ARCT-032, therapy for all with CF, showing safety in Phase 1 trial

Inhalation treatment aims to bring healthy CFTR protein to patients' lungs

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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ARCT-032, a messenger RNA inhalation treatment being developed by Arcturus Therapeutics to restore a working protein in the lungs of cystic fibrosis (CF) patients, showed safety in healthy adults and early signs of potential efficacy in a small group of patients taking part in a Phase 1/1b clinical trial.

“We are pleased … that single doses at all dose levels in healthy volunteers and two doses in the first four CF participants were safe and well tolerated with no serious adverse events,” Juergen Froehlich, MD, chief medical officer of Arcturus, said in a company press release.

While only a small number of patients have been treated with ARCT-032 in the ongoing Phase 1/1b trial (NCT05712538) taking place in New Zealand, a trend toward better lung function was reported in these four adults after two inhaled doses.

“It is encouraging to see favorable lung function improvements,” Froehlich said. Up to an additional four CF patients are expected to be treated and followed in the study’s second part.

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Larger, multiple-dose trial of ARCT-032 in CF patients may follow

The company is looking forward “to completing the Phase 1b trial shortly and to evaluate the further potential for lung function improvement of treatment with ARCT-032 in people with CF in a larger, multiple-dose clinical study,” Froehlich added.

Trial findings were delivered by David Geller, MD, vice president of pulmonary and rare diseases at Arcturus, in the presentation “Inhaled LUNAR®-CFTR mRNA (ARCT-032) is safe and well-tolerated: A Phase 1 study,” given at the 47th European Cystic Fibrosis Conference, which took place June 5-8 in Glasgow, Scotland.

CF is caused by mutations in the CFTR gene, which codes for a protein that helps maintain the right balance of fluid in the airways and other body surfaces. When the protein is faulty or not made at all, thick mucus builds to cause respiratory and other disease symptoms.

When producing a protein, cells do not use DNA directly. Instead, its genetic instructions are copied to a molecule called messenger RNA (mRNA), which carries the instructions from the gene to the protein-producing machinery in cells.

ARCT-032, also known as LUNAR-CFTR, is encased in tiny, fat-like particles to deliver healthy copies of CFTR mRNA to cells in the lungs, allowing them to produce their own protein. This approach has the potential to treat all patients regardless of the CF-causing mutations they carry.

Preclinical studies in a ferret model of CF showed that ARCT-032, administered directly into the animals’ trachea (windpipe), delivered its mRNA payload to cells in the lungs, where it improved mucus clearance in the airways.

Trend toward better lung function seen in four treated patients

These preclinical data supported the launch of the trial’s Phase 1 part testing ARCT-032’s safety and tolerability against a placebo in 32 healthy adults. The therapy was inhaled using a nebulizer in single ascending doses ranging from 3 to 27 mg.

Reported side effects in these adults “were generally considered mild” with “no clinically significant findings,” the researchers wrote in an abstract to the presentation. They included transient fever-like reactions, such as elevated temperature associated with headache, muscle pain, back pain, or nausea.

A review of safety data favored moving to the trial’s 1b phase, testing ARCT-032’s safety and tolerability in up to eight adults with CF. All enrolled patients are treated with two doses of ARCT-032 inhaled via a nebulizer about two days apart, and then followed for four weeks. Exploratory study measures include changes in lung function and mucus clearance.

Of the four treated and evaluated patients to date, one — a 40-year-old woman — carried two copies of a class 1 mutation that results in little to no CFTR protein being produced. The other three — two women and one man, ages 24 to 43 — had at least one copy of the disease’s most common F508del mutation and were being treated with Trikafta (elexacaftor/tezacaftor/ivacaftor).

Interim data revealed an early trend toward better lung function, the company reported. The patients’ forced expiratory volume in one second, a measure of how much air can be quickly and forcefully exhaled, increased on average by 5.8% after eight days, or five days after their second dose.

As with healthy adults, the treatment was seen to be generally safe in patients with no serious adverse events reported.

ARCT-032 has been given both a rare pediatric disease and orphan drug designation by the U.S. Food and Drug Administration, and it recently received orphan designation in the European Union. These designations are designed to support and speed the development of treatments for rare diseases.