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The Drugs for Neglected Disease initiative (DNDi) and the Medicines for Malaria Venture (MMV)—nonprofit product development partnerships (PDPs) and members of the Global Health Technologies Coalition—have teamed up to ensure two treatments for malaria continue to reach the patients who need them most. The treatments—two fixed-dose artemisinin combination therapies (ACTs) known as ASAQ and ASMQ—were developed by DNDi and partners and launched in 2007 and 2008, respectively; going forward, MMV will work with those partners to ensure these drugs remain available and accessible in countries where they are most needed. Dr. Bernard Pécoul, CEO of DNDi, passes the ball to Dr. David Reddy, CEO of MMV. (Photo credit: MMV) To commemorate the handover, DNDi CEO Dr. Bernard Pécoul passed the ball—a literal rugby ball—to MMV CEO Dr. David Reddy during a side event at the 68th World Health Assembly in Geneva, Switzerland. We’re joined by Jean-René Kiechel, PhD, Senior Pharma Advisor & Product Manager of DNDi and George Jagoe, Executive Vice President of Access & Product Management at MMV to learn more about this handover and the existing and potential impact of these medicines. Q: What impact could ASAQ and ASMQ have in the fight against malaria? The FACT (Fixed-Dose Artesunate Combination Therapy) consortium was formed in 2002 to develop combinations of artesunate (AS) with amodiaquine (AQ) or mefloquine (MQ). These treatments were recommended by the World Health Organization (WHO) in response to increasing chloroquine resistance, but were not available in easy-to-use fixed-dose combinations (FDCs). The FACT consortium was transferred to DNDi when the organization was created in 2003. It led to the creation of two FDCs: ASAQ: In 2007, ASAQ Winthrop® became the first treatment to be launched by DNDi. It was developed by a number of partners across almost the full development range, from formulation work to post-registration studies. There were significant challenges to overcome, including developing a stable bilayer formulation of the two drugs, together with the aluminum blister packaging designed to withstand the rigors of a tropical environment. Manufacturing and distribution of this stable formulation were undertaken by Sanofi, who were already providing co-blistered Coarsucam™ to Africa at the time, and who committed to making the generic ASAQ Winthrop® available at less than US$1 per adult treatment for the public market. ASAQ’s low price and prequalified status, which allows purchase by procurement agencies, led to price decreases not only of ASAQ but also for other ACTs. Lower drug costs led to increased patient access to high quality treatments. To date, more than 400 million treatments of ASAQ have been distributed worldwide, including products developed by generic companies. ASMQ: Launched in 2008, ASMQ was developed in collaboration with Farmanguinhos/Fiocruz, a Brazilian public pharmaceutical company. A South-South technology transfer agreement to Cipla Ltd in India ensured a second supplier of the treatment, principally for the Asian market but also for Africa. Recent results from a multi-center trial carried out in Africa showed ASMQ is as efficacious as artemether-lumefantrine—Africa’s most widely adopted treatment—in children under 5 years of age, and is well tolerated. ASMQ also demonstrated high cure rates and good efficacy in a number of studies in Asia and Latin America, including a large intervention study in Brazil with more than 23,000 patients. In a study comparing five ACTs in Myanmar, ASMQ FDC showed the highest cure rates, the lowest rates of gametocyte carriage (which are believed to affect the transmissibility of malaria), and provided the best post-treatment suppression of malaria. By the end of 2014, 832,000 ASMQ treatments had been distributed. Q: DNDi and MMV are both product development partnerships. What value do you see in collaborating with one another and what inspired this handover? In May 2015, in order to ensure the best future implementation of these two treatments, DNDi handed over its malaria program to MMV. MMV is a long-term partner of DNDi, and is managing the largest portfolio to date of antimalarial drugs—from all phases of drug discovery, development, and delivery. Collaboration is at the heart of the PDP model. The PDP is a form of public-private partnership whereby a varied collection of partners collaborate in a flexible, 'virtual' model. This includes biotech, pharma (large and start-up), nongovernmental organizations (NGOs), academia, and private and public sponsors who operate in the disease-endemic countries or globally. A key requirement for these participants from very different backgrounds is agreement on a specific common goal and specific objectives that address the disease in question while at the same time being guided by WHO priorities, the needs of country control programs, and ad hoc experts. The direct, open dialogue between partners who normally do not work together (and may even compete) promotes creativity and out of the box thinking. It fosters the innovation and creativity required to overcome the many challenges that arise in product development. PDPs such as MMV and DNDi have helped to address major market failings in malaria drug development. By enhancing the focus of drug research partners and by mobilizing donor funding for this critical work, both organizations have shown that this model of research and development can make a huge impact on the lives of patients suffering from diseases that have historically been neglected by most pharma companies. Thanks to the collaborative approach that MMV and DNDi have taken in orchestrating the hand-off of ASMQ and ASAQ, both organizations have been able to refine their focus areas for the future. Q: What role have diverse geographic and cross-sector partnerships had in the development and introduction of ASAQ and ASMQ? Both ASAQ and ASMQ demonstrate the ability of innovative private-public partnerships, with a strong commitment from endemic countries, to develop, deliver, and disseminate new high-quality, affordable treatments within a short time frame. ASAQ Winthrop® is a case in point: the partnership that led to the development and registration of ASAQ Winthrop® had to ensure the new drug's successful launch and adoption by endemic countries. First among the many partners needed at this crucial stage are endemic countries' national malaria control programs. Sanofi and DNDi engaged in collaborations with a number of other partners to facilitate the implementation and availability of ASAQ Winthrop®, including experts, WHO, research institutes, funding agencies, and other NGOs. For example, DNDi coordinated a clinical study with the Indian Council of Medical Research to facilitate the adoption of a new anti-malarial policy in India. This study allowed for the registration of ASAQ Winthrop® in India. DNDi also convened an independent panel of experts, the FACT Implementation Advisory Group, to provide independent advice and critical guidance about issues related to implementation and rational use of ASAQ Winthrop®, ensuring equitable access. Another example of the power of partnerships is the DNDi partnership with Sanofi, MMV, and national malaria control programs in Africa. The aim is to collect high-quality data on ASAQ effectiveness and safety, as part of a Risk Management Plan. This is the first of its kind to be submitted to the WHO, and the first to be set up entirely in Africa. It involved some 15,000 patients in one of the studies carried out in Côte d’Ivoire, collecting data on the drug’s safety and effectiveness in real-life conditions. Results are expected to be published by the end of 2015. Q: What are the next steps in ensuring these products are available to the people who need them most? To support uptake of new medicines like ASMQ and ASAQ, several hurdles must be overcome. These include: Inclusion of the medicines by WHO in standard treatment guidelines. Adoption by national disease control programs. National registration by drug regulatory authorities. Education and training on the use of the medicines. Dissemination of new safety and efficacy evidence post-launch. Mobilization of requisite funding for procurement and introduction. As a widely used ACT, ASAQ has met many of these challenges and will continue to play an important role in malaria treatment for many years to come. With new evidence emerging about ASMQ’s efficacy and tolerability, MMV and partners will target broader registration and use of this drug in Latin America, Southeast Asia (where its role in containing drug-resistant strains of malaria is critical), and in Africa, where it has had little use to-date.

Testing for tuberculosis in the lab. Photo: PATH/Mike Wang A new study published in PLOS Medicine indicates that multi-drug resistant tuberculosis (TB) is less contagious than drug-susceptible TB. Researchers followed 1,055 “household contacts”—relatives, neighbors, or friends living in close proximity—of 213 patients with multi-drug resistant TB and 2,362 household contacts of 487 patients with drug-susceptible TB for three years in Lima, Peru. Contacts of patients with drug-susceptible TB were nearly 50 percent more likely to become infected, with 4.8 percent developing the disease compared to 3.3 percent for contacts of multi-drug resistant TB patients. According to Dr. Louis Grandjean, the study's lead author, the TB bacteria experiences a "'fitness' cost" in which it becomes less infectious as it mutates to become resistant to antibiotics. The authors note, however, the possibility that future strains of drug-resistant TB could develop to be fitter. The Indian Ministry of Health is proposing major reforms at the Central Drugs Standard Control Organization (CDSCO)—the national regulatory authority of India. The proposal seeks to improve the CDSCO, using the US Food and Drug Administration (FDA) as its model. One of the key reforms would be a major increase in staffing, from 561 employees to 1,800 by 2025, and the Ministry of Health estimates that the overhaul would cost US$272 million. The announcement comes as the FDA ramps up inspections of foreign pharmaceutical manufacturing plants, and after several high-profile crackdowns on Indian manufacturers. The government of the Republic of Equatorial Guinea has committed $36.75 million for phase 2 and 3 clinical trials of an experimental malaria vaccine, in partnership with three oil and gas companies—Marathon Oil Corporation, Noble Energy Inc., and AMPCO—which will be contributing an additional $11.75 million. The vaccine was developed by Sanaria Inc. and initial trials suggest that it is both safe and effective. The funding will cover additional trials with 450 participants in 2016, and 3,000 participants in 2017 to 2018. The government of Equatorial Guinea and Sanaria Inc. have also signed an agreement to explore the possibility of establishing clinical laboratories and vaccine manufacturing centers in Equatorial Guinea. GHTC member Treatment Action Group and Yale University’s Global Health Justice Partnership filed a federal lawsuit against the FDA for withholding clinical trial data for two costly hepatitis C drugs that were approved by the FDA in December 2013 and October 2014. Both drugs were developed by pharmaceutical company Gilead Sciences and are intended to cure, not merely treat hepatitis C, according to the complaint, which also notes that 12-week regimens of the drugs cost $94,500 and $84,000, respectively. The two advocacy organizations requested the release of the clinical trial data from both Gilead Sciences and the FDA; Gilead denied the request, and the FDA responded that it will take 18 to 24 months to even consider releasing the data. Treatment Action Group and the Global Health Justice Partnership are arguing that the FDA’s response violates the US Freedom of Information Act, and that the data is needed so that doctors, patients, and policymakers can evaluate the “safety, efficacy, and cost-effectiveness” of the drugs.

This Independence Day, GHTC is taking a break from our cookouts and parades to celebrate America’s extraordinary contributions to advancing innovation to save lives around the world. The US government has long played a leading role in the development of new technologies to diagnose, treat, and prevent diseases and conditions impacting people living in the world’s poorest places. US leadership in global health research and development (R&D) is a testament to our nation’s character, our ingenuity and entrepreneurial spirit, and our dedication to improving human lives worldwide. Below GHTC takes a look at America’s contributions to global health innovation: The US government is the largest funder of global health R&D in the world. The US government is by far the largest funder of global health R&D—contributing around 45 percent of total investment and 70 percent of all government investment each year. Even when measured as a proportion of gross domestic product (GDP), the US government remains the largest funder of global health R&D. Between 2000-2013, the US government invested over US$18 billion in global health R&D. While this may sound like an extraordinary amount of money, annual US investment in global health R&D represents only a tiny fraction of overall US government spending—less than one-tenth of one percent of our GDP. While US investment in global health R&D nearly doubled between 2000 and 2009, funding has been largely stagnant, or on the decline, since then. A sustained and robust US investment in R&D by the United States is critical to delivering the next generation of health technologies to address both existing and emerging diseases and conditions. The US government contributes more than just funding to advance global health R&D. Five federal agencies that are engaged in global health R&D—the US Agency for International Development, National Institutes of Health, Centers for Disease Control and Prevention, Department of Defense, and the Food and Drug Administration—contribute much more than just funding. The US government has been involved in the development of many breakthrough technologies that are transforming global health. Between 2000 and 2010, the US government was involved in the development of over half (25) of the 45 global health products. The US government has been involved in the development of lifesaving innovations, including: Antiretroviral treatments, which have dramatically extended the lives of those living with HIV and AIDS. A vaccine that protects against meningitis A, costing less than $.50 per dose, which been delivered to more than 251 million people in Africa’s meningitis belt since its launch in 2010. A pediatric antimalarial drug, which has had 300 million treatments delivered to children suffering from malaria in 50 endemic countries since 2009. US investment is fueling a robust pipeline of global health products with the promise to save and improve lives. As of 2012, the US government was involved in the development of 200 of the 365 global health products in the development pipeline. Promising innovations under development receiving support from the US government include: A preventative HIV and AIDS vaccine that could dramatically reduce new infections. New tools to prevent and treat malaria, including medicines that will both protect against the disease and prevent its transmission. Vaccines to prevent tuberculosis (TB), which are in various phases of clinical trials. New cost-effective diagnostics for malaria, TB, and neglected tropical diseases (NTDs). New vaccines for NTDs—such as dengue fever, Chagas disease, and leishmaniasis. US contributions to global health R&D are having a ripple effect beyond saving and improving lives. US contributions to global health innovation not only saves lives, but also produce direct benefits for Americans by creating jobs, strengthening US competitiveness in research and technology, improving US relations abroad, and enhancing our health and national security. US investments also drive economic progress and reduce poverty in low- and middle-income countries (LMICs). Between 2000 and 2011, health improvements accounted for about 11 percent of economic growth in LMICs. The development of new health technologies will ultimately provide LMICs with the solutions they need to tackle their most pressing health challenges and chart a course for self-sustainment. So this Fourth of July, as you enjoy your burger and watch fireworks light up the sky, take a moment to celebrate America’s contributions to global health. While there is much more to be done, Americans should take pride in our nation’s efforts to advance innovation to save lives worldwide.

In this guest post, Kerry Aradhya—a science writer from GHTC member FHI 360—discusses a new website launched by FHI 360 to increase global access to resources that will help advance contraceptive research and development (R&D). Over the past several decades, overall investment in contraceptive R&D has declined dramatically. The result? Renewed commitment and partnerships will be required to ensure that new contraceptive methods advance through the development pipeline and that access to the final products is affordable and equitable. This is especially true in low-resource settings where unmet need for family planning remains high. With funding from the Bill & Melinda Gates Foundation, FHI 360 has developed a new website to increase global access to resources that will help move these ideas into practice. Launched in June 2015, the Contraceptive Technology Innovation (CTI) Exchange includes a resource library focused on contraceptive research, development, registration, and introduction and a blog that offers timely news, events, and commentary on topics that are moving contraceptive innovation forward. Here are four reasons you should visit the CTI Exchange today: 1. Diverse partnerships are critical for advancing contraceptive innovation. A wide range of groups—including donors, academia, nongovernmental organizations, and private industry—will need to work together to find innovative solutions to reduce unmet need for family planning and to bring products to market that better serve women and men around the world. As a platform for collaboration and knowledge sharing, the CTI Exchange facilitates the development of these partnerships. 2. New and existing resources are at your fingertips. Looking for information related to contraceptive R&D, regulatory requirements, quality assurance, or advocacy? The CTI Exchange’s resource library provides easy access to more than 130 resources and is frequently updated to incorporate new releases. Several of GHTC’s resources are included, and the Global Health Regulatory Requirements Database is currently a “featured resource” on the site. 3. A new database highlights contraceptive products in the development pipeline. A new key resource on the CTI Exchange—Calliope, the Contraceptive Pipeline Database—includes information about more than 170 contraceptive products that are in development or are being marketed on a limited basis. The database can be used to explore past and ongoing product development efforts, identify opportunities for future investments, and learn about products that may be available in the near future. 4. Your knowledge and experiences can be shared widely. Through its resource library and blog, the CTI Exchange facilitates the sharing of information among a global consortium of partners. Because your knowledge and experience is needed to grow the site, the CTI Exchange invites you to participate. Contribute resources. Write blog posts. Ask questions. Visit the exchange today!