vimirogant (AGN-242428) / AbbVie - LARVOL DELTA

Nuclear receptor RORγ inverse agonists/antagonists display tissue- and gene-context selectivity through distinct activities in altering chromatin accessibility and master regulator SREBP2 occupancy. (PubMed, Pharmacol Res) - "We report here that inverse agonists/antagonists of RORγ such as VTP-43742 derivative VTP-23 and TAK828F, which can potently inhibit the inflammatory gene program in Th17 cells, unexpectedly lack high potency in inhibiting the growth of TNBC tumor cells. In contrast, antagonists such as XY018 and GSK805 that strongly suppress tumor cell growth and survival display only modest activities in reducing Th17-related cytokine expression...Together, our study shows for the first-time that structurally distinct RORγ antagonists possess different or even contrasting activities in tissue/cell-specific manner. Our findings also highlight that the activities at natural chromatin are key determinants of RORγ modulators' tissue selectivity."

Journal • Breast Cancer • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer • IL17A

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P2 | N=292 | Completed | Sponsor: Allergan | Active, not recruiting ➔ Completed

Trial completion • Dry Eye Disease • Ophthalmology

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P2 | N=292 | Active, not recruiting | Sponsor: Allergan | Recruiting ➔ Active, not recruiting | N=72 ➔ 292

Enrollment change • Enrollment closed • Dry Eye Disease • Ophthalmology

Discovery of N-(2-benzyl-4-oxochroman-7-yl)-2-(5-(ethylsulfonyl) pyridin-2-yl) acetamide (b12) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist. (PubMed, Bioorg Chem) - "Clinical proof-of-concept (PoC) with small molecule inverse agonists of RORγt has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases...In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule RORγt modulation as a therapeutic target for the treatment of inflammatory diseases."

Journal • Dermatitis • Dermatology • Immunology • Inflammation • Psoriasis • IL17A • IL6 • ROR1

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P2; N=72; Recruiting; Sponsor: Allergan; Trial primary completion date: Sep 2021 ➔ Feb 2022

Clinical • Trial primary completion date • Dry Eye Disease • Ophthalmology

Discovery of 2-(Ortho-Substituted Benzyl)-Indole Derivatives as Potent and Orally Bioavailable RORγ Agonists with Antitumor Activity. (PubMed, J Med Chem) - "Herein, we describe new 2-(ortho-substituted benzyl)-indole derivatives as RORγ agonists by scaffold hopping based on clinical RORγ antagonist VTP-43742...After rational optimization for structure-activity relationship and pharmacokinetic profile, we identified a potent RORγ agonist compound 17 that was able to induce the production of IL-17 and IFNγ in tumor tissues and elicit antitumor efficacy in MC38 syngeneic mouse colorectal tumor model. This is the first comprehensive work to demonstrate the in vivo antitumor efficacy of an RORγ agonist."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Immunology • Inflammation • Oncology • Solid Tumor • IFNG • IL17A

Retinoic acid-related orphan receptor gamma (RORγ) inverse agonists/antagonists for the treatment of inflammatory diseases - where are we presently? (PubMed, Expert Opin Drug Discov) - "The main reasons were lack of efficacy (topical) or safety signals (oral) as well as, amongst other things, thymic lymphomas as seen with BMS-986251 in a preclinical study and liver enzyme elevations in humans with VTP-43742. Possibilities to mitigate these risks could be the use of RORγt inverse agonists with different chemical structures not interfering with thymocytes maturation and no liver tox inducing properties. With few new frontrunners (e.g. ABBV-157 (cedirogant), BI 730357 or IMU-935) this is still an exciting time for this novel treatment approach."

Journal • Hematological Malignancies • Immunology • Inflammation • Lymphoma • Oncology • IL17A

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P2; N=72; Recruiting; Sponsor: Allergan; Active, not recruiting ➔ Recruiting; Phase classification: P1/2 ➔ P2

Clinical • Enrollment open • Phase classification • Dry Eye Disease • Ophthalmology

Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis. (PubMed, Sci Rep) - "However, oral RORγ antagonists (VTP43742, TAK828) with high systemic exposure showed toxicity in phase I/II clinical trials and terminated development. Topical application of SHR168442 in Vaseline exhibited excellent efficacy in the imiquimod-induced and IL-23-induced psoriasis-like skin inflammation mouse models and correlated with the reduction of Th17 pathway cytokines, IL-6, TNFα and IL-17A. This work demonstrated restricted skin exposure of RORγ antagonist may provide a new topical treatment option as targeted therapeutics for mild to moderate psoriasis patients and may be suitable for the treatment of any other inflammatory disorders that are accessible locally."

Journal • Dermatitis • Dermatology • Immunology • Inflammation • Psoriasis • IL17A • IL6 • TNFA

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Active, not recruiting; Sponsor: Allergan; Trial completion date: Dec 2020 ➔ Sep 2021; Trial primary completion date: Dec 2020 ➔ Sep 2021; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Dry Eye Disease • Ocular Infections • Ophthalmology

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Recruiting; Sponsor: Allergan; Trial completion date: Sep 2020 ➔ Dec 2020

Trial completion date • Dry Eye Disease • Ocular Infections • Ophthalmology

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Recruiting; Sponsor: Allergan; Active, not recruiting ➔ Recruiting; Trial completion date: Jun 2020 ➔ Sep 2020; Trial primary completion date: Jun 2020 ➔ Sep 2020

Clinical • Enrollment open • Trial completion date • Trial primary completion date • Conjunctivitis • Dry Eye Disease • Ophthalmology

Vitae Pharmaceuticals: Wells Fargo Securities Healthcare Conference (Vitae Pharma, 11th Annual Wells Fargo Securities Healthcare Conference) - "Clear and consistent signal of efficacy from PASI score changes in both the 350mg and 700mg dose groups"

P2a data • Psoriasis

Vitae Pharmaceuticals: Wells Fargo Securities Healthcare Conference (Vitae Pharma, 11th Annual Wells Fargo Securities Healthcare Conference) - "Clear and consistent signal of efficacy from PASI score changes in both the 350mg and 700mg dose groups"

P2a data • Psoriasis

An Ascending Multiple Dose Study With VTP-43742 in Healthy Volunteers and Psoriatic Patients (clinicaltrials.gov) - P1/2; N=108; Recruiting; Sponsor: Vitae Pharmaceuticals, Inc.

New P1/2 trial • Biosimilar • Immunology • Inflammation • Psoriasis

Vitae Pharmaceuticals: Wedbush PacGrow Healthcare Conference (Vitae Pharma) - Anticipated patent protection until 2035

Anticipated patent expiry • Psoriasis

VTP-43742: Launch for psoriasis in 2022 (Allergan) - Annual Report 2017

Launch • Psoriasis

Emerging systemic drugs in the treatment of plaque psoriasis. (PubMed, Expert Opin Emerg Drugs) - "There seems to be limited room for development of novel biologics, as the existing ones are extraordinarily safe, effective, and convenient with few injections. Patients would prefer a safe, effective oral treatment; however, JAK inhibitors seem unlikely to fill this role completely."

Journal • Dermatology • Dermatopathology • Immunology • Psoriasis • IL17A

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Active, not recruiting; Sponsor: Allergan; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Recruiting; Sponsor: Allergan; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses. (PubMed, J Med Chem) - "With the clinical proof-of-concept inferred from a small molecule inhibitor VTP-43742 for psoriasis and recent inflow of several RORc inhibitors into the clinic for therapeutic interventions in autoimmune diseases, this field continues to evolve. This review briefly summarizes the RORc inhibitors disclosed in the literature and discusses the progress made by these inhibitors in combating autoimmune diseases."

Journal

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Not yet recruiting; Sponsor: Allergan; Trial completion date: Sep 2020 ➔ Jun 2020; Trial primary completion date: Sep 2020 ➔ Jun 2020

Clinical • Trial completion date • Trial primary completion date

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Not yet recruiting; Sponsor: Allergan; Initiation date: Sep 2019 ➔ Feb 2020

Clinical • Trial initiation date

A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease (clinicaltrials.gov) - P1/2; N=72; Not yet recruiting; Sponsor: Allergan

Clinical • New P1/2 trial