AZD2693 / Ionis, AstraZeneca - LARVOL DELTA

AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: two randomized phase I trials. (PubMed, J Hepatol) - P1 | "AZD2693 reduced liver PNPLA3 with an acceptable safety and tolerability profile. These findings support the continued development of AZD2693."

Journal • P1 data • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • CRP • IL6 • PNPLA3

A Phase I Study to Investigate the Effect of Hepatic Impairment on the PK, Safety, and Tolerability of AZD2693 (clinicaltrials.gov) - P1 | N=35 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Hepatology

A Phase I Study to Investigate the Effect of Hepatic Impairment on the PK, Safety, and Tolerability of AZD2693 (clinicaltrials.gov) - P1 | N=35 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology

AZD2693, a potent PNPLA3 antisense oligonucleotide, decreases hepatic PNPLA3 mRNA and liver fat content in participants with presumed MASH and homozygous for the PNPLA3 148M risk allele (EASL-ILC 2024) - "AZD2693 treatment induced a potent reduction of liver PNPLA3 mRNA with a safety, tolerability and PK profile consistent with that of other ASOs. Therapeutic knock-down of PNPLA3 is impacting proposed mechanistic drivers in homozygous PNPLA3 148MM risk allele patients. These data support the continued development of AZD2693 in the FORTUNA Ph2b study."

Late-breaking abstract • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • CRP • PNPLA3

FORTUNA: A Study to Evaluate AZD2693 in Participants Who Are Carriers of the PNPLA3 148M Risk Allele With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis (clinicaltrials.gov) - P2 | N=175 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • PNPLA3

A Phase I Study to Investigate the Effect of Hepatic Impairment on the PK, Safety, and Tolerability of AZD2693 (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jul 2024 ➔ Oct 2024 | Trial primary completion date: Jul 2024 ➔ Oct 2024

Trial completion date • Trial primary completion date • Hepatology

A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients (clinicaltrials.gov) - P1 | N=74 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • PNPLA3

FORTUNA: A Study to Evaluate AZD2693 in Participants Who Are Carriers of the PNPLA3 148M Risk Allele With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2

Phase classification • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • PNPLA3

A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • PNPLA3

A Phase I Study to Investigate the Effect of Hepatic Impairment on the PK, Safety, and Tolerability of AZD2693 (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

A Phase I Study to Investigate the Effect of Hepatic Impairment on the PK, Safety, and Tolerability of AZD2693 (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Hepatology

A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients (clinicaltrials.gov) - P1 | N=74 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Nov 2023 ➔ Mar 2024 | Trial primary completion date: Nov 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • PNPLA3

Study to Assess the Safety, Tolerability, and Pharmacokinetics (Movement of Drugs Within the Body) of AZD2693 in Healthy Participants (clinicaltrials.gov) - P1 | N=44 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion

FORTUNA: A Study to Evaluate AZD2693 in Participants Who Are Carriers of the PNPLA3 148M Risk Allele With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis (clinicaltrials.gov) - P2b | N=232 | Recruiting | Sponsor: AstraZeneca

New P2b trial • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • PNPLA3

A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2023 ➔ Nov 2023 | Trial primary completion date: Jun 2023 ➔ Nov 2023

Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis

Study to Assess the Safety, Tolerability, and Pharmacokinetics (Movement of Drugs Within the Body) of AZD2693 in Healthy Participants (clinicaltrials.gov) - P1 | N=44 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed

"Does not bode well for NASH assets ION839 and ION455🤔 🤞" (@dr_muniyappa)

Hepatology • Non-alcoholic Steatohepatitis

"It took us a while to randomize but my research nurse was relentless in her pursuit…AZD2693/placebo being delivered SQ to lower the mRNA expression of PNPLA3. Personalized treatment of NASH based on genetics!! @DrLoomba @NoureddinMD @AlkhouriNaim @ajay_duseja @nagachalasani" (@rajVuppaLanchi)

Clinical • Hepatology • Non-alcoholic Steatohepatitis

Study to Assess the Safety, Tolerability, and Pharmacokinetics (Movement of Drugs Within the Body) of AZD2693 in Healthy Participants (clinicaltrials.gov) - P1 | N=44 | Recruiting | Sponsor: AstraZeneca | Active, not recruiting ➔ Recruiting | N=22 ➔ 44 | Trial completion date: Sep 2022 ➔ Mar 2023 | Trial primary completion date: Sep 2022 ➔ Mar 2023

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date

A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients (clinicaltrials.gov) - P1 | N=67 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jan 2023 ➔ Jun 2023 | Trial primary completion date: Jan 2023 ➔ Jun 2023

Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis

Study to Assess the Safety, Tolerability, and Pharmacokinetics (Movement of Drugs Within the Body) of AZD2693 in Healthy Japanese Participants (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed

Study to Assess the Safety, Tolerability, and Pharmacokinetics (Movement of Drugs Within the Body) of AZD2693 in Healthy Japanese Participants (clinicaltrials.gov) - P1; N=22; Recruiting; Sponsor: AstraZeneca; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study to Understand the Safety, Tolerability, and Activity of Drug in Body Over a Period of Time of AZD2693, in Subjects of Non-Childbearing Potential in Overweight But Otherwise Healthy Subjects, and Healthy Chinese and Japanese Subjects (clinicaltrials.gov) - P1; N=73; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed

Clinical • Trial completion • Hepatology • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity

Study to Assess the Safety, Tolerability, and Pharmacokinetics (Movement of Drugs Within the Body) of AZD2693 in Healthy Japanese Participants (clinicaltrials.gov) - P1; N=22; Not yet recruiting; Sponsor: AstraZeneca

Clinical • New P1 trial

A Study to Understand the Safety, Tolerability, and Activity of Drug in Body Over a Period of Time of AZD2693, in Subjects of Non-Childbearing Potential in Overweight But Otherwise Healthy Subjects, and Healthy Chinese and Japanese Subjects (clinicaltrials.gov) - P1; N=73; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity