Breakthroughs Blog: FDA

Earlier this year, the World Health Organization (WHO) declared the outbreak of Zika in Latin America a Public Health Emergency of International Concern. The virus, spread by the Aedes aegypti mosquito, was once considered innocuous, causing a mild illness and lasting for only a handful of days. However, the virus has since been linked to devastating birth defects and neurological complications and has spread to more than 60 countries. The virus’s virulence took the research community by storm: although it was discovered in 1947, only 25 scientific papers were published on the topic prior to the current outbreak. As the scientific community learns more about the virus and the disease, the need for tools to prevent, detect, and treat it has become undeniable. On February 22, US President Barack Obama submitted a request to Congress for US$1.9 billion in emergency funding to combat the virus, a critical move, as the US government is unrivaled as the largest funder of global health research and development (R&D). However, 146 days later, Congress has yet to reach a deal, and the US agencies leading the fight against Zika are running out of money. In the meantime, these agencies have made impressive strides in advancing Zika R&D using limited funding and leveraging cross-sector partnerships. An unprecedented number of private-sector partners have also entered the hunt for Zika countermeasures, building out a robust pipeline in record time. Below, we highlight the most promising vaccine, drug, and diagnostic candidates as well as vector control approaches. Vaccines There are currently more than 35 Zika vaccine projects underway, and at least 3 have completed successful animal trials. Inovio Pharmaceuticals and GeneOne Life Sciences partnered to develop a DNA-based vaccine, using a unique delivery approach—electroporation—in which a device is applied to the injection site, sending out electrical pulses that enhance the vaccine’s ability to enter human cells. The vaccine successfully prompted an immune response, including the production of protective antibodies, in both mice and monkeys. In late June, the experimental vaccine became the first to be approved for human clinical trials by the US Food and Drug Administration (FDA). The phase 1 trial, which will enroll 40 healthy adults, is intended to evaluate the safety and tolerability; however, the team will also monitor its ability to induce an immune response. Meanwhile, two more vaccine candidates have proven effective in mice. The candidates include a DNA-based vaccine and one composed of an inactivated version of the Zika virus, the first supported by the US National Institutes of Health (NIH) and the second developed by the US Walter Reed Army Institute of Research. The latter will be tested in phase 1 clinical trials by the US National Institute of Allergy and Infectious Diseases and then transferred to French pharmaceutical company Sanofi for further clinical development. Sanofi is also working on a vaccine of its own; however, it won’t enter clinical trials until 2017. After several months of feasibility studies, British pharmaceutical company GlaxoSmithKline has announced that it will be partnering with the NIH to test its RNA-based vaccine in animals. To date, no DNA or RNA vaccines have been approved for use in humans, although they are often called the future of vaccines. Drugs Due to the dearth of knowledge about the virus and the difficulty of conducting clinical trials and using novel drugs in pregnant women—a key target population for Zika control—the WHO has stated, “It is unlikely at this stage that therapeutics will constitute a priority activity.” However, efforts are underway, both to discover novel treatments and to repurpose existing medicines. Australian biotech company Biotron announced recently that two compounds in their library have proven effective against Zika in test tubes. They will continue to conduct laboratory tests to better assess the safety and efficacy of the compounds in humans. Researchers at the US National Center for Advancing Translational Sciences are screening their compound library—with half a million entities— and have identified a novel drug, which is safe for use in humans and currently in clinical trials for cancer, that prevented the virus from killing progenitor cells, which play a critical role in the neurological system and fetal development. Researchers at the University of California, San Diego are embarking on an ambitious study to virtually screen more than 20 million compounds against the virus. The program—OpenZika—uses a research collaboration platform to harness the power of volunteers’ computers and smartphones. Participants download the software, and when their computer or phone is inactive, it runs calculations to predict how a compound will interact with the virus in the lab. Researchers are also looking at repurposing existing drugs as Zika treatments. Chloroquine—which both prevents and treats malaria—has successfully protected against Zika virus in vitro. A team at Katholieke Universiteit Leuven has identified an experimental treatment for hepatitis C that delayed the manifestation of Zika-related symptoms in mice. And scientists at the University of California, San Francisco reported that the antibiotic azithromycin—which has long been used in pregnant women—blocked the virus from multiplying in petri dishes. Diagnostics As of March, more than 30 diagnostics for the virus were under development, and the FDA has sanctioned the use of five tests—four that detect current infection and one to assess previous exposure—under its Emergency Use Authorization program. However, rapid, point-of-care diagnostics are desperately needed. Eighty percent of cases are asymptomatic, and initial symptoms—fever, rash, joint pain—are nonspecific. Thus, early and accurate diagnosis is critical to ensure appropriate treatment. A team of Harvard University and Massachusetts Institute of Technology researchers have designed a paper-based test that can diagnose cases within a few hours. The device is appropriate for low-resource settings: it’s cheap, it can be stored or shipped at room temperature, and the results are easy to interpret. The tool contains miniscule sensors that change color in the presence of a specific genetic sequence. To ensure accurate detection of the virus, the team developed sensors that can detect 24 different genetic sequences found in the Zika genome. The device has been tested using samples from infected monkeys and has proven to be effective at detecting even low quantities of the virus. Although the results are easy to read—a positive sample turns the strip purple—the team has also created a simple electronic reader that determines the quantity of the virus in the sample. Vector Control As vaccines, drugs, and diagnostics against the virus inch their way through the R&D pipeline, health officials are ramping up vector control efforts against the Aedes aegypti mosquito. New techniques are also underway, and the FDA is currently accepting public comment on a proposal to expand testing of genetically engineered mosquitoes. The mosquitoes mate with the local population, resulting in offspring that die before reaching adulthood and are consequently not able to spread diseases. A trial of the mosquitoes in Brazil led to an 82 percent decrease in the Aedes aegypti population in just nine months. Scientists are using innocuous bacteria and fungi to combat the spread of Zika. Male mosquitoes infected with the Wolbachia bacteria do not produce viable offspring, and tests across the United States have reduced the population of the closely related Aedes albopictus mosquito by an estimated 70 percent. Meanwhile, the Metarhizium brunneum fungus is used as a natural pesticide, killing mosquito larvae. Meanwhile, in North Hempstead, New York, bats have been enlisted in the fight against Zika. The city is building and hanging bat houses in parks to attract the animals, as they can eat more than 1,000 mosquitoes in an hour.

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.

Aedes Aegypti mosquito which carries the Zika virus. Photo: CDC/James GathanyOn Tuesday, the Obama administration announced that it will transfer nearly US$600 million in remaining Ebola funds to fight the growing threat of Zika virus. But many questions remain. Where is the money going? From what accounts will it come? And what does this mean for the Global Health Security Agenda (GHSA) programming which is supposed to help protect against these threats in the future?In February, the President requested $1.9 billion in emergency appropriations to combat the Zika virus outbreak, but authorization was stalled by members of Congress who suggested the Administration reallocate existing funds instead. The Administration continues to stress that the full request is still needed to fight both Zika and complete the Ebola response. With the announcement of the transfer of funds, the Administration is signaling that the risk of waiting for Congress to act on a supplemental funding is too great, and deploying additional funding to address Zika is essential in the short-term—before the summer weather leads to a broader spread of the mosquito-carried virus.Reallocating Ebola funding to address Zika carries consequences. While the Administration acknowledges that some Ebola funds remained unspent, much of this money has been allocated to implement the GHSA—a commitment to help at least 30 countries prevent, detect, and respond to emerging disease threats. GHSA has not received any direct appropriations, largely due to sentiment that remaining Ebola balances should cover the cost. Additionally, as the Ebola response remains unfinished—health systems in West Africa remain fragile and we have not yet developed approved Ebola vaccines or treatments—diverting funding before we have finished the job remains risky.Where is the money going? From where will it come? Vaccine researcher. Photo: NIAID, NIH Because the US Centers for Disease Control and Prevention (CDC) is focused on research and development (R&D) for Zika vaccines, treating those infected, and combating the mosquitoes that spread the virus, many expect the bulk of the $600 million transfer to be directed to CDC Zika efforts. The Washington Post reports that 75 percent of the transfer will go to CDC and the rest to foreign aid accounts. It remains uncertain from what accounts the Ebola transfers will come—and subsequently the impact on programs currently funded through the Ebola supplemental. It seems likely that much of the transfer may come from accounts at the US Agency for International Development and State Department, which as of December 31, 2015, had $400 million in programmed Ebola funds that will expire at the end of fiscal year 2016. Other accounts with remaining funds include: $1.031 billion at CDC for domestic, international, and global health security $363 million at Public Health and Social Services Emergency Fund, which houses the Biomedical Advanced Research and Development Authority $45 million at the US National Institutes of Health $14 million at the US Food and Drug Administration Funds in these accounts do not appear to have expiration dates. As we do not yet know for certain which accounts will fund the $600 million transfer, the impact of this decision on implementation of the GHSA is also uncertain.If funds are transferred from CDC accounts, GHSA efforts could be delayed or stalled. It also remains to be seen whether the Administration will receive additional funding to supplement the Zika response. While Congress has not acted on a request for a stand-alone supplemental funding, members have suggested they are open to providing additional funding in the future should the reallocation of existing funds prove insufficient to both addressing Zika and completing the Ebola response. The possibility remains that we could see additional funding for Zika as part of the regular appropriations process, which is likely to progress in the coming months. 

Pyramax® Granules (Photo: MMV) After four successful Phase 3 clinical trials enrolling more than 3,500 patients in 18 countries, the European Medicines Agency (EMA) has granted Pyramax® Granules, a pediatric malaria medicine, a positive opinion under Article 58—a mechanism through which the EMA reviews and issues a scientific opinion on products that are not intended for use in Europe. Pyramax® Granules is a combination of two antimalarials and was developed by Medicines for Malaria Venture (MMV), a member of the GHTC, in partnership with Shin Poong Pharmaceutical Co. Ltd. The treatment is designed to be easy for children to consume: its bitter taste is masked and it is taken in liquid form, as children often struggle to swallow pills. Next, MMV and Shin Poong will work to introduce Pyramax® Granules as well as Pyramax®, the tablet version which is suitable for adults, in malaria-endemic countries. A recent article in NPR: Goats & Soda examines Zika virus, a disease transmitted by the same mosquito vector of dengue fever and chikungunya, that has been rapidly spreading throughout South America and the Pacific Islands in recent years. One in five individuals infected with the virus experience Zika fever, which in addition to fever involves rashes, joint pain, conjunctivitis, headaches, vomiting, and muscle pain. Cases of Zika fever are likely underdiagnosed, as awareness of the disease is limited and its symptoms are similar to infections associated with other members of the Flaviviridae virus family, including dengue fever, yellow fever, West Nile, and Japanese encephalitis. There are no reported deaths to date, but there is growing evidence that the virus can be transmitted sexually or from mother to infant during pregnancy. As there are no vaccines or drugs for Zika fever, treatment involves addressing the symptoms, using fever reducers and painkillers. A group of global health advocacy organizations—including GHTC members the Drugs for Neglected Diseases initiative, TB Alliance, Infectious Diseases Society of America Center for Global Health Policy, Sabin Vaccine Institute, and Treatment Action Group—sent an open letter to the US Senate Health, Education, Labor and Pensions (HELP) committee, calling for amendments to the priority review voucher (PRV) program at the US Food and Drug Administration (FDA) to ensure it adequately incentivizes research and development (R&D) for neglected diseases, as intended. Under the program, companies that receive FDA approval for a drug for a neglected disease (see list of eligible diseases) are awarded a voucher for expedited FDA review (six months rather than ten) of a future product. The vouchers are transferable and have been sold at increasing rates, the most recent going for US$350 million. The letter calls for PRVs to only be awarded for products that are "truly new" as two of the six vouchers that have been awarded were for products that had long been in use outside of the United States.[1] The organizations are also calling for recipients of the voucher to be required to develop a strategy to ensure the product is made affordable and accessible to patients in the countries in which the eligible disease is endemic. The United Kingdom (UK) announced last week the creation of the Ross Fund which will provide £1 billion ($1.5 billion) over five years to fight malaria and other infectious diseases. The funding, which will come from the UK overseas aid budget, includes £90 million for malaria eradication; £100 million for infectious disease R&D; £115 million for the development of drugs, diagnostic, and insecticides for malaria, tuberculosis, and other infectious disease resistance; and £188 million for biodefense and rapid response systems for epidemic preparedness. Global Good has developed a cooler that can store and transport vaccines at freezing temperatures for over a month using just ice and no electricity. The Arktek cooler uses vacuum thermal insulation, an approach used to preserve spacecraft entering extreme temperatures. The cooler has been tested in Senegal (with support from GHTC member PATH) and Ethiopia, and last year, the Arktek was modified for use in Ebola vaccine clinical trials, during which the cooler kept the vaccines between -76 and -112 degrees Fahrenheit for three days. [1] There are two separate PRV programs at the FDA, one for neglected tropical diseases and one for rare pediatric diseases. Of the six PRVs that have been awarded, three each have been for neglected tropical diseases and rare pediatric diseases. Since the beginning of the PRV program, six PRVs have been awarded—three for neglected tropical diseases and three for rare pediatric diseases.