SpliSense’s SPL84 shows good safety profile in 1st clinical trial in CF

CF treatment candidate targets specific mutation called 3849+10 kb C-to-T

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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SPL84, an experimental treatment being developed for people with cystic fibrosis (CF) that’s caused by a specific mutation, showed a good safety profile in a first clinical trial in healthy volunteers, according to its developer, SpliSense.

Spurred by these positive results, SpliSense now is planning a Phase 2 clinical trial to test SPL84 in CF patients who carry this mutation, known as 3849+10 kb C-to-T. The company expects to launch the new trial early in 2024.

“We are extremely excited with the safety profile of SPL84 as demonstrated in this Phase 1 study, paving the way to our Phase 2 efficacy study, that we plan to initiate in the first half of next year,” Gili Hart, PhD, SpliSense’s CEO, said in a company press release.

To date, there is no approved CF treatment specifically for patients carrying the 3849 +10 Kb C->T mutation, Hart noted.

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CF is caused by mutations in the gene CFTR, which provides instructions for making a protein with the same name. A lack of functional CFTR protein leads to the production of abnormally thick and sticky mucus, which causes most CF symptoms.

The 3849+10 kb C-to-T mutation is a type of class 1 CF-causing mutation called a splicing mutation. When the CFTR gene is used, or read, to make CFTR protein, the gene’s code is copied from a cell’s DNA into a temporary molecule called messenger RNA, which then is used as a template to make the protein.

The CFTR gene’s messenger RNA normally undergoes a series of modifications, called RNA splicing, to form a mature protein-coding sequence. The 3849+10 kb C-to-T mutation causes problems with this process, and as a consequence, RNA from a CFTR gene carrying this mutation cannot be used to produce working CFTR protein.

Because the 3849+10 kb C-to-T mutation prevents the production of CFTR protein, people carrying the mutation generally don’t respond to treatment with CFTR modulators. Those are medications that can work to boost the protein’s functionality in people with specific mutations. It is estimated that more than 1,400 people worldwide carry this specific mutation.

“Although currently available treatments managed to significantly increase life expectancy in the past few decades, they are focused on symptomatic treatments and there is still a significant unmet medical need for a CF cure. In particular CF patients carrying the 3849 +10 Kb C->T mutation have no specific approved treatment,” Hart said.

SPL84, previously called SPL84-23, is an RNA-based therapy called an antisense oligonucleotide, or ASO, which is designed to correct the splicing deficit caused by the 3849+10 kb C-to-T mutation. By correcting splicing, the therapy aims to allow cells to make a working CFTR protein. Experiments done in laboratory models have shown that it can boost CFTR activity as designed in cells carrying the mutation.

“Our lead product, SPL84, managed to completely restore CFTR activity [in] the CF gold standard pharmacological model,” Hart said.

SPL84 is administered by inhaling it into the lungs. A team led by scientists at SpliSense recently published data showing that the therapy is widely distributed in the lungs in mouse and monkey models, and that the medication is stable in CF mucus. That study, “Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients,” was published in Nucleic Acid Therapeutics

With the results announced today supporting [SPL84’s] safety in humans, we hope to be able to deliver in the foreseeable future a life-changing treatment for CF patients.

The first Phase 1 trial, launched late last year, enrolled 32 healthy male volunteers. Participants each received a single administration of SPL84 at one of four doses — 20, 40, 80, or 160 mg — or a placebo.

The study’s main goal was to evaluate SPL84’s safety, and results were positive: there were no serious side effects reported, nor were there any noteworthy changes in laboratory findings associated with the experimental treatment, as well as no changes significant in pulmonary function.

“With the results announced today supporting [SPL84’s] safety in humans, we hope to be able to deliver in the foreseeable future a life-changing treatment for CF patients,” Hart said.

The experimental therapy has been granted orphan drug status in both the U.S. and Europe. That designation is designed to speed the development of treatments for rare diseases, defined in the U.S. as affecting fewer than 200,000 people and in the European Union as being diagnosed in fewer than 1 in 2,000 individuals.