cedirogant (ABBV-157) / AbbVie, Inventiva - LARVOL DELTA

Pharmacological Management of Psoriasis: Current Landscape and Future Perspectives. (PubMed, Recent Adv Inflamm Allergy Drug Discov) - "Numerous novel synthetic agents, such as JAK/STAT inhibitors [ruxolitinib, peficitinib], TYK2 inhibitors [zasocitinib, ropsacitinib], RORꝩT inhibitors [cedirogant], A3AR agonists [piclodenoson], and CXCR2 antagonists [vimnerixin] are undergoing extensive clinical trials and have demonstrated beneficial outcomes in multiple phases of these trials. Deucravacitinib, an orally administered TYK2 inhibitor, has recently received FDA approval for the treatment of moderate to severe plaque psoriasis...Moreover, these pathways can be exploited to personalize anti-psoriatic therapy, minimize side effects, and maximize therapeutic outcomes. Altogether, the integration of biological agents and synthetic agents can overcome the challenges associated with the management of the repertoire of psoriatic pathophysiology and symptoms."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • CXCR2 • IL23A • TYK2

Endogenous plasma riboflavin is not a viable BCRP biomarker in human. (PubMed, Clin Transl Sci) - "We have recently demonstrated that co-administration of 375 mg once daily (q.d.) cedirogant, an in vitro BCRP inhibitor, significantly increased rosuvastatin (an OATP1B1/1B3 and BCRP substrate) exposures but did not change the levels of the OATP1B endogenous biomarker coproporphyrin-I, demonstrating that cedirogant is a clinical BCRP inhibitor. Contrary to expectations, 375 mg q.d. oral administration of cedirogant did not increase riboflavin levels. These data strongly suggest that endogenous plasma riboflavin is not a viable biomarker for BCRP inhibition in humans."

Biomarker • Journal

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

Cedirogant in adults with psoriasis: a phase 2, randomized, placebo-controlled clinical trial. (PubMed, Clin Exp Dermatol) - P2 | "Patients with psoriasis who received cedirogant showed PASI improvement and cedirogant was generally well tolerated. Results should be interpreted in the context of early study termination. Cedirogant development has been discontinued."

Clinical • Journal • P2 data • Dermatology • Immunology • Psoriasis • IL17A • IL23A

Pharmacokinetics, Safety, and Tolerability of Cedirogant in Healthy Japanese and Chinese Adults. (PubMed, Clin Pharmacol Drug Dev) - "The cedirogant regimens tested were generally well tolerated, and no new safety issues were identified. The results supported enrollment of Japanese and Chinese subjects in subsequent clinical trials for cedirogant."

Journal • PK/PD data • Dermatology • Immunology • Psoriasis • IL17A

Cedirogant Population Pharmacokinetics and Pharmacodynamic Analyses of Interleukin-17A Inhibition in Two Phase I Studies in Healthy Participants and Participants with Moderate to Severe Psoriasis. (PubMed, Clin Pharmacol Drug Dev) - "Model-estimated half-maximal inhibitory concentration and maximum inhibition values for cedirogant inhibition of ex vivo IL-17A were 0.56 mg/L and 0.76, respectively. The established relationship between cedirogant exposure and biomarker effect supported dose selection for the Phase 2 dose-ranging study in patients with PsO."

Journal • P1 data • PK/PD data • Dermatology • Immunology • Psoriasis • IL17A

Pharmacokinetics, safety, and efficacy of cedirogant from phase I studies in healthy participants and patients with chronic plaque psoriasis. (PubMed, Clin Transl Sci) - "The studies consisted of single (20-750 mg) and multiple (75-375 mg once-daily [q.d.]) ascending dose designs, with effect of food and itraconazole on cedirogant exposure also evaluated. Psoriasis Area and Severity Index (PASI) and Self-Assessment of Psoriasis Symptoms (SAPS) assessments demonstrated numerical improvement with treatment of cedirogant 375 mg q.d. compared with placebo. The PK, safety, and efficacy profiles of cedirogant supported advancing it to phase II clinical trial in psoriasis patients."

Journal • P1 data • PK/PD data • Dermatology • Immunology • Psoriasis

Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels. (PubMed, Antiviral Res) - "Our results demonstrated (i) an antiviral activity of the clinically relevant RORγ modulators cedirogant and others, (ii) that isoform RORγ1 acts as the responsible determinant and drug target in the analyzed cell culture-based models, (iii) a selectivity of the antiviral effect for RORγ1 over related receptors RORα and RORβ, (iv) a late-phase inhibition exerted by cedirogant in HCMV replication and (v) a mechanistic link to the cellular cholesterol biosynthesis. Combined, the data highlight this novel RORγ-specific antiviral targeting concept and the developmental potential of RORγ-directed small molecules."

Journal • Cytomegalovirus Infection • Herpes Zoster • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Varicella Zoster • ROR1

A Study to Assess Adverse Events and Disease Activity With Cedirogant (ABBV-157) in Adult Participants With Moderate to Severe Psoriasis (clinicaltrials.gov) - P2 | N=156 | Terminated | Sponsor: AbbVie | Phase classification: P2b ➔ P2

Phase classification • Dermatology • Immunology • Psoriasis

Pharmacokinetics, Safety, and Efficacy of Cedirogant (ABBV-157) in Patients With Moderate-to-Severe Plaque Psoriasis (AAD 2023) - "At D28, the mean (SD) percent change from baseline in PASI/SAPS was −33.2% (28.9%)/−46.5% (31.4%) with cedirogant and −18.7% (19.6%)/2.0% (78.0%) with placebo. Overall, cedirogant was well tolerated in patients with moderate-to-severe plaque psoriasis with a PK profile generally similar to profiles in healthy volunteers, and resulted in a greater percent change in PASI/SAPS vs placebo at D28."

Clinical • PK/PD data • Dermatology • Immunology • Inflammation • Psoriasis

Pharmacokinetics, Safety, and Tolerability of Cedirogant, a ROR?t Inverse Agonist, in Healthy Volunteers (AAD 2023) - "In both studies, cedirogant was generally well tolerated with no discontinuations or serious adverse events due to cedirogant. The favorable pharmacokinetics, safety, and tolerability profiles of cedirogant supported further investigation in clinical trials with psoriasis patients."

Clinical • PK/PD data • Dermatology • Immunology • Psoriasis

Population Pharmacokinetic and Pharmacodynamic Analyses of Cedirogant in Healthy Subjects and Subjects with Moderate to Severe Psoriasis (AAD 2023) - "The model-predicted maximum percentage of ex-vivo IL17A inhibition from baseline ranged from 64% for 75 mg QD to 73% approaching Imax for 375 mg QD dose. The established relationship between cedirogant exposure and biomarker effect served as the basis for dose selection for the Phase 2 dose-ranging study for cedirogant in psoriasis."

Clinical • PK/PD data • Dermatology • Immunology • Psoriasis • IL17A • IL23A

A Study to Assess Adverse Events and Disease Activity With Cedirogant (ABBV-157) in Adult Participants With Moderate to Severe Psoriasis (clinicaltrials.gov) - P2b | N=156 | Terminated | Sponsor: AbbVie | Trial completion date: Mar 2023 ➔ Nov 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Mar 2023 ➔ Nov 2022; Company Decision

Adverse events • Trial completion date • Trial primary completion date • Trial termination • Dermatology • Immunology • Psoriasis

A Study to Assess Safety of Cedirogant and How Cedirogant Moves Through the Body in Adult Participants With Mild, Moderate and Severe Hepatic Impairment (clinicaltrials.gov) - P1 | N=6 | Terminated | Sponsor: AbbVie | N=24 ➔ 6 | Recruiting ➔ Terminated; Strategic considerations

Enrollment change • Trial termination • Hepatology

A Study to Assess Adverse Events and Disease Activity With Cedirogant (ABBV-157) in Adult Participants With Moderate to Severe Psoriasis (clinicaltrials.gov) - P2b | N=200 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Adverse events • Enrollment closed • Dermatology • Immunology • Psoriasis

"Cedirogant… Abbvie/inventiva … phase2 h1 2023 @JacobPlieth" (@FcRnMabs)

P2 data

A Study to Assess Safety of Cedirogant and How Cedirogant Moves Through the Body in Adult Participants With Mild, Moderate and Severe Hepatic Impairment (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: AbbVie | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

A Study to Assess Safety of Cedirogant and How Cedirogant Moves Through the Body in Adult Participants With Mild, Moderate and Severe Hepatic Impairment (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: AbbVie

New P1 trial • Hepatology

Inventiva receives a €4 million milestone payment from AbbVie for cedirogant Phase IIb initiation (GlobeNewswire) - "Inventiva...announced the receipt of a €4 million milestone payment from AbbVie. It follows the inclusion of the first patient with psoriasis in the ongoing Phase IIb clinical trial with cedirogant (ABBV-157), an oral RORg inverse agonist jointly discovered by Inventiva and AbbVie for the treatment of autoimmune diseases...This collaboration with AbbVie enables Inventiva to receive payments upon the achievement of clinical, regulatory and commercial milestones, as well as tiered royalties on product sales, from mid single-digit to low double-digit."

Financing • Immunology • Psoriasis

A Study to Assess Adverse Events and Disease Activity With Cedirogant (ABBV-157) in Adult Participants With Moderate to Severe Psoriasis (clinicaltrials.gov) - P2b; N=200; Recruiting; Sponsor: AbbVie; Not yet recruiting ➔ Recruiting

Adverse events • Clinical • Enrollment open • Dermatology • Immunology • Psoriasis

Inventiva reports 2021 first half financial results and provides a corporate update (GlobeNewswire) - "Publication by AbbVie of the study design of the Phase IIb clinical trial with cedirogant: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety and efficacy of cedirogant in adult patients with moderate to severe psoriasis. AbbVie plans to enroll about 200 adult participants in approximately 45 sites, who will receive oral daily doses of cedirogant or placebo capsules for 16 weeks...The trial is expected to start in November 2021 and be completed in March 2023."

New P2b trial • Trial completion date • Immunology • Psoriasis

A Study to Assess Adverse Events and Disease Activity With Cedirogant (ABBV-157) in Adult Participants With Moderate to Severe Psoriasis (clinicaltrials.gov) - P2b; N=200; Not yet recruiting; Sponsor: AbbVie

Adverse events • Clinical • New P2b trial • Dermatology • Immunology • Psoriasis

Inventiva Reports First-Half of 2021 Financial Information (GlobeNewswire) - "Next key milestones expected...Initiation by AbbVie of a Phase IIb clinical trial with cedirogant – expected in the second half of 2021."

New P2b trial • Immunology • Psoriasis

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

Inventiva reports first quarter 2021 financial information and updates on the collaboration with AbbVie in auto-immune diseases (GlobeNewswire) - "Decision by AbbVie to move into Phase IIb clinical development with cedirogant in psoriasis, following promising results in its Phase Ib clinical trial...Initiation by AbbVie of a Phase IIb clinical trial with cedirogant – expected in the second half of 2021."

New P2b trial • Immunology • Psoriasis