Phase 2 trial possible in ARCT-032, inhaled mRNA therapy for CF

Ascending dose study sought for patients not helped by CFTR modulators

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by Steve Bryson, PhD |

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Arcturus Therapeutics plans to soon submit an application to the U.S. Food and Drug Administration (FDA) seeking permission to begin testing multiple ascending doses of ARCT-032, an inhaled experimental treatment for cystic fibrosis (CF).

The planned Phase 2 study, supported by promising safety and preliminary efficacy data from a Phase 1/1b trial, is designed to identify a safe and effective dose for further trials in people with CF who do not benefit from CFTR modulators.

Data from the Phase 1/1b study “are supportive of expanding our clinical program to the U.S. and other regions with a Phase 2 multiple ascending dose protocol, and I look forward to a successful conduct and outcome of this planned study,” Juergen Froehlich, MD, chief medical officer of Arcturus, said in a company press release.

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mRNA therapy aims to equip cells to produce their own CFTR protein

Cystic fibrosis is due to mutations in the CFTR gene that disrupt the production or function of the CFTR protein. As a result, thick and sticky mucus builds in the lungs and other organs.

CFTR modulators are a class of medicines designed to increase the processing and/or function of the CFTR protein. However, these therapies don’t work for all types of CFTR gene mutations, particularly class 1 mutations that result in little or no CFTR protein being made.

ARCT-032 is an inhaled medicine with the potential to benefit patients who don’t respond to or can’t use CFTR modulators, which, according to Arcturus, encompasses about 15% of all with CF.

The therapy contains the messenger RNA (mRNA) molecule, a template copied from DNA with information for making the CFTR protein. Delivered to the lungs using tiny, aerosolized fat-like particles, ARCT-032 aims to provide cells with the means to produce their own CFTR protein.

“CFTR replacement using mRNA therapeutics is an area of significant medical interest, as it may benefit null [no CFTR production] patients and potentially many other CF patients,” Froehlich said.

In preclinical studies using a CF ferret model, ARCT-032 delivered its mRNA payload directly to cells in the lungs, where it helped to clear mucus from the airways.

Based on these findings, Arcturus launched a Phase 1/1b study (NCT05712538) that first tested ARCT-032’s safety and tolerability against a placebo in 32 healthy adults. Using a nebulizer, participants inhaled the therapy in single ascending doses ranging from 3 to 27 mg.

Reported adverse events were generally mild, and included transient fever-like reactions, such as an elevated temperature with headache, back pain, muscle pain, or nausea.

Trend toward healthier lungs being seen in CF patients in Phase 1b study

After a review of safety data, the trial then enrolled seven adults with CF, most on CFTR modulators and one with class I mutations and poor lung function. The seventh and final participant is to be dosed soon, the company noted in its release.

All those enrolled are treated with two doses of ARCT-032, given about two days apart, and followed for four weeks.

To date, no serious side effects have been reported in any trial participant, and no fever-like reactions have been seen within the target dose range of the planned Phase 2 study.

Interim data showed an early trend toward better lung function, with an average increase of 5.8% five days after the second dose. Lung function in the patient with class 1 mutations improved by 4% eight days after receiving two administrations, with no fever-like reactions, Arcturus reported.

“The safety profile of ARCT-032 observed in Phase 1 and after two administrations in Phase 1b for patients dosed to date, including the trend of lung function improvement in the Class I participant, is encouraging,” Froehlich noted.

ARCT-032 was granted rare pediatric disease and orphan drug designations by the FDA, and orphan status in the European Union as a potential CF treatment. These designations intend to support and speed the development of therapies for rare diseases.