Kat Kelley

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.

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.

Researchers at the Durham University in the United Kingdom have received a US$100,000 grant from the Bill & Melinda Gates Foundation to test the feasibility of training dogs to detect malaria. Dogs have been trained to use their keen sense of smell to detect other diseases, including certain cancers, and studies suggest that malaria infection causes a distinct odor, and that unique chemicals can be found on the breath of patients. The team plans to recruit 400 children in the Gambia, including many who are currently infected with malaria. The children will wear nylon socks for 24 hours, which will then be used to train the dogs to identify malaria based on odors in the sweat and skin. If successful, this approach to malaria testing would be quick and cheap, and would not require any equipment or a laboratory setting. A new, commercially-available diagnostic can predict premature births, a critical tool as half of all preterm births occur in women without known risk factors. Between 2011 and 2013, the Utah-based Sera Prognostics enrolled more than 5,500 pregnant women at 11 sites across the United States, and confirmed that the quantity of two proteins in the blood can indicate risk for preterm birth. The test can be administered at 19 or 20 weeks into the pregnancy; pregnancy normally lasts 40 weeks and delivery before 37 weeks is considered preterm. The test—PreTRM®—tells a woman her percentage risk, and currently costs $945, however, Sera Prognostics is working with the Bill & Melinda Gates Foundation to develop tools more suitable for low-income countries. Startup NextGen Jane is developing a “smart tampon” that would collect menstrual blood each month and test for a range of diseases and conditions, including sexually transmitted infections, endometriosis, polycystic ovarian syndrome, uterine fibroids, cervical cancer, and more. Many of these conditions are asymptomatic, and consequently go undetected until significant damage has been done. The team at NextGen Jane has a working prototype—a device that siphons menstrual blood from tampons—and is conducting clinical trials for several of the diagnostics themselves, which identify biomarkers for different conditions in menstrual blood. The tool will connect to a database, allowing women to analyze the data and track their reproductive health over time. The team anticipates having a complete product—combined diagnostics and the delivery mechanism—within the next year, which will be commercially available within three to four years.

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.