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TB Alliance announced last week a new agreement with Takeda Pharmaceutical Company Limited to advance novel compounds that show promise as potential treatments against tuberculosis (TB). The compounds were first identified through a recent program in which the partners screened the entirety of Takeda’s chemical library, comprised of 20,000 unique compounds. Existing TB treatment regimens can be onerous for both patients and health systems, requiring four pills per day for at least six months, and only 50 percent of patients with drug-resistant TB are cured after a two-year regimen with more toxic drugs. New drugs against TB are critically needed, and TB Alliance has not only developed multiple products, but has the largest pipeline of TB medicines in history. Both the screening program and the research moving forward are supported by the Global Health Innovative Technology (GHIT) Fund, a cross-sector partnership that invests in research and development for neglected diseases. For years, experts have known that mosquitoes are more effective at transmitting disease than a scientist with a needle, and new research suggests that the key is in the insect’s saliva. To study the impact of mosquitoes' saliva, researchers at the University of Leeds first injected a close relative of the chikungunya virus into mice, recording few symptoms and zero deaths. Next, the team allowed uninfected mosquitoes to bite the mice, and then scientists injected the virus into the mice through the site of the bite. The infection proved to be more virulent, and more than a third of the mice died. Molecules in the saliva prompt an inflammatory response, as the immune system sends neutrophils and macrophages—which combat pathogens by consuming them. The team determined that certain viruses are able to infect the macrophages, enabling the virus to replicate and travel throughout the body. Researchers at Harvard University have created a platform for rapidly and prolifically generating macrolides, a class of compounds containing some of the most common antibiotic and antifungal medicines. Macrolides were first developed in the 1950s, by tweaking microorganisms with antimicrobial properties to make them more effective and safe for use in humans. However, reliance on these natural microorganisms has made it difficult to produce new macrolides or adapt existing ones, and past efforts to develop synthetic macrolides have involved more than fifty steps—an arduous process with no guarantee that the final product will be effective. However, the team at Harvard has developed eight synthetic structures and has designed a method for rapidly combining them, and using just these eight structures and their derivatives, have created more than 300 synthetic macrolides. The team has begun to screen these macrolides for activity against different bacteria, and have identified two that are active against a bacterium that has developed resistance to vancomycin, which is considered an antibiotic of last resort. One drug candidate developed using this technique has recently been tested in two phase 3 clinical trials, proving to be effective against advanced intra-abdominal infections but ineffective against complicated urinary tract infections. The team will continue to screen the more than 300 synthetic macrolides, advancing those that prove most promising in the lab.

Editor’s note: This is the first post in a two-part series on the history of GHTC and lessons learned by the organization in coalition building. The series coincides with the launch of a case study examining GHTC as a model of successful coalition building in the global health space. Last month GHTC celebrated an important milestone: seven years ago in May, we received our first grant from the Bill & Melinda Gates Foundation. It was a critical moment that allowed the coalition to dramatically scale up our staff and activities and develop into the organization we are today. Passing this milestone made us realize that GHTC has spent the past seven years so focused on looking forward, that we haven’t taken any time to look back—to reflect on where we’ve come from and what we’ve achieved. So we reached out to former and current staff and members to help us tell the story of the birth of GHTC. The spark for GHTC’s creation: PDPs come together Following the failure of the Vaccine for the New Millennium Act (VNMA)—which aimed to incentivize greater private-sector engagement in neglected disease research and development (R&D)—to pass the Senate in 2001, the Gates Foundation sponsored a meeting of the product development partnerships (PDPs) it funded. The goal: to strategize other policy solutions to increase public- and private-sector funding for global health R&D. Out of this meeting, GHTC’s predecessor was born. The PDPs decided to form a working group—called the Incentives Working Group (IWG)—to collaborate to develop and champion policy solutions to support global health R&D. While deciding to work together does not seem like a radical choice, at the time it was a new way of doing business for the organizations involved. In a world of limited donor funding, each PDP and advocacy organization had been largely focused on securing support for its own products, priorities, or health areas. This left systematic and cross-cutting challenges for R&D largely unaddressed. The IWG was the first step toward changing that approach. “Before GHTC, there was no platform for organizations to work together toward common R&D advocacy goals. There wasn’t a place for people to come together to understand and discuss the barriers that they all faced...there was no voice for advocacy for R&D.” ~ Rachel Wilson, founder and principal of Catalysts for Change, former senior director of Advocacy and Public Policy at PATH, and a key player in the development of GHTC Two early wins generate momentum In the first half of the decade, two critical health crises—the 2001 anthrax attacks and a severe flu vaccine shortage—captured the attention of the American public and provided legislative opportunity for the IWG to further its aims. In response to fears of future bioterror threats like anthrax, Congress introduced the Project Bio Shield Act to incentivize pharmaceutical companies to develop treatments for potential bioterror agents. IWG members recognized the potential of this bill to generate new R&D financing for other health threats, like neglected global infectious diseases, and successfully advocated for the bill’s expansion to address other neglected diseases. The act was signed into law in 2004. Around the same time, a severe flu vaccine shortage in the United States prompted Senators Richard Lugar (R-IN) and John Kerry (D-MA) to reintroduce the VNMA. This time, IWG worked closely with the senators’ offices to draft and introduce language into the bill to establish a new idea to incentivize private-sector investment in neglected disease R&D known as an advance market commitment (AMC)—a mechanism which would provide an up-front financial commitment to subsidize the future purchase of a vaccine or health product not yet developed and available. While the group succeeded in getting the AMC language into the bill, unfortunately the legislation once again failed to pass Congress in 2005. Though disappointed with the result, the IWG members would shortly have a new incentive mechanism to champion. In 2006, the academic and health community was abuzz with a new idea proposed by researchers at Duke University—the creation of a priority review voucher (PRV) to incentivize product developers to invest in R&D for neglected diseases in exchange for expedited regulatory review of a future product at the US Food and Drug Administration (FDA). IWG joined other partners in advocating for legislation that would put PRVs into practice. In 2007, the FDA Amendments Act was passed with an amendment creating the first PRV. With two key legislative wins under its belt, it was clear to IWG members that the model of working together to advocate with one collective voice was producing powerful results. But finding time, resources, and consensus to move forward remained major challenges. “There was a significant need for someone to help keep the momentum going, because keeping a handful of people working together on an ad hoc basis is not sustainable.” ~ Mitchell Warren, executive director at AVAC and key player in the development of GHTC IWG rebranded: GHTC is formalized Recognizing these challenges, IWG’s core active members began taking steps to transition this ad-hoc collaborative effort into a formal coalition. In 2007, the group officially named itself the Global Health Technologies Coalition, and PATH offer to serve as secretariat to help bring structure, capacity, and permanence to the group’s activities. GHTC in its official capacity was soon put to the test in early 2008, when the President’s Emergency Plan for AIDS Relief (PEPFAR) was up for reauthorization. GHTC members recognized this as a legislative opportunity to potentially expand PEPFAR programming to not only focus on increased access to HIV and AIDS interventions, but also on developing new tools and technologies to fight the epidemic. After an extensive advocacy effort to engage with policymakers and educate them about the importance of R&D and AMCs, GHTC members and partners succeeded in getting their desired language around AMCs incorporated into the reauthorization bill, which was signed into law in July 2008. Having the PEPFAR bill reflect the importance of R&D was a significant win for the new organization. “Without the coalition, these policy achievements really wouldn’t have happened, because you needed a critical mass of groups pushing together saying ‘this is important to all of us.’” ~ Peg Willingham, head of Global Advocacy & Policy at HarvestPlus, former senior director at Aeras, and longtime GHTC member On the heels of this success, GHTC ramped up efforts to expand its membership base, and PATH submitted a proposal to the Gates Foundation seeking independent funding to expand GHTC’s efforts, which it secured in early 2009. With new funding, GHTC was able to hire a director and a small staff to support its activities. But with expansion and increased capacity came new challenges. As GHTC membership ballooned, it became more difficult for coalition members to reach consensus and agree on areas of advocacy to pursue. To confront these challenges, GHTC developed “terms of reference” to clearly define the principles that would guide the group’s advocacy efforts which all members had to endorse and established an elected steering committee to provide strategic guidance to the coalition. While putting these practices in place initially cost GHTC some of its members, it was a critical action that enabled the coalition to remain focused and unified in its advocacy and grow into the coalition it is today. “Since its formalization, GHTC’s focus has been unwavering; it’s been protected by members and staff in a way that is greatly appreciated by the global health community. GHTC’s ability and willingness to focus on single issues and not sway in the context of a very dynamic political environment is something that fellow advocates, industry, and government representatives truly value.” ~ Kaitlin Christenson, PATH strategy advisor and first coalition director of GHTC GHTC today: Growing presence and lasting impact “GHTC is a force multiplier; it amplifies and really helps the greater cause in a way the individual groups simply couldn’t do by themselves.” ~ Peg Willingham Fourteen years after its inception as the IWG and nine years after its establishment as the GHTC, the coalition continues to serve as an influential voice in the global health field and remains the only cross-platform and cross–health areas advocacy coalition for global health R&D. Today GHTC has more than 25 active members, a full-time staff of five, and the coalition is increasingly expanding its efforts to engage not only with US actors but also multilateral organizations. The coalition has achieved many remarkable policy successes in its short history and in doing so it has laid the groundwork for future progress, proving the power of working together and speaking with one voice. “Over the last decade, GHTC has evolved into a powerful and trusted voice in the global health community. The organization now has a strong foundation of success to build upon as we continue to advance innovation to save lives.” ~ Erin Will Morton, current director of GHTC

The House Energy & Commerce Committee recently passed an amendment—attached to an unrelated bill—that would add requirements for eligibility to the Tropical Disease Priority Review Voucher (PRV) program at the US Food and Drug Administration (FDA). The PRV program, established by Congress in 2007, is intended to incentivize research and development (R&D) for drugs for which there is a critical need but a limited market opportunity. Under the program, the regulatory sponsor of an approved drug for a tropical or rare pediatric disease is awarded a voucher which expedites FDA review of a future product by four months. These vouchers enable companies to enter the market sooner, and several have been sold between companies for up to US$350 million. Of the three vouchers that have been awarded for tropical disease drugs, two were awarded to companies that weren’t actually involved in the drug’s development—they had merely acquired rights to the drug—and in one case, the drug was already approved by other regulatory authorities and available in 80 countries. The amendment, introduced by Congressman G.K. Butterfield (D-NC), would require the regulatory sponsor to demonstrate the need for the product (i.e., the global burden of the disease and demand for the product) and elucidate their plan to ensure access to the product. Vienna-based researchers have developed a vaccine against Toxic Shock Syndrome (TSS), a rare, life-threatening condition resulting from an extreme immune system response to a Staphylococcus infection. TSS is associated with the use of super absorbent tampons, and an estimated half of cases occur in menstruating women. In a phase 1 clinical trial, the vaccine candidate—which contains a detoxified strain of Staphylococcus—proved to be safe and successfully prompted an immune response. The vaccine will next be tested in a larger, phase 2 trial. The team anticipates the vaccine will last for five years and will be used to protect individuals with a compromised immune system who are at greater risk for TSS. Nature took an in-depth look at drug repositioning, in which a medicine developed to treat one disease or condition is used to treat another. Drug repositioning is not a new concept; leading drugs against HIV and AIDS and erectile dysfunction were once intended to treat cancer and angina, respectively. However, the practice is becoming more common. Since 2011, the number of journal articles published on repurposed drugs has increased sixfold to an average of 30 per month and each year three to four new companies focused solely on the practice are established. Generic medicines are a common target, however, there are also many drugs that have passed phase 1 or clinical trials, proving to be safe for use in humans, but that did not have the intended effect. This approach makes drug development cheaper and faster, as phase 1 trials can often be skipped. Repositioning a drug costs $300 million and takes 6.5 years, compared to $2 to 3 billion and 13 to 15 years when starting from scratch. However, phase 1 trials may still be needed if the drug needs to be delivered in a different way or if a different dose is needed. Additionally, many pharmaceutical companies have massive, untapped compound libraries and new technology and software have made it easier to discover ways in which distinct conditions manifest similarly on a molecular level, which allows them to better identify promising compounds to screen for a given condition or disease.

Schistosomiasis, the second most common parasitic disease, infects more than 240 million people each year, and can result in liver failure, bladder cancer, and even death. Schistosomiasis is treated using the antiparasitic drug Praziquantel, however, resistance to the drug has been reported in Kenya and Uganda. Despite its efficacy, the mechanism of action of Praziquantel remains a mystery; scientists don’t understand how it combats schistosomiasis. By comparing the genomes of parasites that are sensitive and resistant to the drug, researchers at the Texas Biomedical Research Institute and the University of Texas have identified genes that are associated with resistance, and have received a US$3.5 million grant from the US National Institutes of Health to further examine the individual genes and mutations that confer resistance. The team will collect parasite eggs from patients in Kenya and Uganda before and after treatment with Praziquantel; the eggs from patients who are cured and those that remain infected will be classified as sensitive and resistant to the drug, respectively. They will then sequence the parasites’ genomes, honing in on the genes and mutations linked to resistance, with the goal of better understanding how resistance develops. This information is critical to developing drugs that are effective against Praziquantel-resistance parasites and diagnostics that can detect resistance. Researchers at the All India Institute of Medical Sciences (AIIMS) have completed successful animal trials of an oral vaccine against hepatitis B using a nanotechnology platform that could be adapted for other viruses. Oral vaccines are challenging to develop, as the key components are often degraded in the stomach before they can be absorbed through the intestines. However, they offer significant advantages: they don’t require needles and consequently there’s no risk of blood contamination, many don’t need to be kept cold, and they often spread more thoroughly throughout the immune system. The existing vaccine against hepatitis B is injectable and requires three to four doses, whereas the vaccine under development at AIIMS could be potent enough to require just a single dose. The team used nanoparticles to house the antigen—the part of the vaccine that triggers an immune response—and covered the nanoparticles in a protective surface that can survive the stomach. The vaccine will next be tested in human clinical trials, which the team hopes to complete by 2021. The World Health Organization (WHO) is proposing new guidelines for yellow fever vaccination in emergencies, as alarming outbreaks in Angola, Uganda, and Peru intensify due to a limited global supply. Clinical trials suggest that the vaccine is effective at much smaller doses, and the WHO is expected to recommend that member states use just one fifth of the standard dose. However, the studies were conducted exclusively in adults, raising concerns that the fractional dose might not be enough to protect children. It’s also unclear if the smaller dose would provide lifelong immunity, and the WHO’s proposal will likely recommend a booster to be administered at a later time. Once complete, the proposal will be submitted to the WHO’s Strategic Advisory Group of Experts on Immunization for review, and if approved, will be implemented if the outbreak reaches emergency levels.