Breakthroughs Blog: Research Roundup

A new study suggests that with basic training, individuals can learn to accurately and safely test themselves for HIV and AIDS. Nearly 17,000 adult and adolescent citizens of urban Malawi were provided with testing kits, and within a year, more than three-fourths had self-tested. Across sub-Saharan Africa, only one-fourth of adults have recently been tested for HIV and AIDS, and only half of people living with HIV and AIDS know their status. The research team conducted repeat HIV and AIDS tests on 1,649 participants, and in 99.4 percent of cases, the results of self-testing proved accurate. The results also suggest that HIV and AIDS self-testing is culturally acceptable in urban Malawi and that pre- and post-test counselling was adequate, as no testing-related partner violence or suicides were reported. As the stigma surrounding HIV and AIDS remains a significant barrier to both testing and treatment, HIV and AIDS self-testing could be a game changer in curbing the epidemic. Photo: CDC/ James Stewart Researchers at the University of Queensland in Australia and the University of California, Berkeley have identified a protein—nonstructural protein 1 (NS1)—that may be the key to the dengue virus’ virulence. The virus infects nearly 400 million people each year, resulting in 22,000 deaths, primarily from fluid loss and damage to the blood vessels. The discovery dates back to the early 2000s, when a study in Thailand revealed a correlation between NS1 levels and the severity of the disease in patients. Further research demonstrated that NS1 attaches itself to another molecule which enables it to bind to blood vessel walls; NS1 also prompts the immune system to produce cytokines—proteins that weaken the blood vessels. Essentially, NS1 causes the immune system to react as it does to bacterial infections. These findings could pave the way for both a vaccine and a treatment against dengue fever. The team at Berkeley has demonstrated that NS1 could be used in a dengue vaccine, as the immune system readily detects NS1, rather than the dengue virus itself. In mice, NS1 provided protection against all four strains of the dengue virus, at rates of 60 to 100 percent efficacy. Furthermore, Dr. Paul Young of the University of Queensland believes that a drug for sepsis that is currently in clinical trials could be an effective treatment for dengue. The Drugs for Neglected Diseases initiative (DNDi) has completed phase I human clinical trials for SCYX-7158 (AN5568), a drug candidate with the “potential of becoming the first ever, oral-only, single-dose treatment” for human African trypanosomiasis (sleeping sickness), according to DNDi’s Dr. Antoine Tarral. The compound was identified by Anacor Pharmaceuticals, Inc. as part of DNDi’s lead optimization program, through which partners screened compounds from Anacor’s chemical library to identify those that combat sleeping sickness in a laboratory setting. The candidate was tested for safety and tolerability, as well as its effect on and interaction with the body, in 128 healthy volunteers. Due to the trials’ successful results, DNDi and partners will initiate phase 2 and 3 studies in 2016 in the Democratic Republic of the Congo. The leading treatment for sleeping sickness—also developed by DNDi—requires injections, and consequently skilled personnel; prior to the 2009 introduction of this therapy, the best option was an arsenic-based drug with extreme side effects.

Pharmaceutical company AbbVie is paying United Therapeutics US$350 million for its priority review voucher (PRV)—which expedites the US Food and Drug Administration’s (FDA) review of a product by four months—and EP Vantage speculates on their motive. The FDA awards PRVs to pharmaceutical companies that receive FDA approval for drugs to treat neglected tropical diseases (NTDs) or rare pediatric diseases. The PRVs provide an incentive for companies to invest in research and development for these diseases. To date, six PRVs have been awarded—three each for NTD and rare pediatric disease treatments—and four have been sold. The PRVs have been sold at increasing prices, with the previous three purchased for $67, $125, and $245 million. While AbbVie has seven products currently in phase 3 clinical trials, EP Vantage argues that the PRV will likely be saved for use with filgotinib—a treatment for rheumatoid arthritis (RA)—which is currently in phase 2 trials and on track for a 2018 market introduction. For chronic conditions such as RA, patients are hesitant to switch medications, meaning an earlier launch can have an impact on sales for years. However, a number of new RA drugs are expected to reach the market before filgotinib: Eli Lilly's baricitinib could be launched as early as 2016, and as the US patent for AbbVie’s blockbuster RA drug Humira expires in late 2016, filgotinib could face competition from generic or biosimilar versions of Humira as well. Researchers at the University of California, Santa Barbara (UCSB) are proposing a novel approach for identifying drug-resistant bacteria, challenging the standard method that has been used for more than 70 years. Normally, doctors collect biological samples from sick patients, and the sample is placed on petri dishes filled with a medium known as Müller-Hinton agar, on which nearly any bacteria in the sample will readily grow. They can test the bacteria’s drug-resistance by monitoring how it grows or subsides when exposed to different antibiotics. Patients are then prescribed an antibiotic that caused the bacteria to subside on the petri dish. However, the chosen antibiotic is sometimes unable to fight off the infection in the body, despite its demonstrated ability to combat it in the lab. In these cases, the bacteria can develop resistance to new drugs, making it even harder to treat. Led by Dr. Michael Mahan, the team at UCSB used a less common medium, LPM, which mirrors the conditions within human cell (i.e., it is much more acidic and is low in phosphate and magnesium) and discovered that bacteria may be more sensitive or more resistant to different antibiotic compounds in different settings. According to Mahan, the use of a medium such as LPM could enable doctors to more accurately predict how a patient will react to a certain antibiotic. Furthermore, their findings could lead to the identification of new antibiotic compounds. According to Mahan, there are “millions of chemical compounds that were excluded as antibiotics…but they were never tested since standard [Müller-Hinton agar] petri plates ruled them out.” Photo: PATH/Aaron Joel Santos NBC News reports on three recently released studies that show progress toward the development of an oral flu vaccine and a universal flu vaccine. Biotech company Vaxart, Inc. recently completed early phase 1 clinical trials of an experimental oral flu vaccine, which proved to be both safe and effective. These results have prompted the production of antibodies that are “strongly associated with protection in humans” in three-fourths of participants, according to flu vaccine expert Dr. John Treanor. An injectable vaccine goes straight to the bloodstream and is rapidly detected by the immune system; however, Vaxart had to “come up with a different way of getting the flu gene into the intestines and have the immune system recognize the flu gene as foreign,” according to Vaxart Founder and Chief Scientific Officer Sean Tucker. Meanwhile, teams of researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and Scripps Research Institute have been working on universal flu vaccine candidates. There are several different types of influenza strains that affect humans, including H1 and H3 strains of influenza A as well as influenza B strains. Seasonal flu vaccines protect against three to four strains, based on which are predicted to be most virulent that year, and they train the immune system to detect and attack the virus’ hemagglutinin protein, which is uniquely shaped for each strain. Both NIAID’s and Scripps’ universal flu vaccine candidates use the stem of hemagglutinin, which looks the same for, and should grant protection against, all H1 and H5 (avian influenza) strains. Both candidates have proved safe and effective in mice.

A new paper-based diagnostic can test for Ebola, dengue, and yellow fever in just ten minutes without running water, electricity, lab equipment, or highly-trained personnel. “We purposely designed it to be very simple not only to assemble but also to use and to read out,” says lead developer Dr. Kimberly Hamad-Schifferli, a Massachusetts Institutes of Technology professor. Initial symptoms for these three hemorrhagic fevers are nonspecific, making them hard to diagnose, and existing diagnostic methods—while more accurate—are impractical for low-resource settings. This paper-based diagnostic currently costs US$20, although Hamad-Schifferli believes it could be manufactured for even less. The test uses red, orange, and green nanoparticles to test for Ebola, yellow fever, and dengue respectively, and just by identifying the colors that appear on the strip, a diagnosis can be made. Photo: PATH/Gabe Bienczycki An experimental vaccine against Middle East Respiratory Syndrome (MERS) will be tested on humans later this year in clinical trials run by Inovio Pharmaceuticals and GeneOne Life Science. The vaccine, which was developed by researchers at the University of Pennsylvania in partnership with Inovio, the US and Canadian governments, and the Universities of Washington and South Florida, will be the first against MERS to advance to human clinical trials. The team took a novel approach to developing the vaccine, using an artificially engineered DNA sequence, rather than material from the MERS virus itself. The DNA prompts the recipient’s immune system to produce a protein that is unique to the MERS virus, which in turn triggers the production of protective proteins—known as antibodies—that detect that unique MERS protein and attack it. The vaccine successfully induced the production of these protective proteins in mice, monkeys, and camels, and as it does not contain any live viral material; it’s anticipated to be safer than traditional vaccines. Gilead Sciences Inc., a California-based biotechnology company, is aiming to cure HIV and AIDS and hepatitis B and one candidate—GS-9620—has shown promise in combatting both infections in animal studies. “Gilead is the leader in HIV,” according to Andrew Cheng, executive vice president of Clinical Research and Development Operations at Gilead Sciences, and he’s got a point: 80 percent of new HIV and AIDS patients start treatment using a Gilead product. Their expertise in antivirals expands beyond HIV and AIDS; the company has doubled its sales over the past two years, due to the market introduction of Sovaldi and Harvoni—drugs that cure Hepatitis C in 90 percent of patients. Existing treatments for HIV and AIDS prevent active, HIV-infected cells from reproducing, however, inactive cells are able to escape detection, effectively hiding from the immune system. GS-9620 is one of several drug candidates that uses a method known as “shock and kill” to wake the latent, infected cells, enabling the immune system to identify and attack them. The treatment successfully triggered viral activity in monkeys and is now being tested in humans. The treatment has also been tested in woodchucks infected with Hepatitis B, and within a month, the virus was completely undetectable. Researchers at the University of Pennsylvania and the University of Ulm in Germany have discovered a molecule that attacks both HIV-infected cells and a protein in semen that enhances the infectivity of the HIV virus. The molecule—CLR01—latches onto viral membranes, known as viral envelopes, but passes over cell membranes. This suggests that the molecule is unlikely to have any major side effects and that it might be successful in combatting other sexually transmitted viruses. The tweezer-shaped molecule also targets and suppresses molecules in the semen that attach to the HIV virus and help it bind to human immune cells, ultimately making the virus 10,000 times more virulent. CLR01 has been successfully tested in zebrafish and mice and will next be tested for safety in efficacy in nonhuman primates. According to the researchers, mass producing CLR01 is relatively simple, making it a microbicide candidate.

The US Food and Drug Administration (FDA) approved the first 3D-printed drug last week, paving the way for the technology to be used to customize medical care to individual patients. 3D printing is a manufacturing process that involves using a computer to create an object one layer at a time. In the case of the recently approved Spritam—a treatment for epilepsy—the printing allowed for greater control over formulation of the drugs, resulting in the creation of the first 1,000 milligram tablets that remain easily dissolvable despite their large size. The use of 3D printers could ultimately enable hospitals to produce their own medicines, adjusting the dose for individual patients. Meanwhile, at the University College London School of Pharmacy, researchers are exploring the possibility of using 3D printing to create uniquely shaped drugs. Drugs are absorbed at different rates depending on the surface area and volume of the tablet, and by adjusting the shape of a tablet (i.e., creating a pyramid or doughnut shaped pill) the rate at which a drug’s active ingredients are released could be manipulated. Leaders at the FDA and the US Department of Health and Human Services propose mechanisms and protocol to expedite drug development in public health emergencies in The New England Journal of Medicine, stating “if we are to act on lessons learned [from the Ebola outbreak] there is no time to waste.” The authors note that limited research capacity delayed the testing of experimental treatments, calling for efforts to strengthen clinical trial infrastructure globally. The outbreak also prompted debate about research ethics in emergency settings (i.e., whether it was ethical to administer untested therapies and the ethics of using placebos in an outbreak). Consequently, the authors recommend that processes for ethical review of studies in outbreaks be streamlined. Finally, the authors stress the need for coordination between health and regulatory authorities, researchers, and product developers. In the Ebola outbreak, the US government partnered with West African governments, academic institutions in both regions, and product developers at every stage. Clinical trials of different therapies were conducted concurrently, allowing partners to have a single, shared control group. The authors note that to facilitate collaboration for rapid drug development in outbreaks, there is a need to establish “model agreements” regarding data management and intellectual property rights. BiondVax Pharmaceuticals announced last week that those vaccinated with an experimental flu vaccine in 2012 had stronger immune responses to strands of influenza that didn’t even exist three years ago. The vaccine was developed to provide broad protection against different strands of influenza, in contrast to the seasonal flu vaccine which protects against the three to four strands of influenza predicted to be the most virulent that year. In 2012, the vaccine (M-001) was tested in phase II clinical trials in which 90 participants—all aged 65 or older—received the vaccine and 30 served as the control group. The vaccine successfully triggered an immune response, including the development of antibodies against several different strains of influenza. Earlier this year, BiondVax exposed blood plasma collected from participants in the 2012 trial to a strain of influenza that did not exist in 2012, and discovered protective antibodies against the strain in 50 percent of the plasma samples from those that received the vaccine, compared to just 10 percent of the samples from those in the control group. As BiondVax’s President Ron Babecoff explains, the vaccine “provides a safety net by broadening the immunogenicity [immune response] to existing and future flu strains.” Next, the vaccine will be tested in phase 3 clinical trials. Blood smear revealing Trypanosoma brucei parasites, which cause African sleeping sickness. (Photo: CDC/ Dr. Mae Melvin) A simple innovation—blue cloth and fine netting sprayed with insecticide between two sticks—could wipe out African sleeping sickness in a mere five to six years. African sleeping sickness is transmitted by tsetse flies, which breed along rivers looking for “something that contrasts with the green vegetation,” according to entomologist Steve Torr, “and for some reason they’re especially attracted to bright blue.” The flies are attracted to the blue cloth and the insecticide kills them within three minutes. The contraption is currently being tested in northern Uganda, where more than 17,000 have been installed over 1,500 square miles; in less than two years, the population of tsetse flies has been reduced by 90 percent. Only 1 in 1,000 flies carry the parasite, and the flies only reproduce once every nine days—whereas mosquitoes lay hundreds of eggs each day—bringing Torr’s team to the estimate of five to six years to both reduce the tsetse population, and eliminate the parasite from the remaining population.