AZD2693 / Ionis, AstraZeneca - LARVOL DELTA

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=0 | Completed | Sponsor: AstraZeneca | N=22 ➔ 0

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

A PNPLA3 antisense oligonucleotide, AZD2693, for the treatment of MASH in I148M homozygous participants: results from the phase 2b FORTUNA study (EASL 2026) - "After 52 weeks of treatment, AZD2693 (25 mg or 50 mg) was not better over placebo for either the histological resolution of MASH or the improvement in fibrosis in homozygous carriers of the PNPLA3 rs738409 risk allele with non-cirrhotic MASH and fibrosis."

P2b data • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • PNPLA3

Britain’s AstraZeneca (AZ) said on the 6th (local time) that it halted development of the antisense oligonucleotide class investigational drug “AZD2693.” (Chosun Biz) - "In its third-quarter earnings report that day, the company said it 'failed to demonstrate efficacy in a phase 2b clinical trial in patients with MASH and liver fibrosis.'"

Discontinued • P2b data • Metabolic Dysfunction-Associated Steatohepatitis

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=220 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

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

ENHANCED SCREENING EFFICIENCY: OVER 90% PREVALENCE OF F2–F4 FIBROSIS IN PNPLA3 HOMOZYGOUS PARTICIPANTS WITH MASH IN THE AZD2693 FORTUNA PHASE 2B STUDY (AASLD 2025) - P2 | "In this study, homozygosity for the PNPLA3 rs738409 148M risk allele enhanced clinical biopsy-screening efficiency for participants with significant F2–F4 fibrosis."

P2b data • Cardiovascular • Diabetes • Dyslipidemia • Fibrosis • Hepatology • Hypertension • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Type 2 Diabetes Mellitus • PNPLA3

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