A Phase-II, Randomised, Double-blind, Parallel-group, Proof-of-concept Trial to Investigate ABBV-4083 Given for 7 or 14 Days or in Combination With Albendazole in Subjects With Onchocerca Volvulus Infection, Comprising: Part 1 to Investigate Safety, Tolerability, Efficacy for Dose-Ranging and Pharmacokinetics; Part 2 to Investigate Efficacy of Selected Doses, Safety, Tolerability and Pharmacokinetics

Onchocerciasis is a major public health problem in affected countries that causes disease-induced disability, and overall loss of economic productivity. The purpose of this study is to determine how safe and effective ABBV-4083 in combination with albendazole is in treating participants with Onchocerciasis.
ABBV-4083 is an investigational drug being developed for the treatment of onchocerciasis. This study is conducted in 2 parts. In part 1, participants are randomly assigned to 1 of 5 groups, called treatment arms to determine the most efficient treatment combination. Each group receives a different treatment. In part 2, participants are randomly assigned to 1 of 4 treatment arms. Approximately 444 or 486 adult participants with a diagnosis of onchocerciasis will be enrolled in approximately 2 sites in Democratic Republic of Congo.
Participants in Part 1 will receive different treatment combinations of ABBV-4083 and/or albendazole and/or matching placebo capsules for 14 days. Participants in Part 2 will receive the most effective treatment combination(s) determined in Part 1 for 14 days followed by ivermectin or matching placebo capsules at Month 6; duration of treatment is 24 months.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests and checking for side effects.

开始日期2021-05-22

申办/合作机构

AbbVie, Inc.

[+1]

PACTR202104600961505 / Suspended临床2期IIT

A Phase-II, Randomised, Double-blind, Parallel-group, Proof-of-concept Trial to Investigate ABBV-4083 given for 7 or 14 Days or in Combination with Albendazole in Subjects with Onchocerca volvulus Infection, comprising:Part 1 to Investigate Safety, Tolerability, Efficacy for Dose-Ranging and Pharmacokinetics;Part 2 to Investigate Efficacy of Selected Doses, Safety, Tolerability and Pharmacokinetics

开始日期2021-04-30

申办/合作机构

Drugs for Neglected Diseases initiative

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项与 Anti-Wolbachia therapy(AbbVie) 相关的文献（医药）

2024-11-01·CLINICAL PHARMACOLOGY & THERAPEUTICS

Coproporphyrin‐I as a Selective OATP1B Biomarker Can Be Used to Delineate the Mechanisms of Complex Drug–Drug Interactions: Cedirogant Case Study

Article

作者: Badawi, Mohamed ; Savaryn, John P. ; Qian, Yuli ; Hao, Shuai ; Gannu, Shashikanth ; Salem, Ahmed Hamed ; Klein, Cheri E. ; Liu, Wei ; Mohamed, Mohamed‐Eslam F. ; Kikuchi, Ryota ; Eldred, Ann

Cedirogant is an inverse agonist of retinoic acid‐related orphan receptor gamma thymus developed for the treatment of chronic plaque psoriasis. Cedirogant induces cytochrome P450 (CYP) 3A4 while inhibiting P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3 in vitro. Static drug–drug interactions (DDIs) predictions suggested possible clinical induction of CYP3A4, and inhibition of P‐gp, BCRP, and OATP1B1, leading to challenges in interpreting DDI studies between cedirogant and substrates of CYP3A, P‐gp, BCRP, and OATP1B1/3. Here the effects of cedirogant on the pharmacokinetics of two statin drugs were investigated in healthy participants. Coproporphyrin‐I (CP‐I), a selective endogenous OATP1B biomarker, was used to assess the impact of cedirogant on OATP1B. 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. Cedirogant did not increase CP‐I exposures, indicating no clinical OATP1B inhibition. The increased rosuvastatin exposure and minimal change in atorvastatin exposure with co‐administration of cedirogant is attributed to BCRP inhibition and interplay between P‐gp/BCRP inhibition and CYP3A induction, respectively. 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.

2024-09-01·TRENDS IN PARASITOLOGY

The long and winding road towards new treatments against lymphatic filariasis and onchocerciasis

Review

作者: Pfarr, Kenneth ; Fischer, Peter U ; Kazakov, Alexander ; Hübner, Marc P ; Specht, Sabine ; Hoerauf, Achim ; Risch, Frederic

Although lymphatic filariasis and onchocerciasis have been targeted for global elimination, these helminth infections are still a major public health problem across the tropics and subtropics. Despite decades of research, treatment options remain limited and drugs that completely clear the infections, and can be used on a large scale, are still unavailable. In the present review we discuss the strengths and weaknesses of currently available treatments and new ones in development. 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.

2023-07-01·PLoS neglected tropical diseases

A Phase-I pharmacokinetic, safety and food-effect study on flubentylosin, a novel analog of Tylosin-A having potent anti-Wolbachia and antifilarial activity.

Article

作者: Snodgrass, Linda ; Gallenberg, Loretta ; Porcalla, Ariel R ; Kwatra, Nisha V ; Neenan, Melina ; Carter, David C ; Marsh, Kennan C ; Kempf, Dale J ; Cohen, Daniel E ; Carr, Robert A ; Klein, Cheri E ; Zhao, Weihan ; Alami, Negar

BACKGROUND:

The parasitic filariae responsible for onchocerciasis and lymphatic filariasis are host to an endosymbiotic bacterium, Wolbachia, which is essential to the fertility and development of the parasites. We performed a Phase-I pharmacokinetic, safety and food-effect study on single and multiple ascending doses of flubentylosin (ABBV-4083), a macrolide antibacterial with activity against Wolbachia, intended to sterilize and eliminate the parasites.

METHODS:

Seventy-eight healthy adults were exposed to flubentylosin; 36 were exposed to single ascending 40, 100, 200, 400 or 1000 mg doses; 12 received 1000 mg in the food-effect part; and 30 received multiple ascending daily doses of 100 mg for 7 days, 200 mg for 7 or 14 days, or 400 mg for 7 or 14 days. Twenty-two subjects received placebo.

RESULTS:

Maximum concentrations (Cmax) of flubentylosin were reached after 1-2 hours, with a half-life < 4 hours at doses ≤ 400 mg. Cmax and AUC increased in a more than dose-proportional manner, with similar exposure after multiple dose administration. The most frequently reported adverse events were nausea (8/78, 10%) and headache (6/78, 8%). Two subjects given a single dose of flubentylosin 1000 mg in the food-effect part experienced reversible asymptomatic ALT and AST elevations at Grade 2 or Grade 4, with no elevation in bilirubin, deemed related to study drug. The effect of food on exposure parameters was minimal. No treatment-related serious adverse events were reported.

DISCUSSION:

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.

项与 Anti-Wolbachia therapy(AbbVie) 相关的新闻（医药）

2023-02-09

·Endpoints

Updated: AbbVie leaves some oncology programs out of 2023 pipeline highlights

In an investor update Thursday morning, AbbVie left eight programs out of its pipeline highlights it shared with investors, as compared to what exists on the R&D page of its website, last refreshed in December. A Phase III study of Rinvoq in Takayasu arteritis , a rare group of disorders in which blood vessels become inflamed, was not included. The JAK inhibitor is approved for indications like rheumatoid arthritis and carries with it a black box warning. There’s also the removal of late-stage veliparib in breast and ovarian cancers after multiple failures for the PARP inhibitor were announced years ago . A company spokesperson noted the programs remain ongoing. “The updates listed in the slide from this morning highlight our key programs of interest for the investment community and is not a comprehensive snapshot of our entire pipeline,” the spokesperson wrote in an email. Further down the pipeline, AbbVie was quiet on Phase II assets ABBV-4083 in filarial diseases and its Allergan-snagged AGN-231868 in dry eye. A different Allergan asset continues in dry eye, according to the Chicago-area pharma giant’s pipeline update Thursday. Down in Phase I, AbbVie left out four oncology drug candidates. The company reneged on solid and hematologic tumor assets ABBV-155 and ABBV-621 , an IV-infused drug candidate also known as eftozanermin alfa . Small cell lung cancer asset ABBV-011 no longer shows up on the pipeline, and the same goes for ABBV-368 in solid tumors. AbbVie previously nixed a Phase Ib study of ABBV-368 in combination with Idera’s (Aceragen as of last month) tilsotolimod. In its update, AbbVie reminded investors of its four regulatory submissions: Rinvoq for Crohn’s disease; the Genmab-partnered CD3xCD20 bispecific epcoritamab for relapsed/refractory diffuse large B-cell lymphoma; ABBV-951 for advanced Parkinson’s disease and Qulipta for chronic migraine prevention . Editor’s note: This article has been updated to include comment and additional context from an AbbVie spokesperson that the programs remain ongoing.

临床1期临床3期临床2期上市批准临床终止

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