Sionna expands its pipeline of CFTR modulators with AbbVie’s assets
Company has acquired rights to develop, market three compounds
Sionna Therapeutics has gained the rights to develop and market three of AbbVie’s clinical-stage compounds, a move that expands the company’s pipeline of small molecules that are designed to restore the function of the CFTR protein, which is faulty or absent in cystic fibrosis (CF).
The compounds include galicaftor (ABBV-2222) and navocaftor (ABBV-3067), which have been tested in combination or — in the case of navocaftor — alone in a Phase 2 clinical study (NCT03969888), and ABBV-2851, which is now in Phase 1 of clinical testing.
CF occurs due to mutations in the CFTR gene that result in thick mucus building up in the lungs and other organs. The most common mutation, F508del, maps to a region of CFTR called NBD1. When mutated, this region becomes unstable, causing the protein to misfold.
Sionna plans to select licensed compounds to pair with one of its own small molecules, which are designed to stabilize NBD1 and prevent CFTR from folding into the incorrect shape that affects how it functions. This should fully restore the protein’s function.
“Our strategy is to build a CF franchise anchored on our novel correctors that stabilize the NBD1 of the CFTR protein,” Mike Cloonan, president and CEO of Sionna, said in a company press release that announced the license agreement.
Earlier this year, Sionna raised $182 million to advance the development of its NBD1 stabilizers. Two second-generation NBD1 stabilizers, called SION-451 and SION-719, are expected to move into Phase 1 clinical testing this year.
Improved CFTR function by stabilizing NBD1 region
Despite CFTR modulators being available, many people with CF still don’t achieve normal CFTR function. The new approach of stabilizing the NBD1 region, combined with CFTR correctors and potentiators, could provide more effective therapeutic options.
“With the CF therapies available today, approximately two-thirds of people still do not achieve normal CFTR function,” said Patrick Flume, MD, professor of medicine and pediatrics at the Medical University of South Carolina in Charleston, and clinical advisor to Sionna.
In a human bronchial epithelial cell model of the airways, a test that helps predict how well a medication may work in CF, combining an NBD1 stabilizer with AbbVie’s compounds outperformed the current standard of care, with some combinations achieving normal CFTR function.
Earlier preclinical work has shown the company’s first candidate, SION-638, helped the faulty CFTR protein reach the cell surface, where it normally acts to control the flow of salt and water, and how thick mucus is.
SION-638, which is being tested in a Phase 1 clinical study, performed even better when combined with the approved CFTR modulators elexacaftor, tezacaftor, and ivacaftor, which can be found alone or in different combinations in Vertex Pharmaceuticals’ Kalydeco, Orkambi, Symdeko, and Trikafta.
In a Phase 2 clinical study with 78 adults with CF, an oral combination of ABBV-2222 plus ABBV-3067 appeared to perform about as well as approved dual combinations at improving lung function and lowering sweat chloride levels, which are abnormally high in CF.
“Combining NBD1 stabilizers with just one complementary CFTR modulator gives us the potential to deliver superior efficacy over the current standard of care,” Cloonan said. The agreement with AbbVie will enable the company to set “multiple options,” he said.
Under the terms of the agreement, AbbVie will receive an upfront payment and will be eligible to receive payments on development milestones along with royalties on future sales, if any of the compounds are approved.
As with SION-638, Sionna plans to complete its Phase 1 study of SION-109 in healthy volunteers this year. SION-109 works via a different mechanism, by targeting the interface between NBD1 and another region called ICL4. The company is considering its use in a dual combination with an NBD1 stabilizer.
Flume calls it “encouraging to see that NBD1 modulators combined with the three licensed programs from AbbVie have the potential for superior efficacy compared to standard of care … I look forward to seeing these novel double combinations advanced in clinical development.”
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