Breakthroughs Blog: Research Roundup

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.

A woman's hands holding a SILCS diaphragm. (Photo: PATH/Patrick McKern) Last week, GHTC member PATH launched the Caya® contoured diaphragm in the United States, after developing and testing nearly 200 prototypes to ensure the product was safe, effective, and user friendly. PATH collected input from women and health care providers across the globe throughout the research and development (R&D) process, ultimately creating an innovative contraceptive that protects against sexually transmitted infections, has no side effects, and is discreet, comfortable, easy to use, and “one-size fits-most." The Caya® diaphragm, which is now available in 25 countries, is an important addition to existing contraceptive options, as it is the first diaphragm introduced in the United States in 50 years. In 2014, the World Health Organization (WHO) recognized the Chinese Food and Drug Administration as a functioning regulator; China has now developed two vaccines—for Japanese encephalitis and influenza—that have received WHO prequalification, a sign that a product is safe and effective. A representative of the Bill & Melinda Gates Foundation, which has worked with the Chinese government to enhance its vaccine R&D capacity, said that the second prequalification “may be the start of China truly becoming a player in global health.” China recently established a system that regulates manufacturing for pharmaceutical products based on the European Medicines Agency’s (EMA) and US Food and Drug Administration’s (FDA) standards. However, China’s regulatory system still has some barriers to overcome, as the regulatory approval process takes much longer than the EMA’s or FDA’s. Additionally, the Chinese government requires vaccines and drugs to be packaged individually—which is not conducive to international shipping—and there are currently no guidelines on how a manufacturer can obtain a license in China if clinical trials are conducted abroad. A vaccine candidate for the Middle East Respiratory Syndrome (MERS) has been successfully tested in mice and will progress to Phase I clinical trials shortly. The vaccine uses a weakened strand of a poxvirus—known as Modified Vaccinia virus Ankara—that has been altered to display a certain protein unique to the MERS virus. The immune system recognizes the protein as foreign, and develops antibodies and T cells to combat MERS. In the lab, the MERS virus was not able to reproduce in vaccinated mice despite exposure to “high levels” of the virus. The vaccine was developed by the Ludwig Maximilian University of Munich’s Institute for Infectious Diseases and Zoonoses, and the German Center for Infection Research has already committed 1.5 million euros for the Phase I clinical trials. The results of a massive trial for a new pneumonia vaccine were announced last week, demonstrating a major reduction in cases of the disease responsible for fifteen percent of deaths in children under five years of age. The vaccine, known as PCV-10, protects against ten different bacteria that can cause pneumonia. The trial lasted seven years, during which time the vaccine was given to 35,000 children in the Kenyan town of Kilifi. Eighty percent of vaccinated children demonstrated greater resistance to pneumonia. The town saw a 42.7 percent reduction in cases overall, and a 95 to 100 percent reduction in invasive pneumococcal disease—the most deadly form of pneumonia.

Photo: Medicines for Malaria Venture The Medicines for Malaria Venture (MMV)—a member of the GHTC—and the University of Dundee’s Drug Discovery Unit have developed an antimalarial compound that could treat drug-resistant cases of malaria with a single dose. The compound has been tested in both human blood and mice and the researchers involved believe it could ultimately be administered for only US$1 per dose. MMV has entered an agreement with pharmaceutical company Merck KGaA to advance the compound through the research and development (R&D) pipeline, transferring the rights to develop and commercialize any resulting product. Researchers at the US National Institutes of Health (NIH) have developed a vaccine that has protected against leishmaniasis in monkeys. Leishmaniasis infects one million people per year and is caused by the Leishmania parasite, transmitted through the bite of phlebotomine sand flies. Scientists noted that monkeys bitten by uninfected phlebotomine sand flies were less susceptible to future infections, and subsequently determined that a protein in the flies’ saliva—known as PdSP15—triggers an immune response. Seven of ten monkeys receiving an injection of PdSP15 developed immune cells against the Leishmania parasite and were significantly less likely to get the disease than members of the control group. Human cells also reacted to PdSP15 in a laboratory setting, indicating the potential of the protein in protecting humans from leishmaniasis. The fastest and most accurate tuberculosis (TB) test is expensive—$17,000 per machine and an additional $10 per test—and not conducive for use in rural settings because it requires electricity, refrigeration, and access to a computer. The test, known as GeneXpert is significantly more sensitive than traditional TB diagnostics, and its use increases successful diagnosis by 39 percent. Its popularity among health officials and donors has demonstrated that there is a major market for TB diagnostics, and has galvanized private-sector investments in TB R&D. There are now 191 TB diagnostics in the pipeline, and the manufacturers of GeneXpert are working to make the technology cheaper and to develop a remote, cloud-based version of the test. Since 2010, the Pediatric Trials Network has been conducting research to determine the safety and appropriate dosage of different medicines for young children, including premature infants. Children are often excluded from clinical trials, due to issues of consent and communication, and consequently, many drugs are not tested on children before entering the market. The NIH-funded Pediatric Trials Network has gathered research from nearly 90 sites and 3,500 children across the United States, and the results have often been counterintuitive. Medical professionals often determine the appropriate dosage of a drug based on a child’s weight, however the Network’s research has indicated that underdeveloped organs, particularly in premature infants, may struggle to fully process the drugs, ultimately requiring a higher dose per pound.

The zoonotic Middle East Respiratory Syndrome (MERS), which World Health Organization (WHO) Director-General Dr. Margaret Chan called “a threat to the entire world” has spread to South Korea. More than 100 cases and 10 deaths have been reported, making it the largest outbreak outside of the Arabian Peninsula. While there are currently no vaccines or treatments for MERS, researchers are confident that with adequate political will and funding, such products could be rapidly advanced. Photo: PATH/Nguyen Ba Quang Dr. Matthew Frieman, a professor and researcher at the University of Maryland School of Medicine, has developed an experimental vaccine in partnership with vaccine company Novavax Inc. that successfully protected mice against the MERS virus. Greffex, another vaccine company, has already worked with the US National Institute of Allergy and Infectious Diseases to develop a vaccine that triggers the production of antibodies—proteins that protect against the disease—in mice. Dr. Frieman and Greffex CEO John Price agree that funding and political will are the only barriers to the development of a MERS vaccine. According to Price, Greffex could develop a MERS vaccine candidate in less than a month with a sample of the virus, but they lack the funding to conduct clinical trials. Researchers have also struggled to obtain the needed information and materials—including samples of the virus—from scientists in Saudi Arabia. In the meantime, Frieman is working to test existing, approved drugs for the treatment of MERS, and has identified 27 drugs that have demonstrated potential in combatting MERS in a laboratory setting. At this year’s G7 summit, leaders of seven countries—including Canada, France, Germany, Italy, Japan, the United Kingdom, and the United States— pledged to advance research and development (R&D) for neglected tropical diseases and new antibiotics. The members of the G7 committed to supporting everything from basic research through the development of “easily usable and affordable drugs, vaccines and point-of-care [diagnostics].” The G7 Leaders' Declaration also endorses the WHO Global Action Plan on Antimicrobial Resistance and the WHO Global Observatory on Health Research and Development, highlighting the need for improved coordination of global health R&D. In a New York Times op-ed, Gregg Gonsalves and Mark Harrington, co-founders of the Treatment Action Group, reflected on lessons learned about the US Food and Drug Administration’s (FDA) drug approval process during the US HIV and AIDS epidemic. The article comes as Congress is considering the 21st Century Cures Act, a bill intended to advance medical breakthroughs, in part through FDA reform. The legislation includes several provisions to expedite the approval of drugs and medical devices based on what Gonsalves and Harrington consider to be “lower standards.” The authors assert that while innovative regulatory pathways—such as the Accelerated Approval Program—enabled early access to new HIV and AIDS drugs, pharmaceutical companies were still required to demonstrate the safety and efficacy of products before they entered the market. Additionally, in the case of preliminary approval, companies were expected to continue and complete clinical trials. To protect patient safety, Gonsalves and Harrington argue that such standards should be upheld, reminding Congress that those standards “paved the way for the development and approval of breakthrough drugs [that] have been proven to be effective and safe.” There are nearly 170 contraceptives products in the R&D pipeline, from discovery, through product development, to regulatory review. Researchers, advocates, funders, and procurement agencies can now find information about these products all in one place through Calliope, the Contraceptive Pipeline Database, a new resource developed by GHTC member FHI 360. Calliope includes information regarding the R&D stage, the partners, the active pharmaceutical ingredients, the delivery and duration, and the mechanism by which the technologies prevent pregnancy. The contraceptive pipeline is diverse, and includes vaccines, microbicides, implants intrauterine devices and balls, pills, and even microchips. The exchange was created to galvanize contraceptive R&D for low-resource settings through knowledge sharing and the facilitation of cross-sector partnerships.