First Clinical Trial Begins for RNA-based Therapy SPL84 for CF

SpliSense treatment would be first for certain CF splicing mutation

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A person in a baseball cap speaks through a megaphone to make an announcement.

SpliSense has launched a Phase 1/2 clinical trial to test SPL84, its inhaled treatment candidate for cystic fibrosis (CF) patients carrying a common disease-causing splicing mutation.

As of now, no specific treatment is available for people with CF who carry this particular mutation. Called 3849+10 kb C-to-T, it affects more than 1,400 people worldwide.

“Currently available treatments focus on treating the symptoms of the disease, while we address the underlying genetic cause of the disease,” Gili Hart, PhD, CEO of SpliSense, said in a company press release announcing the trial’s launch.

Hart said her company is “offering hope of restoring the defective protein and generating adequate lung function in patients suffering from CF with the benefit of an easy-to-use and less frequent treatment approach.”

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First-in-human test of CF treatment

CF is caused by mutations in the gene CFTR, which codes for a protein of the same name that works as a channel to control the flow of water and salts in and out of cells. A CF-causing mutation leads to a defective CFTR protein.

Certain mutations affect the splicing process of CFTR’s messenger RNA molecule — whereby gene pieces are either cut out or pieced together, as in a puzzle, to produce a working protein. These mutations are generally not very responsive to CFTR modulators, which act on the CFTR protein, not on the gene.

In particular, the 3849+10 kb C-to-T splicing mutation leads to the degradation of CFTR’s mRNA molecules, and to the production of a shorter, non-functional protein.

SpliSense’s experimental therapy was designed to address such disease-causing mutations.

SPL84 is an antisense oligonucleotide (ASO), a type of molecule that targets specific mRNA sequences and masks the mutated region.

The ASO is administered through inhalation, directly reaching the lungs cells where they are taken up. Once inside the cells, the ASO drives the production of a corrected CFTR mRNA molecule and a fully working version of the CFTR protein.

This first clinical study aims to assess SPL84’s safety, tolerability, and pharmacokinetics — its movement into, through, and out of the body. It also will evaluate the treatment’s preliminary effectiveness.

The study contains two parts. In part one, healthy volunteers will be randomly assigned to a placebo or single ascending doses of SPL84.

In part two, CF patients with the 3849+10 kb C-to-T splicing mutation will receive multiple ascending doses of the therapy or a placebo. SPL84 will be administrated on a weekly or every-other-week regimen.

The clinical study comes on the heels of promising early data showing that SPL84 restored the activity of the faulty CFTR protein in lab-grown cells from a CF patient carrying the 3849+10 kb C-to-T splicing mutation in both CFTR gene copies.

Also, in cells from patients with the splicing mutation in one gene copy and another mutation in the other copy, SPL84 restored CFTR protein activity to levels closer to those in healthy people carrying only one CFTR mutation.

“Our lead product, SPL84, has shown to have completely restored CFTR activity in the CF gold standard pharmacological model, suggesting potential cure for these patients,” Hart said.

SPL84 was granted orphan drug status by the U.S. Food and Drug Administration and the European Medicines Agency. This designation aims to accelerate SPL84’s clinical development and review by providing regulatory support and financial benefits.

The company’s CF program contains two other ASOs, SPL23 and SPL16, to potentially treat CF caused by other mutations. Additionally, SpliSense is developing therapies for other lung diseases, such as idiopathic pulmonary fibrosis.

“This program is our first-in-human and will serve as proof of concept of our pulmonary platform for our additional promising programs, including muco-obstructive diseases and IPF, the latter of which is expected to enter the clinic next year,” Hart said.

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