#NACFC2022 – SION-638 Restored CFTR Protein Function

Sionna Therapeutics' shares preclinical data about its lead pipeline product

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Note: This story was updated Nov. 9 to note that experiments done with Sionna’s CFTR modulators used a different investigational NBD1 stabilizer than SION-638.

SION-638, a first-in-class small molecule that is being developed by Sionna Therapeutics, improved the stability and functionality of the CFTR protein  in the most common type of mutation that causes cystic fibrosis (CF).

That’s according to preclinical data presented at the 2022 North American Cystic Fibrosis Conference (NACFC), taking place in Philadelphia, Pennsylvania, in the poster, “Novel Modulator Combinations Address the NBD1 Stability Defect Central to ΔF508-CFTR Dysfunction and Enable Full Correction.” The research was funded by Sionna and the CF Foundation, with prior support from Genzyme and Sanofi.

CF is caused by mutations in the CFTR protein, which functions like a gate on the surface of cells to control the movement of water and chloride in and out of the cell. The most common type of CF-causing mutation is called F508del. This mutation is present in about nine of every 10 CF patients.

The F508del mutation causes a particular region of the CFTR protein, called the first nucleotide-binding domain, or NBD1, to be unstable. As a result, the protein is rapidly degraded before it gets to the cell’s surface, so it’s unable to function. Sionna launched earlier this year with the aim of developing therapies to stabilize this protein region. SION-638, designed to be given orally, is the company’s lead product.

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“We know that full CFTR correction may require NBD1 stabilization, but for decades researchers have concluded that NBD1, as a target, is undruggable,” Greg Hurlbut, PhD, co-founder and senior vice president of discovery research at Sionna, said in a press release.

Mike Cloonan, Sionna’s president and CEO, added: “Currently available modulators increase the function of CFTR, providing eligible patients with clinical benefits, but do not enable most people with CF to achieve normal levels of CFTR function. We believe NBD1 is essential to normalize the function of CFTR.”

In the NACFC poster, Hurlbut presented data from biochemical tests that showed SION-638 is able to bind to the NBD1 domain of CFTR with high affinity, both in the wild-type (unmutated) version of the protein as well as in CFTR protein carrying the F508del mutation. Tests also showed that SION-638 increased the stability of the protein, both wild-type and F508del mutated.

“We have shown that our novel small molecules successfully bind to this important target in CF, potentially enabling full restoration of CFTR function in people with the [F508del] mutation,” Hurlbut said.

Results also showed that SION-638 treatment could increase the amount of F508del-mutated CFTR protein that is transported to the cell’s surface, where the protein needs to be in order to function correctly. With SION-638 alone, this effect was fairly modest, but the therapy showed synergistic effects with other approved therapies that act to stabilize CFTR protein function.

Specifically, co-treatment with SION-638, plus the CFTR modulators elexacaftor, tezacaftor, and ivacaftor led to levels of F508del CFTR on the cell surface similar or above to what’s seen for the wild-type protein. These three modulators make up the triple-combination therapy Trikafta, sold by Vertex, which is approved in the U.S. to treat patients with the F508del mutation (among other mutations) ages 6 and older.

Further experiments in an airway cell model harboring the F508del mutation (called CFHBE) showed that co-treatment with SION-638 and the components of Trikafta improved the mutated protein’s functionality beyond what is achieved with the Trikafta components only, with chloride ion transport restored to wild-type levels. Similar results were seen upon co-treatment with  a NBD1 stabilizer and investigational CFTR modulators developed by Sionna that complement NBD1 stabilization.

‘Multiple paths’

“What we have done here is we enabled multiple paths to full correction of [F508del] function so that we can take patients that have less than full function and give them full function, because we think that that’s important to their long-term health,” Hurlbut said in an interview with Cystic Fibrosis News Today. “So, that’s really our goal.”

“This represents, you know, over 12 years of work,” Hurlbut said. He added that Sionna has done multiple pharmacology and safety studies, also looking at formulations for dosing in humans. “We have very robust packages of data.”

Sionna is conducting tests that intend to support an investigational new drug application, which is a formal request in the U.S. to begin clinical testing of SION-638. Assuming all goes well, the company hopes to begin a Phase 1 trial in the first half of 2023.

“We are moving forward aggressively with our development programs and look forward to  submitting an Investigational New Drug (IND) application for our first NBD1 corrector, SION-638,” Cloonan said.

Note: The Cystic Fibrosis News Today team is providing in-depth coverage of the 2022 North American Cystic Fibrosis Conference (NACFC) Nov. 3–5. Go here to see the latest stories from the conference.

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