Sionna to Test Small Molecules in Lab, Trials as Treatments for CF

Phase 1 trial now testing safety of SION-638 in healthy volunteers

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Sionna Therapeutics is forging ahead in the new year with its preclinical and clinical programs aimed at developing small molecules — such as SION-638 — as possible treatments for cystic fibrosis (CF).

An ongoing Phase 1 trial, now enrolling participants, is testing SION-638 in healthy volunteers. Dosing began shortly after the U.S. Food and Drug Administration (FDA) cleared the company to test the investigational therapy in humans.

The study’s goal is to evaluate both the safety of SION-638 and its pharmacokinetics — that is, how it moves into, through, and out of the body. Data are expected in the second half of this year,

“We formed Sionna to deliver therapies that could be transformational for people living with CF,” Mike Cloonan, Sionna’s president and CEO, said in a press release.

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SION-638, an oral small molecule, is leading Sionna’s pipeline.

That pipeline includes a number of other small molecules that — like SION-638 — have been designed to target a region of the CFTR protein called NBD1.

This is the region where occurs a change that’s blueprinted in the CFTR gene as F508del, the most common of many mutations known to cause CF.

SION-638 improves CFTR’s stability and functionality by binding to the NBD1 region with high affinity. The potential treatment also was shown to promote the transport of mutated CFTR protein to the cell’s surface, where it acts to control the flow of water and chloride ions.

The molecule’s effect was boosted when tested alongside the approved CFTR modulators elexacaftor, tezacaftor, and ivacaftor.

“Data continue to reinforce the opportunity to improve CFTR function for modulator-eligible patients,” Cloonan said, adding,  “Modulators that provide normal CFTR function could have a significant impact on clinical outcomes for people with CF.”

The company also is placing its bets on the development of small molecules that target complementary mechanisms other than the NBD1 region.

That’s the case with SION-109, a small molecule designed to target the interface between NBD1 and another region of the CFTR protein called ICL4.

Plans are underway to file an Investigational New Drug (IND) application with the FDA for SION-109 in the first half of 2023. An IND apllication is a key step toward obtaining regulatory clearance to conduct a clinical trial.

Sionna also has designated two more small molecules that target the NBD1 region as development candidates. They are SION-719 and SION-451, and they have been shown promise to fully correct the faulty CFTR protein in lab-grown airway cells when given in combination with a small molecule that targets either ICL4 or yet another region of the CFTR protein called TMD1.

These two molecules also were shown to be safe in two species.

“We are progressing with our lead candidate and multiple Series 2 modulators targeting NBD1, as well as complementary mechanisms, to target multiple domains of CFTR,” Cloonan said. “This strategy will support future development of proprietary combination treatments with the potential to achieve full CFTR correction.”

Cloonan will share an overview of how far the company has come at this year’s J.P. Morgan’s Healthcare Conference on January 10 in San Francisco, California.

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