Kat Kelley

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.

The Drugs for Neglected Disease initiative (DNDi) and the Medicines for Malaria Venture (MMV)—nonprofit product development partnerships (PDPs) and members of the Global Health Technologies Coalition—have teamed up to ensure two treatments for malaria continue to reach the patients who need them most. The treatments—two fixed-dose artemisinin combination therapies (ACTs) known as ASAQ and ASMQ—were developed by DNDi and partners and launched in 2007 and 2008, respectively; going forward, MMV will work with those partners to ensure these drugs remain available and accessible in countries where they are most needed. Dr. Bernard Pécoul, CEO of DNDi, passes the ball to Dr. David Reddy, CEO of MMV. (Photo credit: MMV) To commemorate the handover, DNDi CEO Dr. Bernard Pécoul passed the ball—a literal rugby ball—to MMV CEO Dr. David Reddy during a side event at the 68th World Health Assembly in Geneva, Switzerland. We’re joined by Jean-René Kiechel, PhD, Senior Pharma Advisor & Product Manager of DNDi and George Jagoe, Executive Vice President of Access & Product Management at MMV to learn more about this handover and the existing and potential impact of these medicines. Q: What impact could ASAQ and ASMQ have in the fight against malaria? The FACT (Fixed-Dose Artesunate Combination Therapy) consortium was formed in 2002 to develop combinations of artesunate (AS) with amodiaquine (AQ) or mefloquine (MQ). These treatments were recommended by the World Health Organization (WHO) in response to increasing chloroquine resistance, but were not available in easy-to-use fixed-dose combinations (FDCs). The FACT consortium was transferred to DNDi when the organization was created in 2003. It led to the creation of two FDCs: ASAQ: In 2007, ASAQ Winthrop® became the first treatment to be launched by DNDi. It was developed by a number of partners across almost the full development range, from formulation work to post-registration studies. There were significant challenges to overcome, including developing a stable bilayer formulation of the two drugs, together with the aluminum blister packaging designed to withstand the rigors of a tropical environment. Manufacturing and distribution of this stable formulation were undertaken by Sanofi, who were already providing co-blistered Coarsucam™ to Africa at the time, and who committed to making the generic ASAQ Winthrop® available at less than US$1 per adult treatment for the public market. ASAQ’s low price and prequalified status, which allows purchase by procurement agencies, led to price decreases not only of ASAQ but also for other ACTs. Lower drug costs led to increased patient access to high quality treatments. To date, more than 400 million treatments of ASAQ have been distributed worldwide, including products developed by generic companies. ASMQ: Launched in 2008, ASMQ was developed in collaboration with Farmanguinhos/Fiocruz, a Brazilian public pharmaceutical company. A South-South technology transfer agreement to Cipla Ltd in India ensured a second supplier of the treatment, principally for the Asian market but also for Africa. Recent results from a multi-center trial carried out in Africa showed ASMQ is as efficacious as artemether-lumefantrine—Africa’s most widely adopted treatment—in children under 5 years of age, and is well tolerated. ASMQ also demonstrated high cure rates and good efficacy in a number of studies in Asia and Latin America, including a large intervention study in Brazil with more than 23,000 patients. In a study comparing five ACTs in Myanmar, ASMQ FDC showed the highest cure rates, the lowest rates of gametocyte carriage (which are believed to affect the transmissibility of malaria), and provided the best post-treatment suppression of malaria. By the end of 2014, 832,000 ASMQ treatments had been distributed. Q: DNDi and MMV are both product development partnerships. What value do you see in collaborating with one another and what inspired this handover? In May 2015, in order to ensure the best future implementation of these two treatments, DNDi handed over its malaria program to MMV. MMV is a long-term partner of DNDi, and is managing the largest portfolio to date of antimalarial drugs—from all phases of drug discovery, development, and delivery. Collaboration is at the heart of the PDP model. The PDP is a form of public-private partnership whereby a varied collection of partners collaborate in a flexible, 'virtual' model. This includes biotech, pharma (large and start-up), nongovernmental organizations (NGOs), academia, and private and public sponsors who operate in the disease-endemic countries or globally. A key requirement for these participants from very different backgrounds is agreement on a specific common goal and specific objectives that address the disease in question while at the same time being guided by WHO priorities, the needs of country control programs, and ad hoc experts. The direct, open dialogue between partners who normally do not work together (and may even compete) promotes creativity and out of the box thinking. It fosters the innovation and creativity required to overcome the many challenges that arise in product development. PDPs such as MMV and DNDi have helped to address major market failings in malaria drug development. By enhancing the focus of drug research partners and by mobilizing donor funding for this critical work, both organizations have shown that this model of research and development can make a huge impact on the lives of patients suffering from diseases that have historically been neglected by most pharma companies. Thanks to the collaborative approach that MMV and DNDi have taken in orchestrating the hand-off of ASMQ and ASAQ, both organizations have been able to refine their focus areas for the future. Q: What role have diverse geographic and cross-sector partnerships had in the development and introduction of ASAQ and ASMQ? Both ASAQ and ASMQ demonstrate the ability of innovative private-public partnerships, with a strong commitment from endemic countries, to develop, deliver, and disseminate new high-quality, affordable treatments within a short time frame. ASAQ Winthrop® is a case in point: the partnership that led to the development and registration of ASAQ Winthrop® had to ensure the new drug's successful launch and adoption by endemic countries. First among the many partners needed at this crucial stage are endemic countries' national malaria control programs. Sanofi and DNDi engaged in collaborations with a number of other partners to facilitate the implementation and availability of ASAQ Winthrop®, including experts, WHO, research institutes, funding agencies, and other NGOs. For example, DNDi coordinated a clinical study with the Indian Council of Medical Research to facilitate the adoption of a new anti-malarial policy in India. This study allowed for the registration of ASAQ Winthrop® in India. DNDi also convened an independent panel of experts, the FACT Implementation Advisory Group, to provide independent advice and critical guidance about issues related to implementation and rational use of ASAQ Winthrop®, ensuring equitable access. Another example of the power of partnerships is the DNDi partnership with Sanofi, MMV, and national malaria control programs in Africa. The aim is to collect high-quality data on ASAQ effectiveness and safety, as part of a Risk Management Plan. This is the first of its kind to be submitted to the WHO, and the first to be set up entirely in Africa. It involved some 15,000 patients in one of the studies carried out in Côte d’Ivoire, collecting data on the drug’s safety and effectiveness in real-life conditions. Results are expected to be published by the end of 2015. Q: What are the next steps in ensuring these products are available to the people who need them most? To support uptake of new medicines like ASMQ and ASAQ, several hurdles must be overcome. These include: Inclusion of the medicines by WHO in standard treatment guidelines. Adoption by national disease control programs. National registration by drug regulatory authorities. Education and training on the use of the medicines. Dissemination of new safety and efficacy evidence post-launch. Mobilization of requisite funding for procurement and introduction. As a widely used ACT, ASAQ has met many of these challenges and will continue to play an important role in malaria treatment for many years to come. With new evidence emerging about ASMQ’s efficacy and tolerability, MMV and partners will target broader registration and use of this drug in Latin America, Southeast Asia (where its role in containing drug-resistant strains of malaria is critical), and in Africa, where it has had little use to-date.

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.