ARO-PNPLA3 / Arrowhead Pharmaceuticals, Madrigal Pharma - LARVOL DELTA

Madrigal Adds Clinical-Stage siRNA Asset Targeting PNPLA3 to its MASH Pipeline (The Manila Times) - "Madrigal Pharmaceuticals...announced an exclusive global license agreement with Arrowhead Pharmaceuticals for ARO-PNPLA3, a clinical-stage, small interfering RNA (siRNA) asset targeting patatin-like phospholipase domain-containing protein 3 (PNPLA3), a key genetic driver of MASH. The license of ARO-PNPLA3 adds to Madrigal’s pipeline with a precision medicine approach for patients at high risk of MASH....Arrowhead will receive an upfront payment of $25 million, additional payments of up to $975M if certain milestones are achieved and royalties on net sales."

Licensing / partnership • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Phase 1 trials provide proof-of-concept for ARO-PNPLA3 as a potential precision-medicine approach in MASH (The Manila Times) - "Reductions in liver fat up to 46% (as measured by MRI-PDFF) at 12 weeks following a single dose at the highest dose level tested in PNPLA3 I148M homozygous patients; Rapid onset of effect, with reductions observed at six weeks and sustained through at least 24 weeks; No clinically meaningful adverse events were observed; No effect on liver fat content was observed in heterozygous participants at any of the doses studied; Results from a second Phase 1 trial conducted in Japan (n=9) support these findings."

First-in-human • P1 data • Metabolic Dysfunction-Associated Steatotic Liver Disease

Association Between PNPLA3 Inhibition and Gout: A Drug Target Mendelian Randomization Study. (PubMed, Int J Endocrinol) - P1 | "ARO-PNPLA3 is a therapeutic agent designed to target PNPLA3, but its long-term effects remain uncertain...In addition, PNPLA3 inhibition also increased triglyceride (TG) levels, which partially mediate the relationship between PNPLA3 inhibition and gout. Trial Registration: ClinicalTrials.gov identifier: NCT04844450."

Journal • Fibrosis • Gout • Hepatology • Immunology • Inflammatory Arthritis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Rheumatology • PNPLA3

Preclinical and Clinical Pharmacokinetics of JNJ-75220795, an siRNA Therapeutic Targeting PNPLA3, for Metabolic Dysfunction-Associated Steatohepatitis. (PubMed, J Clin Pharmacol) - "Based on the overall data, JNJ-75220795 was primarily localized to the liver and exhibited sustained hepatic exposures, which confer prolonged pharmacodynamic effects in the target organ. The favorable PK profiles of single subcutaneous doses observed in the phase 1 studies support continued clinical development of JNJ-75220795 for the treatment of MASH."

Journal • PK/PD data • Preclinical • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • PNPLA3

LDL-C and TC mediate the risk of PNPLA3 inhibition on cardiovascular diseases. (PubMed, J Clin Endocrinol Metab) - "This study suggests that PNPLA3 inhibition increases the risk of major CVDs. Moreover, blood LDL-C and TC may mediate a significant proportion of the associations between PNPLA3 inhibition and coronary atherosclerosis, coronary heart disease, or myocardial infarction."

Journal • Acute Coronary Syndrome • Atherosclerosis • Atrial Fibrillation • Cardiovascular • CNS Disorders • Congestive Heart Failure • Coronary Artery Disease • Dyslipidemia • Heart Failure • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Myocardial Infarction • PNPLA3

A Single and Multiple Ascending Dose Study of Subcutaneously Administered JNJ-75220795 (clinicaltrials.gov) - P1 | N=55 | Completed | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Completed | N=112 ➔ 55 | Trial completion date: Jan 2024 ➔ Mar 2023 | Trial primary completion date: Jan 2024 ➔ Mar 2023

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hepatology

A Study of JNJ-75220795 in Japanese Participants (clinicaltrials.gov) - P1 | N=9 | Terminated | Sponsor: Janssen Pharmaceutical K.K. | N=18 ➔ 9 | Trial completion date: Jun 2023 ➔ Feb 2023 | Recruiting ➔ Terminated; Business Judgement

Enrollment change • Trial completion date • Trial termination

A Single and Multiple Ascending Dose Study of Subcutaneously Administered JNJ-75220795 (clinicaltrials.gov) - P1 | N=112 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Nov 2022 ➔ Jan 2024

Trial primary completion date • Hepatology

Arrowhead Pharmaceuticals Gains Full Rights to NASH Candidate ARO-PNPLA3 with Promising Phase 1 Results (Arrowhead Press Release) - "'The vast human genetic data in support of this target are compelling and supported by a strong pathophysiologic mechanistic understanding,' said Rohit Loomba, M.D...'The Phase 1 data on ARO-PNPLA3 are extremely encouraging and I look forward to seeing this molecule progress to a later stage clinical study.'"

Media quote

"$JNJ returning ARO-PNPLA3 (JNJ-75220795) to $ARWR follows collapse of the companies' deal in hep B. See @JacobPlieth's previous take https://t.co/mAOD32p3FP" (,@ByMadeleineA)

Hepatitis B • PNPLA3

A Study of JNJ-75220795 in Japanese Participants (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Janssen Pharmaceutical K.K. | N=27 ➔ 18

Enrollment change

A Study of JNJ-75220795 in Japanese Participants (clinicaltrials.gov) - P1 | N=27 | Recruiting | Sponsor: Janssen Pharmaceutical K.K. | Trial completion date: Nov 2022 ➔ Jun 2023

Trial completion date

A Single and Multiple Ascending Dose Study of Subcutaneously Administered JNJ-75220795 (clinicaltrials.gov) - P1; N=112; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Nov 2022 ➔ Jan 2024

Clinical • Trial completion date • Hepatology

A Study of JNJ-75220795 in Japanese Participants (clinicaltrials.gov) - P1; N=27; Recruiting; Sponsor: Janssen Pharmaceutical K.K.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • MRI

"$ARWR Arrowhead Announces JNJ-75220795 in Development for NASH https://t.co/z9TeFHEOJO" (,@stock_titan)

Hepatology • Non-alcoholic Steatohepatitis

A Study of JNJ-75220795 in Japanese Participants (clinicaltrials.gov) - P1; N=27; Not yet recruiting; Sponsor: Janssen Pharmaceutical K.K.

Clinical • New P1 trial • MRI

A Single and Multiple Ascending Dose Study of Subcutaneously Administered JNJ-75220795 (clinicaltrials.gov) - P1; N=88; Recruiting; Sponsor: Janssen Research & Development, LLC; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Hepatology

A Single and Multiple Ascending Dose Study of Subcutaneously Administered JNJ-75220795 (clinicaltrials.gov) - P1; N=88; Not yet recruiting; Sponsor: Janssen Research & Development, LLC

New P1 trial • Hepatology