IPF trial of RNAi therapy starts dosing patients, healthy volunteers

Trial testing safety, efficacy of Arrowhead's novel candidate ARO-MMP7

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by Steve Bryson, PhD |

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Dosing has begun in a clinical trial evaluating ARO-MMP7, Arrowhead Pharmaceuticals’ investigational RNA interference (RNAi) therapy for idiopathic pulmonary fibrosis (IPF).

Expecting to enroll up to 56 healthy volunteers and 21 adults with IPF, the Phase 1/2a trial (NCT05537025) — dubbed AROMMP7-1001 — will evaluate the therapy’s safety, tolerability, and pharmacological properties. It also will assess the impact of the RNAi therapy on lung function.

The trial is testing ARO-MMP7 in single and multiple increasing doses.

“ARO-MMP7 offers a novel approach to potentially address the significant unmet medical need that exists for patients with IPF, who experience progressive decline of lung function, despite currently available therapies,” James Hamilton, MD, Arrowhead’s chief of discovery and translational medicine,  said in a press release.

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In IPF, progressive scarring (fibrosis) in the lungs involves the ongoing overproduction of the extracellular matrix (ECM) — the network of molecules that supports and surrounds cells. Matrix metalloproteinase-7 (MMP7) is an enzyme that helps maintain ECM balance, which is normally tightly controlled.

MMP7 is thought to participate in fibrosis in IPF because the MMP7 gene that encodes the enzyme is overactive in IPF patients. In addition, some studies have demonstrated that animal models with an MMP7 deficiency are relatively protected from induced lung fibrosis.

IPF patients also have high levels of the enzyme in their bloodstream, making it a well-established biomarker to identify those with fibrotic lung disease and accurately predict their outcomes.

ARO-MMP7, delivered by inhalation, is an RNA-based therapeutic designed to selectively target the MMP7 gene and suppress, or interfere, with the enzyme’s production. Its goal is to lower MMP7 levels, slow or halt the progression of lung fibrosis, and improve lung function.

Eligible healthy participants must be adult non-smokers with lung and heart test results in the normal range at trial screening. IPF patients must be 45 or older, have stable disease, and not take any other antifibrotic therapy during the study.

All participants will be randomly assigned to receive single or multiple doses of ARO-MMP7, or placebo, both given by inhalation.

ARO-MMP7 offers a novel approach to potentially address the significant unmet medical need that exists for patients with IPF, who experience progressive decline of lung function, despite currently available therapies.

The trial’s primary goal is to assess the therapy’s safety, as assessed by the number of participants who experience treatment-emergent adverse events (side effects). Such side effects will be recorded until the end of the study (up to 85 days) or until MMP7 levels in sputum are at least 70% higher than they were at the study’s start, whichever occurs first.

Tests examining how the medicine moves into, through, and out of the body — called pharmacokinetics — and its impact on the body, or pharmacodynamics, also will be conducted.

Also being performed will be lung function tests to assess changes in forced expiratory volume (FEV1) and forced vital capacity (FVC) over the course of the study. FEV1 measures the amount of air forcibly exhaled in one second, while FVC measures the total amount of air exhaled after a deep breath.

Diffusing capacity for carbon monoxide (DLCO) — a parameter that measures how well lungs are able to transfer inhaled gas into the bloodstream — also will be assessed.

The study is slated for completion in August 2024.

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