Phase II year
2017
(last award dollars: 2018)
Phase II Amount
$1,500,000
An Oral Ultra Long-Acting Ivermectin for Malaria Elimination Despite effective treatments, malaria remains a scourge of sub-Saharan Africa. Additional interventions beyond those currently available are needed to eliminate the disease. One strategy with increasing support is addition of ivermectin, a well-known and safe drug used for treating onchocerciasis and other diseases, to current mass drug administration (MDA) campaigns with artemisinin regimens. Ivermectin has a unique activity in interrupting malaria transmission in endemic areas by reducing the life expectancy of the vector anopheles mosquitos that bite subjects who have ivermectin in their blood. Modeling, as well as proof of concept field studies, have shown that long (10 plus day) courses of small doses of ivermectin, in combination with short courses of currently used artemisinin combination MDA, have the potential to reduce the efficiency of malaria transmission, reduce malaria cases, and potentially lead to disease elimination. Treating even 50% of the population in this way can reduce disease transmission to levels that can protect the whole population, including children under 5 most at risk. To be effective, repeat dosing every three days would currently be necessary, limiting feasibility. Development of an ultra long-acting oral ivermectin formulation that achieves single dose administration and prolonged low level blood exposure could dramatically change current treatment options, reduce malaria morbidity and potentiate malaria elimination efforts. No existing oral delivery system can prolong therapeutic blood levels for small molecules therapeutics beyond 12-24 hours. We have developed prototype oral capsules based on Lyndra's gastric residence technology that can achieve 7-14 days of sustained therapeutic ivermectin levels in a pig model and have shown similar efficacy with other drugs in multiple large animal models. The goal of this grant is to develop an optimal ivermectin dosage form that 1) achieves consistent and efficacious blood levels of ivermectin for 14 days from a single dose administration, 2) develop a reproducible and scalable low cost manufacturing capability, and 3) evaluate these dosage forms with respect to pharmacokinetics and gastric retention in beagle dogs. Formulations will be developed to pharmaceutical grade standards of in vitro release and stability under Tropical Zone 4b standards. Methods of production compatible with low cost of goods production and scale will be prototyped. Dosage forms will be evaluated in extensive preclinical pharmacology studies in beagles, including stress conditions, and a toxicology study will be performed. This grant will deliver a product ready for IND-enabling studies and create capability for GMP production of clinical specimens for a phase 1 human pharmacokinetic (PK) study of ultra long-acting Lyndra-Ivermectin. This Direct to Phase II grant builds on three years of work and ample preliminary data.
Public Health Relevance Statement: Ultra long-acting oral therapies will dramatically change healthcare delivery. Preliminary work shows that Lyndra's gastric residence technology can sustain therapeutic efficacy of ivermectin beyond one week, and modeling suggests that such a treatment could dramatically improve the efficacy of current malaria mass drug administration campaigns. This grant will support pre-clinical development of oral ultra long-acting ivermectin dosage forms including formulation development, manufacturing, pharmacology, and toxicology to facilitate rapid advancement into human testing.
Project Terms: Africa South of the Sahara; Alcohols; Animal Model; Anopheles Genus; Area; Artemisinins; Attention; base; Beds; Biological Assay; Bite; Blood; Canis familiaris; capsule; Child; Clinical; Clinical Research; Combined Modality Therapy; Compliance behavior; Contracts; cost; Culicidae; Data; Development; Diagnostic radiologic examination; Dimensions; Disease; disease transmission; Dosage Forms; Dose; Drug Compounding; Drug Kinetics; Drug usage; effective therapy; Elastomers; Emerging Technologies; Evaluation; experience; Exposure to; Family suidae; Fatty acid glycerol esters; field study; Formulation; gastric retention; Geometry; global health; Goals; Grant; health application; health care delivery; Hour; Human; improved; In Vitro; in vivo; Individual; Insecticides; Interruption; Intervention; Ivermectin; Killings; Lead; Life Expectancy; Malaria; malaria transmission; mechanical properties; meetings; melting; Methods; Modeling; Monitor; Morbidity - disease rate; novel; Onchocerciasis; Oral; Performance; Pharmaceutical Preparations; Pharmaceutical Technology; Pharmacologic Substance; Pharmacology and Toxicology; Pharmacology Study; Phase; Polymers; Population; pre-clinical; preclinical development; preclinical evaluation; Procedures; Process; Production; prototype; Quality Control; Regimen; Reproducibility; research and development; research clinical testing; residence; Residual state; Risk; Safety; scale up; Schedule; Scourge; small molecule therapeutics; Specimen; stability testing; Stomach; Stress; System; Technology; Testing; Therapeutic; Time; tool; Toxic effect; Toxicology; Treatment Efficacy; Variant; vector; vector transmission; Work
