Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.

There is a significant need for improved treatments for onchocerciasis and lymphatic filariasis, diseases caused by filarial worm infection. In particular, an agent able to selectively kill adult worms (macrofilaricide) would be expected to substantially augment the benefits of mass drug administration (MDA) with current microfilaricides, and to provide a solution to treatment of onchocerciasis / loiasis co-infection, where MDA is restricted. We have identified a novel macrofilaricidal agent, Tylosin A (TylA), which acts by targeting the worm-symbiont Wolbachia bacterium. Chemical modification of TylA leads to improvements in anti-Wolbachia activity and oral pharmacokinetic properties; an optimized analog (ABBV-4083) has been selected for clinical evaluation.

Déclaration de conflit d'intérêts

Competing interests: TWvG is a paid consultant to DNDi and has advised on their helminth programs. DJK is an unpaid consultant to DNDi. DJK KM, MJT, MPH, JDT and SAW are non-paid members of the MacroDA consortium. TWvG has been a non-paid member of the External Scientific Advisory Committee (ESAC) for the Anti-Wolbachia Consortium (A*WOL). RFK, BSB, RC, DS, JM, MR, KM, and DJK are employees of AbbVie. HM is a paid consultant to AbbVie. TWvG is an employee of Franciscan University, acting as an unpaid consultant to AbbVie. The other authors declare no competing interests. TWvG, DJK, and KCM are inventors on patent/patent application EP3116888A1 (“4"-O-substituted Tylosin A Derivatives”) held by AbbVie that covers 4"-0-substituted tylosin a derivatives. TWvG, DJK, and KCM are inventors on patent/patent application US20150259374/US10072040 (“Tylosin A Analogs and Derivatives”) held by AbbVie that covers Tylosin a analogs and derivatives. TWvG, DJK, and KCM are inventors on patent/patent application US20160200757 (“Tylosin A Analogs and Derivatives”) held by AbbVie that covers Tylosin a analogs and derivatives. TWvG, DJK, and KCM, MJT, SAW, LF, and JT are inventors on patent/patent application US20170368088 (“Treatment of Filarial Diseases”) held by AbbVie that covers Treatment of Filarial Diseases. TWvG, DJK, and KCM, MJT, SAW, LF, and JT are inventors on patent/patent application EP3242662A1-A4 (“Treatment of Filarial Diseases”) held by AbbVie that covers Treatment of Filarial Diseases. This study was performed under a partnership agreement between AbbVie and the Liverpool School of Tropical Medicine, which has confidentiality provisions. Compounds were provided to the University of Bonn through the Anti-Wolbachia Consortium (A*WOL). ABBV-4083 and related compounds are available from AbbVie under a material transfer agreement.