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Earlier this month, advocates from the Community Research Advisors Group (CRAG)—an international, community-based advisory body working to ensure the engagement of affected communities in tuberculosis (TB) research conducted by the Centers for Disease Control and Prevention (CDC) —published an article in The Lancet offering a community perspective on the use of the drug bedaquiline to treat drug-resistant and drug-susceptible TB. The US Food and Drug Administration (FDA) approved bedquiline for the treatment of drug-resistant tuberculosis—via an accelerated approval process—in December 2012, making it the first new drug from a novel class approved to treat TB in more than 40 years. Laia Ruiz Mingote and Dorothy Namutamba—co-chairs of CRAG— and Mike Watson Frick—TB/HIV Program Officer at GHTC member organization, Treatment Action Group—are among the article’s co-authors, and join us to answer questions about the article and discuss the benefits and risks of using bedaquiline to treat TB. Bedaquiline is the first new drug from a novel class approved to treat TB in more than 40 years. PATH/Katrina Peach Q: Bedaquiline has been shown to be effective in treating drug-resistant TB in combination with other drugs, but it also has some serious side-effects and risks. Explain what those are. In Phase II studies, bedaquiline showed promising activity against multidrug-resistant TB (MDR-TB). The drug reduced the average time to a negative TB culture from 18 to 12 weeks and increased the proportion of participants with a negative culture at 6 months from 58 percent to 79 percent. However, bedaquiline posed several safety concerns that should be addressed before testing the drug in people with drug-susceptible TB. Most attention has focused on bedaquiline’s association with QT prolongation—a potentially serious disturbance in the heart’s electrical rhythm. Other TB drugs also cause QT prolongation, including moxifloxacin and the other new MDR-TB drug, delamanid (developed by the company Ostuka). Other side effects of bedaquiline include liver toxicity, accumulation of phospholipids in cells, and even death. In one Phase II trial, a significantly higher number of participants receiving bedaquiline died than those receiving placebo. While these deaths did not have a common cause and occurred months after the trial, the FDA could not rule out the possibility that bedaquiline played a role. Since bedaquiline has a long half-life, meaning that it remains in the body for a long time, the drug may continue to pose a side effect risk to patients even after they stop taking it. Q: Given its side effects and risks, do you still believe bedaquiline merited accelerated approval by the FDA? Do you believe other countries should also approve bedaquiline’s use for drug-resistant TB? The accelerated approval was necessary. There are few effective treatment options for patients with MDR-TB and extensively drug-resistant TB (XDR-TB), and many of these patients are unable to tolerate existing options, as they also have strong side effects and risks of their own including hearing loss, neurological disturbances, and skin discoloration. However, there is a need for more information and clinical data to know how to manage the risks tied to bedaquiline. We have to make it clear that bedaquiline is not for all TB patients, but rather only for those people who are unable to tolerate other MDR-TB drugs to which their TB is susceptible or who might not survive without access to bedaquiline, as there are no other treatment options. In countries and regions with high incidence of drug-resistant TB, bedaquiline is a necessary and important addition to second- and third-line therapies. Yet most countries have been slow to approve bedaquiline, meaning that most patients can only access it through unreliable compassionate use mechanisms. Other countries, particularly those of the former Soviet Union, lack the legal frameworks that enable compassionate use. In countries with high incidence of drug-resistant TB, bedaquiline is an important addition to second- and third-line therapies. PATH/Nguyen Ba Quang Additionally, the high price of bedaquiline may discourage its use among patients who need it most. Janssen—the company that developed bedaquiline—has announced a tiered pricing scheme in which the price of bedaquiline varies depending on a country’s Gross National Income: high-income countries will pay about $30,000, middle-income countries will pay $3,600 and low-income countries will pay $900. Countries with the most severe MDR-TB epidemics are usually middle-income countries including South Africa, India, Russia, and China. While South Africa may be able to access the lowest price of bedaquiline, it’s unclear whether Janssen will extend the lower $900 price to other middle-income countries like China, where second-line TB drugs are not provided for free by the government. Can Chinese TB patients really afford bedaquiline at a price of $3,600? Even in high-income countries, the steep price of the drug can drain the general budget of TB programs, especially considering the high cost of other second-line drugs used to treat MDR-TB. Finally, in ensuring access to the treatment, Janssen must also make every effort to track safety and patient outcomes in people who receive bedaquiline. In the United States, a patient registry exists in theory, but many doctors do not know about the registry, and those who do have had difficulty enrolling patients into it. In the absence of a Phase III clinical trial of bedaquiline, patient registries may offer the best way to obtain additional safety data. Q: Clinical trial data on bedaquiline’s use for drug-resistant TB suggests it could also be effective in shortening treatment time for drug-susceptible TB as part of a first-line therapy combination. What are your concerns about the inclusion of bedaquiline in trials exploring its use for drug-susceptible TB? As mentioned, bedaquiline is a game changer in cases of MDR- and XDR-TB. However, for drug-susceptible TB, we have a well-established standard of care and other options for shortening treatment using existing drugs—such as rifapentine which is manufactured by Sanofi—or investigational drugs— such as PA-824 which was developed by the TB Alliance—that so far lack the safety signals observed in the Phase II trials of bedaquiline. The CDC’s Tuberculosis Trials Consortium will soon begin a Phase III study to see if replacing rifampicin with rifapentine can shorten drug-susceptible TB treatment from 6 to 4 months. The TB Alliance is also testing a 4-month drug-susceptible TB treatment regimen that uses a combination of PA-824, moxifloxacin, and pyrazinamide. Patients with drug-susceptible TB face a very different risk-benefit trade-off than people with drug-resistant TB. Currently, drug-susceptible TB has a safe and effective standard of care, although we agree that at six months, it is too long and there is the necessity to make it shorter. It is because of the safety of the regular regimen that, together with the current data, bedaquiline may not offer the best way forward for shortening drug-susceptible TB treatment. We believe that before studying bedaquiline for drug-susceptible TB, we need much more information about this new drug, its long-lasting presence in the body and common side effects. In addition, the use of bedaquiline in first line treatment could, in fact, risk an increase in resistance, leaving patients with fewer treatment options.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. This month, after nearly ten years of effort, the first batch of malaria drugs manufactured with a new, semisynthetic form of a key ingredient, artemisinin, will start reaching African countries battling the disease. The lifesaving drugs, manufactured by Sanofi—a French pharmaceutical company—are the first of their kind to use semisynthetic artemisinin in place of the plant-derived form of artemisinin used in the past. The new shipment marks a milestone in global health, potentially improving access to treatment for the millions of people, mostly African children, sickened by malaria every year. The Global Coalition to Advance Preterm Birth Research (GCAPR), a new partnership initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the March of Dimes Foundation, the Bill & Melinda Gates Foundation, and GHTC member the Global Alliance to Prevent Prematurity and Stillbirth, has been created to take on the high rate of preterm births and help prevent the health risks associated with them. An estimated 15 million babies are born preterm every year and more than 1 million die within the first 30 days of birth. The National Institutes of Health’s National Institute of Allergy and Infectious Diseases has performed a successful early-stage clinical trial for a vaccine against mosquito-borne viral illness chikungunya. There are currently no vaccines or specific drugs to prevent or treat chikungunya, and as of this month there have been more than 570,000 confirmed or suspected cases reported throughout North and South America. The first-ever Africa Leaders Summit this month was a clear example that partnerships between the United States and African nations are strong and building momentum. The summit was a busy few days with a flurry of announcements, but the practical implications of the summit for global health innovation were examined by GHTC Policy Officer Ashley Bennett in a recent post on Breakthroughs. In The Huffington Post’s blog, Dr. Jonathan Mermin—director of the Center for Disease Control and Prevention’s National Center for HIV and AIDS, Viral Hepatitis, STD, and TB Prevention—writes about the need for new tools to fight tuberculosis (TB). He states, “Until we have better ways of detecting and treating TB, thousands of Americans and millions of people worldwide will continue to suffer from an illness that should have been consigned to history long ago.”

  In this post, PATH Vice President of Product Development, David Kaslow, writes about the first-ever shipment of semisynthetic artemisinin (ssART)—a new type of malaria treatment that marks a significant milestone in the fight against malaria. This post originally appeared on the PATH blog on August 12. Malaria drugs made with semisynthetic artemisinin make their way to patients This month, after nearly ten years of effort, the first batch of malaria drugs manufactured with a new, semisynthetic form of the key ingredient, artemisinin, will start reaching African countries battling the disease. The lifesaving drugs, manufactured by our partner Sanofi, a French pharmaceutical company, are the first of their kind to use ssART in place of the plant-derived form of artemisinin used in the past. The new shipment marks a milestone in global health, potentially improving access to treatment for the millions of people, mostly African children, sickened by malaria every year. The story of ssART—and the bold partnership that brought it from concept to use—highlights the crucial role international markets play in shaping global health, and the power of collaborative innovation to improve the systems that bring lifesaving products to the people who need them. Soothing a volatile market The first batch of malaria drugs manufactured with a new, semisynthetic form of the key ingredient, artemisinin, will start reaching African countries battling the disease. Photo: PATH In 2004, doctors worldwide were increasingly using a powerful group of drugs called artemisinin-based combination therapies (ACTs), to treat malaria infection. That was good news for children and families everywhere. But as more countries sought ACTs, the supply and price of artemisinin—which was derived only from a slow-growing plant called Artemisia annua, or Asian sweet wormwood—fluctuated wildly. Changes in demand and supply from year to year created a volatile up-and-down cycle of pricing and supply. In 2005, for example, the price of artemisinin was at a high of US$1,100 per kilogram. That price sparked more farmers to plant sweet wormwood, creating an oversupply in 2007 that caused the price to plummet to just $180 per kilogram. That cut the incentive to grow sweet wormwood again, which resulted in a 2009 shortage that drove prices back up over the next two years, to an average of $530 per kilogram in 2011. These fluctuations strained markets, and made it difficult for leaders, manufacturers, and others to stabilize and plan global supply, risking a global shortage. In short, the lifesaving drugs that millions of children, families, and communities relied upon were tied to a supply structure struggling under the push and pull of a volatile market. Worldwide, a market challenge had turned into a crucial global health imperative.   A groundbreaking partnership Solving the challenge took a groundbreaking partnership, led by PATH’s Drug Development program, which brought together experts in research, pharmaceutical product development, and public health. In 2004, the partnership set out to develop a new manufacturing process to produce high-quality, year-round, and affordable artemisinin to supplement the plant-based supply. Over a decade of work, our combined innovation and vision brought a promising concept from small laboratory batches, to large-scale production, and on to global markets. Now, as the first shipment of ssART-based malaria drugs—1.7 million treatments of Sanofi’s gold-standard ACT, Artesunate Amodiaquine Winthrop®—make their way to customers for the first time, we’ve reached the goal we set out to achieve ten years ago. Semisynthetic artemisinin opens a new future for the global artemisinin market. In doing so, it offers new security for the millions of people who rely on ACTs in countries where malaria is a constant threat. By providing a year-round source, ssART helps to manage imbalances in supply and demand, maintain stable and affordable pricing, and keep the market on an even course—ultimately expanding access to ACTs. The future Over a decade of work, PATH's combined innovation and vision brought a promising concept from small laboratory batches, to large-scale production, and on to global markets. Photo: PATH Of course, ssART is only one part of the solution. Eliminating and controlling malaria requires a highly integrated strategy, including new vaccines and diagnostics, expanded surveillance and control, strong partnerships with governments, and much more. I think I can speak for all of our partners when I say that we won’t be satisfied until that very last patient is cured of malaria. Until then, however, the sustained production of ssART, and the careful integration of our product into global markets, has the potential to change the landscape of global health. For the first time in history, artemisinin shouldn’t be a limiting factor in our work to develop and deploy lifesaving treatments. Even more, ssART provides clear evidence that with expertise, hope, and tenacity, it is possible for public and private sector leaders to achieve a bold humanitarian goal. Together, we’re paving the way for a robust, reliable supply of antimalarial drugs. And by continuing to work together, we can create a market where supply chains, farmers, extractors, manufacturers, and funders all align to create a healthier future for women and children worldwide. More Information About the semisynthetic artemisinin project Video: Steve Davis discusses this shared value partnership

The African Leaders Summit highlighted several initiatives to stimulate innovation. Photo: PATH/Gabe BienczyckAs the first-ever US-Africa Leaders Summit came to a close last week, it was clear that the energy around the partnerships between the United States and African nations are strong and building momentum. This was perhaps best exemplified by the enthusiasm in the room as President Obama and the First Lady spoke to a large crowd at the Young Africans Leadership Initiative symposium—an event that illustrated the Summit’s theme of ‘Investing in the Next Generation.’ Forty-five African heads of state gathered with US government officials and advocates to forge a path forward for partnership between the United States and African nations. Importantly, amid these discussions were several calls for initiatives to stimulate science, technology, and innovation as a way to harness African nations’ growing interest and capacity for locally-driven solutions.The summit was a busy few days with a flurry of announcements. We’ve seen over $37 billion in commitments announced by the US government and various stakeholders, including several targeting health issues like malaria, preventable childhood death, and reproductive, maternal, and newborn health. But beyond the state dinners and the official speeches—and the huge array of side events and discussions—what does the Summit really mean for global health innovation? What will its practical impact be? Here are four key takeaways:1. There is a paradigm shift taking place from traditional forms of aid to new multi-sectoral partnerships for developmentAs major US bilateral global health and development programs have shifted (as others have noted) from providing emergency relief toward more sustainable development models based on trade partnerships and private sector investment, support for science and innovation infrastructure and programming is evolving as well. There is growing recognition that new health technologies no longer emerge from one country’s labs or a handful of Western research institutes, but instead from all corners of the globe. This new paradigm was robustly reflected throughout the Summit.2. The United States is ready to shake up the status quo to support innovationAt several Summit events such as the National Academy of Sciences (NAS)-hosted symposium on Innovation and Impact, it was clear just how global the innovation ecosystem has become. National academies for science and technology and new public-private partnerships are growing capacity for innovation and product development in countries that previously had little or none. It is essential to ensure that new tools are acceptable and accessible to the populations that need them and that local research and innovation efforts are supported. Our global system of funding, introducing, and scaling new health tools must adapt to make this a reality. There are signs that the US government recognizes this shift and is ready to explore new ways of promoting innovation—such as leveraging the new US Agency for International Development (USAID) Global Development Lab to support new models of collaboration. Dr. Lona Stoll—director of the Center of Global Solutions at the Lab—called on participants to partner in breaking down barriers to innovation, and to this aim, USAID announced last week that it will be contributing $1.5 million to the World Bank’s regulatory harmonization trust fund to support regulatory harmonization efforts in Africa—a notable start.3. The world is watching: Will these commitments have teeth?The exciting commitments and pledges lauded at the Summit must be more than just words. While many funding and technical assistance commitments were made, in the next few months we’ll see if the United States and its allies in the private sector and other sovereign states fulfill their promises. Many across the health, science, and development sectors are wondering how pledges made this month will be tracked and reported on. In order to bolster global health research and development partnerships with African states, commitments made last week must also be carried forth to other global discussions—such as those around the post-2015 sustainable development goals—in order to maximize their impact.4. To fight threats to health in Africa and elsewhere, we need to act nowAs the White House outlined, in our increasingly interconnected world, the US government needs a coordinated, proactive global health approach that brings the full force of US expertise in research, and innovation to the global fight against disease. There is no example as prescient as the current Ebola outbreak in Western Africa to illustrate the urgent need for strong US government support for an adaptive global health system and investment in new vaccines, drugs, diagnostics, and other global health tools.