adriforant (ZPL 3893787) / Novartis - LARVOL DELTA

Targeting Intracellular Pathways in Atopic Dermatitis with Small Molecule Therapeutics. (PubMed, Curr Issues Mol Biol) - "Although biologic agents such as dupilumab, tralokinumab, and lebrikizumab have revolutionized AD management, their high costs, injectable administration, and limited global accessibility highlight the need for alternative options...This review provides a comprehensive analysis of key agents including Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib, ruxolitinib, delgocitinib), phosphodiesterase 4 (PDE4) inhibitors (crisaborole, difamilast, roflumilast, apremilast), as well as STAT6 degraders (KT621, NX3911), aryl hydrocarbon receptor modulators, histamine H4 receptor antagonists (adriforant, izuforant), and sphingosine-1-phosphate receptor modulators (etrasimod, BMS-986166). We summarize their mechanisms of action, pharmacological profiles, and pivotal clinical trial data, emphasizing their potential to address unmet therapeutic needs. Finally, we discuss safety concerns, long-term tolerability, and future directions for integrating small molecule..."

Journal • Review • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • STAT6

Decoding ligand recognition and constitutive activation of histamine H3 and H4 receptors. (PubMed, Acta Pharmacol Sin) - "In this study, using cryo-electron microscopy, we present an inactive structure of H4R bound to a selective antagonist, adriforant, and two Gi-coupled structures of H3R and H4R in complex with histamine...Our findings also uncovered distinct antagonistic mechanisms for H3R and H4R and identified the role of aromatic amino acids on extracellular loop 2 in modulating the constitutive activity of H3R and H4R. These findings advance our knowledge of the functional modulation of histamine receptors, providing a foundation for the development of targeted therapeutics for neurological and immune-related disorders."

Journal • Allergy • Narcolepsy • Sleep Disorder

Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice. (PubMed, Eur J Pharmacol) - "Our results suggest that functional inhibition of histamine receptor 4 by adriforant reduces itch and inflammation in vivo. The effects observed in mice, however, did not translate to clinical efficacy in patients as the Ph2b clinical trial with adriforant did not meet pre-specified efficacy endpoints. Given the complex pathogenesis of AD, antagonism of histamine receptor 4 alone appears insufficient to reduce disease severity in AD patients, despite the effects seen in mouse models."

Journal • Preclinical • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • Pruritus

ZESTExt: A Study to Assess the Safety and Efficacy of ZPL389 With TCS/TCI in Atopic Dermatitis Patients (clinicaltrials.gov) - P2; N=123; Terminated; Sponsor: Novartis Pharmaceuticals; N=230 ➔ 123; Trial completion date: Dec 2022 ➔ Aug 2020; Recruiting ➔ Terminated; Trial primary completion date: Nov 2022 ➔ Jul 2020; Coe terminated due to lack of efficacy

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study to Assess the Safety and Efficacy of ZPL389 in Patients With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2; N=293; Terminated; Sponsor: Novartis Pharmaceuticals; Trial completion date: Jan 2021 ➔ Aug 2020; Recruiting ➔ Terminated; Trial primary completion date: Dec 2020 ➔ Aug 2020; Lack of efficacy

Clinical • Trial completion date • Trial primary completion date • Trial termination • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

Novartis Second Quarter and Half Year 2020 (Novartis) - "Project discontinued for ZPL389 in atopic dermatitis."

Discontinued • Atopic Dermatitis • Dermatology

Novartis takes $485m hit after axing eczema drug from pipeline (pharmaphorum) - "Novartis has axed development of its mid-stage eczema drug ZPL389, taking a $485 million hit in the process."

Commercial • Atopic Dermatitis • Dermatology

ZPL389: Initiation of P2 trial in atopic dermatitis in 2018 (Novartis) - R&D Update

New P2 trial • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation

Efficacy and safety of histamine H receptor antagonist ZPL-3893787 in atopic dermatitis. (PubMed, J Allergy Clin Immunol) - "These results showed for the first time that ZPL-3893787 improved inflammatory skin lesions in patients with AD, confirming H4 receptor antagonism as a novel therapeutic option."

Clinical • Journal

ZESTExt: A Study to Assess the Safety and Efficacy of ZPL389 With TCS/TCI in Atopic Dermatitis Patients (clinicaltrials.gov) - P2; N=230; Recruiting; Sponsor: Novartis Pharmaceuticals; N=360 ➔ 230

Clinical • Enrollment change

Adriforant: Completion of P2 ZEST trial (NCT03517566) for moderate-to-severe atopic dermatitis in H1 2021 (Novartis) - Q1 2020 Results

Trial completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation

ZPL 3893787: Completion of P2 ZESTExt trial (NCT03948334) for atopic dermatitis in 2023 (Novartis) - Q4 and FY 2019 Results

Trial completion date

ZPL 389: Regulatory submission for atopic dermatitis in 2024 or later (Novartis) - Q4 and FY 2019 Results

Regulatory

ZPL 389: Regulatory submission for atopic dermatitis in 2024 (Novartis) - R&D Day

Regulatory

ZPL 389: Initiation of P3 trial for atopic dermatitis in 2021 (Novartis) - R&D Day

New P3 trial

ZPL 3893787: Completion of P2 ZEST trial (NCT03517566) for moderate to severe atopic dermatitis in H1 2021 (Novartis) - Q3 2019 Results

Trial completion date

A Study to Assess the Safety and Efficacy of ZPL389 in Patients With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2; N=360; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Mar 2020 ➔ Jan 2021; Trial primary completion date: Mar 2020 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date

ZESTExt: A Study to Assess the Safety and Efficacy of ZPL389 With TCS/TCI in Atopic Dermatitis Patients (clinicaltrials.gov) - P2; N=360; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Jan 2022 ➔ Dec 2022; Trial primary completion date: Jan 2022 ➔ Nov 2022

Clinical • Trial completion date • Trial primary completion date

ZPL 3893787: Completion of P2 ZESTExt trial (NCT03948334) for atopic dermatitis in 2022 (Novartis) - Q2 2019 Results

Trial completion date

Novel systemic drugs in treatment of atopic dermatitis: results from phase II and phase III studies published in 2017/2018. (PubMed, Curr Opin Allergy Clin Immunol) - "A couple of promising novel therapeutical targets have recently been investigated and published in clinical trials on atopic dermatitis."

Journal • P2 data • P3 data

ZESTExt: A Study to Assess the Safety and Efficacy of ZPL389 With TCS/TCI in Atopic Dermatitis Patients (clinicaltrials.gov) - P2; N=360; Recruiting; Sponsor: Novartis Pharmaceuticals

Clinical • New P2 trial

ZPL 389: Regulatory submission for atopic dermatitis in 2022 (Novartis) - Q1 2019 Results

Regulatory

A study to assess the safety and efficacy of ZPL389 with concomitant or intermittent use of TCS and/or TCI in atopic dermatitis patients (clinicaltrialsregister.eu) - P2; N=360; Ongoing; Sponsor: Novartis Pharma AG

Clinical • New P2 trial

A Study to Assess the Safety and Efficacy of ZPL389 in Patients With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2; N=360; Recruiting; Sponsor: Novartis Pharmaceuticals; Not yet recruiting ➔ Recruiting; Trial completion date: Aug 2019 ➔ Mar 2020; Initiation date: Jun 2018 ➔ Nov 2018; Trial primary completion date: Aug 2019 ➔ Mar 2020

Clinical • Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date

A study to assess the safety and efficacy of ZPL389 with concomitant or intermittent use of TCS and/or TCI in atopic dermatitis patients (clinicaltrialsregister.eu) - P2; N=306; Ongoing; Sponsor: Novartis Pharma AG

Clinical • New P2 trial