Breakthroughs Blog: Antimicrobial resistance

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.

At last week’s World Health Assembly, the World Health Organization (WHO) and the Drugs for Neglected Diseases initiative launched the Global Antibiotic Research and Development (GARD) Partnership, an initiative to develop new antibiotics to combat the growing threat of antimicrobial resistance. More than EU€2 million has been pledged to the GARD Partnership, from nonprofit Médecins Sans Frontières and the governments of Germany, the Netherlands, South Africa, and the United Kingdom. This innovative financing approach will enable the partnership to delink the costs of research and development (R&D) from sales and product price; new treatments can be sold affordably and promoted responsibly, without the pressure to recoup the costs of R&D. During the incubation period, the partnership will finance three to four projects while developing a long-term business plan, with the goal of becoming an independent entity by the end of 2017. At a recent meeting of G7 finance ministers and central bank governors, World Bank President Jim Yong Kim announced the creation of an insurance fund to fight pandemics, which will provide up to US$500 million for pandemic response in the world’s poorest countries. The Pandemic Emergency Financing Facility will be funded by reinsurance markets and World Bank–issued catastrophe bonds, which have been used to respond to natural disasters. Premiums will be covered by the World Bank and development partners. Funding eligibility will be determined by the size, growth, and spread of an outbreak and will be limited to pandemics in 78 low-income countries, caused by certain virulent, infectious diseases, including influenza, SARS, MERS, Ebola, and other zoonotic diseases. The facility was established in collaboration with the WHO and insurance providers Swiss Re and Munich Re. The Japanese government has committed US$50 million to the facility. Researchers at the Icahn School of Medicine in New York have identified a protein on the Zika virus that inhibits the human immune system from effectively combatting the virus. The protein—NS5—blocks signals between Zika-infected cells and the immune system; consequently, the immune system fails to produce the potent antiviral interferon. NS5 plays a similar role in other flaviviruses, including dengue and West Nile, but the mechanism by which NS5 prevents interferon production varies. The study suggests that altering or removing NS5 would enable the immune system to swiftly attack the virus. The team believes that a vaccine against the virus could be developed using a live strain of Zika, weakened by modifying or removing NS5. Meanwhile, Australian biotechnology company Biotron announced last week the identification of two compounds in its library that are effective against Zika virus in test tubes. The company specializes in HIV and AIDS and hepatitis C treatments and uses a broad antiviral platform to target specific proteins known as vioporins that are also found in the Ebola, MERS, and Zika viruses.

Last week, the Review on Antimicrobial Resistance, commissioned by United Kingdom Prime Minister David Cameron, released its final report, Tackling Drug-Resistant Infections Globally: final report and recommendations. The report details ten recommendations and calls for funding and incentive mechanisms to spur research and development (R&D) for new antibiotics, rapid diagnostic tests, and preventative vaccines. The research, development, and use of new and existing vaccines could limit the dependence on antimicrobials, while rapid diagnostic tests preclude unnecessary antibiotic prescriptions. To stimulate antimicrobial R&D, the report calls for the creation of a global innovation fund to support basic research and market-entry rewards to incentivize pharmaceutical companies to bring new antibiotics to market. The report calls for US$2 billion over five years for the fund, and the United Kingdom and Chinese governments have each pledged $72 million for these efforts. While new antibiotics are critical to combatting the spread of antimicrobial resistance, their use must be restricted and market limited to prevent new drug-resistant infections. Consequently, the report calls for market-entry rewards of $0.8 to $1.3 billion to incentivize the development of new antibiotics. While implementing the report’s recommendations would cost $40 billion over the next decade, current trends suggest that drug-resistant infections will cost the global economy $100 trillion between now and 2050. The White House announced last week the establishment of the National Microbiome Initiative to catalyze and fund research on microbiomes, develop new platforms for curating and sharing microbiome data, and to build the microbiome workforce through training and educational opportunities. The Initiative will be launched with an investment of $121 million from five federal agencies as well as funding from more than 100 private organizations including $100 million from the Bill & Melinda Gates Foundation. A microbiome is the makeup of microorganisms (i.e., bacteria) in a given ecosystem. While the human microbiome is the most well-known, the purview of the Initiative goes much farther, and will even support microbiome research in space.  Researchers in Ireland have created a coating that can be applied to surfaces such as smartphones, door knobs, or countertops which kills 99.99 percent of strains of Methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (E. Coli), and Trichophyton rubrum. MRSA and E. Coli spread rapidly within hospitals (MRSA can survive on surfaces for up to five months) and T. rubrum—which causes athlete’s foot and other fungal infections—is primarily transmitted via surfaces or objects (i.e., damp floors, towels). The coating is comprised of titanium oxide, fluoride, and copper and is sprayed and baked onto a surface, after which it becomes indiscernible to the eye. The bacteria and fungi are not able to spread on the coating and die within 24 hours. The team, led by Dr. Suresh Pillai of the Institute of Technology, Sligo, believes the coating could be used in hospitals and laboratories but also on smartphones, ATMs, and even food packaging.

This coming week the “who’s who” of the global health community (as well as some much more modest global health advocates such as your humble author) will make the annual trek to Geneva, Switzerland, for the 69th World Health Assembly (WHA), where World Health Organization (WHO) member states will collectively decide WHO’s plans for the coming year. This year’s agenda is packed and includes many topics that could impact global health research and development (R&D). Below are the agenda items GHTC will be tracking in Geneva and topics we’ll dig into in more detail at a May 23 side event and webinar we are cohosting with the Geneva Centre for Security Policy, Global Health R&D: What’s at stake during the 69th WHA? Framework of engagement with non-State actors WHO routinely engages with a variety of non-State actors (NSAs)—any organization other than a member state. These collaborations support core components of WHO’s global health strategy. Some have argued, however, that WHO’s current ad-hoc approach to managing such engagements undermines its independence and impartiality. As I have written previously, the current draft framework runs the very real risk of excluding key WHO partners and actors in the global health R&D community. Given the significant member state pushback against the proposal, it will be fascinating to see how the tension is resolved.   Health in the 2030 Agenda for Sustainable Development With the approval of the Sustainable Development Goals (SDGs) in September 2015, the global development community has been trying to sort out how to implement and measure programming to achieve what are, by all admissions, extremely ambitious targets. WHO is no different, and has been hard at work laying out strategies to achieve the various components of goal 3, the “health SDG.” It is particularly heartening that target 3.b specifically commits member states to supporting health R&D. What shape this will take, and how WHO will engage are definitely hot topics to watch at this WHA.   Global Action Plan on Antimicrobial Resistance Following the 68th WHA’s adoption of the Global Action Plan on Antimicrobial Resistance (AMR), WHO has been working to develop strategic options to achieve the plan’s goals and will be presenting a progress update and an options paper to WHA this year for input. GHTC is closely monitoring plans for the R&D objective, which states: “… develop the economic case for sustainable investment that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions.” While the options paper is quite broad, in the R&D space the WHO Secretariat is specifically asking for input on methods to de-link R&D costs from sale price, how best to support access to innovative antimicrobials, and how to develop a prioritization mechanism to support appropriate R&D on AMR specifically. Given the danger that the global rise of AMR represents, the discussion is likely to be extensive and intense.   Follow-up to the report of the Consultative Expert Working Group (CEWG) on Research and Development: Financing and Coordination (Report of the open-ended meeting of Member States) GHTC has been following the CEWG process for some time as it winds its way forward after what has already been a decade-long process. The prototype R&D observatory is now online, and the demonstration projects are returning their progress reports. The WHO Special Program for Research and Training in Tropical Diseases (TDR) has prepared an analysis that outlines how a pooled fund and R&D observatory could work to identify unmet needs and channel funds to those R&D projects. While almost everyone agrees that additional funds and greater coordination are sorely needed, as we heard at GHTC’s webinar on CEWG, the jury is still split on the CEWG’s specific proposals. While it is unlikely that the CEWG process will come to an end at this WHA, the number of concerns that can be ironed out with all the decision-makers in the room will be telling in regards to future prospects.   For more analysis on these subjects, read GHTC’s fact sheet on Research and development at the 69th World Health Assembly.