Authors

K Pfarr¹;  ¹ Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Germany

Discussion

The bacterial DNA-dependent RNA polymerase inhibitor Corallopyronin A (CorA) binds to a different site than rifampicin, killing rifampicin-resistant Staphylococcus aureus. CorA also kills the Gram-negative Wolbachia endobacteria of filarial nematodes that cause onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis). Depleting the essential endosymbionts causes worm sterility and slow adult worm killing. Using the Litomosoides sigmodontis infection model in Mongolian gerbils, we demonstrated that CorA depletes Wolbachia from microfilariae and adult filariae by more than 2-logs and is macrofilaricidal. The macrofilaricidal effect can be reached with a 2 weeks regimen and can be further reduced to ten days by administering CorA and albendazole, a significant advance over the current 4-week doxycycline regimen. We have also demonstrated macrofilaricidal activity using the Onchocerca ochengi mouse model. To develop CorA as a novel solution to filarial infection, we have conducted standard non-GLP ADMET studies. In-vitro toxicity tests (off-target, AMES, micronucleus, hERG, phototoxicity) demonstrated that it is non-toxic and pharmacologically safe; in vivo toxicity studies in rats and dogs measured a maximal tolerated dose (MTD) of 1000 mg/kg in both species. Seven-day repeated dose studies in rats and dogs demonstrated no prohibitive safety issues: predicted NOEL=150 mg/kg/d; predicted HED=4 mg/kg. CorA drug substance is heterologously produced in genetically modified Myxococcus xanthus and has been upscaled 15 m3 (kilograms) in 2022 at Bio Base Europe Pilot Plant (Belgium). The Helmholtz Centre for Infection Research purified this large amount of material, achieving 90-95% pure HQ-RGM material. With amorphous solid dispersion formulation principles, two solid oral formulations were developed that increased stability (>3 months at 30 °C, >6 months at 5 °C) and oral bioavailability (mouse >59%, dog>53%) compared to neat CorA. We are establishing drug product production at GMP facilities. GLP safety and toxicology studies will be conducted in 2024. After finalization of the pre-clinical work, we plan to enter the clinical phase I in 2025/2026