Front and Center in the Fight against TB

William Looney: A signpost of progress against disease is the capacity of institutions to innovate—to stay one step ahead of the contagion. How do you read the current climate for innovation, and is the pace sufficient to register gains against TB?

Mel Spigelman: Innovation is the key driver for progress. Many people associate innovation with research in the classical sense of the word, but innovation is not the exclusive province of the scientist; in global health, innovation is also a social imperative and a responsibility to be borne by everyone in the field. The good news is that, after decades of nearly no innovation, the past five years have seen major strides in exploring innovative approaches to discovering, developing, and now delivering tools to combat TB.

Innovation is a hallmark of the TB Alliance. Our very organizational platform is in many ways an innovation. We were the first TB drug-based organization to be structured as a Product Development Partnership (PDP). Our sole purpose is to produce an innovative set of therapies that significantly advance the standard of care for treating TB and bring those innovations to where they are most needed. The establishment of the Alliance back in February 2000 occurred when there was not a single new drug in development to treat TB—the last real breakthroughs, the first combination therapies, date back to the 1950s and 1960s. We've worked to lower the barriers to TB drug development so that industry partners are more willing to participate. Today, we have more than 20 new drug projects in various stages of development; three are in advanced Phase II or III trials. There are 10 drugs in total in the global pipeline.

More important, we recently completed the first clinical trial that validates a new drug development paradigm that could decrease the time it takes to develop novel TB treatments by about 75 percent—from decades to years. The trial, called NC001 or New Combination 1, tests multiple novel drugs together early in the development cycle, with the goal of advancing the best combination of drugs—the way TB treatment is given. This is an approach that could be used in other diseases areas for which combination treatment is also a necessity, like malaria, cancer, and hepatitis. For TB, this is a major innovation because a novel regimen could be used for treating both drug-sensitive and drug-resistant TB in a single, shorter, safer, and improved cycle of therapy—an advance that has the potential to be truly transformative.

WL: What you are saying is that innovation is as much about broad process improvements—of which the Alliance's NC001 trial is an example—as it is about individual product advances?

MS: Exactly. As a PDP, the science behind a new product is important, but if you do not innovate right through the entire value chain, all that is innovative about the science could come to naught. In addition to classical scientific innovation, the TB Alliance has a three-step test in evaluating the potential impact of our work: Will the therapy be affordable? Will it be made available? Will it be adopted? The premise is that we might have the most innovative single drug, but if it is not combined in the best regimen and we cannot get those drugs into the places where they will have a significant clinical impact, and the right patients cannot afford or do not have access to them, we will have failed. This is why one of our priorities is seeding our PDP delivery platform at the country level, such as the memorandum of understanding (MOU) we signed in March with the International Scientific Exchange Foundation of China (ISEFC). The agreement will pave the way for the formation of the first Chinese PDP dedicated to global health called the Global Health Research and Development Center of China, or GHRC, facilitating the transfer of technologies and skills between TB Alliance and GHRC to help develop new global health tools and contain the spread of TB both in and outside of China. We are also pursuing a similar arrangement with a government agency in India to engage that country in the global development of new drugs and regimens for TB.

WL: Do you believe the PDP structure is still relevant now that the TB Alliance is entering its second decade?

MS: Yes—more than ever, given the growing need to leverage multiple public and private sources of funding and partnership. What we need is not just the discovery of individual new drugs, but the coordinated efforts of all drug sponsors and relevant institutions to make the process of new therapy development and introduction faster, cheaper, and better. We will never defeat TB unless we make that happen. Today, we have multiple companies who are willing to work and even test their drugs together, and coordinated efforts in multiple spheres on the parts of government institutions, academic centers of excellence, and even civil society. The strategy is embedded in the Critical Path to TB Drug Regimens (CPTR) initiative, where we work with major drug companies, regulators, multilateral institutions like the World Health Organization (WHO), and a variety of other partners to streamline competencies around developing and making available shorter, more effective multidrug therapies. In another partnership, the TB Alliance is working with the CDC and the NIAID with funding from the FDA and the Bill and Melinda Gates Foundation to set up a mechanism through which biomarkers for TB could be quickly identified and validated. Effective new biomarkers for TB treatment effects could revolutionize the process of TB drug R&D

WL: These examples provide some metrics to demonstrate to Big Pharma that working with you is not an exercise in irrelevance.

MS: We should rename the PDP concept and call it instead the PIP: the Product Impact Partnership. Our true goal is not development of products, but [maximization of] the impact of the products we develop. Impact is also critical in today's challenging economic climate, when it is more important than ever to demonstrate a significant return on investment, whether one uses public or private resources.

Perhaps the greatest challenge we face today is that of tremendously constrained resources. Given the scope of the challenge, TB drug R&D is still woefully underfunded. The Gates Foundation has been essential to the financing effort, as the Alliance would likely not exist without Gates Foundation support. However, when you compare even the total Gates Foundation support of all PDPs to what Big Pharma spends every year just on R&D, it becomes obvious that multiple other mechanisms of support are necessary. And we also should not forget the leveraging capacity of organizations like the TB Alliance; through a variety of mechanisms, the total cost or value of TB Alliance programs is more than twice our investment—meaning every dollar given to the TB Alliance produces roughly $2 in impact.

WL: Can you identify the Alliance's most promising compounds in development?

MS: NC001 is the first Phase II, proof-of-concept study of a novel regimen that combines two new or unapproved TB compounds, PA-824 and moxifloxacin, with one current TB drug, pyrazinamide. The results of our recently completed study of this regimen are very exciting, as this regimen does not include the established older drugs, isoniazid or rifampicin, resistance to which defines multidrug resistant TB (MDR TB). As predicted in the preclinical models, this regimen appears to perform at least as well as our best standard therapy for drug-sensitive TB. This would be particularly important for MDR TB, where the current therapy now takes more than two years to treat and is so complex and expensive that less than 10 percent of patients with MDR TB are presently even treated. The new combination would cost a fraction of what health systems pay now. Similarly, the data emerging from NC001 are equally encouraging on the results of a combination of a novel drug discovered by Johnson&Johnson's Tibotec subsidiary, called TMC207, when that drug is combined with pyrazinamide.

WL: What about vaccines?

MS: The one TB vaccine in use, BCG, is extremely old, and confers minimal protection or benefit. Thus, the need for highly effective TB vaccines is also great. Improved immunogenicity and protection are needed, with the ultimate objective of preventing TB either entirely or at varying stages of infection. PDPs have also played tremendous roles in the area of TB vaccines. For example, Aeras, a PDP focusing on TB vaccines, has multiple vaccine candidates in its pipeline with two vaccine candidates currently being tested in three Phase II (b) clinical trials.

WL: Administering a "global alliance" must come with its share of challenges. What hurdles have you had to surmount in leading the organization?

MS: The greatest challenge I find today is mobilizing the resources that will allow us to proceed quickly to deliver on our mission. TB is a disease of the poor and neglected. Therefore, there are precious few with any significant clout willing to advocate for funding the innovative work that needs to be done to make TB a disease of the past. In addition, bringing together the many disparate partners necessary for success always carries with it some unique challenges. There are always potential tensions in any set of relationships as broad as the ones we have. Managing those tensions requires from me two things: to set a goal for the organization that is very specific, with parameters that are non-negotiable; and the ability to understand what drives each of our 120 partnering stakeholders, so that we can anticipate problems before they occur. This latter capability is very important for any organization to build and maintain the trust of its partners. We may not always agree, but we have to be open, honest, and truly understand the constraints within which our partners work. It is crucial for everyone at the Alliance to realize that all successful partnerships work when all parties feel successful and derive benefit from the partnership—a 'win-win' proposition. Working with Big Pharma can also present challenges related to the size of the organizations and the fact that there are not infrequently competing interests within such large organizations. Ensuring alignment with especially large partners can be difficult, whether they are in the private or public sectors.

WL: Is the fact that the Alliance has yet to bring any of its compounds to full registration approval a drain on morale?

MS: We have had sufficient successes that morale has not been an issue. While it would be great to have a product registered, we are proud of what we have accomplished in a brief period of time. The size and diversity of the pipeline, the number of drugs in clinical development, the scope and depth of our partnerships, the innovative initiatives ranging from discovery research through our market access work—all these and other accomplishments have maintained morale. Interestingly, a common theme we hear from so many of our partners is that the morale within their organizations is always extremely high among those individuals who work on neglected diseases.

WL: Based on your practical exposure to the PDP field, what are the key elements of a good partnership?

MS: Clarity, consensus, and consistency about the rationale of the partnership—and why you are in it—is paramount. We must be aware of a potential partner's real needs and whether these needs complement our own. It's all about relationship alignments, of a joined-up purpose and shared motivation. These attributes cannot be covered adequately in a contract; the relationship has to be grounded in the human interest because no legal document can possibly cover all that might go wrong. So if you don't have that primal feeling of trust going in, stay away. The other factor I would cite is that every one of our partners is unique. You can't work to address their needs in a cookie cutter fashion—for example, some of our industry partners want to be involved in all aspects of the value chain, from discovery research through marketing, while others want to focus on one specific aspect and hand the baton off to us.

WL: What's next up for the Alliance?

MS: Product registration, introduction of new regimens, and impact on the global TB epidemic. We now know it can be done and we can be successful. How quickly we can accomplish these goals will be very dependent on our ability to generate increasing funding and resources. Innovative funding models like advanced market commitments, unique partnerships with selected governments, greater involvement of the private sector—all these elements will be important in defining our impact.