2011 Stakeholders Association Meeting
Each year the Stakeholders Association of the TB Alliance convenes to evaluate recent progress to accelerate and ensure the development of new, faster-acting drugs that will revolutionize TB control.
The 11th Annual TB Alliance Stakeholders Association (SHA) Meeting was held on 24 October 2011, preceding the 42nd Union World Conference on Lung Health. The meeting gathered Stakeholder representatives to discuss and provide input on the TB Alliance's progress and challenges, particularly as the organization embarks on the next phase of regimen development and nears completion of the Phase III REMox trial.
SHA President Dr. Maarten van Cleeff, presiding over the meeting, welcomed attendees including the four new Stakeholder organizations — Population Services International (PSI), the Clinton Health Access Initiative (CHAI), the National Centers for TB Control and Prevention (NCTB) of the China CDC, and Rede Brasileira de Pesquisa em Tuberculose (REDE-TB) — which diversify the expertise and geographic representation of the Stakeholders Association.
Regimen development and approaches to enable access to improved therapies were the focus of the meeting. Over the past year, the TB Alliance and its partners have proved the feasibility for its vision, said President and CEO Dr. Mel Spigelman. "We now know that it's possible to shorten and simplify treatment for both drug-sensitive and multi-drug resistant TB to two months, based on preclinical studies," he said.
Download Dr. Mel Spigelman's overview slides
Dr. Carl Mendel, TB Alliance's Senior Vice President of Research & Development, presented the results of the NC001, or New Combination 1, trial. The six-arm study tested together PA-824, moxifloxacin, and pyrazinamide in a Phase II EBA trial, along with other promising two-drug combinations. NC001 proved the viability of the path for regimen development, Dr. Mendel said, and showed that the three-drug combination performed markedly better than the standard TB treatment regimen. With these results, the TB Alliance will now proceed to a 2-month "SSCC" study to further explore this regimen and other building blocks of future regimens. Because the combination does not contain rifampicin or isoniazid, there is promise to treat both drug-sensitive and drug-sensitive TB with a single combination treatment. The three-drug treatment could be particularly transformative for MDR-TB by reducing the duration of treatment from 2 years to 4 months — and costing a fraction of today's therapies.
To advance novel regimens efficiently, it's important to rethink the development and regulatory pathway. Today, MDR-TB drugs are typically tested in a separate development program from DS-TB — a prohibitively lengthy and expensive process due to the fact that new regimens are compared against control groups receiving the standard of care, which for MDR-TB is up to 30 months in duration with drug costs ranging from 5 to 6 figures per patient. Dr. Mendel walked Stakeholders through a new paradigm of a unified development pathway for MDR-TB and DS-TB that drastically reduces the time and cost needed to develop novel regimens that will be effective for all who are sensitive to them. "This approach marks a major shift in thinking." Dr. Mendel noted, "Patients should be treated based on what they are sensitive to, rather than what they are resistant to." He also noted that all regimens should be introduced within the context of appropriate diagnostic testing.
Download Dr. Carl Mendel's R&D slides
Another major finding of the NC001 trial was the validation of the mouse model, said Zhenkun Ma, Chief Scientific Officer. Working with John Hopkins University, the model showed more than 300 potential 3- and 4-drug combinations that would shorten treatment compared with today's current treatment — including a number of combinations that show promise to shorten treatment to 2 months. Promising combinations will be prioritized, he said.
Dr. Ma also gave a number of other updates. TBA-354, a new generation nitroimidazole under development with partners at the Auckland Cancer Society Research Centre and the University of Illinois, advanced into preclinical development. A pyrazinamide (PZA) analog program was initiated to identify a next generation PZA, ideally to overcome PZA resistance, with partners BioDuro and Yonsei University. THPP, a novel compound class with a novel mode of action under development with GlaxoSmithKline, advanced into lead optimization. Finally, four discovery projects were discontinued because they did not meet their milestones.
Lack of funding means the TB Alliance has been forced to deprioritize discovery work in favor of the more advanced clinical programs. Although increased contributions from partners have offset some of the effects, a robust pipeline is critical to producing the next generation of compounds, so further investment is greatly needed.
Download Dr. Zhenkun Ma's Discovery slides
As moxifloxacin and new regimens advance through the pipeline, the TB Alliance will have to dramatically scale up the amount of work devoted to access. The organization's Vice-President of Access, Elizabeth Gardiner, spoke about key challenges confronting such work and introduced Stakeholders to the newly formed Access Advisory Committee, which will provide advice on strategy moving forward. With the results from a study of the private sector conducted in 10 high-burden countries and published in PLoS One journal, Ms. Gardiner said that we now know the private sector is a critical part of the access equation, with some countries delivering as many pills in the private sector as in the public sector. The TB community must identify private sector channels that can do this well. Other key challenges outlined included the pathway forward for pediatric medicines, and the challenge of expanding drug-sensitivity testing — not only for new drugs tomorrow, but for standard TB care today.
Download Ms. Elizabeth Gardiner's Access slides
Stakeholders raised key concerns and provided valuable advice on a variety of topics surrounding TB regimen development and delivery. Timing and success factors of rapid adoption of new technologies and models for improving the diagnosis and management of treatment, especially for patents with MDR-TB, were raised as key issues. The TB Alliance was encouraged to generate pharmacoeconomic data and engage in early discussions with countries and the WHO to ensure adoption of new regimens and identified patients and advocates from TB-affected communities as key partners in generating demand. The need for coordination with other drug developers and regulators was also highlighted. Participants suggested that efficiencies might be found by collaborating with other product developers to assess and build clinical capacity for large-scale trials. The importance of engaging regulatory authorities in discussions regarding combination testing of new regimens early in the development process was also stressed.