Phase 1 trial of CM001, ‘molecular prosthetic’ for all with CF, underway

Therapy to create artificial ion channel in cells independent of CFTR protein

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Dosing has begun in a Phase 1 clinical trial of CM001, an inhaled treatment designed to act as a molecular prosthetic in cells and treat cystic fibrosis (CF) regardless of a patient’s underlying mutation, Cystetic Medicines, the therapy’s developer, announced.

Most immediately, the company expects that CM001 may be an effective option for the roughly 1 in 10 CF patients whose disease-causing mutations make them ineligible for treatment with CFTR modulators.

“The initiation of our Phase 1 trial for CM001 represents an important step forward in our mission to find a treatment for everyone with CF, especially the final 10 percent of people with CF who cannot benefit from CFTR modulators,” Martin Burke, MD, PhD, co-founder of Cystetic, said in a company press release.

The trial, taking place in New Zealand, is testing the safety, tolerability, and pharmacological properties of a dry powder formulation of CM001 administered using a portable inhaler.  Single-ascending, followed by multiple-ascending, doses of the therapy are being tried in healthy volunteers with plans to begin testing in CF patients later this year, Cystetic stated. Results are expected in 2024.

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CF is caused by mutations in the gene that provides instructions for making the protein CFTR. This protein normally sits on the surface of cells and acts like a gated channel: by opening or closing the ‘gate,’ the protein allows chloride ions (salt molecules) to flow in and out of the cell.

Under normal circumstances, the flow of salts through the CFTR protein helps the body to produce wet, slippery mucus. But with CF, the protein does not work as it should and causes mucus to be abnormally thick and sticky, building up in organs to ultimately drive most disease symptoms.

Most people with CF have mutations that allow the production of a CFTR protein that is unstable or dysfunctional. CFTR modulator therapies work to bind to the defective protein and help restore its function in patients with eligible mutations. However, these therapies are of no benefit for roughly 10% of patients with little to no CFTR protein.

CM001 consists of an antifungal called amphotericin B, a naturally occurring small molecule that forms ion channels in cells to work as a molecular prosthetic, Cystetic reports on a company webpage. Just like a prosthetic leg is used to replace the actions of a missing limb, this molecular prosthetic is inserted into cells to perform functions usually done by the CFTR protein. Theoretically, this could help to restore more normal mucus production and ease disease symptoms, regardless of the patient’s specific mutations.

Inhaled formulation allows for ‘targeted delivery’ to person’s lungs

“The concept of molecular prosthetics has the potential to alter the treatment landscape for cystic fibrosis in a profound way,” said Jeffry Weers, Cystetic’s chief technology officer. “Our team is particularly optimistic with regard to the proprietary inhaled formulation CM001, which allows for efficient targeted delivery directly to the lungs, thereby potentially avoiding side effects and enabling optimal dosing regimens.”

“We’re hopeful that … this could be a first opportunity to regain ion-channel-like function in the airway and thereby address CF at its roots,” Burke said in a separate press release from the University of Illinois Urbana-Champaign, where the potential treatment was pioneered.

The molecular prosthesis approach has shown promise in preclinical studies, which were funded in part by the nonprofit organization Emily’s Entourage.

“I am profoundly proud and excited to see that the strategic investment made by Emily’s Entourage to enable key early-stage research into the molecular prosthetics approach has yielded this promising new drug candidate that might benefit everyone with CF, including those of us in the final 10 percent,” said Emily Kramer-Golinkoff, founder of Emily’s Entourage.

“Based on encouraging pre-clinical results and initial biomarker studies in the noses of people with CF not on modulators, we are excited about the potential for this molecular prosthetic approach to restore anion channel function in a way that is independent of CFTR,” said Burke, a chemistry professor at the university.

If trial results are positive, researchers hope that the molecular prosthesis approach might also be applied to diseases beyond CF.

“Cystic fibrosis is one of hundreds of diseases that currently remain incurable because they’re caused by loss of protein function,” Burke said. “The hope is that if we can succeed in CF, this molecular prosthetics approach could become a general way to treat diseases caused by loss of protein function.”