GHIT Fund announces US$16.7 million to support development of new drugs, vaccines and diagnostics

Oct 31 2017

The Global Health Innovative Technology (GHIT) Fund, a unique Japanese public-private partnership formed to battle infectious diseases around the globe, today announced US$16.7 million to support development of new compounds for fighting malaria and tuberculosis, a leishmaniasis vaccine and drug, and a treatment for a long-ignored flesh-eating infection. The new investments also will allow scientists to pursue a critically needed diagnostic tool for detecting a relapsing form of malaria when it is hiding in the liver during its dormant phase.

Breakthroughs in Malaria: in Children and in Novel Drug Compounds

Among new support for malaria drug development is US$1.59M to Medicines for Malaria Venture (MMV) and Takeda Pharmaceuticals to develop an antimalarial drug candidate DSM265. DSM265 targets an essential enzyme, dihydroorotate dehydrogenase (DHODH), which is a critical part of the parasite making its own DNA. This completely new mode of action for an antimalarial drug will be critical in the face of resistance to both the artemisinin and partner-drug components of the current gold standard artemisinin combination treatments (ACTs) for malaria. In early-stage human testing, DSM265 has exhibited an exciting potential to both cure and prevent malaria caused by the deadly Plasmodium falciparum malaria parasite. It has already been tested in patients, where, in a study last year, 12 out of 13 patients with P. falciparum malaria were cured with a single dose of 400-milligrams. The final medicine would be a combination of DSM265 with another active compound, and so we expect even better results with a combination medicine.

"It's very exciting to see how far this partnership has progressed since the study we funded back in 2013, because the need for new malaria drugs has intensified significantly," said BT Slingsby, MD, PhD, MPH, who is CEO of the GHIT Fund. "We are optimistic that this team--which like all GHIT work combines Japanese innovation and leadership with deep expertise in global health--has all the skills necessary to overcome the remaining challenges."

Funding from GHIT will allow MMV and Takeda to develop an oral formulation of the drug that is more suited for children. DSM265 is a low-solubility, high-permeability drug and therefore needs investment in formulation technologies to improve its bioavailability. In addition, the projected cost to make the drug is higher than for other antimalarials, and so efforts are underway to improve the synthesis and lower the cost of material. The ideal final formulation has to use as low a volume of liquid as possible, since it has to be given to children who have fever and are feeling sick.

New treatments for malaria are a top global health priority. Parasites resistant to the world's most potent malaria drug, artemisinin, are reportedly spreading in Southeast Asia, prompting concern that artemisinin resistance could eventually emerge in Africa, where 90 percent of the world's malaria deaths occur. Disease experts fear if that happens, a decade of progress that has seen malaria deaths in Africa fall dramatically could be severely eroded.

To further assist the search for new malaria drugs, GHIT Fund also announced today new support of US$2.64M for an ongoing partnership between Eisai Co., Ltd. (Eisai) and Medicines for Malaria Venture (MMV) to further develop compounds, coming from earlier studies using the GHIT Fund's Hit-to-Lead Platform. The Hit-to-Lead collaboration identified compounds belonging to Eisai that were capable of killing the malaria parasite in vitro. This new work has also demonstrated the mode of action of these compounds. Analyses by Eisai and MMV have shown that the compounds inhibit the synthesis of an important molecule, glycosylphosphatidylinositol (GPI), which is used by many proteins as a way to anchor themselves to a parasite's cell surface. What is exciting is that these new compounds stop key GPI-anchored proteins appearing on the surface of the malaria parasite. This is a completely new mode of action for an antimalarial drug.

Flushing Out a Secretive Form of Relapsing Malaria

GHIT is also investing US$728,833 in a partnership among the Institute of Tropical Medicine at Nagasaki University, the Netherland's-based Biomedical Primate Research Centre, and the National Institute of Technology at Japan's Kumamoto College to advance their efforts to develop a diagnostic tool for identifying a relapsing form of malaria while in its dormant phase.

The Plasmodium vivax parasite is one of the two most common causes of malaria in humans. While not as deadly as malaria caused by P. falciparum, after a patient recovers from a vivax malaria infection, a form of vivax parasites known as hypnozoites remain in the liver where they can be reactivated weeks, months or even years later to cause another round of illness. And equally important, every time they remerge, they can be passed along to mosquitoes that feed on the infected individual, which means vivax malaria is particularly difficult to eliminate from areas where it is common.

However, if there were a reliable test for detecting dormant vivax malaria, it would be possible to identify who was still carrying the disease, treat them with drugs that can kill the hypnozoites, and wipe out what malaria fighters call the "hidden reservoir" of vivax malaria.

The GHIT-funded work to develop a diagnostic tool is based on the scientists' collective expertise in identifying products or "metabolites" generated by dormant vivax hypnozoites that they believe can be detected outside of the liver and detecting subtle changes in liver activity and metabolism that may signal the presence of dormant vivax.

Screening Japanese Compound Libraries for New Breakthroughs

In addition, GHIT is providing new funding of US$49,500 for MMV and Eisai, and US$65,836 for MMV and Astellas to screen compounds from their library that have yet to be assessed for their potential to fight malaria infections.

Fighting a Severely Neglected Tissue Destroying Infectious Disease

Mycetoma, a serious, and one of the most neglected tropical diseases, is known for slowly and progressively destroying soft tissue, particularly on the feet. In advanced cases, it often leads to amputation of the limb. It is endemic in tropical and subtropical countries in the so-called "mycetoma belt" that includes, among other countries, Venezuela, Ethiopia, India, Mexico, Sudan, Senegal and Somalia. The main victims of this neglected tropical disease are poor, young individuals who contract mycetoma from either bacteria or fungi, probably through a minor injury on the foot. While bacteria may be treated successfully with repeated courses of antibiotics, the fungal type is much more difficult to treat. Currently, only itraconazole is available but it is expensive and must be taken twice a day for at least a year--and even then, surgery is needed and the infection may recur.

GHIT is awarding US$2.52M to the Eisai Co., Ltd. and DNDi to help fund a Phase IIb clinical trial in Sudan with the Mycetoma Research Center in Khartoum. The trial will compare a new drug candidate, fosravuconazole, with itraconazole. Fosravuconazole is already being tested in humans as a potential treatment for Chagas disease; results so far have provided evidence that it is safe and well tolerated. For the Sudan trial, researchers plan to recruit 138 patients who will be divided into three groups or "arms." Two study arms will receive the fosravuconazole in weekly oral doses of 200 and 300 milligrams respectively. In a third arm, patients will receive itraconazole, the standard treatment. After three months, an interim analysis will be done to see which fosravuconazole dose appears best in terms of efficacy and safety so that the study will continue with two arms; one arm with fosravuconazole and one arm with itraconazole (in the world of clinical trials, this is sometimes called a "drop the loser" design).

Novel DNA Vaccine That Could Both Prevent and Treat Leishmaniasis

GHIT is also investing US$4.09M to pursue a potentially groundbreaking vaccine candidate that is being formulated to either prevent or treat leishmaniasis. The project partners are drawn from the European Vaccine Initiative (EVI), Nagasaki University, German biotech firm Mologen AG, Charité--Universitätsmedizin Berlin (corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health), and the London School of Hygiene and Tropical Medicine (LSHTM). Support from the GHIT Fund is intended to help the team complete preclinical development of their leishmaniasis vaccine candidate and lay the groundwork for conducting a Phase I clinical trial to test safety and immune response in humans.

Leishmaniasis is a disease caused by parasites spread by sand flies. It is common in parts of Asia, the Middle East, Africa and Latin America, where it can cause a variety of problems for those infected. The cutaneous form of the disease can lead to moderate or disfiguring skin sores, while visceral leishmaniasis, which attacks internal organs, is frequently fatal. No vaccine is currently licensed for any form of human leishmaniasis, and available drug treatment options are limited. Moreover, drugs are increasingly compromised by drug resistance.

The GHIT Fund is supporting work on a candidate vaccine that takes aim at leishmaniasis with an innovative design that aligns with the complex immune mechanisms that must be triggered to effectively treat or prevent the disease.

Survivors of leishmaniasis, who develop lifelong immunity, have found that they needed more than antibodies to fight off an infection and T cells, known as key workhorses of the human immune system, are important for immunity against leishmaniasis. Yet conventional vaccines do not effectively rally the required T cells.

To overcome this obstacle, the team supported by GHIT has developed what is known as a DNA vaccine that is "T cell-directed." This type of vaccine employs a different approach to delivering disease antigens. Instead of using the disease antigens themselves, this leishmaniasis vaccine candidate employs various sequences of DNA that are intended to instruct human cells to produce five different leishmaniasis antigens that in turn will serve as targets for the immune response.

In a related project, the GHIT Fund has awarded US$4.92M to the Geneva-based Drugs for Neglected Diseases initiative (DNDi) and the Japanese oligonucleotide specialized contract development & manufacturing organization GeneDesign, Inc. to advance a drug candidate for fighting cutaneous leishmaniasis towards human clinical trials. The GHIT investment will support manufacturing, formulation and preclinical safety studies to determine whether the drug candidate, known as CpG D35, has the potential to be used as a treatment by itself or to improve patient outcomes by being combined with the chemotherapy drugs currently used to deal with the disease.

Intensifying the Search for New TB Drugs

Finally, GHIT Fund has awarded US$99,986 to Astellas Pharma Inc. and the TB Alliance to screen compounds from Astellas' compound library to search for potential drug candidates for fighting tuberculosis. The screening work will be conducted at the University of Illinois at Chicago (UIC) campus. Drug-resistant TB is a major public health concern worldwide, prompting an intense hunt for new drugs to fight the disease. Also, even when existing drugs are effective, the treatment regime can require patients to take four harsh drugs every day for six months.