Breakthroughs Blog: Medicines

In this guest post, Isabela Ribeiro, MD—head of the Chagas program at the Drugs for Neglected Diseases initiative (DNDi)—discusses the devastating toll of Chagas and ongoing efforts to develop new treatments and drug regimens for the disease. Valentine’s Day seems like a fitting occasion to shine some needed light on a disease that can begin with a late-night “kiss” but ends with a broken heart. I’m talking about Chagas, the leading cause of infectious heart disease in Latin America. The T. cruzi parasite that causes the illness is transmitted by the “kissing bug,” a blood-sucking insect found in the Americas that thrives in houses made from straw, sticks, and adobe brick. Kissing bugs feed at night, biting the face, sometimes around the lips (hence their name), where they can deposit feces infected by the T. cruzi parasite. Chagas disease can also be transmitted from mother to child or even through blood transfusions. The acute stage of Chagas disease happens soon after infection. But the chronic stage lasts a lifetime as the parasites hide in the heart and other organs. More than 30 percent of those infected will develop serious cardiac, digestive, or neurological disorders. Up to eight million people are infected and more than 12,000 deaths occur each year, in most cases from heart failure. What is so remarkable about this silent killer is the deep neglect that surrounds it. Chagas is endemic to all countries in Latin America and increased migration and population movement means there are now cases throughout the world, including approximately 300,000 in the United States. Less than 1 percent of those infected around the globe are estimated to be on treatment. Only two drugs exist to treat Chagas disease—benznidazole and nifurtimox. Both are effective, but have undesirable side effects and require a long treatment course. Nevertheless, governments can and must do much more to scale up access to testing and treatment with these existing tools. In the United States, neither drug has been approved by the US Food and Drug Administration. Treatments are only available through the US Centers for Disease Control and Prevention under investigational protocols and compassionate use. The past decade has seen new actors enter into Chagas research and development (R&D), including DNDi, the Sabin Vaccine Institute, and other institutions. New technologies are enabling researchers to screen much larger libraries of compounds for potential drug candidates. The first clinical trials for Chagas in more than 40 years are being held, providing both new formulations and new regimens of existing drugs and desperately-needed knowledge and data about this poorly understood disease. Drug discovery is a slow process with many ups and downs. One class of antifungals known as “azoles” generated a good deal of hope, but recent clinical trials have shown that they are not as effective as current drugs. Nevertheless, DNDi is currently looking into combination treatments with these drugs. Increased open collaboration should hopefully lead to new drug candidates. One important development is DNDi’s Lead Optimization Latin America project, which is a rare example of early R&D for neglected diseases taking place in an “endemic” region. There is still a long way to go to break the silence around this disease and ensure the needs of millions of neglected patients are met. As is often the case with neglected diseases, it is the poorest and most vulnerable communities that are the most affected. New technologies to test, treat, and prevent the parasite hold the key to future progress against Chagas disease, but a larger global effort is needed today to scale up access to treatment for those who need it most.

In this guest post, Dr. Mel Spigelman—president and CEO of the TB Alliance—writes about advancing the first-ever drug regimen designed to treat both drug-sensitive and some forms of multi-drug resistant tuberculosis (TB) to a global Phase III clinical trial. Receiving treatment for multi-drug resistant TB (MDR-TB), which afflicts nearly half a million people around the world, is one of the harshest experiences modern medicine has to offer. Treatment lasts up to two years, with more than 14,000 pills and daily injections for the first six month of treatment. Side effects range from nausea to permanent hearing loss and worse. Compounding matters is that this treatment only works about half the time, and is even more challenging to administer in patients also receiving therapy for HIV and AIDS. While this sounds extremely bleak, those who experience this care are fortunate. The above situation represents the best MDR-TB care available. Many TB and MDR-TB patients are unable to receive an accurate diagnosis. These patients have an even harder time with drug-resistant TB, and many ultimately die. Based on positive results from earlier clinical studies, TB Alliance is advancing the first-ever drug regimen designed to treat both drug-sensitive and some forms of multi-drug resistant tuberculosis (TB) to a global Phase III clinical trial. Photo: PATH/Gabe Bienczycki Today, however, there is hope. Better yet, those infected with drug-sensitive (or “normal”) TB—eight million people around the world—can also enjoy this hope. By the end of 2014, a new global clinical trial will begin testing the first ever drug regimen designed to treat both versions of TB in 50 sites on four continents. The trial, known as STAND (Shortening Treatments by Advancing Novel Drugs), will test a novel drug combination, or regimen. Traditionally, individual drugs were developed, then added or substituted into the existing treatment, enabling incremental progress. But the STAND trial, which tests a regimen called PaMZ, represents an opportunity to transform treatment. PaMZ promises to shrink the length of time patients are treated by more than a year for some forms of MDR-TB. As a completely oral regimen, it would eliminate injections and reduce the extraordinary demands that a TB diagnosis places on both patients and healthcare providers. Additionally, this regimen was developed for compatibility with commonly used antiretroviral drugs, which would improve patient care for the millions infected with both TB and HIV. With such a vastly reduced amount of medicine, PaMZ is expected to reduce the cost of MDR-TB treatment by over 90 percent in some countries. In the case of drug-sensitive TB, the regimen projects to be competitive with current treatment. Such cheaper, faster, simpler cures would provide amazing benefits not just to patients but for communities and national health care systems overly stressed from such an intractable disease. This regimen has been advanced to date thanks to the commitment of a series of partners including the Bill & Melinda Gates Foundation, the UK Department for International Development the Australian Department for Foreign Affairs and Trade, the US Agency for International Development, Irish Aid, and the Directorate-General for International Cooperation in the Netherlands. Now, as preparations for the STAND trial begin, we call for continuing as well as new support to bring this promising treatment through its final hurdle before it can be made available to the millions in need. TB has afflicted mankind since the time of the Pharaohs. The current first-line treatment for TB was assembled almost half a century ago; while the disease has continued to evolve, new medicines have been few and far between. TB is second only to HIV as the leading infectious killer of adults worldwide, and is also the leading infectious cause of death among people with HIV and AIDS. Hope has been a scarce commodity for TB patients today, especially those who have MDR-TB. We owe it to the millions of these patients—and the millions more to come—to move the STAND trial to the finish line. In this day and age, taking medicine and getting cured should be an easy sprint, not a gruesome marathon. To learn more about the STAND trial, click here.

This post was originally featured on path.org on January 27, 2013 and was written by PATH’s Drug Development program. The post is the first in a three-part series. To see future posts in this series, check out path.org. In December, PATH hosted a Transformative Innovations event in Palo Alto, CA with a panel discussion on ways that public and private sectors can work together to save lives. In three installments, we’ll bring you excerpts of the discussion from our panelists Ponni Subbiah and Anurag Mairal, program leaders of PATH’s Drug Development and Technology Solutions programs, respectively, and Joel Segre, an independent strategy consultant focused on product development and distribution challenges in global health. In our first post, Ponni shares her insights into what makes a partnership successful and reflects on the potential for innovation coming from nontraditional sources. Q: One of the shifting paradigms of the future is that innovation will be multidirectional and come from anywhere in the world. What impacts do you see this having on solving global health challenges? PS: It’s quite exciting because it makes our work truly global, not a pushed-down approach to solving global health problems. We’re transitioning from a world where interventions were done to and for countries to a world where innovation happens with countries. Every sector is realizing that you’re missing opportunities by not tapping into local talent. Even though many of our end users lack access to education, their insights, experiences, and knowledge are invaluable to creating a successful end product. The playing field is becoming more even, and partnerships are now happening at the local level. The younger generation, especially, is much more global and informed in outlook than previous generations, and they’re all about innovation and creativity. The question is, how do we capitalize on that energy and harness it to accomplish global health goals? Traditionally, especially in the private sector, many local affiliate leaders of international companies were from high-income countries. This is changing with the recognition that developing a talent pipeline at the local level is critical for long-term success within a region or country. Similarly, one of PATH’s goals is to identify leaders on the ground to build a stronger presence in countries. We need strong leaders who are well connected and influential so we can build strong and fruitful relationships with governments and civil-society organizations.   Dr. Ponni Subbiah with Wolfgang Laux from Sanofi, PATH's manufacturing partner on the project to create semisynthetic artemisinin. Photo: PATH Q: PATH has pioneered the idea that innovation is not just about technology but about the way in which you engage with partners, the business models you deploy, and the way you think about creating markets. What lessons have you learned about how to do this effectively, how to make sure that partnerships result in real impact, rather than more talk and transaction costs? PS: One of the most critical lessons we’ve learned is that for a partnership to be successful, we have to do the due diligence at the beginning when we’re selecting partners. We need to make sure that the organization we partner with has not only the technical capabilities and areas of expertise needed for the project’s success but also institutional support for the nonprofit aims of the project, especially from senior leadership. It’s important to have those senior leaders on board to be champions for the humanitarian side of an endeavor and to help us drive the project forward. Once a partner is selected, sitting down from the get-go and having a clear discussion about what each organization hopes to get from the project, what the incentives are, deliverables, etc. is key. These kinds of big-picture discussions, aside from the day-to-day communications that take place, should occur at set intervals, at least every six months, because these variables may change over the course of the project. If the goals of a project change, it will require some course correction to get back on track. Another critical element of a successful partnership is building trust and transparency. Though we’re all very connected technologically speaking, I find that it’s still important to have face-to-face meetings. Connecting in person and getting to know someone’s personality and work style changes the way we work together, usually for the better. I think it fosters more open interactions and makes people more willing to be flexible and cooperative. In this field especially, when our partners are all over the globe, we have to be cognizant of creating enough opportunities for face-to-face meetings. We try to provide time and support to make sure team members get this opportunity to connect. What goes hand in hand with building trust and transparency is the ability to have tough discussions. Teams that actually go through some tough discussions and overcome them are the great teams; teams that don’t challenge each other and avoid putting issues on the table never get to that great team level. Each partner brings a different strength and area of expertise to the partnership, and accordingly, each partner is under different institutional demands and pressures. We have to make choices about the battles we pick and where and how we can compromise to move projects forward, given that everyone is committed to a high-quality end result. As a nonprofit, some of the most important qualities we can bring to the table are expertise in global health, flexibility, and patience. We have to be accustomed to change. With the start and end of each phase of a project, new partners may come aboard and others may become less involved in day-to-day activities. Each project team has to do the same thing—understand where each partner is coming from, identify the critical areas that need further discussion, and then work together to problem solve. For more Innovation. Transformation. Inspiration., stay tuned to the Drug Development blog for the next two installment with Dr. Anurag Mairal and Joel Segre, and follow them on Twitter and Facebook. More information PATH’s Drug Development program PATH’s Technology Solutions program The NGO challenge: stay ahead of the curve Semisynthetic artemisinin achieves WHO prequalification

Hing Sham, PhD, joined PATH recently as head of research and preclinical development for the Drug Development program. Hing has more than 30 years in the private pharmaceutical industry, where he led major projects for various diseases, including HIV, cancer, diabetes, and Alzheimer’s. In this guest post, Hing answers questions about the risks associated with drug development and the intricacies involved in bringing a drug to market. This is the second post in a three-part series on drug development. Q: Drug discovery and development is a long process. Estimates of the cost to develop a drug up to the point of regulatory approval can range from $150 million to $1.3 billion. Could you summarize drug development in just a few words? A: In a few words, drug development is not for the faint of heart! What I mean by that is drug development is one of the most complicated and high-risk businesses in the world. When you think about what we’re trying to do, which is basically to correct a physiological process so it functions the same way it would in a healthy individual, it’s very complex and riskier even than going to the casino. In drug development, from choosing the right target to successfully completing multiple phases of clinical trials to clearing regulatory hurdles, there are many things that can go wrong. Under the best circumstances, your success rate is around 20 percent. It’s definitely a worthwhile endeavor, but each new hurdle brings with it a new set of anxieties. Hing Sham, PhD, joined PATH recently as head of research and preclinical development for the Drug Development program. Credit: PATH/Elena Pantjushenko. Q: What is the most exciting part of drug discovery? A: For me, the most exciting moment is when the different puzzle pieces come together to form a clear profile of a potentially successful drug candidate. Before this can happen, you have to have already chosen the correct target to treat within the human body and then have chosen the right compound from thousands of possibilities to target that mechanism for the desired effect. In addition, you have to determine that the compound has gone through the right testing to ensure that it’s in the best position to clear clinical trials and other safety hurdles. When all of that begins to align for the first time, it’s very exciting. Q: One concept you’ve emphasized as inherent to successful drug development is the importance of “failing early.” What does it mean to fail early, and why is that a good thing? A: Failing early isn’t a new idea in the drug development industry, but it’s a term that’s gained popularity as philanthropic foundations have encouraged a shift to the left in the product development pipeline. It is important to answer core questions early to avoid spending resources on products that will not be able to move forward and will languish in the “valley of death,” the term for scientific discoveries that don’t fit the criteria for further development. Failing early doesn’t mean that a team is encouraged to fail. Instead, it means that when the data are discouraging, the team should accept that, and move on to more promising prospects. Q: Is it difficult to keep your judgment clear and make these tough calls? A: I think, even if the results indicate you’re heading in the wrong direction, the desire to see your efforts through is part of human nature. As a researcher, it’s tempting to come up with other experiments that could enhance your understanding of a drug, even though they aren’t necessarily critical to the core questions under investigation. Within a project, stakeholders must engage in rigorous debates to determine what the critical questions are for a project’s success. Making these determinations early on provides the best framework for evaluating a drug candidate’s promise at various stages of development. Q: What do you find most fulfilling about your work? A: After 30 years in the private pharmaceutical industry, I have an immense appreciation for what the private sector does in devoting resources to research for lifesaving therapies. Now with PATH, I feel I have the unique opportunity to bridge the best of the private and nonprofit sectors to tackle a tremendous need for efficacious drugs for diseases unique to poor countries. It’s fulfilling to know that our work is bringing the best science to bear on some of the world’s most challenging health issues.