Breakthroughs Blog: Research Roundup

Later this year, French pharmaceutical company Sanofi plans to launch a vaccine for dengue fever, the first on the market for an infection for which nearly half of the world’s population is at risk. Sanofi has spent more than US$1.5 billion over 20 years on the research and development (R&D) of this dengue vaccine and expects it to be not only lifesaving, but also highly profitable. Dengue fever is endemic in a number of low- and middle-income countries in Asia and Latin America and is spreading into high-income countries in southern Europe as well as Japan and the United States. In preparation for the launch, Sanofi has invested more than $300 million in a manufacturing facility for the vaccine with the capacity to produce 100 million vaccines each year. Pharmaceutical companies Takeda, Merck & Co., Inc., and GlaxoSmithKline are also developing vaccines for dengue fever, and Takeda’s candidate could be on the market by 2020. The US Food and Drug Administration (FDA) granted a Breakthrough Therapy Designation to pharmaceutical company Bristol-Myers Squibb for its HIV treatment BMS-663068, based on the results of phase 2 clinical trials. The designation expedites FDA review in order to accelerate the availability of drugs for serious or life-threatening conditions and in cases where preliminary evidence suggests that the new product would offer significant advantages over current treatments. BMS-663068 is the first antiretroviral drug that actually prevents the HIV virus from attaching to and entering human immune cells. The designation is limited to use of the drug for “treatment-experienced” HIV patients who are developing resistance to other antiretroviral treatments. A new study suggests that the appearance of a pill can impact a patient’s perception of its efficacy. The study asked more than 100 participants each from the United States, China, and Colombia to rate images of pills on anticipated bitterness, ability to fight off headaches, and how hard it is to swallow, based solely on the shape and color of the pill. Across all three countries, participants perceived white pills as the most effective, and diamond-shaped pills—in contrast to round or oval pills—as the most difficult to swallow. A majority of US participants considered green pills to be the least effective and believed that red pills would lead to greater mental alertness. Past research has also suggested that a pill’s appearance can impact use; a study from 2014 indicates that when generic manufacturers change the shape or color of a pill, nearly one-third of patients will stop using the medication. On Monday, July 20, the Center for Global Development published The White House and the World, a report with concrete policy recommendations for the next US president on everything from energy and climate to migration and trade. The report notes that the United States often serves as the “first responder” in outbreaks and is a leader in global health, but calls for clear leadership—including the appointment of a global health coordinator—and pathways for coordination across US agencies. The report highlights the needs for reform at major multilateral organizations such as the World Health Organization and suggests that the United States should spearhead reform efforts and use those platforms to advance US priorities. The report identifies ways for the United States to provide technical assistance—through an office of Global Health Trade, Economics, and Knowledge Exchange—with partners in low- and middle-income countries, ultimately calling for a shift from the “aid-based status quo” and positioning the United States as a “forward-looking and strategic investor” in global health. The Guardian took an in-depth look at the status of antimicrobial R&D, including antibiotic drug discovery, alternative treatments for drug-resistant bacteria, and improved diagnostics. In the 1950s through the 1970s, researchers were discovering around twelve new antibiotics each year just by examining soil samples and identifying compounds—generated by the one percent of micro-organisms that can grow in normal laboratory settings—that could fight off bacteria. A new device known as iChip allows scientists to cultivate microbes while still in soil, enabling them to work with the other 99 percent of micro-organisms. Researchers at Northeastern University have identified 25 potential compounds using iChip, including one that demonstrates promise against drug-resistant tuberculosis and that the team believes could be available for use in humans within five years. According to Dr. Kim Lewis, the project’s lead researcher, “the rule of thumb is you need 50 promising leads for one drug, [so] we will keep searching for more.” Dr. Matt Cooper, a professor of chemistry at the University of Queensland, is also searching for new antimicrobial compounds. Earlier this year, he established the Community for Open Antimicrobial Drug Discovery, which will collect thousands of chemicals and test them for antibiotic potential. While Lewis and Cooper search for new compounds, others look for alternative or supplemental treatments for drug-resistant bacteria. The London-based biotech company Helperby Therapeutics has developed a “resistance breaker,” which Chief Scientific Officer Anthony Coates describes as “punching holes in the membrane of bacteria” to enhance the ability of existing antibiotics to combat the bacteria. David Livermore, a professor of medical microbiology at the University of East Anglia, is calling for rapid diagnostics to improve the diagnosis and treatment of drug-resistant infections. Livermore compares the current use of antibiotics to “carpet bombing in the second world war,” killing off all bacteria in patients, including protective bacteria in the human gut, and leaving a vacuum in which harmful bacteria can develop resistance. Because antibiotics are cheap and used by patients for a short amount of time, however, large pharmaceutical companies can be hesitant to invest in their R&D. As Cooper explains, the “low-hanging fruit[s]” have been discovered, and government investment is now needed to return to the “golden era” of antibiotic drug discovery.

An experimental, aerosol vaccine completely prevented infection from Ebola in monkeys, and will be tested in human clinical trials shortly. The vaccine was tested on twelve monkeys, with four each receiving one and two doses, two receiving a liquefied version of the vaccine, and a control group comprised of the remaining two monkeys. Four weeks after vaccination, all 12 monkeys received a massive dose of the virus, 1,000 times the fatal amount. While the two unvaccinated monkeys became ill, all ten of the vaccinated monkeys remained healthy, and the researchers found no trace of the virus in their blood. Aerosol vaccines are easy to administer and do not require a trained health professional, and thus are ideal for use in an outbreak or a country without a robust health workforce. Earlier this year, Apple Inc. launched ResearchKit, an open source software framework to facilitate the collection of health information in clinical trials, and soon two major pharmaceutical companies—GlaxoSmithKline and Purdue Pharma—may be utilizing the software. The software makes it easy for researchers to create their own iPhone applications to connect with participants in clinical trials and is already being used by academic institutions and nonprofits for data collection. Not only can these applications survey participants, but they can measure hand tremors in patients with Parkinson’s disease, physical activity in relation to cardiovascular disease, and geographic locations that exacerbate the symptoms of asthma. The software provides researchers more frequent access to a greater number of participants. Researchers are also looking into connecting other devices to the software, for example, asthma inhalers that transmit data via Bluetooth. While smartphones, and in particular iPhones, are less prevalent in low- and middle-income countries, the software could be used by health professionals or researchers for data collection. Already, smartphones are being used to perform eye exams in Kenya, pasteurize milk for breast milk banks in South Africa, and could soon be used to detect infection with Loa loa filariasis in Africa. Photo: CDC/ Dr. Mae Melvin Researchers at the Duke-NUS Graduate Medical School in Singapore have discovered an antibody—a protein in the immune system that identifies and combats specific pathogens—against one of the four viruses that causes dengue fever. The team, led by Shee-Mei Lok, a professor of Emerging Infectious Diseases at the university, first identified the specific part of the virus that triggers the production of antibodies in mice and believes that a vaccine comprised of just that part of the virus could provide protection from infection. Lok hopes to create a cocktail treatment against dengue fever using antibodies against each of the four types, and the team is continuing their research to identify an antibody against DENV-4, the one virus responsible for dengue fever for which there is not a known antibody. Bats are the natural reservoir, or host, for more than 65 viruses, bacteria, and other pathogens that infect humans, including Ebola, rabies, and the coronaviruses responsible for SARS and MERS. A team of researchers surveyed 1,270 people in rural Ghana, shedding light on the interactions between bats and humans and consequently, how these diseases are transmitted to humans. Two-thirds of respondents reported physical contact with bats, with 37 percent having been bitten, scratched, or exposed to the urine of bats. While only 17 percent of Ghanaians reported interacting with bats at work or at home, nearly half regularly visit bat caves.

Photo: CDC/ Melissa Dankel With the looming threat of a post-antibiotic era—in which minor infections are fatal due to growing drug resistance—world leaders are examining remedies for treating bacterial infections from the pre-antibiotic era. One such treatment, known as phage therapy, uses live viruses that attack bacteria and ignore human cells. The method, which was discovered in the early twentieth century, was largely abandoned after the discovery of penicillin and is currently only in use in Russia, Georgia, and Poland. Nearly a century later, the European Commission is funding a US$4.2 million clinical trial to test phage therapy on 220 patients in France, Belgium, and Switzerland. The study will use a cocktail of these viruses—known as bacteriophages—developed by French company Pherecydes Pharma. Phage therapy is expected to be an option of last resort to treat infections that are resistant to three or four drugs. American pharmaceutical company Johnson & Johnson will initiate clinical trials of an experimental HIV vaccine that completely prevented HIV infection in half of the monkeys that received the shot. Vaccinated and unvaccinated monkeys were exposed to simian immunodeficiency virus—a relative of HIV—on six occasions, after which all of the unvaccinated monkeys were infected. The clinical trial will include 400 healthy volunteers from the United States, East Africa, South Africa, and Thailand. If the vaccine appears to be safe and effective, Johnson & Johnson plans to commence phase 2b trials within the next two years. Each year, a new flu vaccine is developed to protect against the three to four strains of the influenza virus that are expected to be most virulent. The vaccine is comprised of antibodies—proteins developed by the immune system—against those selected strains. However, new research out of Rockefeller University could pave the way for the development of a universal flu vaccine that would provide lifetime protection against all strains of human influenza. The team at Rockefeller noticed that humans naturally develop sialylated antibodies—antibodies with sialic acid at one end—after receiving a seasonal flu vaccine, specifically the H1N1 vaccine. The team then vaccinated mice with either the standard H1N1 vaccine or an experimental vaccine that included sialyated antibodies against H1N1. The two vaccines provided equal protection from H1N1, however, only the vaccine containing sialyated antibodies provided protection against other strains of H1 influenza. In the lab, the researchers determined that the sialic acid allows antibodies to attach to human immune cells as well as the virus, and consequently coordinate the human immune response by prompting the production of broadly protective antibodies, rather than antibodies specific to one strain of the virus. The US Court of Appeals for the Second Circuit—one of 12 regional courts in the United States that reviews decisions made by local, district courts—upheld a district court’s decision against “product hopping,” a mechanism by which brand name pharmaceutical companies prevent competition from generic manufacturers by slightly adapting a product and removing the original from the market. In this case, pharmaceutical company Actavis had altered Nameda, a drug for Alzheimer's disease, and planned to remove the original version from the market, claiming that the new version is superior. However, the court ruled in People of the State of New York v. Actavis PLC that such action would be “unlawfully anticompetitive” and would violate the US Sherman Anti-Trust Act. The exclusivity period of the original version of Nameda was set to expire in July 2015, after which time generic versions of the drug could enter the market, while the exclusivity period of the new version would not expire until 2029. The court’s decision states that Actavis’ motivation for removing the original version from the market was to inhibit sales of generic versions of the original formulation of Nameda, as automatic substitution laws allow pharmacists to provide a generic version when a brand name drug is prescribed.

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.