected diseases.

"As these programs are successful, we hope to expand our current efforts and establish programs in new disease areas," he adds.

The TB Alliance also reached an agreement with Colorado State University to test whether inhibition of menaquinone biosynthesis—a key component of the energy generation system in M. tuberculosis (M.tb)—has the potential to eradicate the disease in vivo.

According to Spigelman, the most promising compounds will be employed in an animal model of TB, and a more advanced discovery program could be developed if the studies are successful. Inhibition of menaquinone biosynthesis is a novel approach and therefore compounds that inhibit this process have the potential to be effective against drug-resistant disease.

The third collaboration, with the Institute of Microbiology (IMCAS), a member institute of the Chinese Academy of Sciences, will discover and develop novel anti-TB agents from natural sources, including microbial metabolites and traditional Chinese medicines.

The fourth collaboration announced is with New York Medical College to explore the type 1 topoisomerase (Topo 1) enzyme that facilitates the unwinding of DNA, which is required during normal cell processes.

On all four projects, the TB Alliance and its partners will work collaboratively based on a well-defined research plan with clearly assigned responsibilities.

Spigelman points out that collaborations on early stage projects bolster the strength of the TB Alliance's development portfolio.

"The nature of tuberculosis requires that it be treated with several different drugs at once so a patient can be fully cured, and therefore, stop the emergence of resistance," he points out. "Though we are optimistic about our drugs in clinical development, as well as drugs developed by others that have reached clinical stages, no one or two new drugs will act as a magic bullet."

Spigelman says drug discovery and development at TB Alliance and within its collaborations aims to identify novel drugs and regimens that will have maximum impact on TB treatment and control.

"New drugs should meet one or more of the major unmet medical needs in current TB therapies as well as being affordable, widely adopted and available to those who need them," Spigelman says.

The TB Alliance programs seek to produce drugs that meet most of its criteria, including to shorten the duration of treatment; prove effective against sensitive and resistant disease; possess improved safety profiles; elicit no significant drug-drug interactions, including with ARVs; are affordable; and suitable for once-daily oral treatment.

Discovery and development programs are selected, based on the balance of these criteria, through a rigorous, multi-layered process.

"Following preliminary evaluation by TB Alliance staff, project proposals are reviewed by expert independent consultants, as well as the TB Alliance scientific advisory committee and board of directors," says Spigelman. "At the discovery stage, it is not always possible to be certain the extent to which a project will ultimately fit the above criteria. However, all four projects focus on novel targets or mechanisms of action, which indicates the potential to be active against both drug-sensitive, and drug-resistant disease, and were to determined to have promising profiles in relation to the above criteria."

According to Spigelman, the TB Alliance must ensure a steady stream of promising drug candidates progresses toward the clinic and work to maintain the momentum driven by a recently reinvigorated global TB drug development infrastructure.

"Additionally, it is natural and expected that our portfolio will experience attrition as projects progress," he says. "To maintain its strength it is essential that we continue to populate our portfolio with promising discovery-stage projects that fit our criteria and make use of innovative science."

As a result, the TB Alliance will continue to seek mutually beneficial collaborations, according to Spigelman.

"The TB Alliance has assembled the largest portfolio of potential new TB drugs in history, currently 20 projects deep," he says. "The TB Alliance continues to actively evaluate potential projects in both the preclinical and clinical phases of development. Additional partnerships with several other organizations are currently in negotiations."

TB Alliance teams with J&J to push new TB drug through clinic

SEATTLE—Johnson & Johnson announced last month at the Pacific Health Summit that it has joined with the nonprofit Global Alliance for TB Drug Development to speed commercialization of its experimental tuberculosis drug, known as TMC207.
The pact teams the TB Alliance and J&J's newly formed Tibotec Inc. for the development of new drugs to fight tuberculosis.

The two organizations will share their expertise and resources in the development of TMC207, which could become the first TB drug with a new mechanism of action in four decades. The interim data from an ongoing Phase II study of TMC207 were recently published in the New England Journal of Medicine.

The drug, designed to interfere with an enzyme needed by the bacteria responsible for tuberculosis to store energy, could become the first TB medicine with a new mechanism of action in 40 years. In the placebo-controlled study of 47 patients with multidrug-resistant TB (MDR-TB), it was found that 48 percent of patients receiving TMC207 in combination with standard treatment converted to negative sputum culture after eight weeks compared with 9 percent of those who received placebo and standard treatment.

The collaboration will maximize the expertise and resources from both the public and private sectors with the intent to improve the treatment of one of the world's oldest and most deadly diseases.

"We see tremendous potential in this collaboration and in the future of TMC207 as part of a critically-needed new TB regimen," says Dr. Mel Spigelman, TB Alliance president and CEO. "Since the TB Alliance was founded, we have assembled the largest pipeline of new TB drugs in history, but this progress is only possible with the commitment of our partners. Tibotec has tremendous scientific prowess, a commitment to fighting infectious diseases, and is an essential long-term partner in our fight to end one of the greatest epidemics of our time."

Under the terms of the agreement, J&J will continue to develop TMC207 for the treatment of multiple-drug resistant TB, and on approval will establish an access program to ensure the compound reaches people in developing countries.

The agreement grants the TB Alliance a royalty-free license for the worldwide development and access to TMC207 in the field of drug-susceptible TB.

In addition, J&J will collaborate with the TB Alliance on a discovery research program to identify new compounds for the treatment of TB. The rights for any new compounds will belong to the TB Alliance under a royalty-free license.

Dr. Paul Stoffels, global head of pharmaceutical research and development at Johnson & Johnson, says that to make a meaningful contribution to the global fight against TB, the company knew it had to take a novel approach.

"Our collaboration with the TB Alliance represents a major step forward in the fight against TB as the two organizations combine their expertise and resources in the quest to make new TB treatments available," he says.

This announcement marks the first collaboration initiated by the newly created Tibotec Global Access and Partnerships Program. The program is creating a sustainable portfolio of medicines—both marketed and in development—that are designed to address major health challenges in resource-poor countries.

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