Introduction and Background of the Project

1.Introduction

The United Nations Sustainable Development Goal #3 “Ensure healthy lives and promote well-being for all at all ages” aims to improve global health by 2030, including the elimination of neglected tropical diseases. Onchocerciasis (river blindness) and lymphatic filariasis (lymphedema, hydrocele and elephantiasis) are two such neglected tropical diseases that afflict 72.4 million people in sub-Saharan Africa, South East Asia, and parts of Latin America, causing morbidity and exacerbating poverty. Current drugs used to control and eliminate these infections mainly kill just the larvae of these worms. Because the adult worms survive for several years, treatment must occur annually/bi-annually (for onchocerciasis more than 15 years). A drug that would kill the adult worms would accelerate the elimination of these diseases. In addition, it would provide a tool to control reemergence of the infections.
One of the safest ways to kill the adult worms is to target their essential intracellular bacterial called Wolbachia. These bacteria are found in several species of worms that infect humans. When they are killed and depleted, the worms become sterile (permanent block in production of larva) and the adult worms slowly die. The latter is important to avoid over activating the immune system that can cause disease associated with these infections, e.g., severe dermatitis. The current antibiotics that are effective against Wolbachia cannot be widely used for several reasons. Therefore, new antibiotics that kill the Wolbachia in the worms are needed. We are developing Corallopyronin A (CorA) for use in humans to treat people with onchocerciasis and lymphatic filariasis. Our preclinical studies have shown that CorA is safe and nontoxic.

2.Project objective

The objective of this project is to progress CorA through final preclinical development activities to prepare for the first in human trial (phase 1).

3.Project design

To achieve this goal, we will conduct the following studies to improve our knowledge of CorA and produce GMP drug substance that will be used in the phase 1 trial. Because CorA is a predicted substrate of enzymes that detoxify substances in the body, we will determine the metabolism of CorA by the enzymes that are predicted to metabolize CorA. Prior to applying for a phase 1 trial authorization, new drugs must be shown to be nontoxic. Therefore, we will conduct a GLP toxicity study, including measuring plasma levels of CorA. With the latter data, we will refine our PK/PD model that will allow us to determine the best human dose and regimen for the phase 1 trial. Our research and innovation packages will provide us with a better understanding of the chemical nature of CorA (e.g., can it be crystalized or co-crystallized?) that may be used to improve the production or stability of CorA. With the GHIT funding we will also produce CorA material for the phase 1 study, including highly pure standards needed for bioanalysis of plasma samples in the phase 1 study.

How can your partnership (project) address global health challenges?

The neglected tropical diseases onchocerciasis and lymphatic filariasis are major burdens of disease in tropical countries. The WHO Road Map for Neglected Tropical Diseases 2021-2030 lists the combined at-risk population as 1.1 billion, with 72.4 million cases, resulting in 2.9 million Disability Adjusted Life Years. Drugs used in mass drug administration (MDA) programs are not adulticidal, require years of repeated intake to achieve interruption of transmission, and are difficult to broadly use where loiasis is co-endemic due to the potential to induce severe adverse reactions. Additionally, there are populations for whom the MDA drugs sub-optimally work. Furthermore, as MDA lowers prevalence, MDA should change to identifying and treating infected individuals (“test & treat”), requiring a drug with adulticidal and/or long-term sterilizing activity.

Safe and effective adulticidal activity is achieved by targeting the essential Wolbachia endobacteria of filarial nematodes. We published definitive studies demonstrating that doxycycline depletes Wolbachia, causing worm sterility and slow adult worm death; a desired effect to avoid inducing inflammatory responses by rapid worm death. Although effective against Wolbachia, doxycycline is not recommended for MDA due to ≥4 weeks daily treatment and contraindications for children

What sort of innovation are you bringing in your project?

CorA is a novel antibiotic against the Wolbachia endosymbionts and we have shown in animal infections that CorA safely and slowly kills the adult worms. Because the target of CorA is at a different position in the molecule, there is no cross-resistance with rifampicin. Thus, CorA can be used in areas with undiagnosed tuberculosis infections without driving resistance. 

Role and Responsibility of Each Partner

The University Hospital Bonn (“Universitätsklinikum Bonn”, UKB) is the Designated Development Partner and will be responsible for the overall management of the project; liaising with all partners and the GHIT Fund Management Team. The UKB will also sponsor the pre-clinical GLP safety and toxicology studies and Dirofilaria immitis infection model study, conduct the CorA solid state stability experiments, coordinate production of pre-GMP CorA, and prepare documents for a formal scientific advice with the German regulatory agency the Federal Institute for Drugs and Medical Devices (BfArM). The UKB, led by Prof. Hoerauf has over 20 years of experience in R&D of new treatments for onchocerciasis and lymphatic filariasis from discovery, through pre-clinics and clinical/field studies.

Eisai Co., Ltd. will provide industry standard preclinical development expertise as we progress to the clinical development stage. Chemical synthesis of CorA will be investigated as a complementary path to the production of CorA. Eisai will also provide expert consulting on non-clinical CMC, DMPK and safety/toxicology studies. Furthermore, Eisai will discuss Regulatory and Clinical Strategy with UKB.

The Helmholtz Centre for Infection (HZI) will clarify the CorA drug substance, i.e. define the purity, conduct quality assurance of the CorA produced by the GMP-company contracted to produce CorA for use in humans, and upscale a yeast heterologous production method as possible path to reducing the production costs. The team has over 20 years of industrial and academic experience in natural product discovery and development.

Others (including references if necessary)

UN Sustainable Development Goals https://sdgs.un.org/goals

WHO Road Map for Neglected Tropical Diseases 2021-2030

https://www.who.int/teams/control-of-neglected-tropical-diseases/ending-ntds-together-towards-2030

Onchocerciasis https://www.who.int/news-room/fact-sheets/detail/onchocerciasis

Lymphatic Filariasis https://www.who.int/news-room/fact-sheets/detail/lymphatic-filariasis

Becker, T., Krome, A.K., Vahdati, S., Schiefer, A., Pfarr, K., Ehrens, A., Aden, T., Grosse, M., Jansen, R., Alt, S., Hesterkamp, T., Stadler, M., Hübner, M.P., Kehraus, S., König, G.M., Hoerauf, A., and Wagner, K.G. (2022). In vitro-in vivo relationship in mini-scale-enabling formulations of corallopyronin A. Pharmaceutics 14, 1657. https://www.mdpi.com/1999-4923/14/8/1657

Ehrens, A., Schiefer, A., Krome, A.K., Becker, T., Rox, K., Neufeld, H., Aden, T., Wagner, K.G., Müller, R., Grosse, M., Stadler, M., König, G.M., Kehraus, S., Alt, S., Hesterkamp, T., Hübner, M.P., Pfarr, K., and Hoerauf, A. (2022). Pharmacology and early ADMET data of corallopyronin A, a natural product with macrofilaricidal anti-wolbachial activity in filarial nematodes. Front Trop Dis 3, 983107. https://www.frontiersin.org/articles/10.3389/fitd.2022.983107/full

Krome, A.K., Becker, T., Kehraus, S., Schiefer, A., Gutschow, M., Chaverra-Munoz, L., Huttel, S., Jansen, R., Stadler, M., Ehrens, A., Pogorevc, D., Muller, R., Hubner, M.P., Hesterkamp, T., Pfarr, K., Hoerauf, A., Wagner, K.G., and Konig, G.M. (2022). Corallopyronin A: antimicrobial discovery to preclinical development. Nat Prod Rep 39, 1705-1720.

https://www.ncbi.nlm.nih.gov/pubmed/35730490

Schäberle, T.F., Schiefer, A., Schmitz, A., König, G.M., Hoerauf, A., and Pfarr, K. (2014). Corallopyronin A – A promising antibiotic for treatment of filariasis. Int J Med Microbiol 304, 72-78. https://www.ncbi.nlm.nih.gov/pubmed/24079981

Schiefer, A., Hübner, M.P., Krome, A., Lämmer, C., Ehrens, A., Aden, T., Koschel, M., Neufeld, H., Chaverra-Muñoz, L., Jansen, R., Kehraus, S., König, G.M., Pogorevc, D., Müller, R., Stadler, M., Hüttel, S., Hesterkamp, T., Wagner, K., Pfarr, K., and Hoerauf, A. (2020). Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections. PLoS Negl Trop Dis 14, e0008930. https://doi.org/10.1371/journal.pntd.0008930

Schiefer, A., Schmitz, A., Schäberle, T.F., Specht, S., Lämmer, C., Johnston, K.L., Vassylyev, D.G., König, G.M., Hoerauf, A., and Pfarr, K. (2012). Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo. J Infect Dis 206, 249-257. https://www.ncbi.nlm.nih.gov/pubmed/22586066