flubentylosin (ABBV-4083) / AbbVie - LARVOL DELTA

Development of alternative treatments for filarial diseases (ASTMH 2024) - "Successful repurposed drugs include benzimidazoles, ivermectin and moxidectin. The Drugs for Neglected Diseases initiative (DNDi) is investigating emodepside (with Bayer AG) and ABBV-4083 (with the Anti-Wolbachia (AWOL) consortium and AbbVie), along with multiple partners...Recent studies show its strong activity against Trichuris trichiura and hookworm infections in humans. Here, we present emodepside results for Onchocerca volvulus , recent failures, and considerations for patient access to new medicines."

Late-breaking abstract • Infectious Disease • Ophthalmology

The long and winding road towards new treatments against lymphatic filariasis and onchocerciasis. (PubMed, Trends Parasitol) - "Novel candidates (corallopyronin A, DNDi-6166, emodepside, and oxfendazole) are currently moving through (pre)clinical development, while the development of two candidates (AWZ1066S and ABBV-4083/flubentylosin) was recently halted. The preclinical R&D pipeline for filarial infections continues to be limited, and recent setbacks highlight the importance of continuous drug discovery and testing."

Journal • Review • Infectious Disease

Coproporphyrin-I as a Selective OATP1B Biomarker Can Be Used to Delineate the Mechanisms of Complex Drug-Drug Interactions: Cedirogant Case Study. (PubMed, Clin Pharmacol Ther) - "Cedirogant (375 mg once daily) increased rosuvastatin maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUCtau) by 141% and 55%, respectively when co-administered, whereas atorvastatin Cmax increased by 40% with no effect on its AUCtau compared with administration of rosuvastatin/atorvastatin alone. Correlation analysis with data from two investigational drugs (glecaprevir and flubentylosin) demonstrated that OATP1B1 R-value of > 1.5 and [Cmax,u]/[OATP1B1 IC50] of > 0.1 are associated with > 1.25-fold increase in CP-I Cmax ratio. This demonstrates the utility of CP-I in disentangling mechanisms underlying a complex DDI involving multiple transporters and enzymes and proposes refined criteria for static OATP1B inhibition predictions."

Biomarker • Journal • Breast Cancer • Dermatology • Immunology • Oncology • Psoriasis • Solid Tumor • CYP3A4

Update ABBV-4083/flubentylosin development (ASTMH 2023) - No abstract available

Study to Assess Adverse Events, Change in Disease Activity and How Oral ABBV-4083 Capsules When Given Alone or In Combination With Albendazole Capsules Moves in The Body of Adult Participants With Onchocerca Volvulus Infection (clinicaltrials.gov) - P2 | N=153 | Terminated | Sponsor: AbbVie | N=444 ➔ 153 | Trial completion date: Dec 2025 ➔ Aug 2023 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Aug 2023; Strategic considerations

Adverse events • Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Infectious Disease

A Phase-I pharmacokinetic, safety and food-effect study on flubentylosin, a novel analog of Tylosin-A having potent anti-Wolbachia and antifilarial activity. (PubMed, PLoS Negl Trop Dis) - "Flubentylosin 400 mg for 14 days was the maximum tolerated dose in this first-in-human, Phase-I study in healthy adults. Based on preclinical pharmacokinetic/pharmacodynamic modeling, flubentylosin 400 mg once daily for 7 or 14 days is expected to be an effective dose. A Phase-II, proof-of-concept study with flubentylosin using these regimens is currently ongoing in patients with onchocerciasis in Africa."

Journal • P1 data • PK/PD data • Infectious Disease • Pain

The pipeline for drugs for control and elimination of neglected tropical diseases: 1. Anti-infective drugs for regulatory registration. (PubMed, Parasit Vectors) - "Considering drugs approved for an NTD by at least one stringent regulatory authority: fexinidazole, included in WHO guidelines for Trypanosoma brucei gambiense African trypanosomiasis, is in development for Chagas disease. Moxidectin, registered in 2018 for treatment of individuals ≥ 12 years old with onchocerciasis, is undergoing studies to extend the indication to 4-11-year-old children and obtain additional data to inform WHO and endemic countries' decisions on moxidectin inclusion in guidelines and policies...Considering drugs in at least Phase 2 clinical development, a submission is being prepared for registration of acoziborole as an oral treatment for first and second stage T.b. gambiense African trypanosomiasis. Bedaquiline, registered for tuberculosis, is being evaluated for multibacillary leprosy. Phase 2 studies of emodepside and flubentylosin in O. volvulus-infected individuals are ongoing; studies for Trichuris trichuria and hookworm are planned. A..."

Journal • Review • Dengue Fever • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Study to Assess Adverse Events, Change in Disease Activity and How Oral ABBV-4083 Capsules When Given Alone or In Combination With Albendazole Capsules Moves in The Body of Adult Participants With Onchocerca Volvulus Infection (clinicaltrials.gov) - P2 | N=444 | Recruiting | Sponsor: AbbVie | Trial completion date: Jan 2025 ➔ Dec 2025 | Trial primary completion date: Jan 2025 ➔ Dec 2025

Adverse events • Combination therapy • Trial completion date • Trial primary completion date • Infectious Disease

A mouse infection model and long-term lymphatic endothelium co-culture system to evaluate drugs against adult Brugia malayi. (PubMed, PLoS Negl Trop Dis) - "A selected culture system was validated as a drug screen using reference anti-Wolbachia (doxycycline, ABBV-4083 / flubentylosin) or direct-acting compounds (flubendazole, suramin). Drug studies confirmed significant Wolbachia depletions or direct macrofilaricidal activities could be discerned when female B. malayi were cultured for 14 days. We therefore demonstrate a novel methodology to generate adult B. malayi in vivo and accurately evaluate drug efficacy ex vivo which may be adopted for drug screening with the dual benefit of reducing overall animal use and improving anti-filarial drug development."

Journal • Preclinical • Infectious Disease • IL4R • IL5

Current perspective of new anti-Wolbachial and direct-acting macrofilaricidal drugs as treatment strategies for human filariasis. (PubMed, GMS Infect Dis) - "Current treatment recommendations by the WHO include mass drug administration with ivermectin for the treatment of onchocerciasis and a combination of ivermectin, albendazole and diethylcarbamazine (DEC) for the treatment of lymphatic filariasis in areas that are not co-endemic for onchocerciasis or loiasis...Thus, to achieve the elimination of transmission of onchocerciasis and the elimination of lymphatic filariasis as a public health problem by 2030, the WHO defined in its roadmap that new alternative treatment strategies with macrofilaricidal compounds are required. Within a collaboration of the non-profit organizations Drugs for Neglected Diseases initiative (DNDi), the Bill & Melinda Gates Foundation, and partners from academia and industry, several new promising macrofilaricidal drug candidates were identified, which will be discussed in this review."

Journal • Review • Infectious Disease

Anti-Wolbachia drugs for filariasis. (PubMed, Trends Parasitol) - "Refined screening models integrated with robust pharmacokinetic/pharmacodynamic (PK/PD) driven optimisation and selection strategies have delivered the first two drug candidates specifically designed to target Wolbachia. AWZ1066S and ABBV-4083 are currently progressing through clinical trials with the aim of delivering safe and effective macrofilaricides to support the elimination of onchocerciasis and lymphatic filariasis."

Journal • Review • Infectious Disease

Study to Assess Adverse Events, Change in Disease Activity and How Oral ABBV-4083 Capsules When Given Alone or In Combination With Albendazole Capsules Moves in The Body of Adult Participants With Onchocerca Volvulus Infection (clinicaltrials.gov) - P2; N=444; Recruiting; Sponsor: AbbVie; Not yet recruiting ➔ Recruiting

Adverse events • Clinical • Combination therapy • Enrollment open • Infectious Disease

Study to Assess Adverse Events, Change in Disease Activity and How Oral ABBV-4083 Capsules When Given Alone or In Combination With Albendazole Capsules Moves in The Body of Adult Participants With Onchocerca Volvulus Infection (clinicaltrials.gov) - P2; N=444; Not yet recruiting; Sponsor: AbbVie

Adverse events • Clinical • Combination therapy • New P2 trial • Infectious Disease

Preclinical development of an oral anti-Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis. (PubMed, Sci Transl Med) - "Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis (Brugia malayi and Litomosoides sigmodontis) and onchocerciasis (Onchocerca ochengi). Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti-Wolbachia macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis."

Journal • Preclinical

In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae. (PubMed, PLoS Negl Trop Dis) - "Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4-6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3-4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed."

Journal

Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity. (PubMed, PLoS Negl Trop Dis) - "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."

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