Arrowhead Seeks Clinical Trials for ALS, Muscular Dystrophy RNAi Therapies

Arrowhead Pharmaceuticals is gearing up to advance its first RNA interference (RNAi) therapies targeting neurodegenerative diseases into clinical trials, with clinical application submissions for SOD1-amyotrophic lateral sclerosis (ALS) and facioscapulohumeral muscular dystrophy (FSHD) therapies in the last couple of months.^1,2

“FSHD is a debilitating disease caused by the aberrant expression of the DUX4 gene in skeletal muscle. ARO-DUX4 engages the RNA interference pathway to selectively inhibit DUX4 expression and is a promising strategy to reverse the downstream myotoxicity of DUX4 and potentially enable stabilization or improvement in muscle function in patients. We believe ARO-DUX4 has the potential to be an impactful new medicine for patients,” Chris Anzalone, PhD, president and chief executive officer, Arrowhead, said in a statement.¹ “As previously communicated, we are in discussions with external parties regarding the most appropriate path for the clinical development and commercialization of ARO-DUX4 with the goal of bringing this promising product candidate to patients in need as expeditiously as possible.”

Arrowhead submitted the application for ARO-DUX4 to the New Zealand Medicines and Medical Devices Safety Authority for review by the Standing Committee on Therapeutic Trials in July 2023.¹ If approved, the company plans to initiate the phase 1/2a dose-escalating ARODUX4-1001 trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-DUX4 in up to 52 adult patients with FSHD type 1.

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ARO-DUX4 is an investigational RNAi therapeutic designed to reduce expression of the human double homeobox 4 (DUX4) gene, overexpression of which is myotoxic and can lead to muscle degeneration in patients with FSHD. It is Arrowhead’s first clinical candidate using its proprietary Targeted RNAi Molecule (TRiMTM) platform to target genes in skeletal muscle.

In June 2023, Arrowhead submitted the application for ARO-SOD1 to an ethics committee in compliance with the Clinical Trial Notification process of the Australian Department of Health and Ageing, Therapeutic Goods Administration.² If approved, the company plans to initiate the phase 1 dose-escalating, placebo-controlled AROSOD1-1001 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-SOD1 in up to 24 adult patients with ALS believed to be cause by superoxide dismutase 1 (SOD1) mutations.

ARO-SOD1 is also an investigational RNAi therapeutic designed to reduce expression of SOD1 in the central nervous system (CNS) and is Arrowhead’s first therapeutic candidate developed with the TRiMTM platform designed for delivery to the CNS.

“The ARO-SOD1 program entering clinical studies represents the further expansion of our proprietary TRiMTM platform, which now includes product candidates addressing a multitude of diverse disease areas that target the liver, lung, muscle, and CNS,” Anzalone said in a previous statement.²

REFERENCES

1. Arrowhead Pharmaceuticals files for regulatory clearance to initiate a phase 1/2 study of ARO-DUX4 for facioscapulohumeral muscular dystrophy. News release. Arrowhead Pharmaceuticals. July 17, 2023. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-files-regulatory-clearance-initiate-0 
2. Arrowhead Pharmaceuticals files for regulatory clearance to initiate a phase 1 study of ARO-SOD1. News release. Arrowhead Pharmaceuticals. June 27, 2023. https://mjhassoc.sharepoint.com/sites/GeneTherapyLive/_layouts/15/doc.aspx?sourcedoc={932a81e2-ca05-4bde-bd6f-3a3e9a1efc77}&action=edit