Elexacaftor/Ivacaftor/Tezacaftor

Sionna Therapeutics has axed a cystic fibrosis add-on program after flunking a phase 2 trial, eliminating a would-be challenger to Vertex Pharmaceuticals’ empire. The biotech plans to “take actions to preserve capital while evaluating next steps.” Massachusetts-based Sionna has emerged as a potential threat to Vertex in recent years, tapping private and public investors to fund development of internal candidates and assets licensed from AbbVie. The phase 2a PreciSION CF study represented a key test of Sionna’s aspirations to disrupt the cystic fibrosis market by stabilizing NBD1 to improve on the efficacy of Vertex’s drugs. The trial enrolled 15 adults with cystic fibrosis homozygous for F508del on a stable dose of Vertex’s Trikafta. Participants received one of Sionna’s NBD1 stabilizers, SION-719, or placebo on top of Trikafta. Patients originally on SION-719 switched to placebo, and vice versa, later in the trial. Sionna linked SION-719 to a mean placebo-adjusted reduction in sweat chloride of 1.0 mmol/L. The level of activity wasn’t statistically significant, nor was it clinically meaningful based on expectations set by the biotech and experts before the readout. The company had set (PDF) itself the goal of achieving a 10 mmol/L improvement in sweat chloride. Cystic fibrosis experts set the bar lower, TD Cowen analysts said in a note to investors last month, but still wanted to see an improvement of at least 5 to 7 mmol/L. Such a change would be clinically meaningful and support further development, the experts said, but Sionna fell well short of even that lower target. Sionna highlighted potential confounders in its phase 2 data, including higher-than-anticipated levels of variability in individual sweat chloride levels and differences in Trikafta exposure levels between the SION-719 and placebo periods. But while the biotech is assessing the impact of such factors on the data, it has already decided to end development of SION-719 as an add-on to standard of care. When the markets opened Monday, investors sent Sionna’s share price down 90% to $4.85 from a Friday closing price of $50.59. Vertex’s stock went in the opposite direction, climbing a more modest 6% to $525. BMO analysts framed Sionna’s failure as evidence that Vertex’s “competitive moat remains deep and wide.” “Removal of Sionna as [a] key competitor represents a meaningful positive for Vertex, reaffirming the company's dominance in cystic fibrosis,” the analysts said in a note to investors. “With Sionna failing to show meaningful improvement in sweat chloride with the addition of its NBD1 stabilizer, we see [a] significantly reduced threat to Vertex’s existing [cystic fibrosis] franchise.” Sionna shared news of the phase 2 failure, along with data from a phase 1 trial of its other drug candidates in healthy volunteers. Participants received the NBD1 stabilizer SION-451 in combination with either SION-2222 or SION-109, correctors that target CFTR. Target exposures exceeded the level Sionna set before the PreciSION CF readout, and SION-451 plus SION-2222 emerged as the preferred combination. The biotech is now “actively analyzing the phase 2a data and our translational framework to help assess the potential profile and next steps for ‘451 plus ‘2222 dual combination,” Sionna CEO Mike Cloonan said on a conference call with investors to discuss the data. Given the phase 2a failure, the path forward for SION-451 “remains less clear,” BMO analysts said.