−Removed: We are a clinical-stage biopharmaceutical company on a mission to revolutionize the current treatment paradigm for cystic fibrosis (“CF”) patients by developing novel medicines that normalize the function of the cystic fibrosis transmembrane conductance regulator (“CFTR”) protein to deliver clinically meaningful benefit to CF patients.
+Added: We are a clinical-stage biopharmaceutical company on a mission to revolutionize the current treatment paradigm for cystic fibrosis (“CF”) by developing novel medicines that normalize the function of the cystic fibrosis transmembrane conductance regulator (“CFTR”) protein to deliver clinically meaningful benefit to people with CF.
CF is a progressive and life-threatening genetic disease caused by inherited mutations in the CFTR gene, which lead to insufficient CFTR function.
−Removed: While advances in the discovery and development of CFTR modulators have significantly improved the lives of people living with CF, at least two-thirds of patients on the current standard of care do not have normal CFTR function, defined as sweat chloride levels below 30 mmol/L.
−Removed: Patients with reduced CFTR function can experience debilitating multi-system complications that lead to significantly reduced quality of life and shorter life expectancy.
−Removed: Our goal is to deliver differentiated medicines for people living with CF that can restore their CFTR function to as close to normal as possible by directly stabilizing CFTR’s nucleotide-binding domain 1 (“NBD1”).
+Added: While advances in the discovery and development of CFTR modulators have significantly improved the lives of people with CF, at least two-thirds of patients on the current standard of care do not have normal CFTR function, defined as sweat chloride levels below 30 mmol/L.
+Added: Patients with reduced CFTR function can experience debilitating multi-system complications that lead to significantly impaired quality of life and shorter life expectancy.
+Added: Our goal is to deliver differentiated medicines for people with CF that can restore their CFTR function to as close to normal as possible by directly stabilizing CFTR’s nucleotide binding domain 1 (“NBD1”).
Despite having long been identified as a critical component for proper CFTR function, NBD1 has been considered “undruggable,” and none of the currently approved CF therapies directly stabilizes NBD1.
−Removed: Worldwide revenue for approved CFTR modulators was approximately $11 billion in 2024 and is expected to grow to $15 billion by 2029.
−Removed: Leveraging more than a decade of our co-founders’ research on NBD1, we are advancing a pipeline of small molecules engineered to correct the defects caused by the F508del genetic mutation, which resides in the NBD1 domain.
+Added: Leveraging more than a decade of our co-founders’ research on NBD1, we are advancing a pipeline of small molecules engineered to correct the defects caused by the F508del genetic mutation, the most common CFTR mutation, which occurs in the NBD1 domain.
Approximately 90% of people with CF carry at least one copy of the F508del genetic mutation.
−Removed: We believe stabilizing NBD1 is central to unlocking dramatic improvements in clinical outcomes and quality of life for CF patients.
−Removed: The NBD1 domain of the CFTR protein, as illustrated in Figure 1, plays a key role in the folding, stability and trafficking of CFTR to a cell’s surface, where it normally functions to conduct chloride and other ions and regulate the flow of water.
−Removed: Within the NBD1 domain, F508del severely destabilizes CFTR, preventing normal folding and trafficking of CFTR to a cell’s surface and impairing chloride channel function.
−Removed: We have employed biophysical, cell-based and virtual screening campaigns and extensive use of structural biology to guide the optimization of novel small molecule NBD1 stabilizers.
−Removed: CFTR Structure
−Removed: In February 2025, we disclosed interim data from two ongoing randomized, double-blinded, placebo-controlled Phase 1 clinical trials of our highly potent NBD1 stabilizers—SION-719 and SION-451—evaluating the safety, tolerability and PK of single ascending doses ("SAD") and multiple ascending doses ("MAD") of each product candidate in healthy subjects.
−Removed: As of the interim data cutoff date of January 14, 2025, five SAD cohorts
−Removed: and three MAD cohorts of SION-719 had been completed, with over 60 healthy subjects dosed, and six SAD cohorts and three MAD cohorts of SION-451 had been completed, with over 70 subjects dosed.
−Removed: Both SION-719 and SION-451 were generally well tolerated based on interim Phase 1 clinical data as of the interim data cutoff date.
−Removed: In these trials, at both single and multiple doses, SION-719 and SION-451 exposures were achieved that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit if SION-719 or SION-451 were administered as part of a dual combination or as an add-on to the standard of care (“SOC”).
−Removed: Since reporting interim data, we have completed dosing in the MAD part of the Phase 1 trial of SION-451, and the final MAD cohort of the SION-719 trial, evaluating 120 mg of SION-719, is planned.
−Removed: The additional completed cohorts evaluated 225 mg and 25 mg (fed) of SION-451 and 160 mg of SION-719, dosed twice daily ("BID") over 10 days.
−Removed: All MAD data, including from the recently completed cohorts, remain blinded to individual subject treatment assignment.
−Removed: Both compounds were generally well tolerated in these additional cohorts.
−Removed: The Part C of each trial, in which we are evaluating the effect of food on the PK of each product candidate and the bioequivalence of a table formulation, is ongoing.
−Removed: Topline data from the Phase 1 trials are expected in the first half of 2025.
−Removed: We are also developing a portfolio of complementary CFTR modulators designed to work synergistically with our NBD1 stabilizers to improve CFTR function, as seen in preclinical models.
−Removed: In July 2024, we in-licensed three clinical-stage compounds from AbbVie Global Enterprises Ltd.
−Removed: (“AbbVie”) to expand our portfolio of combination product opportunities, including galicaftor (SION-2222), which targets CFTR’s transmembrane domain 1 (“TMD1”), and has completed Phase 2 clinical trials.
−Removed: In December 2024, we completed a Phase 1 clinical trial evaluating SION-109, which targets CFTR’s intracellular loop 4 (“ICL4”) region.
−Removed: Our vision is to build a CF franchise anchored by our NBD1 stabilizers to deliver clinically meaningful benefit to CF patients.
−Removed: We believe our robust pipeline of NBD1 stabilizers and complementary modulators provide multiple potential pathways to achieving that vision, either in combination with each other to produce a proprietary combination CF therapy, or in combination with the current standard of care.
−Removed: We plan to evaluate multiple NBD1 stabilizer candidates and complementary modulator candidates and select the most promising candidates to advance into later-stage development.
−Removed: Initially, we intend to evaluate an NBD1 stabilizer candidate in combination with the current standard of care in a Phase 2a proof-of-concept trial, expected to begin in the second half of 2025.
−Removed: In parallel, we will determine the proprietary dual combination that we believe is optimal to advance into a later-stage clinical trial in CF patients, as illustrated in Figure 2.
−Removed: Our NBD1 Stabilizers Have Multiple Potential Pathways to Deliver Clinically Meaningful Benefit to CF Patients
−Removed: Central to our development strategy is our use of the industry standard, clinically predictive preclinical cystic fibrosis human bronchial epithelial (“CFHBE”) model to measure CFTR function.
−Removed: The CFHBE model uses lung cells from CF patients and has been highly predictive of clinical outcomes for approved CFTR modulators.
−Removed: Vertex Pharmaceuticals, Inc.
−Removed: (“Vertex”), the manufacturer of the five approved CFTR modulators, has demonstrated that increased chloride transport in the CFHBE model is strongly correlated with improved CFTR function in CF patients.
−Removed: In head-to-head preclinical studies using the CFHBE model, we evaluated several of our proprietary dual combinations (combining each of SION-719 and SION-451 with each of SION-2222 and SION-109) in direct comparison to elexacaftor/tezacaftor/ivacaftor (“ETI”) (which we synthesized using methods described in publicly available sources), with all compounds at their respective highest effective dose (“E max ”).
−Removed: In other head-to-head preclinical studies using the CFHBE model, we evaluated “add-on” combinations (SION-719 and ETI, and 451 and ETI), in direct comparison to ETI alone, with all compounds at E max .
−Removed: In all of these studies, whether evaluating a proprietary dual combination or an “add-on” combination of an NBD1 stabilizer and ETI, we observed a marked improvement in CFTR protein activity of more than 1.5-fold relative to ETI alone.
−Removed: The CFHBE model has helped us identify active compounds and predict the potential clinical exposures needed to achieve a target level of clinical activity in humans.
−Removed: We intend to continue to leverage insights from the CFHBE model as we make critical pipeline prioritization and development decisions.
−Removed: Our proprietary portfolio includes NBD1 stabilizers and complementary modulators.
−Removed: There are two types of complementary modulators:
−Removed: correctors, which partially improve CFTR protein folding to aid its trafficking to the cell surface, and potentiators, which increase CFTR channel function by enabling chloride flow through the cell membrane.
−Removed: We believe the synergistic approach of combining NBD1 stabilizers with complementary modulators provides the highest probability of normalizing CFTR function for CF patients.
+Added: We believe stabilizing NBD1 is central to unlocking dramatic improvements in clinical outcomes and quality of life for people with CF.
+Added: The NBD1 domain of the CFTR protein, as illustrated in Figure 1 below, plays a key role in the folding, assembly, stability and trafficking of CFTR to a cell’s surface, where it normally functions as an ion channel to regulate chloride and water transport.
+Added: Within the NBD1 domain, F508del severely destabilizes CFTR, disrupting its proper assembly, impairing half-life and decreasing chloride channel function.
+Added: We have employed biophysical, cell-based and virtual screening campaigns and extensive use of structural biology to guide the optimization of our novel small molecule NBD1 stabilizers.
+Added: We are also advancing a portfolio of complementary CFTR modulator candidates designed to work synergistically with our NBD1 stabilizers to improve CFTR function, as seen in preclinical models.
+Added: We believe our robust pipeline provides multiple potential pathways to achieve our mission, either through development of an NBD1 stabilizer and a complementary modulator in combination with each other to produce a proprietary dual combination, or an NBD1 stabilizer administered in combination with the standard of care for CF.
+Added: While we have prioritized development of a proprietary dual combination, we believe both development pathways offer attractive commercial opportunities.
+Added: The following table summarizes our clinical stage pipeline:
+Added: Our proprietary portfolio is anchored by our NBD1 stabilizers and our complementary modulators.
Our portfolio includes:
−Removed: • SION-719 and SION-451, our highly potent NBD1 stabilizers, are both in Phase 1 trials in Australia to evaluate their pharmacokinetic (“PK”) profile, safety and tolerability in healthy subjects.
−Removed: We have completed dosing in the SAD parts of both trials and the MAD part of the SION-451 trial;
−Removed: the final MAD cohort of the SION-719 trial is planned.
−Removed: Both NBD1 stabilizers have been generally well tolerated in these ongoing trials based on interim data to date.
−Removed: Topline results from our SION-719 and SION-451 Phase 1 clinical trials are expected in the first half of 2025.
−Removed: • Galicaftor (SION-2222) and SION-2851 are TMD1-directed CFTR correctors.
−Removed: Galicaftor was generally well-tolerated in Phase 1 and Phase 2 trials.
−Removed: Improvement in sweat chloride as a monotherapy and improvements in sweat chloride and lung function as a combination therapy with navocaftor were observed.
−Removed: SION-2851 has completed a Phase 1 single ascending dose (“SAD”) trial in healthy volunteers.
−Removed: • SION-109, an ICL4-directed CFTR corrector, has been evaluated in a recently completed Phase 1 clinical trial in healthy volunteers.
−Removed: SION-109 was generally well tolerated at all dose levels administered in all parts of this Phase 1 trial.
−Removed: The target exposure for SION-109 as part of a dual combination with SION-451 or SION-719 was achieved with single and multiple doses.
−Removed: • Navocaftor (SION-3067), a potentiator, has been evaluated in Phase 2 trials, where it demonstrated potential as a combination therapy.
−Removed: Figure 3 below captures the targeted binding locations within the CFTR structure for our pipeline of NBD1 stabilizers and complementary modulators.
−Removed: Our Multi-Prong Approach to Potentially Improving CFTR Function
−Removed: Our current portfolio of programs is summarized in Figure 4 below:
−Removed: Our Proprietary Pipeline of Product Candidates for the Treatment of CF
−Removed: Clinical trials for galicaftor, SION-2851, and navocaftor were conducted by AbbVie or Galapagos NV.
−Removed: Our mission is to revolutionize the current treatment paradigm for CF patients by developing novel medicines that normalize the function of the CFTR protein to deliver clinically meaningful benefit to CF patients.
+Added: • SION-719, which is being evaluated as an add-on to the standard of care :
+Added: SION-719, a highly potent NBD1 stabilizer, is currently in a Phase 2a proof-of-concept trial in CF patients, called PreciSION CF.
+Added: The trial is evaluating SION-719 when administered with the standard of care for CF, Vertex Pharmaceuticals, Inc.’s (“Vertex”) Trikafta.
+Added: Topline data from this trial is anticipated in mid-2026.
+Added: In June 2025, we announced positive topline data from a Phase 1 trial of SION-719, which evaluated its pharmacokinetic (“PK”) profile, safety and tolerability in healthy volunteers.
+Added: • SION-451, which is being evaluated in combinations with SION-2222 and SION-109 :
+Added: SION-451, a highly potent NBD1 stabilizer, is currently being evaluated in dual combinations with each of galicaftor (SION-2222) and SION-109, two of our complementary modulators, in a Phase 1 trial in healthy
+Added: Topline data from this trial is anticipated in mid-2026.
+Added: In June 2025, we announced positive topline data from the single agent portion of the Phase 1 trial, which evaluated SION-451’s PK profile, safety and tolerability in healthy volunteers.
+Added: • SION-2222 , a corrector that targets CFTR’s transmembrane domain 1 (“TMD 1”), was generally well tolerated in Phase 1 and Phase 2 trials previously conducted by AbbVie Global Enterprises Ltd.
+Added: Improvement in sweat chloride as a monotherapy and improvements in sweat chloride and lung function as a combination therapy with navocaftor (SION-3067), a potentiator, were observed.
+Added: • SION-109 , a corrector that targets CFTR’s intracellular loop 4 (“ICL4”) region, has been evaluated in a Phase 1 clinical trial in healthy volunteers, which was completed in 2024.
+Added: • Additional complementary modulators :
+Added: We have additional CFTR modulators in our portfolio.
+Added: SION-2851, a TMD1-directed CFTR corrector, has completed a Phase 1 single-ascending dose (“SAD”) trial in healthy volunteers.
+Added: SION-3067, a potentiator, has been evaluated in Phase 2 trials, where it demonstrated potential as a combination therapy.
+Added: Our pipeline of product candidates target distinct binding sites across the CFTR structure, as depicted in Figure 3 below:
+Added: Our mission is to revolutionize the current treatment paradigm for CF by developing novel medicines that normalize the function of the CFTR protein to deliver clinically meaningful benefit to people with CF.
The key pillars of our strategy are:
−Removed: • Advance our novel NBD1 stabilizers .
−Removed: Topline data from our Phase 1 clinical trials of SION-719 and SION-451 are expected in the first half of 2025.
−Removed: After completion of a drug-drug interaction trial, we plan to initiate a Phase 2a proof-of-concept trial in the second half of 2025 to evaluate an NBD1 stabilizer in combination with the current standard of care in CF patients, as well as combination MAD trial(s) evaluating dual combinations of an NBD1 stabilizer with galifactor (SION-2222) and/or SION-109 in healthy subjects.
−Removed: In preclinical studies using the CFHBE model, the combination of SION-719 or SION-451 with one of our complementary modulators or ETI showed increased chloride transport, which indicates improvement in in vitro CFTR activity.
−Removed: Given the clinically predictive nature of the CFHBE model, we believe these data indicate the potential for an NBD1-anchored dual combination to improve CFTR activity, which we believe will deliver clinically meaningful benefit to CF patients.
+Added: • Advance our novel NBD1 stabilizers leveraging a data-driven approach .
+Added: Leveraging the differentiated profiles of SION-719 and SION-451, we have advanced both product candidates to the next phase of development.
+Added: Figure 4 below presents our strategy for the advancement of SION-719 and SION-451, focusing on distinct development pathways.
• Develop and advance our pipeline of complementary modulators for proprietary combination product development .
−Removed: We are developing a proprietary pipeline of complementary CFTR modulators designed to work synergistically with our NBD1 stabilizers to improve CFTR function, as seen in our CFHBE model.
−Removed: We have several CFTR modulators in development, including galicaftor (SION-2222), a TMD1-directed corrector which has completed Phase 2 clinical trials, and SION-109, an ICL4-directed corrector which completed a Phase 1 clinical trial in December 2024.
−Removed: • Build upon our NBD1-centric CF franchise through a data-driven dual combination path.
−Removed: Our goal is to develop proprietary combination therapies that provide clinically meaningful benefit to CF patients.
−Removed: Based on the results of the combination MAD trial(s) we plan to initiate in the second half of 2025, evaluating dual combinations of an NBD1 stabilizer with galicaftor and/or SION-109 in healthy subjects, we plan to select the most promising proprietary dual combination to advance into Phase 2b dose-ranging trials in patients with CF.
+Added: We are developing a proprietary pipeline of complementary CFTR modulators designed to work synergistically with our NBD1 stabilizers to improve CFTR function, as seen in preclinical models.
• Fortify our CF franchise through continued research efforts and utilization of the translational CFHBE model .
−Removed: We aim to build a CF franchise anchored by our NBD1 stabilizers while executing on our mission to deliver medicines that provide clinically meaningful benefit to CF patients.
+Added: Central to our development strategy is our use of the industry standard, clinically predictive preclinical cystic fibrosis human bronchial epithelial (“CFHBE”) model to measure CFTR function.
The CFHBE model has been highly predictive of clinical outcomes for approved CFTR modulators, and our application of the model provides a key translational roadmap for us to prioritize compounds for further evaluation.
−Removed: We believe the model allows us to determine the target exposure needed to achieve a
−Removed: desired level of clinical activity, such as the level of improvement in a patient’s forced expiratory volume in one second (“FEV 1” ), a measure of lung function, and sweat chloride level, the clinical biomarker of CFTR function.
−Removed: We intend to invest in research activities and leverage insights from the model in our pursuit of delivering additional differentiated product candidates that meaningfully impact the lives of CF patients and facilitate our company’s long-term growth.
+Added: We believe the model allows us to determine the target exposure needed to achieve a desired level of clinical activity, such as the level of improvement in a patient’s forced expiratory volume in one second (“FEV 1” ), a measure of lung function, and sweat chloride level, the clinical biomarker of CFTR function.
+Added: We intend to invest in research activities and leverage insights from the model in our pursuit of delivering additional differentiated product candidates that meaningfully impact the lives of people with CF and facilitate our company’s long-term growth.
We also intend to opportunistically consider strategic in-licensing opportunities to maximize the value of our pipeline.
−Removed: Our Company’s History and Our Team
−Removed: Sionna was founded in 2019 to continue to explore novel approaches to treating CF by targeting NBD1.
−Removed: Our co-founders, Greg Hurlbut, Ph.D., and Mark Munson, Ph.D., spent over a decade extensively researching the NBD1 target as research leaders at Sanofi SA (f/k/a Sanofi Genzyme) (“Sanofi”).
−Removed: Shortly after our inception, we entered into an exclusive license agreement with Sanofi to acquire exclusive worldwide rights to research, develop and commercialize certain compounds designed to stabilize NBD1, as well as an ICL4 corrector.
−Removed: In addition, we have assembled a leadership team with deep expertise in drug discovery and developing CF and other rare disease therapies, launching and commercializing therapeutics globally, and building successful public pharmaceutical companies.
−Removed: Mike Cloonan, our President and Chief Executive Officer, has more than 20 years of leadership experience at global organizations, most recently as Chief Operating Officer at Sage Therapeutics, Inc.
−Removed: and prior to that as Senior Vice President of U.S.
−Removed: Commercial at Biogen, Inc.
−Removed: Charlotte McKee, M.D., our Chief Medical Officer, is a pulmonologist with more than 20 years of drug development experience who, while serving as Vice President of CF and Alpha-1 Antitrypsin Deficiency Clinical Development at Vertex, was instrumental in the development and regulatory approvals of three of Vertex’s five approved CFTR modulators, including Trikafta.
−Removed: Elena Ridloff, C.F.A., our Chief Financial Officer and Head of Corporate Development, has more than 20 years of experience in finance in the life sciences industry, most recently as Chief Financial Officer at ACADIA Pharmaceuticals Inc.
−Removed: Our leadership team is supported by a dedicated team of employees with deep industry-leading expertise, our board of directors, scientific and clinical advisory boards and a group of premier life sciences investors.
−Removed: We also received founding support from the Cystic Fibrosis Foundation (“CFF”), which has been a committed investor and supporter of our research and development work.
−Removed: Prior to our inception, the CFF spent more than a decade funding early-stage F508del corrector discovery work at Sanofi that contributed to our pipeline.
+Added: • Expand and protect our intellectual property estate .
+Added: We have developed a broad patent estate and expect to expand and protect our proprietary know-how and intellectual property.
Overview of Cystic Fibrosis, CFTR Function and the F508del Mutation
−Removed: An estimated 106,000 people have been diagnosed with CF across 94 countries, including approximately 33,000 adults and children living with CF in the U.S., according to the CFF.
−Removed: While life expectancy for CF patients has improved significantly over the years since the first CFTR modulator was approved, the median predicted survival age for individuals with CF born in the U.S.
+Added: An estimated 106,000 people have been diagnosed with CF across 94 countries, which includes approximately 40,000 adults and children living with this disease in the U.S., according to the Cystic Fibrosis Foundation (“CFF”).
+Added: About 1,000 new CF cases are diagnosed every year in the U.S.
+Added: While life expectancy for people with CF has improved significantly over the years since the first CFTR modulator was approved, the median predicted survival age for individuals with CF born in the U.S.
between 2020 and 2024 is still just 65 years, according to the 2024 CFF patient registry.
2 unchanged sentences
CF is caused by mutations to the CFTR gene that result in reduced or no function of the CFTR protein.
−Removed: The disease is autosomal recessive, meaning that two copies of a CFTR mutation are required to cause the disease, either two copies of the same mutation (“homozygous”) or two different mutations (“heterozygous”).
+Added: The disease is autosomal recessive, meaning that two copies of a CFTR mutation are required to cause the disease:
+Added: either two copies of the same mutation (“homozygous”) or two different mutations (“heterozygous”).
+Added: The most common CFTR mutation is F508del, which is a deletion of the amino acid phenylalanine at position 508, which is in NBD1;
approximately 90% of people with CF carry at least one copy of the F508del mutation, and approximately 44% of people with CF are homozygous for F508del.
−Removed: The F508del mutation (a deletion of the amino acid phenylalanine at position 508, in NBD1) is considered a severe CF mutation, and individuals with this mutation tend to fall at the worst end of the CF severity spectrum because they have little or no CFTR function in epithelial cells.
−Removed: In people with CF, mutations in the CFTR gene cause the CFTR protein to become dysfunctional.
+Added: The F508del mutation is considered a severe CF mutation, and individuals with this mutation tend to fall at the worst end of the CF severity spectrum because they have little or no CFTR function in epithelial cells.
The CFTR protein is found on the apical membrane, or surface, of epithelial cells throughout the body, including in the lungs, pancreas, sweat glands, biliary tract and intestines.
The CFTR protein is critical for proper salt and water balance in the cell, which drives production of freely flowing mucus for tissue hydration in the airways, digestive system and other organs.
+Added: In people with CF, mutations in the CFTR gene cause the CFTR protein to become dysfunctional.
When the CFTR protein is not working properly, chloride—a component of salt—gets trapped in cells, as illustrated in Figure 5.
−Removed: Without chloride to attract water to the cell surface, thick mucus accumulates in vital organs such as the lungs, pancreas and gastrointestinal tract and causes
−Removed: multisystem complications, including respiratory infections, chronic lung inflammation, poor nutrient absorption and often progressive respiratory failure, which is the primary cause of death in people with CF.
−Removed: CFTR Regulates Chloride Transport in Epithelial Cells
+Added: Without chloride to attract water to the cell surface, thick mucus accumulates in vital organs such as the lungs, pancreas and gastrointestinal tract and causes multisystem complications, including respiratory infections, chronic lung inflammation, poor nutrient absorption and often progressive respiratory failure, which is the primary cause of death in people with CF.
As illustrated in Figure 6, the CFTR protein includes two nucleotide binding domains (NBD1 and NBD2) and two transmembrane domains (TMD1 and TMD2).
2 unchanged sentences
There are also four intracellular loops that link the nucleotide binding domains to the transmembrane domains and are important to regulating ion channel gating.
−Removed: The CFTR Protein and the F508del Mutation
−Removed: The F508del mutation resides in the NBD1 domain near an interface with the fourth intracellular loop, ICL4, which is particularly critical to the folding of CFTR.
+Added: The F508del mutation occurs in the NBD1 domain near an interface with the fourth intracellular loop, ICL4, which is particularly critical to the folding of CFTR.
When the ICL4 interface is disrupted, as it is by the F508del mutation, CFTR can neither fold nor function properly.
2 unchanged sentences
Current Unmet Need and Market Opportunity
−Removed: While advances in the treatment of patients with CF have improved the lives of patients and resulted in a large commercial market, we believe significant opportunity remains to provide clinically meaningful benefit to CF patients through the development of NBD1-anchored treatments.
−Removed: NBD1 has long been considered an important target to normalize CFTR function because it is the site where the F508del mutation—the most common mutation that causes CF—resides.
−Removed: However, attempts by others to stabilize NBD1 have fallen short,
−Removed: leading to the view that NBD1 is “undruggable.” The current standard of care, Trikafta, as well as the recently approved Alyftrek, are made up of three components that target certain domains of CFTR, but not NBD1.
+Added: While advances in the treatment of CF have improved the lives of people with the disease and resulted in a large commercial market, we believe significant opportunity remains to provide clinically meaningful benefit to people with CF through the development of NBD1-anchored treatments.
+Added: NBD1 has long been considered an important target to normalize CFTR function because it is the site where the F508del mutation—the most common mutation that causes CF—occurs.
+Added: However, attempts by others to stabilize NBD1 have fallen short, leading to the view that NBD1 is “undruggable.” The current standard of care for CF, Trikafta, and Alyftrek, which
+Added: was approved in December 2024, are each made up of three components that target certain domains of CFTR, but not NBD1.
At least two-thirds of patients on Trikafta do not have normal CFTR function, defined as sweat chloride levels below 30 mmol/L.
5 unchanged sentences
Patients who discontinue use of Trikafta or experience tolerability challenges have limited or no alternative treatments available to improve their clinical outcomes or quality of life.
−Removed: Currently, the alternatives for these patients are limited to less efficacious combination products that include one or more components of Trikafta, or Alyftrek, which demonstrated non-inferiority to Trikafta in the primary endpoint of two Phase 3 clinical trials, providing patients with similar FEV1 as Trikafta and sweat chloride level improvements of 3 to 8 mmol/L.
−Removed: Approximately 69% of Alyftrek patients in two Phase 3 clinical trials did not achieve normal CFTR function, defined as sweat chloride levels below 30 mmol/L.
−Removed: Our research with key opinion leaders has indicated the desire for more treatment options for CF patients, support for a new mechanism of action that could provide clinically meaningful benefit for people living with CF, and need for an alternative for those patients who experience tolerability issues on Trikafta.
−Removed: We aim to expand the current treatment paradigm through a proprietary dual combination or as an add-on to the standard of care.
−Removed: Worldwide revenue for approved CFTR modulators was approximately $11 billion in 2024, and it is expected to grow to $15 billion by 2029.
−Removed: Vertex, which markets all five of the currently approved CFTR modulators, reported revenues in 2024 from global sales of its then-approved CFTR modulators of approximately $11.0 billion, more than $10.2 billion of which the company attributed to Trikafta.
−Removed: Vertex's approved CFTR modulators target approximately 92,000 CF patients in North America, Europe and Australia, and more than 20% of eligible patients are currently not on CFTR modulators.
+Added: Current treatment alternatives for these patients are limited to less efficacious combination products that include one or more components of Trikafta, or Alyftrek.
+Added: In two Phase 3 clinical trials, Alyftrek demonstrated non-inferiority to Trikafta in the primary endpoint, providing participants with similar FEV 1 to Trikafta and sweat chloride level improvements of approximately 3 to 8 mmol/L.
+Added: In participants who were homozygous for the F508del mutation, the sweat chloride improvement observed was approximately 3 mmol/L.
+Added: Across both trials, approximately 69% of Alyftrek patients did not achieve normal CFTR function.
+Added: Our research with key opinion leaders has indicated the desire for more treatment options for people with CF, particularly in support of a new mechanism of action that could provide clinically meaningful benefit or an alternative for those patients who experience tolerability issues on Trikafta.
+Added: Worldwide revenue for approved CFTR modulators was approximately $12 billion in 2025, and it is expected to grow to over $15 billion by 2030.
CF screening of newborn infants has served to identify CF patients as early as possible in their lives.
6 unchanged sentences
The current standard of care for people with the F508del mutation is a triple combination product marketed by Vertex as Trikafta (elexacaftor, tezacaftor, ivacaftor and ivacaftor).
−Removed: In addition, in December 2024, Vertex received approval from the FDA for a second-generation, triple modulator combination, Alyftrek, for the treatment of CF in patients aged six years and older who have at least one F508del mutation or another responsive mutation in the CFTR gene.
+Added: In addition, in December 2024, Vertex received approval from the U.S.
+Added: Food and Drug Administration (“FDA”) for a second-generation, triple modulator combination, Alyftrek, for the treatment of CF in patients who have at least one F508del mutation or another responsive mutation in the CFTR gene.
Vertex also markets three other approved CFTR modulators.
None of the approved modulators directly stabilize NBD1.
−Removed: The drugs and their approved indications in the U.S.
−Removed: are summarized in Figure 7.
−Removed: FDA-Approved CFTR Modulators and Summary Indications
Despite the clinical benefits Trikafta provides CF patients, including improved lung function and quality of life, at least two-thirds of people with CF being treated on Trikafta or another approved CFTR modulator do not have normal CFTR function.
3 unchanged sentences
Sweat chloride levels between 30 mmol/L and 59 mmol/L are considered abnormal, indicating partial CFTR dysfunction or “residual function” in diagnostic settings.
−Removed: An observational study of 3,131 individuals with CF from the CFF Registry found that, while treatment with Trikafta resulted in improvements in sweat chloride level to below 60 mmol/L in most patients, two-thirds of patients still had sweat chloride levels above normal levels (i.e., above 30 mmol/L) (Figure 8).
−Removed: Approximately Two-Thirds of Patients on Approved Therapies Do Not Have Normal CFTR Function as Measured by Sweat Chloride Levels
+Added: An observational study of 3,131 individuals with CF from the CFF Registry found that, while treatment with Trikafta resulted in improvements in sweat chloride level to below 60 mmol/L in most patients, two-thirds of patients still had sweat chloride levels above normal levels (Figure 7).
Sweat chloride levels less than or equal to 29 mmol/L indicate that CF is unlikely;
2 unchanged sentences
Two-year interim data from a five-year post-marketing real-world observational trial of patients taking Trikafta showed that mean rates of pulmonary exacerbations and the presence of bacterial pathogens improved but were not normalized after initiating treatment on Trikafta.
−Removed: The three-year interim data, presented at the European CF Society meeting in Glasgow in 2024, showed numerical increases in mean rates of pulmonary exacerbations and decreases in mean lung function compared to the two-year interim data, supporting the opportunity for clinical improvements over the current standard of care.
+Added: The three-year interim data, presented at the European CF Society meeting in Glasgow in 2024, showed numerical increases in mean rates of pulmonary exacerbations and decreases in mean lung function compared to the two-year interim data, supporting the opportunity for clinical improvements over the standard of care.
In addition to continued pulmonary complications, patients also experienced negative mental health side effects, including numerical increases in rates of depression, anxiety disorder and hypertension after initiating treatment on Trikafta.
−Removed: Another side effect associated with ivacaftor is cataracts, which can complicate use and requires monitoring, especially in children.
−Removed: In addition, in December 2024, the Trikafta label was updated to include a boxed warning for the risks of drug-induced liver injury and liver failure.
−Removed: The Alyftrek label includes the same boxed warning.
−Removed: Alyftrek demonstrated non-inferiority to Trikafta in the primary endpoint of two Phase 3 clinical trials, providing patients with similar FEV 1 as Trikafta and sweat chloride level improvements of 3 to 8 mmol/L.
−Removed: Approximately 69% of Alyftrek patients in two Phase 3 clinical trials did not achieve normal CFTR function.
−Removed: These results support our beliefs that NBD1 stabilization is required to meaningfully improve upon the current standard of care and that a high unmet need remains for an alternative therapy that can provide clinically meaningful benefit to CF patients.
+Added: Another side effect associated with ivacaftor (a component of Trikafta) is cataracts, which can complicate use and requires monitoring, especially in children.
+Added: In addition, both the Trikafta and Alyftrek labels include a boxed warning for the risks of drug-induced liver injury and liver failure.
+Added: Alyftrek demonstrated non-inferiority to Trikafta in the primary endpoint of two Phase 3 clinical trials, providing patients with similar FEV 1 as Trikafta and sweat chloride level improvements of approximately 3 to 8 mmol/L.
+Added: In participants who were homozygous for the F508del mutation, the sweat chloride improvement observed was approximately 3 mmol/L.
+Added: Across both trials, approximately 69% of Alyftrek patients did not achieve normal CFTR function.
+Added: These results support our beliefs that NBD1 stabilization is required to meaningfully improve upon the standard of care and that a high unmet need remains for an alternative therapy that can provide clinically meaningful benefit to CF patients.
Research Findings Support NBD1 as a Key Target for Stabilizing F508del-CFTR
Multiple studies by third parties have concluded that NBD1 is a key drug target for correcting the F508del mutation, including in vitro studies that introduced mutations at other sites on NBD1 that suppressed the effect of the F508del mutation.
−Removed: For example, researchers at Utrecht University and University of Texas Southwestern Medical Center identified a second site NBD1 mutation (“I539T”) that rescued the misfolding and
−Removed: instability of F508del-CFTR.
+Added: For example, researchers at Utrecht University and University of Texas
+Added: Southwestern Medical Center identified a second site NBD1 mutation (“I539T”) that rescued the misfolding and instability of F508del-CFTR.
They concluded the “co-translational rescue of F508del NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis.”
5 unchanged sentences
Without a suppressor mutation, no F508del-CFTR is produced (Ø).
−Removed: NBD1 Stabilization Synergizes with Improved Domain-Domain Assembly to Fully Correct F508del-CFTR
Thibodeau, 2010)
7 unchanged sentences
Our programs leverage an industry standard, clinically predictive CFHBE model to measure CFTR protein function in vitro.
−Removed: Activity in this model has been shown to be correlated to chloride transport activity, which in turn, has been shown to be correlated to improved lung function in clinical trials designed to evaluate product candidates in CF patients.
−Removed: We have used, and plan to continue to use, insights from the CFHBE model to inform critical pipeline prioritization and development decisions.
+Added: The CFHBE model uses lung cells from people with CF and has been highly predictive of clinical outcomes for approved CFTR modulators.
+Added: Activity in the CFHBE model has been shown to be correlated to chloride transport activity, which in turn, has been shown to be correlated to improved lung function in clinical trials designed to evaluate product candidates in CF patients.
+Added: We have used, and plan to continue to use, insights from the CFHBE model to identify active compounds, predict potential clinical exposures, and inform critical pipeline prioritization and development decisions.
For example, we selected SION-719 and SION-451 to advance based on their preclinical profiles, including potency in the CFHBE model.
−Removed: We assessed SION-719 and SION-451 in our CFHBE model in direct, head-to-head comparison to ETI, the components of Trikafta.
−Removed: When evaluated in our CFHBE model at E max concentrations, both SION-719 and SION-451, in dual combination with one of our complementary modulators, improved in vitro CFTR protein activity to wild-type, or normal, levels.
−Removed: This was a more than 1.5-fold improvement in CFTR protein activity compared to the improvement in such activity observed with ETI at E max in the same experiment.
+Added: In preclinical studies using the CFHBE model, we evaluated our NBD1 stabilizers in several combinations (including SION-719 with the components of Trikafta (elexacaftor/tezacaftor/ivacaftor, or “ETI”), and SION-451 with each of SION-2222 and SION-109) in direct comparison to ETI alone, with all compounds at their respective highest effective dose (“E max ”), and observed a marked improvement in CFTR protein activity of more than 1.5-fold relative to ETI alone.
We believe that we can leverage the reproducible correlation between chloride transport at different drug exposure levels in the CFHBE model and clinical outcomes to predict the target level of exposure to achieve clinically meaningful benefit in CF patients.
3 unchanged sentences
Cultured CFHBE cells exhibit many of the structural and functional attributes believed to be associated with CF airway disease.
−Removed: Vertex has successfully applied a variation of the CFHBE model with 20% human serum for multiple CFTR modulators advanced to clinical trials, including their five approved modulators.
+Added: Vertex has successfully applied a variation of the CFHBE model with 20% human serum for multiple CFTR modulators advanced to clinical trials, including their five approved modulators, and has demonstrated that increased chloride transport in the CFHBE model is strongly correlated with improved CFTR function in CF patients.
Importantly, the CFHBE model provided key preclinical data on CFTR function to support the clinical evaluation of elexacaftor as part of Trikafta.
8 unchanged sentences
The CFHBE model without 20% human serum, depicted by the blue line, failed to accurately predict the clinical exposure of lumacaftor required for efficacy, even if adjusted for lumacaftor’s measured free fraction in human plasma, depicted by the dotted green line.
−Removed: Our CFHBE Model is Designed to More Accurately Predict the Required Clinical Exposure than Standard CFHBE Model
Using published data from the clinical trials of Vertex’s approved CFTR modulators, we have validated internally our CFHBE model by assessing the relationship between in vitro CFTR protein function, as measured by chloride transport in our CFHBE model, and the mean sweat chloride levels seen in Vertex’s clinical trials of these approved modulators.
2 unchanged sentences
For example, we modeled other third-party modulators previously in development and independently determined that these compounds had insufficient activity to demonstrate target clinical efficacy, which was supported by published clinical trial data.
−Removed: CFHBE Model Has Been Predictive of Sweat Chloride Improvement
Mean improvements in sweat chloride levels in clinical trials have been shown to be correlated with mean improvements in lung function as measured by FEV 1 , as shown in Figure 11 below.
−Removed: Sweat Chloride Has Been Correlated With Lung Function Benefit
We consider our CFHBE model a translational roadmap because of its ability to correlate with sweat chloride improvement in clinical trials, as seen in Figure 10 above, which in turn has been shown to correlate to improved lung function in clinical trials, as shown in Figure 11 above.
−Removed: We have observed this correlation with our CFHBE data and clinical lung function data for approved and investigational CFTR modulators that demonstrated activity in clinical trials, including galicaftor and navocaftor, as shown in Figure 13 below.
−Removed: CFHBE Model Correlates to Improved Lung Function
+Added: We have observed this correlation with our CFHBE data and clinical lung function data for approved and investigational CFTR modulators that demonstrated activity in clinical trials, including SION-2222 and SION-3067, as shown in Figure 12 below.
We believe our CFHBE model allows us to predict the target exposure needed for our product candidates to achieve a desired level of clinical activity, such as the level of improvement in patients’ lung function, as measured by FEV 1 improvement, and sweat chloride levels.
We have tested our product candidates in the CFHBE model at E max and generated a prediction of sweat chloride and FEV 1 changes, based on the documented correlation, observed in clinical trials of approved and investigational modulators, between improvements in sweat chloride levels and improvements in lung function.
−Removed: We believe that the CFTR function
−Removed: improvement observed in our CFHBE model of our product candidates has the potential to translate clinically to deliver clinically meaningful benefit to CF patients.
+Added: We believe that the CFTR function improvement observed in our CFHBE model of our product candidates has the potential to translate clinically to deliver clinically meaningful benefit to CF patients.
Our CF Programs
We have a portfolio of NBD1 stabilizers and complementary modulators that target other regions of the CFTR protein, with the goal of advancing a combination therapy that has the potential to deliver clinically meaningful benefit to CF patients.
−Removed: We plan to advance an NBD1 stabilizer candidate and NBD1 dual combination into Phase 2 clinical trials in CF patients based on initial human data on safety, tolerability and PK in healthy volunteers.
+Added: We believe our robust pipeline provides multiple potential pathways to achieve our goal, either through development of an NBD1 stabilizer and a complementary modulator in combination with each other to produce a proprietary dual combination, or an NBD1 stabilizer administered in combination with the standard of care for CF.
+Added: Leveraging the differentiated profiles of our two lead NBD1 stabilizer product candidates observed in their respective Phase 1 trials, we have advanced both SION-451 and SION-719 to the next phase of development.
NBD1 Stabilizer Program
3 unchanged sentences
We believe the technical challenge associated with NBD1-targeted drug discovery, along with our intellectual property rights, represent a substantial competitive barrier.
−Removed: We selected SION-719 and SION-451 for clinical evaluation based on their potency, PK profiles and safety as observed in preclinical studies.
−Removed: We assessed SION-719 and SION-451 in our CFHBE model in direct, head-to-head comparison to ETI, the components of Trikafta.
−Removed: When evaluated in our CFHBE model at their respective E max concentrations, both SION-719 and SION-451, in dual combination with one of our complementary modulators, improved in vitro CFTR protein activity of F508del-CFTR to wild-type, or normal, levels.
−Removed: This was a more than 1.5-fold improvement in CFTR protein activity compared to the improvement in such activity observed with ETI at E max in the same experiment.
−Removed: Based on predicted exposure levels in the CFHBE model, we believe co-administering SION-719 or SION-451 with a complementary modulator has the potential to achieve clinically meaningful benefit in CF patients.
−Removed: In addition, we have nominated two NBD1 stabilizers with differentiated profiles as development candidates.
−Removed: SION-719 and SION-451
−Removed: Phase 1 Clinical Development
−Removed: We initiated Phase 1 SAD and MAD clinical trials of SION-719 and SION-451 in healthy subjects in July 2024 and August 2024, respectively.
−Removed: These trials are randomized, double-blinded, placebo-controlled trials designed to evaluate safety, tolerability and PK of each product candidate.
−Removed: Both trials are being conducted in Australia, and we intend to enroll up to 120 healthy subjects in each trial.
−Removed: In February 2025, we disclosed interim data from both trials, which is summarized below.
−Removed: Since disclosing interim data, we have completed dosing in the MAD part of the SION-451 trial, and the final MAD cohort of the SION-719 trial, to evaluate 120 mg SION-719, is planned.
−Removed: The additional completed cohorts evaluated 225 mg and 25 mg (fed) of SION-451 and 160 mg of SION-719, each dosed BID over 10 days.
−Removed: All MAD data, including from the recently completed cohorts, remain blinded to individual subject treatment assignment.
−Removed: Both compounds were generally well tolerated in these additional MAD cohorts.
−Removed: There were no serious adverse events (“SAEs”), and most treatment-emergent adverse events (“TEAEs”) were mild to moderate.
−Removed: There were no TEAEs related to liver function tests and no TEAEs that led to discontinuation of trial drug.
−Removed: The Part C of each trial, in which we are evaluating the effect of food on the PK of each product candidate and the bioequivalence of a tablet formulation, is ongoing.
−Removed: We expect topline data for both trials in the first half of 2025.
−Removed: Interim Phase 1 Trial Data for SION-719
−Removed: As of January 14, 2025, the interim data cutoff date, over 60 healthy subjects had been dosed in the Phase 1 clinical trial of SION-719.
−Removed: The trial was designed to enroll eight subjects, randomized 3:1 active:placebo, in each dosing cohort.
−Removed: As of the data cutoff date, five SAD cohorts had been completed, evaluating single doses of 20 mg, 40 mg, 80 mg, 160 mg and 20 mg taken with food to provide a preliminary assessment of the effect of food on PK, and three MAD cohorts had been completed, evaluating 20 mg, 40 mg, and 80 mg of SION-719 BID over 10 dosing days.
−Removed: As of the data cutoff date, all data remained blinded to individual subject treatment assignment, with the exception of selected individual subjects unblinded for administrative and study planning purposes according to the clinical trial protocol.
−Removed: SION-719 was generally well tolerated at all dose levels administered based on interim Phase 1 clinical data as of the data cutoff date of January 14, 2025.
−Removed: There were no SAEs.
−Removed: Most TEAEs were mild to moderate (Grade 1 or Grade 2), and no TEAEs led to the discontinuation of trial drug.
−Removed: The most common TEAEs, occurring in >1 subject, were headache, hypoglycemia and diarrhea.
−Removed: All TEAEs occurring in >1 subject were Grade 1 or Grade 2, except a single Grade 4 hypoglycemia TEAE in a placebo subject in a SAD cohort.
−Removed: There were no TEAEs related to liver function tests.
−Removed: No dose-limiting TEAEs or safety trends of concern have been observed, including in the additional MAD cohort completed after the interim data cutoff date.
−Removed: Increasing exposure was observed with increasing single and multiple doses as of the interim data cutoff date.
−Removed: The concentration targets for SION-719 as an add-on to SOC and as part of a dual combination with SION-2222 or SION-109 were achieved with single and multiple doses.
−Removed: A PK summary of SION-719 data as of the cutoff date of January 14, 2025 is shown in Figures 14 and 15 below.
−Removed: The observed PK was consistent with BID dosing.
−Removed: Preliminary Phase 1 PK Summary for SION-719 in the SAD Portion of the Trial
−Removed: (Each solid line shows mean concentration data from a dosing cohort.
−Removed: Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-719 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to SOC.)
−Removed: Preliminary Phase 1 PK Summary for SION-719 in the MAD Portion of the Trial
+Added: SION-719 — Clinical Data
+Added: Phase 2a PreciSION CF Trial
+Added: In October 2025, we announced the initiation of our ongoing Phase 2a proof-of-concept trial in CF patients, called PreciSION CF, which is evaluating SION-719 when added to the current standard of care.
+Added: trial is designed to evaluate the safety, tolerability, and PK of SION-719 when administered with Trikafta, and to assess change in CFTR function as measured by sweat chloride levels.
+Added: The trial is a two-way crossover trial anticipated to enroll approximately 16 participants with CF who are stable on physician-prescribed Trikafta.
+Added: All participants will be randomly allocated to one of two trial arms and will continue taking Trikafta throughout the trial.
+Added: Participants in “Arm A” will first receive Trikafta in combination with SION-719 for 14 days, and, after a 28-day washout period, will then receive Trikafta in combination with placebo for 14 days.
+Added: Participants in “Arm B” receive the same treatments in reverse order, followed by a 28-day safety follow-up period.
+Added: We expect topline data from the PreciSION CF trial in mid-2026.
+Added: Phase 1 Single Agent Trial of SION-719
+Added: In June 2025, we announced positive topline data from a randomized, double blind, placebo-controlled Phase 1 clinical trial of SION-719 in healthy participants.
+Added: The trial was designed to evaluate the safety, tolerability and PK profile of single and multiple ascending doses (“MAD”) of SION-719, administered as an oral suspension.
+Added: In a Part C of the Phase 1 trial, we evaluated the effect of food on PK and the bioequivalence of a tablet formation compared to the oral suspension used in the Phase 1 SAD and MAD trials.
+Added: A total of 100 healthy adult participants were dosed in this Phase 1 trial.
+Added: The trial was designed to enroll eight participants, randomized 3:1 active:placebo, to each dosing cohort.
+Added: SAD cohorts evaluated single doses ranging from 20 mg to 160 mg in a fasted state;
+Added: 20 mg taken with food was also evaluated in a SAD cohort to provide a preliminary assessment of the effect of food on PK.
+Added: Five MAD cohorts evaluated doses ranging from 20mg to 160mg dosed twice daily (“BID”) over ten dosing days.
+Added: Twenty participants were dosed in the open-label food effect and tablet bioequivalence part evaluating 30 mg and 120 mg single doses each of suspension (fasted), tablet (fasted), and tablet (fed).
+Added: SION-719 was generally well tolerated at all dose levels administered in all parts of this Phase 1 trial.
+Added: A summary table of reported treatment emergent adverse events (“TEAEs”) is shown in Figure 13 below.
+Added: There were no serious adverse events (“SAEs”), and most TEAEs were mild to moderate (Grade 1 or Grade 2).
+Added: No TEAEs led to the discontinuation of trial drug, and no dose-limiting TEAEs were observed.
+Added: The most common TEAEs, occurring in >2 participants, were headache, diarrhea, and nausea.
+Added: There were no TEAEs related to liver function tests in SION-719 treated patients.
+Added: There were no clinically meaningful, treatment-emergent trends in other safety parameters, vital signs or electrocardiograms.
+Added: The data from Part C support the use of a tablet formulation in future trials and indicate that SION-719 can be dosed in a fed or fasted state.
+Added: Safety observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)
+Added: Increasing exposure was observed with increasing single and multiple doses.
+Added: The concentration targets for SION-719 as an add-on to the standard of care and as part of a dual combination with SION-2222 or SION-109 were achieved with single and multiple doses.
+Added: The PK of SION-719 observed in the Phase 1 trial was consistent with BID dosing, and is summarized in Figure 14 below.
Each solid line shows mean concentration data from a dosing cohort on Day 10.
−Removed: Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-719 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to SOC.)
−Removed: Interim Phase 1 Trial Data for SION-451
−Removed: As of January 14, 2025, over 70 healthy subjects had been dosed in the Phase 1 clinical trial of SION-451.
−Removed: The trial was designed to enroll eight subjects, randomized 3:1 active:placebo, in each dosing cohort.
−Removed: Six SAD cohorts had been completed, evaluating single doses of 75 mg, 150 mg, 300 mg and 450 mg, as well as single doses of 75 mg and 25 mg with food to provide a preliminary assessment of the effect of food on PK.
−Removed: Three MAD cohorts had been completed as of the data cutoff date, evaluating 75 mg, 150 mg, and 300 mg of SION-451 BID over 10 dosing days.
−Removed: As of the data cutoff date, all data remained blinded to individual subject treatment assignment.
−Removed: SION-451 was generally well tolerated at all dose levels administered based on interim Phase 1 clinical data as of the data cutoff date of January 14, 2025.
+Added: Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-719 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to the standard of care.
+Added: PK observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)
+Added: Following completion of this Phase 1 trial, we evaluated the achieved clinical exposures of SION-719 in our CFHBE model with a fixed concentration of ETI, to assess SION-719's potential as an add-on to ETI.
+Added: As shown in the CFHBE model, and depicted in Figure 15, at the clinical exposures achieved in the lower dose range of SION-719, SION-719 in combination with ETI has the potential to improve CFTR channel activity above our minimum target for clinically meaningful benefit, including up to wild-type levels.
+Added: In Figure 15, CFTR activity in the model is expressed as a ratio relative to ETI at E max , which is set at a reference value of 1.00.
+Added: Based on these findings, we believe that SION-719, when added to standard of care, has the potential to provide clinically meaningful benefit to CF patients.
+Added: SION-451 — Clinical Data
+Added: Phase 1 Dual Combination Trial
+Added: In August 2025, we announced the initiation of a Phase 1 dual combination trial in healthy volunteers evaluating SION-451 in dual combinations with each of SION-2222 and SION-109, two of our complementary CFTR modulators.
+Added: The trial is designed to evaluate the safety, tolerability, and PK of varying doses of the dual combinations and will inform selection of a dual combination for further development.
+Added: We expect topline data from the trial in mid-2026.
+Added: Phase 1 Single Agent Trial
+Added: In June 2025, we announced positive topline data from the single-agent portion of a randomized, double blind, placebo-controlled Phase 1 clinical trial of SION-451 in healthy participants.
+Added: The trial was designed to evaluate the safety, tolerability and PK profile of single and multiple ascending doses of SION-451, administered as an oral suspension.
+Added: In Part C of the Phase 1 trial, we evaluated the effect of food on PK and the bioequivalence of a tablet formation compared to the oral suspension used in the Phase 1 SAD and MAD trials.
+Added: One hundred and ten total healthy adult participants were dosed in the single-agent portion of this Phase 1 trial.
+Added: The trial was designed to enroll eight participants, randomized 3:1 active:placebo, to each dosing cohort.
+Added: SAD cohorts evaluated single doses of 75 mg to 450 mg while fasted, as well as single doses of 25 mg and 75 mg with food to provide a preliminary assessment of the effect of food on PK.
+Added: Five MAD cohorts evaluated doses between 75mg and 300mg BID over ten dosing days, and 25 mg taken with food to provide a preliminary assessment of the effect of food on PK.
+Added: Twenty-four participants were dosed in the open-label food effect and tablet bioequivalence part, with separate cohorts evaluating 25 mg and 300 mg as single doses of suspension (fasted), tablet (fasted), and tablet (fed).
+Added: SION-451 was generally well tolerated at all dose levels administered.
+Added: A summary table of reported TEAEs is shown in Figure 16 below.
There were no SAEs, and most TEAEs were mild to moderate (Grade 1 or Grade 2).
−Removed: No TEAEs led to the discontinuation of trial drug.
−Removed: The most common TEAEs, occurring in more than one subject, were headache, abdominal pain, contact dermatitis, influenza, presyncope, fatigue and upper respiratory tract infection.
−Removed: All TEAEs occurring in >1 subject were Grade 1 or Grade 2, and many were in an isolated dose cohort that was impacted by an outbreak of respiratory infection in the Phase 1 unit.
−Removed: One Grade 1 TEAE of increased transaminases had been observed, in a subject with influenza A infection.
−Removed: No dose limiting TEAEs or safety trends of concern have been observed, including in the additional MAD cohorts completed after the interim data cutoff date.
−Removed: Increasing exposure was observed with increasing single and multiple doses as of the interim data cutoff date.
−Removed: The concentration targets for SION-451 as both an add-on to SOC and as part of a dual combination with SION-2222 or SION-109 were achieved with single and multiple doses.
−Removed: A PK summary of SION-451 as of the cutoff date of January 14, 2025 is shown in Figures 16 and 17 below.
+Added: No TEAEs led to the discontinuation of trial drug, and no dose-limiting TEAEs were observed.
+Added: Most TEAEs occurring in >2 participants were Grade 1 or Grade 2, and several were in an isolated dose cohort that was impacted by an outbreak of respiratory infection in the Phase 1 unit.
+Added: One Grade 1 TEAE of increased transaminases was observed in a participant with influenza A infection;
+Added: the same participant had transient Grade 3 neutropenia concurrent with influenza A infection.
+Added: There were no other TEAEs related to liver function tests.
+Added: There were no clinically meaningful, treatment-emergent trends in other safety parameters, vital signs or electrocardiograms.
+Added: The data from Part C supported the use of a tablet formulation in future studies and indicate that SION-451 can be dosed in a fed or fasted state.
+Added: Safety observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)
+Added: Increasing exposure was observed with increasing single and multiple doses.
+Added: The concentration targets for SION-451 as both an add-on to the standard of care and as part of a dual combination with SION-2222 or SION-109 were achieved with single and multiple doses.
+Added: A PK summary of SION-451 in the MAD portion of the trial is shown in Figure 17 below.
The observed PK was consistent with BID dosing.
−Removed: Preliminary Phase 1 PK Summary for SION-451 in the SAD Portion of the Trial
−Removed: (Each solid line shows mean concentration data from a dosing cohort.
−Removed: Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-451 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to SOC.)
−Removed: Preliminary Phase 1 PK Summary for SION-451 in the MAD Portion of the Trial
Each solid line shows mean concentration data from a dosing cohort on Day 10.
−Removed: Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-451 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to SOC.)
−Removed: Phase 2 Clinical Development Plans
−Removed: Our current expectations for our clinical development strategy are depicted in Figure 18 below.
−Removed: Our Strategic Development Plan to Advance Our Pipeline of NBD1 Stabilizers and Complementary Modulators
−Removed: Phase 2a Proof-of-Concept Clinical Trial—NBD1 stabilizer + Trikafta
−Removed: We plan to initiate a Phase 2a proof-of-concept trial in CF patients in the second half of 2025, following completion of our Phase 1 clinical trials of SION-719 and SION-451 and a drug-drug interaction trial.
−Removed: We expect the Phase 2a trial to be a two-way crossover trial in which we enroll up to 20 trial subjects with CF who are stable on physician-prescribed Trikafta.
−Removed: All trial subjects will be randomly allocated to one of two trial arms and continue taking Trikafta throughout the trial.
−Removed: Trial subjects in “Arm A” will first receive Trikafta in combination with an NBD1 stabilizer for 14 days, and, after a 28-day washout period, will receive Trikafta in combination with placebo for 14 days.
−Removed: Trial subjects in “Arm B” will receive the same treatments in reverse order.
−Removed: All subjects will have a 28-day safety follow-up period.
−Removed: We expect to select safety as the primary endpoint, and PK and improvements to sweat chloride levels as the secondary endpoints.
−Removed: Combination MAD Clinical Trial(s)—NBD1 stabilizer + galicaftor and/or SION-109
−Removed: We intend to initiate combination MAD trial(s) in the second half of 2025, assessing the safety, tolerability and PK of dual combination(s) of an NBD1 stabilizer with galicaftor and/or SION-109 in healthy volunteers, following completion of combination toxicology studies.
−Removed: Following the completion of such trial(s), we intend to select a dual combination to advance into a Phase 2b dose-ranging trial in CF patients.
−Removed: Preclinical Studies
+Added: Dotted lines represent average PK concentration exposure targets that have the potential, based on our preclinical CFHBE model, to provide clinically meaningful benefit, if SION-451 is administered in a proprietary dual combination with either SION-2222 or SION-109, or as an add-on to the standard of care.
+Added: PK observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)
+Added: Following completion of the single agent portion of this Phase 1 trial, we evaluated the achieved clinical exposures of SION-451 in our CFHBE model with a fixed concentration of SION-109 and SION-2222, to assess their potential in dual combinations.
+Added: As shown in the CFHBE model, and depicted in Figure 18, at these clinical exposures achieved, SION-451 in combination with each of SION-2222 or SION-109 has the potential to improve CFTR channel activity above our minimum target for clinically meaningful benefit, including up to wild-type levels.
+Added: In Figure 18, CFTR activity in the model is expressed as a ratio relative to ETI at E max , which is set at a reference value of 1.00.
+Added: Based on these findings, we believe that SION-451 in a dual combination with a complementary modulator has the potential to provide clinically meaningful benefit to CF patients, and we advanced SION-451 into our ongoing dual combination trial with each of SION-2222 and SION-109.
+Added: Preclinical Studies of SION-719 and SION-451
We have used numerous complementary methods to validate and characterize the activity of our compounds.
−Removed: In addition to the CFHBE model, we have utilized differential static light scattering (“DSLS”) experiments to measure the thermal stability of the NBD1 protein, surface plasmon resonance (“SPR”) studies to evaluate the interaction of SION-719 and SION-451 with the NBD1 domain, and CFTR western blot analysis to assess the impact of NBD1 stabilizers on the folding, maturation and stability of F508del-CFTR.
−Removed: Given the results of these preclinical studies, we believe that we have identified highly potent NBD1 stabilizers with robust preclinical activity.
+Added: In addition to the CFHBE model, we have utilized differential static light scattering (“DSLS”) experiments to measure the thermal stability of the NBD1 protein, surface plasmon resonance (“SPR”) studies to evaluate the interaction of SION-719 and SION-451 with the NBD1 domain, CFTR western blot analysis to assess the impact of NBD1 stabilizers on the folding, maturation and stability of F508del-CFTR, and metabolic pulse-chase analysis studies to assess the impact of SION-719 and SION-451 on F508del-CFTR half-life.
+Added: Given the results of these preclinical studies, we believe that we have identified highly potent NBD1 stabilizers.
SION-719 and SION-451 Increased NBD1 Thermal Stability
7 unchanged sentences
These preclinical models show the ability of SION-719 and SION-451 to improve the stability of NBD1 as compared to ETI, as measured by light scattering techniques.
−Removed: SION-719 and SION-451 Increased Stability of the NBD1 Domain
ΔTagg °C = Change in the temperature at which F508del-NBD1 protein unfolds and aggregates
7 unchanged sentences
SION-719 and SION-451 Restored F508del Folding and Maturation
−Removed: In preclinical studies, we evaluated SION-719 and SION-451 in various combinations, including with ETI, galicaftor, and SION-109 to assess these combinations’ ability to improve CFTR folding, maturation and stability and thereby correct F508del-CFTR.
+Added: In preclinical studies, we evaluated SION-719 and SION-451 in various combinations, including with ETI, SION-2222, and SION-109 to assess these combinations’ ability to improve CFTR folding, maturation and stability and thereby correct F508del-CFTR.
Preclinical studies with both SION-719 and SION-451-based combinations resulted in F508del-CFTR maturation to levels that are similar to wild-type CFTR.
−Removed: We believe these results demonstrated potential synergy between an NBD1 stabilizer and these complementary modulators.
+Added: these results demonstrated potential synergy between an NBD1 stabilizer and these complementary modulators.
The results of studies of CFTR maturation in human CF submucosal gland epithelial (“CFSMEo”) cells by western blot with SION-719 are shown in Figure 20 (top), and the results with SION-451 combinations are shown in Figure 20 (bottom).
Together, the western blots illustrate F508del-CFTR protein in a submucosal-gland epithelial cell line that expresses CFTR, treated with various combinations of CFTR modulators.
−Removed: The high molecular weight bands, labeled C-band, indicate the presence of the active, mature apical glycoform of CFTR (dark bands), which is responsible for CFTR channel function.
+Added: The top molecular weight bands, labeled C-band, indicate the presence of the active, mature apical glycoform of CFTR (dark bands), which is responsible for CFTR channel function.
The compounds were evaluated at their E max .
−Removed: In Figure 20, the far-left column in the C-band is F508del in dimethylsulfoxide (“DMSO”) alone, showing no mature protein, and the far-right column is wild-type CFTR in DMSO with a dark bank indicating the presence of mature CFTR protein.
−Removed: As seen in Figure 20 (top), dual combinations of SION-719 with galicaftor or SION-109, or the addition of SION-719 to ETI, resulted in wild-type levels of corrected F508del-CFTR protein.
−Removed: Treatment with SION-719 as a single agent demonstrated a greater effect on F508del maturation than ETI at
−Removed: On the other hand, there was little improvement in the maturation of F508del-CFTR protein with galicaftor alone, SION-109 alone or ETI at their respective E max concentrations, as indicated by the light gray bands.
+Added: In Figure 20, the far-left column in the C-band is F508del in dimethylsulfoxide (“DMSO”) alone, showing no mature protein, and the far-right column is wild-type CFTR in DMSO with a dark band indicating the presence of mature CFTR protein.
+Added: As seen in Figure 20 (top), dual combinations of SION-719 with SION-2222 or SION-109, or the addition of SION-719 to ETI, resulted in wild-type levels of corrected F508del-CFTR protein.
+Added: Treatment with SION-719 as a single agent demonstrated a greater effect on F508del maturation than ETI at E max .
+Added: On the other hand, there was little improvement in the maturation of F508del-CFTR protein with SION-2222 alone, SION-109 alone or ETI at their respective E max concentrations, as indicated by the light gray bands.
The results with SION-451 presented in Figure 20 (bottom) are similar.
The western blots below demonstrate the importance of NBD1 stabilization to the correction of F508del maturation.
−Removed: F508del-CFTR Maturation in CFSMEo-Cells Was Fully Restored with Our SION-719 and SION-451 Corrector Combinations
+Added: SION-719 and SION-451 Improved the Half-life of F508del-CFTR
+Added: In preclinical studies, we used metabolic pulse-chase labeling analysis to evaluate the impact of NBD1 stabilizers SION-451 and SION-719 on F508del-CFTR half-life at the apical cell surface.
+Added: In these studies, cells expressing F508del-CFTR were labeled to track newly synthesized CFTR protein, and the rate at which the labeled protein declined over time was measured to assess whether treatment with SION-719 or SION-451 increased the half-life of the mature CFTR protein relative to controls.
+Added: We evaluated SION-451 in the presence or absence of SION-2222 or SION-109, and SION-719 in the presence or absence of ETI.
+Added: As shown in Figure 21, treatment with either NBD1 stabilizer, as single agents or in combination with other complementary modulators, increased F508del-CFTR half-life to that of wild-type CFTR.
+Added: In comparison, treatment with ETI alone had a minimal effect on F508del-CFTR half-life.
SION-719 and SION-451 Normalized CFTR Function in CFHBE Model at E max
1 unchanged sentence
The results of the SION-719 and SION-451 studies are shown in Figure 22.
−Removed: In Figure 21, CFTR activity is expressed as a ratio relative to ETI at E max .
+Added: In Figure 22, CFTR activity is expressed as a ratio relative to ETI at Emax.
The vertical bars represent the mean CFTR channel activity (+/- standard error of eight replicates) from a representative study in homozygous F508del CFHBE cells in response to the treatments indicated.
The dashed line represents the average response to ETI in each study.
−Removed: SION-719 and SION-451 Were Highly Active in the CFHBE Model at E max
−Removed: In our CFHBE model, both SION-719 and SION-451, in dual combinations with galicaftor or SION-109, improved in vitro F508del-CFTR activity to wild-type levels, when administered at E max .
−Removed: This was a more than 1.5-fold improvement in CFTR protein activity compared to the improvement in such activity observed with ETI at E max in the same experiment.
+Added: In our CFHBE model, SION-719 when added to ETI and SION-451 in dual combinations with SION-2222 or SION-109, improved in vitro F508del-CFTR activity to wild-type levels, when administered at E max .
As noted above, improvements in CFTR function we observed in our CFHBE model have been highly correlated with mean improvements in sweat chloride levels and mean improvements in lung function.
−Removed: SION-719 and SION-451 Combinations with Galicaftor or SION-109 Were Highly Active in the CFHBE Model at E max
−Removed: Based on our findings in these preclinical studies and the strong correlation between chloride conductance and improved clinical activity, we believe that both SION-719 and SION-451, in combination with a complementary CFTR modulator, have the potential to achieve significant improvement in CFTR function, as measured by sweat chloride levels and lung function, and thereby have the potential to lead to clinically meaningful benefit for CF patients.
−Removed: However, the results observed from our preclinical studies may not necessarily be predictive of clinical outcomes, and actual outcomes may differ.
−Removed: We will need to complete additional clinical studies to determine the safety and efficacy of SION-719 and SION-451.
+Added: Based on our findings in these preclinical studies and the strong correlation between chloride conductance and improved clinical activity, we believe that SION-719 in combination with ETI and SION-451 in combination with a complementary CFTR modulator, have the potential to achieve significant improvement in
+Added: CFTR function, as measured by sweat chloride levels and lung function, and thereby have the potential to lead to clinically meaningful benefit for CF patients.
Setting Initial Clinical Exposure Targets Based on CFHBE Model
To set total plasma concentration targets in our Phase 1 clinical trials with SION-719 and SION-451 in healthy volunteers, we conducted multiple dose response studies of both compounds in our CFHBE model that assessed F508del-CFTR activity as a function of each compound’s concentration in cell culture media supplemented with human serum to 20% by volume.
−Removed: We selected a target exposure for our Phase 1 trials based on an average of these preclinical dose response studies along with studies to define an adequate safety
−Removed: Figure 23 below presents illustrative dose responses of SION-719, as a single agent and in combination with ETI, SION-109 or galicaftor (SION-2222), as a function of the fold efficacy (CFTR activity) of ETI at increasing dose concentrations, in CFHBE cells from single donors.
+Added: We selected a target exposure for our Phase 1 trials based on an average of these preclinical dose response studies along with studies to define an adequate safety margin.
+Added: Figure 23 below presents illustrative dose responses of SION-719, as a single agent and in combination with ETI, SION-109 or SION-2222, as a function of the fold efficacy (CFTR activity) of ETI at increasing dose concentrations, in CFHBE cells from single donors.
The black dotted horizontal line indicates ETI’s improvement in F508del-CFTR activity at E max , the teal horizontal line indicates our minimum target for clinically meaningful improvement in F508del-CFTR activity based on our CFHBE assay, and the green horizontal line represents the lower bound of the CFTR activity range observed across a panel of eight CFTR wild-type CFHBE donors.
1 unchanged sentence
A roughly two-fold increase over ETI, as seen with SION-719 treatment at its E max in each of the three combinations, is in the range of wild-type channel activity.
−Removed: Representative ΔF508/ΔF508 CFHBE Dose-Response of SION-719 as Single Agent and in Combination with ETI, SION-109 or SION-2222
ETI = 3 μM Elexacaftor + 45 μM Tezacaftor + 0.3 μM Ivacaftor.
SION-109 and SION-2222 were used at 3 μM.)
−Removed: Figure 24 below presents illustrative dose responses of SION-451, as a single agent and in combination with ETI, SION-109 or galicaftor (SION-2222), as a function of the fold efficacy (CFTR activity) of ETI at increasing dose concentrations, in CFHBE cells from single donors.
+Added: Figure 24 below presents illustrative dose responses of SION-451, as a single agent and in combination with ETI, SION-109 or SION-2222, as a function of the fold efficacy (CFTR activity) of ETI at increasing dose concentrations, in CFHBE cells from single donors.
A roughly two-fold increase over ETI, as seen with SION-451 treatment at its E max in each of the three combinations, is in the range of wild-type channel activity.
−Removed: Representative ΔF508/ΔF508 CFHBE Dose-Response of SION-451 as Single Agent and in Combination with ETI, SION-109 or SION-2222
ETI = 3 μM Elexacaftor + 45 μM Tezacaftor + 0.3 μM Ivacaftor.
8 unchanged sentences
We have nominated two additional NBD1 stabilizers as development candidates.
−Removed: Complementary Programs
−Removed: We have established a pipeline of proprietary complementary modulators, representing three different mechanisms of action, TMD1-directed correctors, an ICL4-directed corrector, and a potentiator, that can potentially be combined with our NBD1 stabilizers.
−Removed: Our two prioritized clinical-stage complementary modulators are galicaftor (SION-2222) and SION-109.
−Removed: Following completion of our NBD1 stabilizer Phase 1 clinical trials, we plan to evaluate galicaftor and/or SION-109 in dual combination with an NBD1 stabilizer in Phase 1 MAD trials in healthy volunteers.
−Removed: Our portfolio includes additional complementary compounds that we may advance for future combination development with an NBD1 stabilizer, including navocaftor, which has been evaluated in Phase 1 and Phase 2 clinical trials, including in combination with galicaftor, provides our pipeline with a third mechanism of action complementary to NBD1 stabilizers and future opportunities to develop additional combination products to potentially expand our CF franchise.
+Added: Complementary Modulator Programs
+Added: There are two types of complementary modulators:
+Added: correctors, which partially improve CFTR protein folding to aid its trafficking to the cell surface, and potentiators, which increase CFTR channel function by enabling chloride flow through the cell membrane.
+Added: We have established a pipeline of proprietary complementary modulators, representing three different mechanisms of action:
+Added: TMD1-directed correctors, an ICL4-directed corrector, and a potentiator.
+Added: Our two prioritized clinical-stage complementary modulators are SION-2222 and SION-109.
+Added: We are currently evaluating each of SION-2222 and SION-109 in dual combinations with SION-451 in a Phase 1 trial in healthy volunteers.
Clinical Data — Complementary Modulators
−Removed: TMD1 Programs—Galicaftor (SION-2222) and SION-2851
−Removed: In a Phase 2 clinical trial conducted by AbbVie prior to our in-licensing transaction, galicaftor demonstrated clinical activity in improving sweat chloride and lung function as part of a combination trial with navocaftor.
−Removed: Galicaftor has been evaluated in Phase 1, Phase 1b and Phase 2 clinical trials involving healthy subjects and CF patients.
−Removed: Galicaftor was generally well-tolerated at all doses administered.
−Removed: The majority of adverse events were mild to moderate in severity.
−Removed: No serious adverse events were reported in healthy volunteers, and among CF patients, serious adverse events were reported infrequently and consisted of common manifestations of the underlying CF disease.
−Removed: Based on galicaftor’s preclinical profile, we do not expect significant PK or drug/drug interactions with our NBD1 stabilizers or other complementary modulators.
−Removed: The PK profile of galicaftor in CF patients was similar to that observed in healthy volunteers.
−Removed: The activity of galicaftor in patients with CF has been evaluated in three randomized, double-blind, placebo-controlled Phase 2 trials, as summarized below.
−Removed: Trials GLPG-2222-CL-201 and GLPG-2222-CL-202 had at least 80% power to detect selected changes in sweat chloride.
−Removed: In clinical trials, least squares means, or “LS means,” represent the average predicted values of the outcome variable in a statistical model and estimate the effect of a treatment while controlling for other covariates that may influence the outcome.
−Removed: These means provide a clearer comparison between treatment groups by minimizing potential biases from imbalanced covariates.
−Removed: A confidence interval (“CI”) is a range of values, derived from the sample data, that is believed to contain the treatment effect with a specified level of confidence, usually 95%.
−Removed: In clinical trials, the p-value quantifies the probability of observing the trial results (or more extreme results) assuming there is no effect or no difference between treatment groups.
−Removed: A p-value of < 0.05 is generally considered statistically significant, meaning that the probability of the results occurring by chance alone is less than five percent.
−Removed: • Trial M19-530 was a Phase 2 dose-ranging trial conducted by AbbVie in Europe and the U.S.
−Removed: to evaluate the safety, tolerability and efficacy of navocaftor alone and in combination with galicaftor in 76 CF patients that were homozygous for F508del mutation.
−Removed: The primary efficacy endpoint of this trial was
−Removed: absolute change in lung function (ppFEV 1 ) from baseline (day 1) through day 29.
−Removed: The trial was completed in June 2022.
−Removed: • This trial included eight total arms:
−Removed: a single placebo arm, two arms with different doses of navocaftor in combination with placebo for galicaftor, and five treatment arms across a range of doses of galicaftor (doses 10 mg, 30 mg, 100 mg, 200 mg, 300 mg once daily (“QD”)) in combination with navocaftor 150 mg for 28 days.
−Removed: • The mean absolute change from baseline in ppFEV 1 from baseline through Day 29 ranged from -0.1 to 3.5 percentage points for the five dual combination dose groups (navocaftor 150 mg and galicaftor across a range of doses).
−Removed: The least squares means (“LS means”) change from baseline in ppFEV1 was statistically significant in the 200 mg and 300 mg galicaftor combination groups, 3.5 ppFEV 1 (p<0.05) and 3.1 ppFEV 1 (p<0.05), respectively.
−Removed: These data are from the analysis in which all spirometry values were used, regardless of usage status of bronchodilator or airway clearance regimen before spirometry collection.
−Removed: LS means with standard errors (“SE”) and p-values are from mixed-effect model repeat measures analysis.
−Removed: • AbbVie also assessed sweat chloride improvement as a secondary efficacy endpoint.
−Removed: Mean SwCl improvement occurred in all groups with galicaftor 30 mg or higher, with improvement of 18.6 mmol/L in the 200 mg group (p<0.001) and 19.9 mmol/L in the 300 mg group (p<0.001).
−Removed: • Galicaftor was generally well-tolerated in combination with navocaftor in this trial.
−Removed: Most reported AEs were mild to moderate in severity.
−Removed: Two serious adverse events (“SAEs”) occurred in two subjects receiving galicaftor in combination with navocaftor (ileus and cholecystitis acute);
−Removed: both were considered unrelated to the trial drugs by the investigator.
−Removed: • Trial GLPG-2222-CL-202 was a Phase 2 dose-ranging trial conducted by Galapagos in Europe and the U.S.
−Removed: to evaluate the safety and tolerability and the effect on CFTR function (as assessed by sweat chloride), pulmonary function and the Cystic Fibrosis Questionnaire— Revised (“CFQ-R”), which measures health-related quality of life, of galicaftor in 59 CF patients that were homozygous for F508del mutation.
−Removed: The trial was completed in October 2017.
−Removed: • Four doses of galicaftor were tested in this trial (50 mg, 100 mg, 200 mg, 400 mg QD) over 29 days.
−Removed: • Galicaftor was generally well-tolerated in this trial.
−Removed: The majority of reported treatment-emergent AEs were mild or moderate in severity.
−Removed: A total of four SAEs were reported (two after galicaftor, two after placebo) in two subjects in the pooled placebo and one subject in the galicaftor 100 mg QD treatment group, respectively.
−Removed: The three subjects experienced one or two events of infective pulmonary exacerbation of CF, all of which were considered not related to trial drug.
−Removed: • Sweat chloride levels, lung function (ppFEV 1 ) and CFQ-R were also assessed as secondary endpoints.
−Removed: Mean sweat chloride concentrations decreased dose-dependently with increasing doses of galicaftor, with a maximum decrease observed in the 200 mg QD treatment group on days 15 and 29, with statistically significant LS means differences compared to placebo of -11.2 (95% CI, -19.1;
−Removed: p=0.0062) and -15.8 (95% CI, -23.2;
−Removed: p<0.0001) mmol/L, respectively.
−Removed: After termination of the trial drug, mean sweat chloride concentrations returned to baseline values in all treatment groups.
−Removed: Percent predicted FEV 1 and CFQ-R did not significantly improve in any group.
−Removed: • Trial GLPG-2222-CL-201 was a Phase 2 trial conducted by Galapagos in Europe and Australia that evaluated the safety and tolerability and the effect on CFTR function (sweat chloride), lung function (ppFEV 1 ) and CFQ-R of galicaftor in 37 CF patients that were heterozygous for F508del and a gating mutation, receiving ivacaftor.
−Removed: The trial was completed in August 2017.
−Removed: • Two doses of galicaftor were tested in this trial (150 mg or 300 mg QD) over 29 days.
−Removed: • Galicaftor was well-tolerated in this trial.
−Removed: Most treatment-emergent AEs were mild in severity, and there were no SAEs.
−Removed: • Changes from baseline in sweat chloride, ppFEV 1 and CFQ-R at day 29 were also assessed as secondary endpoints.
−Removed: The galicaftor 300 mg QD treatment group had a statistically significant LS means with CI difference compared to placebo of -11.7 (95% CI, -21.1;
−Removed: -2.2) mmol/L (p=0.0170).
−Removed: There were no statistically significant changes in sweat chloride in the 150 mg and 300 mg treatment groups.
−Removed: Lung function and CFQ-R did not significantly improve in any group.
−Removed: All results are described for the modified intent to treat population, which excluded one subject who received an incorrect trial kit.
−Removed: These Phase 2 results demonstrated that galicaftor as a single agent increased CFTR activity in patients with the F508del mutation.
−Removed: The activity of galicaftor in combination with navocaftor in Trial M19-530 was similar to the activity of approved dual combination modulators, as seen via indirect, cross-trial comparisons and as predicted based on our CFHBE model (Figure 25).
−Removed: These data supported the selection of a 200 mg dose QD of galicaftor for subsequent trials in combination with navocaftor.
−Removed: Galicaftor + Navocaftor Combination Showed Similar Activity to Symdeko in Phase 2 Cross-Trial Comparison
−Removed: In addition to galicaftor, we licensed SION-2851 from AbbVie in July 2024.
+Added: TMD1 Programs—SION-2222 and SION-2851
+Added: SION-2222 is currently being evaluated in a dual combination with SION-451 in a Phase 1 healthy volunteer trial.
+Added: In a Phase 2 clinical trial conducted by AbbVie prior to our in-licensing transaction, SION-2222 demonstrated clinical activity in improving sweat chloride and lung function as part of a combination trial with SION-3067.
+Added: SION-2222 has been evaluated in Phase 1, Phase 1b and Phase 2 clinical trials involving healthy participants and CF patients.
+Added: Across these studies, SION-2222 was generally well-tolerated at all doses administered.
+Added: The majority of adverse events (“AEs”) were mild to moderate in severity.
+Added: No SAEs were reported in healthy volunteers, and among CF patients, SAEs were reported infrequently and consisted of common manifestations of the underlying CF disease.
+Added: The PK profile of SION-2222 in CF patients was similar to that observed in healthy volunteers.
+Added: The activity of SION-2222 in patients with CF has been evaluated in three randomized, double-blind, placebo-controlled Phase 2 trials:
+Added: trial M19-530, conducted by AbbVie, and trials GLPG-2222-CL-201 and GLPG-2222-CL-202, conducted by Galapagos NV (“Galapagos”).
+Added: Trial M19-530 was a Phase 2 dose-ranging trial that evaluated the safety, tolerability and efficacy of SION-3067 alone and in combination with SION-2222 in CF patients that were homozygous for F508del mutation.
+Added: The primary efficacy endpoint of this trial was absolute change in lung function (ppFEV1), and the secondary efficacy endpoint was improvement in sweat chloride.
+Added: In this trial, treatment with SION-2222 in combination with SION-3067 was associated with improvements from baseline ppFEV1 and sweat chloride, both compared to placebo, as shown in Figure 25.
+Added: SION-2222 was generally well tolerated in combination with SION-3067.
+Added: Most AEs were mild to moderate.
+Added: Two SAEs were reported in two participants receiving SION-2222 in combination with SION-3067, which investigators considered unrelated to study drug.
+Added: Trial GLPG-2222-CL-202 was a Phase 2 dose-ranging trial that evaluated the safety and tolerability and the effect of SION-2222 on CFTR function (as assessed by sweat chloride), lung function (as assessed by ppFEV 1 ) and the Cystic Fibrosis Questionnaire— Revised (“CFQ-R”), which measures health-related quality of life, in CF patients that were homozygous for F508del mutation.
+Added: In this trial, mean sweat chloride concentrations decreased dose-dependently with increasing doses of SION-2222;
+Added: the decrease was statistically significant in the 200 mg dose group.
+Added: ppFEV1 and CFQ-R did not significantly improve in any group.
+Added: SION-2222 was generally well-tolerated in this trial.
+Added: The majority of reported TEAEs were mild or moderate in severity.
+Added: SAEs reported were considered not related to study drug.
+Added: Trial GLPG-2222-CL-201 was a Phase 2 trial that evaluated the safety and tolerability and the effect of two dose levels of SION-2222 in CF patients that were heterozygous for the F508del mutation and a gating mutation, receiving ivacaftor, on CFTR function (as assessed by sweat chloride), lung function (as assessed by ppFEV 1 ) and CFQ-R.
+Added: In this trial, one SION-2222 treatment group (300 mg once daily) was associated with an improvement in sweat chloride compared to placebo, while other dose treatment groups did not show
+Added: statistically significant changes in sweat chloride.
+Added: ppFEV1 and CFQ-R did not significantly improve in any group.
+Added: SION-2222 was generally well-tolerated in this trial.
+Added: Most TEAEs were mild in severity, and there were no SAEs.
+Added: These Phase 2 results demonstrated that SION-2222 as a single agent increased CFTR activity in patients with the F508del mutation.
+Added: The activity of SION-2222 in combination with SION-3067 in Trial M19-530 was similar to the activity of approved dual combination modulators, as seen via indirect, cross-trial comparisons and as predicted based on our CFHBE model (Figure 25).
+Added: In addition to SION-2222, we licensed SION-2851 from AbbVie in July 2024.
SION-2851 is a potent TMD1-directed corrector that has completed a Phase 1 SAD trial in healthy volunteers.
The trial was conducted by AbbVie and Galapagos in Belgium in 2018.
−Removed: The primary endpoint was safety and tolerability, assessed by the number of subjects with adverse events.
+Added: The primary endpoint was safety and tolerability, assessed by the number of participants with adverse events.
Based on its mechanism of action and preclinical studies, we believe it may be potentially synergistic with NBD1 stabilizers.
1 unchanged sentence
We are also advancing SION-109, which targets the ICL4 interface, for development in combination with an NBD1 stabilizer.
−Removed: In December 2024, we completed a randomized, double blind, placebo-controlled Phase 1 clinical trial of SION-109 in healthy subjects, following clearance of its Investigational New Drug application ("IND") by the U.S.
−Removed: Food and Drug Administration (the "FDA") in June 2023.
−Removed: The trial was conducted in the U.S.
−Removed: and was designed to evaluate the safety, tolerability and PK profile of single and multiple ascending doses of SION-109, administered as an oral suspension.
−Removed: In a Part C of the Phase 1 trial, we evaluated the effect of food on PK and the bioequivalence of a tablet formation compared to the oral suspension used in the Phase 1 SAD and MAD trials.
−Removed: 102 healthy adult subjects were dosed in this Phase 1 trial.
−Removed: The trial was designed to enroll 8 subjects, randomized 3:1 active:placebo, to each dosing cohort.
+Added: SION-109 is currently being evaluated in combination with SION-451 in our ongoing Phase 1 dual combination trial.
+Added: In December 2024, we completed a randomized, double blind, placebo-controlled Phase 1 clinical trial of SION-109 in healthy participants, following clearance of its Investigational New Drug application ("IND") by the FDA in June 2023.
+Added: The trial was designed to evaluate the safety, tolerability and PK profile of single and multiple ascending doses of SION-109, administered as an oral suspension.
+Added: In a Part C of the Phase 1 trial, we evaluated the effect of food on PK and the bioequivalence of a tablet formation compared to the oral suspension used in the Phase 1 SAD and MAD cohorts.
+Added: Over 100 healthy adult participants received SION-109 in this Phase 1 trial.
+Added: The trial was designed to enroll eight participants, randomized 3:1 active:placebo, to each dosing cohort.
Six SAD cohorts evaluated single doses from 50 mg to 400 mg.
−Removed: Five MAD cohorts evaluated from 50 mg to 150 mg BID over 10 dosing days.
−Removed: 15 subjects enrolled in the open-label food effect and tablet bioequivalence part evaluating 100 mg single doses each of suspension fasted, tablet fasted, and tablet fed.
+Added: Five MAD cohorts evaluated from 50 mg to 150 mg BID over ten dosing days.
+Added: Fifteen participants enrolled in the open-label food effect and tablet bioequivalence part evaluating 100 mg single doses each of suspension fasted, tablet fasted, and tablet fed.
SION-109 was generally well tolerated at all dose levels administered in all parts of this Phase 1 trial.
4 unchanged sentences
A 150 mg MAD cohort was repeated with revised sampling guidance, and no increased potassium values were observed.
−Removed: Isolated and transient increases in transaminases were observed associated with four AEs in three subjects in the MAD and Part C (one Grade 1 AE, two Grade 2 AEs and one Grade 3 AE) whose values returned to the normal range in follow-up.
−Removed: Other liver function tests, including bilirubin, were unremarkable.
+Added: Isolated and transient increases in transaminases were observed associated with four AEs in three participants in the MAD and Part C (one Grade 1 AE, two Grade 2 AEs and one Grade 3 AE) whose values returned to the normal range in follow-up.
+Added: Other liver function tests,
+Added: including bilirubin, were unremarkable.
There were no clinically meaningful, treatment-emergent trends in other safety parameters, vital signs or electrocardiograms.
−Removed: Phase 1 TEAEs for SION-109 in the MAD Portion of the Trial
Safety observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)
3 unchanged sentences
The PK observed was consistent with BID dosing.
−Removed: Phase 1 PK Summary for SION-109 in the MAD Portion of the Trial
−Removed: (Each solid line shows mean concentration data for a dosing cohort over 10 days of dosing.
+Added: Each solid line shows mean concentration data for a dosing cohort over ten days of dosing.
Data points for Day 2 through Day 9 are trough (pre-dose) concentrations.
−Removed: The dotted line represents the Cminimum (trough) PK exposure target for SION-109, with the aim to achieve targeted exposure to deliver clinically meaningful benefit when administered in a proprietary dual combination with SION-451 or SION-719, based on CFHBE assay
+Added: The dotted line represents the Cminimum (trough) PK exposure target for SION-109, with the aim to achieve targeted exposure to deliver clinically meaningful benefit when administered in a proprietary dual combination, based on CFHBE assay data.
PK observations in the SAD and Part C portions of the trial were generally consistent with the MAD findings shown.)
−Removed: Potentiator Program—Navocaftor (SION-3067)
−Removed: Navocaftor is a clinical-stage potentiator of CFTR gating activity that we have licensed from AbbVie.
−Removed: Navocaftor provides our pipeline with a third mechanism of action complementary to NBD1 stabilizers and future opportunities to develop additional combination products to potentially expand our CF franchise.
−Removed: Navocaftor has completed Phase 1, Phase 1b and Phase 2 trials in over 300 subjects and was generally well-tolerated in CF subjects and healthy volunteers, with improvements observed in sweat chloride levels in combination with galicaftor.
−Removed: In Phase 1 trials evaluating safety and tolerability in healthy subjects, navocaftor was generally well-tolerated in combination with galicaftor, in each case at doses up to 500 mg BID for 14 days.
−Removed: These trials were conducted in Europe and the U.S.
−Removed: In addition, navocaftor has been generally well-tolerated in both CF subjects and healthy volunteers.
−Removed: When navocaftor was given as a monotherapy or in combination with galicaftor, all AEs were mild to moderate.
+Added: Potentiator Program—SION-3067
+Added: SION-3067 is a clinical-stage potentiator of CFTR gating activity that we have licensed from AbbVie.
+Added: SION-3067 provides our pipeline with a third mechanism of action complementary to NBD1 stabilizers and future opportunities to develop additional combination products to potentially expand our CF franchise.
+Added: SION-3067 has completed Phase 1, Phase 1b and Phase 2 trials and was generally well-tolerated in CF patients and healthy volunteers, with improvements observed in sweat chloride levels in combination with SION-2222.
+Added: When SION-3067 was given as a monotherapy or in combination with SION-2222, all AEs were mild to moderate.
The PK profile in CF patients was similar in healthy volunteers.
−Removed: The activity of navocaftor in patients with CF was evaluated in a randomized, double-blind, placebo-controlled Phase 2 trial in combination with a galicaftor dose range from 10 mg to 300 mg QD, as summarized above.
−Removed: Combination treatment of navocaftor 150 mg QD with galicaftor resulted in improvements in FEV 1 and sweat chloride levels in the homozygous F508del population.
−Removed: As expected, treatment with 50 mg QD or 150 mg QD navocaftor monotherapy for 28 days did not result in improvements in FEV 1 or sweat chloride levels.
+Added: The activity of SION-3067 in patients with CF was evaluated in a randomized, double-blind, placebo-controlled Phase 2 trial in combination with SION-2222, as summarized above.
+Added: Combination treatment of SION-3067 150 mg QD with SION-2222 resulted in improvements in FEV 1 and sweat chloride levels in the homozygous F508del population.
+Added: As expected, treatment with 50 mg QD or 150 mg QD SION-3067 monotherapy for 28 days did not result in improvements in FEV 1 or sweat chloride levels.
Manufacturing
6 unchanged sentences
Given our stage of development, we have not yet established a commercial organization or distribution capabilities.
−Removed: The CF patient populations are well-characterized and clearly identified in the U.S., Canada, Europe and several other regions around the world, with highly active and informed CF patient advocacy groups.
−Removed: Most CF patients are treated at a limited number of centralized CF patient care centers by a team of healthcare professionals who are experts in and dedicated to treating CF.
+Added: The CF patient populations are well-characterized and clearly identified in the U.S., Canada, Europe, Australia, and several other regions around the world, with highly active and informed CF patient advocacy groups.
+Added: Most CF patients are treated at a limited number of centralized CF patient care centers by teams of healthcare professionals who are experts in and dedicated to treating CF.
We plan to independently commercialize our products, if approved, in the U.S.
−Removed: and other regions where we determine it makes commercial sense to do so.
−Removed: Given the established CF patient care centers and identified teams of healthcare professionals, we believe we could commercialize our product(s) for CF with a relatively small specialty sales force that calls on a limited and focused group of prescribing healthcare professionals.
−Removed: At the appropriate time, we will recruit a sales force and a medical affairs team and take other steps to establish the necessary commercial infrastructure.
−Removed: As product candidates advance through our pipeline, our plans may change.
+Added: and in other regions where we determine it makes commercial sense to do so.
+Added: Given the established CF patient care centers and the concentrated group of prescribing healthcare professionals, we believe we could commercialize our product(s) for CF with a relatively small specialty sales force focused on CF treatment centers and prescribers.
+Added: At the appropriate time, and subject to regulatory approval and the scope of any approved indication, we plan to recruit a sales force and expand our medical affairs team and take other steps to establish the necessary commercial infrastructure.
+Added: As our product candidates advance through our pipeline, our plans may change with respect to the timing, scope and manner of commercialization.
The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.
−Removed: While we believe we have competitive advantages, we face substantial competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic research institutions and governmental
−Removed: agencies, and public and private research institutions.
+Added: While we believe we have competitive advantages, we face substantial competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic research institutions and governmental agencies, and public and private research institutions.
This may include other small-molecule drug discovery companies using similar approaches or other types of therapies, such as small molecule, gene therapy, gene editing and/or mRNA therapies.
In particular, we expect to compete with Vertex, which has multiple approved products, as well as additional product candidates in development, for the treatment of CF that would compete with our product candidates, if approved.
−Removed: Vertex is the manufacturer of the five approved CFTR modulators, including the standard of care, Trikafta, a triple combination therapy approved for patients with at least one F508del mutation or responsive mutations based on in vitro data.
−Removed: Vertex's marketed products generated approximately $11 billion in sales in 2024.
−Removed: In addition, in December 2024, Vertex received approval from the FDA for a second-generation, triple modulator combination, Alyftrek, for treatment of CF in patients aged six years and older who have at least one F508del mutation or another responsive mutation in the CFTR gene.
−Removed: Alyftrek demonstrated non-inferiority to Trikafta in the primary endpoint of two Phase 3 clinical trials, providing patients with similar FEV 1 as Trikafta and sweat chloride improvements of 3 to 8 mmol/L.
+Added: Vertex is the manufacturer of the five approved CFTR modulators, including the standard of care, Trikafta, and the triple modulator combination, Alyftrek, approved in December 2024.
Any product candidates that we successfully develop and commercialize will compete with these existing therapies, as well as any new therapies that may become available in the future that are approved to treat the same diseases for which we may obtain approval for our product candidates.
We may also face competition from other companies attempting to develop therapeutics targeting CF.
−Removed: For example, in January 2025, Fair Therapeutics, Inc.
−Removed: announced completion of enrollment in their phase IIb trial evaluating their CFTR modulators.
+Added: For example, in October 2025, Fair Therapeutics, Inc.
+Added: announced final results from a Phase 2b trial evaluating its CFTR modulators.
Multiple companies are developing CF-utilizing nucleic acid therapies, which are compounds that allow expression of a functional CFTR protein and are relevant for the more than 5,000 people with CF who cannot make full-length CFTR protein and are not eligible for CFTR modulators.
5 unchanged sentences
If our product candidates do not offer advantages over available products, we may not be able to successfully compete against current and future competitors.
−Removed: The key factors affecting the success of our products, if approved, are likely to be their potential efficacy, safety, convenience and availability of reimbursement.
+Added: The key factors affecting the success of our products, if approved, are likely to be their potential efficacy, safety, tolerability, convenience and availability of reimbursement.
Intellectual Property
10 unchanged sentences
In some cases, enforcement of these rights may depend on third party licensors.
−Removed: With respect to both licensed and company-owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the
−Removed: future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same.
+Added: With respect to both licensed and company-owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same.
Patent expiration dates noted in the following paragraphs refer to statutory expiration dates and do not take into account any potential patent term adjustment or extension that may be available.
1 unchanged sentence
We co-own with Sanofi a patent family that discloses and covers each of SION-719 and SION-451 and methods of using SION-719 and SION-451 for the treatment of CF.
−Removed: The patent family is in the Patent Cooperation Treaty (“PCT”) stage and is also pending in Argentina and Taiwan.
+Added: The patent family has entered the national phase and is pending in the United States, Argentina, Australia, Brazil, Canada, Chile, China, Colombia, Ecuador, Egypt, Eurasian Patent Organization, European Patent Office, Hong Kong, India, Israel, Jordan, Japan, Mexico, New Zealand, Oman, Peru, Qatar, Saudi Arabia, Singapore, South Africa, South Korea, Taiwan, and the United Arab Emirates.
The statutory expiration for this family is September 2043.
2 unchanged sentences
We exclusively license from Sanofi one patent family that discloses and covers SION-109 and methods of using SION-109 for the treatment of CF.
−Removed: The patent family has entered national phase and is pending in the U.S., the European Patent Office, African Regional Industrial Property Organization, African Intellectual Property Organization, Algeria, Australia, Bahrain, Brazil, Canada, Chile, China, Colombia, Eurasian Patent Office, Ecuador, Egypt, Guatemala, Hong Kong, Honduras, Indonesia, Israel, India, Jordan, Japan, Kuwait, Mexico, Malaysia, New Zealand, Nigeria, Oman, Panama, Peru, Philippines, Saudi Arabia, Singapore, South Africa, South Korea, Sri Lanka, Thailand, the United Arab Emirates and Vietnam.
+Added: The patent family has entered national phase and is pending in the U.S., the European Patent Office, African Regional Industrial Property Organization, African Intellectual Property Organization, Algeria, Australia, Bahrain, Brazil, Canada, Chile, China, Colombia, Eurasian Patent Office, Ecuador, Egypt, Guatemala, Hong Kong, Honduras, Israel, India, Jordan, Japan, Kuwait, Mexico, Malaysia, New Zealand, Nigeria, Oman, Panama, Peru, Philippines, Saudi Arabia, Singapore, South Africa, South Korea, Sri Lanka, Thailand and the United Arab Emirates.
The statutory expiration for this family is November 2040.
−Removed: We exclusively license from AbbVie one patent family that discloses and covers galicaftor and methods of using galicaftor for the treatment of CF.
−Removed: The patent family includes granted patents in the U.S., Albania, Argentina, Austria, Australia, Belgium, Bulgaria, Brazil, Canada, Chile, China, Colombia, Costa Rica, Croatia, Czech Republic, Cyprus, Denmark, Dominican Republic, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Indonesia, Ireland, Israel, Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Malaysia, Mexico, Monaco, Netherlands, Norway, Panama, Peru, Poland, Portugal, Republic of North Macedonia, Romania, Russia, San Marino, Serbia, Singapore, Slovakia, Slovenia, Spain, South Africa, South Korea, Sweden, Switzerland, Turkey, Taiwan, Ukraine, the United Kingdom and Uruguay, and has a statutory expiration date of October 2035.
We exclusively license from AbbVie one patent family that discloses and covers SION-2222 and methods of using SION-2222 for the treatment of CF.
−Removed: The patent family includes granted patents in the U.S., Australia, Brazil, Canada, Chile, China, Colombia, Costa Rica, Dominican Republic, France, Germany, India, Indonesia, Israel, Italy, Japan, Malaysia, Mexico, Panama, Peru, Pakistan, Russia, Singapore, Spain, South Africa, Taiwan, Ukraine, the United Kingdom, Uruguay and Vietnam, and has a statutory expiration date of July 2036.
+Added: The patent family includes granted patents in the United States, Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Costa Rica, Croatia, Czech Republic, Denmark, Dominican Republic, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Mexico, Monaco, Netherlands, Norway, Panama, Peru, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, Uruguay, and Vietnam, and has a statutory expiration date of October 2035.
We exclusively license from AbbVie one patent family that discloses and covers SION-2851 and methods of using SION-2851 for the treatment of CF.
−Removed: The patent family includes granted patents in the U.S., Albania, Austria, Australia, Belgium, Bulgaria, Chile, China, Colombia, Costa Rica, Croatia, Czech Republic, Cyprus, Denmark, Dominican Republic, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Ireland, Israel, Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Macao, Malta, Malaysia, Mexico, Monaco, Netherlands, Norway, Panama, Peru, Philippines, Portugal, Poland, Republic of North Macedonia, Romania, Russia, San Marino, Serbia, Singapore, Slovakia, Slovenia, Spain, South Africa, South Korea, Sweden, Switzerland, Turkey and the United Kingdom, a pending application in Canada, and has a statutory expiration date of May 2037.
+Added: The patent family includes granted patents in the United States, Argentina, Australia, Brazil, Canada, Chile, China, Colombia, Costa Rica, Dominican Republic, France, Germany, India, Israel, Italy, Japan,
+Added: Malaysia, Mexico, New Zealand, Pakistan, Panama, Peru, Philippines, Russia, Singapore, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, Uruguay, and Vietnam, and has a statutory expiration date of July 2036.
+Added: We exclusively license from AbbVie one patent family that discloses and covers SION-3067 and methods of using SION-3067 for the treatment of CF.
+Added: The patent family includes granted patents in the United States, Albania, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, China, Colombia, Costa Rica, Croatia, Cyprus, Czech Republic, Denmark, Dominican Republic, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Ireland, Israel, Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Macau, Malta, Mexico, Monaco, Netherlands, New Zealand, North Macedonia, Norway, Panama, Peru, Philippines, Poland, Portugal, Romania, Russia, San Marino, Serbia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Turkey, United Kingdom, and Vietnam, a pending application in Canada and Ecuador, and has a statutory expiration date of May 2037.
Additionally, the patent family includes granted patents in Argentina and Taiwan, each of which has a statutory expiration date of June 2037.
−Removed: We own two patent applications that each disclose and contain claims that recite the use of our NBD1 stabilizer product candidates in combination with SION-109, galicaftor, SION-3067, Trikafta and/or other modulators for the treatment of CF.
−Removed: The first is a PCT international application and has a statutory expiration of October 2043, and the second is a non-provisional patent application, which has a statutory expiration of March 2045.
+Added: We own two patent applications that each disclose and contain claims that recite the use of our NBD1 stabilizer product candidates in combination with SION-109, SION-2222, SION-3067, Trikafta and/or other modulators for the treatment of CF.
+Added: The first is a Patent Cooperation Treaty international application and has a statutory expiration of October 2043, and the second is a non-provisional patent application (discussed above), which has a statutory expiration of March 2045.
Licensing and Collaboration Agreements
2 unchanged sentences
1 dated May 14, 2020, Amendment No.
−Removed: 2 on June 8, 2020, Amendment No.
−Removed: 3 on December 14, 2021, Amendment No.
−Removed: 4 on January 28, 2022, Amendment No.
−Removed: 5 on February 21, 2023 and Amendment No.
−Removed: 6 on October 28, 2024 (as amended, the “Sanofi License Agreement”), with Sanofi, pursuant to which we have been granted an exclusive, worldwide license to develop, commercialize, manufacture, use, hold, keep, register or dispose of certain compounds, patents and proprietary information and inventions, in each case for therapeutic, prophylactic, prognostic and diagnostic purposes in or for humans, subject to retained rights.
+Added: 2 dated June 8, 2020, Amendment No.
+Added: 3 dated December 14, 2021, Amendment No.
+Added: 4 dated January 28, 2022, Amendment No.
+Added: 5 dated February 21, 2023 and Amendment No.
+Added: 6 dated October 28, 2024 (as amended, the “Sanofi License Agreement”), with Sanofi, pursuant to which we have been granted an exclusive, worldwide license to develop, commercialize, manufacture, use, hold, keep, register or dispose of certain compounds, patents and proprietary information and inventions, in each case for therapeutic, prophylactic, prognostic and diagnostic purposes in or for humans, subject to retained rights.
The licensed and derived rights are directed, among other things, to CFTR modulator therapies which are being utilized in SION-719, SION-109 and SION-451.
1 unchanged sentence
Sanofi and its affiliates retain the right to practice under the licensed patents and use the licensed know-how solely to conduct non-clinical research for all therapeutic, prophylactic, prognostic and diagnostic uses in or for humans, other than for CF;
−Removed: provided, however, that Sanofi will not exercise these retained rights until after December 20, 2024, and will not file any patents that claim a licensed compound.
+Added: provided, however, that Sanofi will not file any patents that claim a licensed compound.
As initial consideration for the license, we paid a non-refundable, upfront payment of $1.5 million, as well as a reimbursement of $0.3 million for Sanofi’s research and development expenses.
16 unchanged sentences
CFF Payment Agreement
−Removed: On December 20, 2019, we entered into a payment agreement (the “CFF Payment Agreement”) with CFF, pursuant to which we agreed to provide CFF with compensation in exchange for the grant of, or forbearance from exercising, certain of CFF’s rights existing under the Research, Development and Commercialization Agreement, dated October 1, 2011, by and between CFF (through an assignment by Cystic Fibrosis Foundation Therapeutics, Inc.) and Genzyme Corporation, an affiliate of Sanofi (the “CFFT-Genzyme Agreement”).
+Added: On December 20, 2019, we entered into a payment agreement (the “CFF Payment Agreement”) with CFF, pursuant to which we agreed to provide CFF with compensation in exchange for the grant of, and forbearance from exercising, certain of CFF’s rights existing under the Research, Development and Commercialization Agreement, dated October 1, 2011, by and between CFF (through an assignment by Cystic Fibrosis Foundation Therapeutics, Inc.) and Genzyme Corporation, an affiliate of Sanofi (the “CFFT-Genzyme Agreement”).
As described above, we have been granted a license to certain compounds, patents and know-how pursuant to the Sanofi License Agreement, some of which were generated as a result of a research plan under the CFFT-Genzyme Agreement.
10 unchanged sentences
Further, a side letter was executed between us and Sanofi, which clarifies the relationship between us, Sanofi and CFF, under which we are obligated to pay Sanofi 20% of the milestones it would have been obligated to pay CFF, net of the milestone amounts it is obligated to pay under the Sanofi License Agreement.
−Removed: If at any time prior to the first commercial sale of a product developed as a result of the CFF Payment Agreement, we cease to use commercially reasonably efforts to develop, and obtain and maintain regulatory approvals for, at least one of our products for therapeutic, prophylactic, prognostic or diagnostic uses in or for humans in specified major markets for a continuous period of 365 days, CFF has the option to exercise rights to an exclusive, irrevocable, worldwide interruption license under our patents, the licensed patents and the licensed know-how, to develop, manufacture, use, sell, offer to sell and import any of our products containing a licensed compound or any compound covered by a licensed patent or incorporating licensed know-how.
+Added: If at any time prior to the first commercial sale of a product developed as a result of the CFF Payment Agreement, we cease to use commercially reasonable efforts to develop, and obtain and maintain regulatory approvals for, at least one of our products for therapeutic, prophylactic, prognostic or diagnostic uses in or for humans in specified major markets for a continuous period of 365 days, CFF has the option to exercise rights to an exclusive, irrevocable, worldwide interruption license under our patents, the licensed patents and the
+Added: licensed know-how, to develop, manufacture, use, sell, offer to sell and import any of our products containing a licensed compound or any compound covered by a licensed patent or incorporating licensed know-how.
Either party may terminate the CFF Payment Agreement for a material breach by the other party, subject to a specified notice and cure period.
3 unchanged sentences
The licensed rights are directed, among other things, to three clinical-stage CFTR modulator therapies:
−Removed: galicaftor (ABBV-2222, now referred to as SION-2222), a TMD1-directed CFTR corrector, navocaftor (ABBV-3067, now referred to as SION-3067), a CFTR potentiator, and ABBV-2851 (now referred to as SION-2851), a TMD1-directed corrector.
+Added: SION-2222, a TMD1-directed CFTR corrector, SION-3067, a CFTR potentiator, and SION-2851, a TMD1-directed corrector.
Under the AbbVie License Agreement, we have assumed all global development and commercialization responsibilities for such therapies.
−Removed: Pursuant to the terms of the AbbVie License Agreement, we must use commercially reasonable efforts to develop, pursue
−Removed: regulatory approval for and commercialize a licensed product.
+Added: Pursuant to the terms of the AbbVie License Agreement, we must use commercially reasonable efforts to develop, pursue regulatory approval for and commercialize a licensed product.
We are also required to achieve certain development milestones within specified time periods for products incorporating intellectual property covered by the AbbVie License Agreement.
−Removed: The license granted to us under the AbbVie License Agreement is subject to certain preexisting rights held by AbbVie and Galapagos NV (“Galapagos”).
+Added: The license granted to us under the AbbVie License Agreement is subject to certain preexisting rights held by AbbVie and Galapagos.
In particular, certain of the licensed patents and other intellectual property rights were developed by or on behalf of Galapagos and are sublicensed to us subject to the terms of the second amended and restated collaboration agreement between Galapagos and AbbVie dated as of October 24, 2018 (the “Galapagos License Agreement”), as amended by a side letter between Galapagos and AbbVie dated as of July 11, 2024.
39 unchanged sentences
• satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMP requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;
−Removed: • satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;
+Added: • satisfactory completion of FDA inspections of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;
• FDA review and approval of the NDA.
2 unchanged sentences
Preclinical studies include laboratory evaluations of the product’s chemistry, purity, toxicity, formulation, and stability as well as in vitro and animal studies to assess potential safety and efficacy and in some cases to establish the rationale for therapeutic use.
−Removed: The conduct of
−Removed: preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety and toxicology studies.
+Added: The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety and toxicology studies.
The IND and IRB Process
13 unchanged sentences
When a foreign clinical trial is conducted under an IND, all FDA IND requirements must be met unless waived.
−Removed: When the foreign clinical trial is not conducted under an IND, such as our ongoing Phase 1 clinical trials of SION-719 and SION-451 being conducted in Australia, the sponsor must ensure that the study is conducted in accordance with GCP, including review and approval by an IEC and informed consent from subjects.
+Added: When the foreign clinical trial is not conducted under an IND, the sponsor must ensure that the study is conducted in accordance with GCP, including review and approval by an IEC and informed consent from subjects.
FDA must be able to validate the data from the study through an on-site inspection if necessary.
In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review of the study.
−Removed: The IRB is charged with protecting the welfare and rights of trial participants and considers whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.
+Added: The IRB is charged with protecting the welfare and rights of trial participants and considers whether the risks to individuals participating in the clinical trials are minimized
+Added: and are reasonable in relation to anticipated benefits.
The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects and must monitor the clinical trial until completion.
1 unchanged sentence
Clinical Trials in Support of an NDA
−Removed: Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigator in accordance with GCP requirements, which include the requirement that all research subjects, or their legal representative, provide their informed consent in writing for their participation in any clinical trial.
+Added: Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include the requirement that all research subjects, or their legal representative, provide their informed consent in writing for their participation in any clinical trial.
Clinical trials are conducted under written study protocols detailing, among other things, the exclusion and inclusion criteria, the objectives of the trial, dosing procedures, subject selection, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
1 unchanged sentence
Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.
−Removed: Some studies also include oversight by an independent group of qualified
−Removed: experts organized by the clinical study sponsor, known as a data and safety monitoring board (“DSMB”), which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety or health risk for subjects or other grounds, such as no demonstration of efficacy.
+Added: Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data monitoring committee ("DMC"), which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety or health risk for subjects or other grounds, such as no demonstration of efficacy.
Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health (“NIH”) for public dissemination on their www.clinicaltrials.gov website.
7 unchanged sentences
The investigational drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk/benefit profile of the product, and to provide adequate information for product approval and labeling of the product.
−Removed: Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.
+Added: Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA, although in some cases a single trial may be considered sufficient.
Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.
These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting.
−Removed: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval on an NDA.
+Added: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval for an NDA.
Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.
7 unchanged sentences
Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements.
−Removed: The manufacturing process must be capable of consistently producing quality batches of the
−Removed: product candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product.
+Added: The manufacturing process must be capable of consistently producing quality batches of the product candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product.
Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
17 unchanged sentences
The FDA will not approve an NDA unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
−Removed: In addition, as a condition of approval, or post-approval if it becomes aware of a serious risk associated with the use of the product, the FDA may require the submission of a Risk Evaluation and Mitigation Strategy (“REMS”), if it determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks and to assure the safe use of the drug.
+Added: In addition, as a condition of approval, or post-approval if it becomes aware of a serious risk associated with the use of the product, the FDA may require the submission of a Risk Evaluation and Mitigation Strategy
+Added: (“REMS”), if it determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks and to assure the safe use of the drug.
If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS.
5 unchanged sentences
In addition, under the Pediatric Research Equity Act of 2003, as amended (“PREA”), certain NDAs or supplements to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
−Removed: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of
−Removed: the product for use in adults, or full or partial waivers from the pediatric data requirements.
+Added: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
A sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial Pediatric Study Plan (“PSP”), within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before initiation of the Phase 3 or Phase 2/3 study.
13 unchanged sentences
Even if the FDA approves a product, depending on the specific risk(s) to be addressed, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.
−Removed: The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.
+Added: The FDA may prevent or limit further marketing of a product based on the results of post-marketing
+Added: studies or surveillance programs.
After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.
8 unchanged sentences
If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product is entitled to orphan product exclusivity.
−Removed: Orphan product exclusivity means that the FDA may not approve any other applications to market the same product for the same indication for seven years,
−Removed: except in certain limited circumstances, including if a subsequent product with the same active ingredient for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.
+Added: Orphan product exclusivity means that the FDA may not approve any other applications to market the same product for the same indication for seven years, except in certain limited circumstances, including if a subsequent product with the same active ingredient for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.
Further, the FDA may approve more than one product for the same orphan indication or disease as long as the products contain different active ingredients.
4 unchanged sentences
may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if a second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.
−Removed: The FDA has historically taken the position that the scope of orphan exclusivity aligns with the approved indication or use of a product, rather than the disease or condition for which the product received orphan designation.
−Removed: However, in Catalyst Pharms., Inc.
−Removed: Becerra , 14 F.4th 1299 (11th Cir.
−Removed: 2021), the court disagreed with this position, holding that orphan-drug exclusivity blocked the FDA’s approval of the same drug for all uses or indications within the same orphan-designated disease.
−Removed: On January 24, 2023, the FDA published a notice in the Federal Register to clarify that the FDA intends to continue to apply its longstanding interpretation of the regulations to all matters outside of the scope of the Catalyst order and will continue tying the scope of orphan drug exclusivity to the uses or indications for which a drug is approved.
−Removed: It is unclear how future litigation, legislation, agency decisions and administrative actions will impact the scope of orphan drug exclusivity.
Expedited Development and Review Programs for Drugs
7 unchanged sentences
The FDA may also review sections of the NDA for a Fast Track designated product on a rolling basis before the completed application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.
−Removed: The FDA’s goal for reviewing a Fast Track application does not begin until the last section of the NDA is submitted.
−Removed: Fast Track designation may be lost if the designation is no longer supported by data emerging in the clinical trial process.
+Added: The FDA’s goal for reviewing a Fast Track application does not begin until the last section of the
+Added: NDA is submitted.
+Added: Fast Track designation may be rescinded if the designation is no longer supported by data emerging in the clinical trial process.
Additionally, a drug may be eligible for designation as a Breakthrough Therapy if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
−Removed: The benefits of Breakthrough Therapy designation include the same benefits as Fast Track designation, plus intensive guidance from the FDA to ensure an efficient drug
−Removed: development program.
+Added: The benefits of Breakthrough Therapy designation include the same benefits as Fast Track designation, plus intensive guidance from the FDA to ensure an efficient drug development program.
Breakthrough Therapy designation comes with all of the benefits of Fast Track designation, which means that the sponsor may file sections of the NDA for review on a rolling basis if certain conditions are satisfied, including an agreement with the FDA on the proposed schedule for submission of portions of the application and the payment of applicable user fees before the FDA may initiate a review.
7 unchanged sentences
Significant improvement may be demonstrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes and evidence of safety and effectiveness in a new subpopulation.
−Removed: A priority review designation is intended to direct overall attention and resources to the evaluation of such applications and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months for an NDA for a new molecular entity from the date of filing.
−Removed: If criteria are not met for priority review, the application for a new molecular entity is subject to the standard FDA review period of ten months after FDA accepts the application for filing.
+Added: A priority review designation is intended to direct overall attention and resources to the evaluation of such applications and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months for an NDA from the date of filing.
+Added: If criteria are not met for priority review, the application is subject to the standard FDA review period of ten months after FDA accepts the application for filing.
Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.
12 unchanged sentences
A 505(b)(2) NDA is an application that contains full reports of investigations of safety and efficacy but where at least some of the information required for approval comes from investigations that were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.
−Removed: This regulatory pathway enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy for an existing
−Removed: product, or published literature, in support of its application.
+Added: This regulatory pathway enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy for an existing product, or published literature, in support of its application.
Section 505(j) establishes an abbreviated approval process for a generic version of approved drug products through the submission of an Abbreviated New Drug Application (“ANDA”).
44 unchanged sentences
Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product.
−Removed: After approval, most changes to the approved product, such as adding new indications or other labeling claims are subject to prior FDA review and approval.
+Added: After approval, most changes to the approved product, such as adding new indications or other labeling
+Added: claims are subject to prior FDA review and approval.
There are also annual prescription drug product program fee requirements for marketed products.
24 unchanged sentences
The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
−Removed: In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“PDMA”), which regulates the distribution of drugs and drug samples at the federal level and sets minimum standards for the registration and regulation of drug distributors by the states.
+Added: In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“PDMA”), which regulates the distribution of drugs and drug samples at the federal level and sets
+Added: minimum standards for the registration and regulation of drug distributors by the states.
Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution.
4 unchanged sentences
The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.
−Removed: The federal government has
−Removed: levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion.
+Added: The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion.
The FDA and other regulatory agencies have also required that companies enter into consent decrees and/or imposed permanent injunctions under which specified promotional conduct is changed or curtailed.
3 unchanged sentences
Clinical Trial Approval
−Removed: In April 2014, the European Union adopted a Clinical Trials Regulation (EU) No 536/2014 (the “Clinical Trials Regulation”) which replaced the previous Clinical Trials Directive 2001/20/EC on January 31, 2022.
+Added: In April 2014, the European Union adopted a Clinical Trials Regulation (EU) No 536/2014 (the “Clinical Trials Regulation”) which replaced the previous Clinical Trials Directive 2001/20/EC on January 31, 2022, subject to transitional provisions which meant that since January 31, 2025, all clinical trials in the EU have been subject to the Clinical Trials Regulation.
The Clinical Trials Regulation is directly applicable in all European Union Member States, meaning no national implementing legislation in each European Union Member State is required.
12 unchanged sentences
Under the above described procedures, before granting the MA, the EMA or the competent authorities of the Member States of the European Union make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.
+Added: Following approval, MA holders are subject to ongoing obligations, including pharmacovigilance and safety reporting requirements.
Data and Market Exclusivity
1 unchanged sentence
The data exclusivity, if granted, prevents generic applicants from referencing the innovator’s preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic (abbreviated) MA, for eight years from the date on which the reference product was first authorized in the European Union.
−Removed: During an additional two-year period of market exclusivity, a generic
−Removed: marketing authorization application can be submitted, and the innovator’s data may be referenced, but no generic or medicinal product can be placed on the European Union market until the expiration of the market exclusivity.
+Added: During an additional two-year period of market exclusivity, a generic marketing authorization application can be submitted, and the innovator’s data may be referenced, but no generic or medicinal product can be placed on the European Union market until the expiration of the market exclusivity.
The overall ten-year period may be extended to a maximum of 11 years if, during the first eight years of those ten years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are determined to bring a significant clinical benefit in comparison with existing therapies.
22 unchanged sentences
Healthcare providers, including physicians, and third-party payors play a significant role in determining what drug products are used by patients.
−Removed: Our current and future arrangements with healthcare providers, third
−Removed: party payors, patients and other parties within the healthcare industry as well as our business operations more generally may implicate broadly applicable fraud and abuse and other healthcare laws and regulations.
+Added: Our current and future arrangements with healthcare providers, third party payors, patients and other parties within the healthcare industry as well as our business operations more generally may implicate broadly applicable fraud and abuse and other healthcare laws and regulations.
Within the U.S., restrictions under applicable federal and state healthcare laws and regulations, including certain laws and regulations applicable only if we have marketed products, include the following:
9 unchanged sentences
• federal and state consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;
−Removed: • the so-called federal “sunshine law” or Open Payments which requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Centers for Medicare & Medicaid Services information related to payments and other transfers of value to teaching hospitals, physicians, and other healthcare practitioners, as well as ownership and investment interests held by physicians and their immediate family members;
+Added: • the so-called federal “sunshine law” or Open Payments which requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Centers for Medicare & Medicaid Services information related to payments and other transfers of value to teaching hospitals, physicians, and other healthcare
+Added: practitioners, as well as ownership and investment interests held by physicians and their immediate family members;
• analogous state laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers, and state laws which regulate interactions between pharmaceutical companies and healthcare providers, require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, require pharmaceutical companies to report information on transfers of value to other healthcare providers, marketing expenditures or pricing information and/or require licensing of sales representatives.
−Removed: State laws also govern the privacy and security of health information in some circumstances, many of which differ from
−Removed: each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
+Added: State laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.
13 unchanged sentences
Within the U.S., the federal government and individual states have aggressively pursued healthcare reform.
−Removed: For example, the Affordable Care Act (“ACA”), implemented in 2010, substantially changed the way healthcare is financed by both governmental and private insurers and contains a number of provisions that affect coverage and reimbursement of drug products and/or that could potentially reduce the demand for pharmaceutical products such as increasing drug rebates under state Medicaid programs for brand name prescription drugs and extending those rebates to Medicaid managed care and assessing a fee on manufacturers and importers of brand name prescription drugs reimbursed under certain government programs, including Medicare and Medicaid.
+Added: For example, the Affordable Care Act (“ACA”), implemented in 2010, substantially changed the way healthcare is financed by both governmental and private insurers and contains a number of provisions that
+Added: affect coverage and reimbursement of drug products and/or that could potentially reduce the demand for pharmaceutical products such as increasing drug rebates under state Medicaid programs for brand name prescription drugs and extending those rebates to Medicaid managed care and assessing a fee on manufacturers and importers of brand name prescription drugs reimbursed under certain government programs, including Medicare and Medicaid.
Other aspects of healthcare reform, such as expanded government enforcement authority, could also affect our business.
Beyond the ACA, there have been ongoing health care reform efforts.
−Removed: Drug pricing and payment reform was a focus of the Trump Administration and has been an ongoing focus of the Biden Administration.
+Added: Drug pricing and payment reform has been an ongoing focus of the Trump Administration and was a focus of the Biden Administration.
For example, federal legislation enacted in 2021 eliminated the statutory cap on Medicaid drug rebate program rebates (currently set at 100% of a drug’s “average manufacturer price”) effective January 1, 2024.
−Removed: example, the Inflation Reduction Act of 2022 (“IRA”) includes a number of changes intended to address rising prescription drug prices in Medicare Parts B and D.
−Removed: These changes, which have varying implementation dates, include caps on Medicare Part D out-of-pocket costs for beneficiaries, Medicare Part B and Part D drug price inflation rebates, a new Medicare Part D manufacturer discount drug program (replacing the ACA Medicare Part D coverage gap discount program) and a drug price negotiation program for certain high spend Medicare Part B and D drugs (with the first set of negotiated prices going into effect January 1, 2026).
+Added: As another example, the Inflation Reduction Act of 2022 (“IRA”) includes a number of changes intended to address rising prescription drug prices in Medicare Parts B and D.
+Added: These changes, which have varying implementation dates, include caps on Medicare Part D out-of-pocket costs for beneficiaries, Medicare Part B and Part D drug price inflation rebates, a new Medicare Part D manufacturer discount drug program (replacing the ACA Medicare Part D coverage gap discount program) and a drug price negotiation program for certain high spend Medicare Part B and D drugs (with the first set of negotiated prices having gone into effect January 1, 2026).
The focus on health care reform, including reform of drug pricing and payment, has continued in the wake of the IRA.
−Removed: President Biden has announced initiatives, including executive orders.
−Removed: that have sought to reduce prescription drug and other health care costs.
−Removed: Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden Administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.
−Removed: For example, in 2022, subsequent to the enactment of the IRA, the Biden administration released an executive order directing the HHS to report on how the Center for Medicare and Medicaid Innovation (“CMMI”) could be leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries, which report proposed various models that CMMI is currently developing.
−Removed: Individual states in the U.S.
−Removed: have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
+Added: The One Big Beautiful Bill Act of 2025 (“OBBBA”), for example, imposed significant reductions in Medicaid funding, additional work requirements for Medicaid recipients, and more frequent reenrollment requirements.
+Added: These changes are expected to place substantial pressure on state Medicaid budgets, reduce enrollment, and limit covered services, which could decrease utilization of, and reimbursement for, our products, if approved.
+Added: The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.
+Added: To date, there have been several recent U.S.
+Added: congressional inquiries, as well as proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.
+Added: The Trump Administration has issued executive orders and supported proposed regulatory initiatives in 2025 that could have a significant impact on the prices that we, or any collaborators, may receive for any approved products.
+Added: On May 12, 2025, President Trump signed an executive order directing the Secretary of HHS to set and communicate most-favored-nation (“MFN”) price targets to manufacturers and propose a rulemaking plan to impose MFN pricing if “significant progress” is not made, and also directing the federal government to support regulatory paths to allow direct-to-patient sales for companies that meet these targets.
+Added: The executive order further states that the Administration will take additional action (for example, examining whether marketing approvals should be modified or rescinded or considering individual drug importation waiver authorities) should manufacturers fail to offer American consumers the MFN lowest price.
+Added: In July 2025, President Trump sent letters to certain pharmaceutical companies demanding that these companies extend MFN pricing to Medicaid and newly launched drugs as well as move to direct-to-consumer models priced at MFN pricing, and soliciting binding commitments by September 29, 2025.
+Added: Since this time, multiple drug manufacturers have announced plans to, for certain of their drugs, lower prices to reflect similar pricing around the world, and to sell these reduced-price drugs on a direct-to-consumer purchasing platform developed by the federal government;
+Added: however, it is not known what results will occur to the extent the recipients of these letters do not reduce their U.S.
+Added: On December 19, 2025, CMS released two proposed rules that would incorporate MFN pricing principles into federal reimbursement for prescription drugs.
+Added: The first proposal, the Global Benchmark for Efficient Drug Pricing Model (“GLOBE”) for Medicare Part B, would require manufacturers of specified single source drugs and sole source biologics to pay incremental rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and eligibility criteria.
+Added: The second proposal, the Guarding U.S.
+Added: Medicare Against Rising Drug Costs (“GUARD”) model for Medicare Part D, would similarly mandate manufacturer rebates for qualifying sole source drugs where the Medicare net price exceeds an MFN benchmark derived from international reference pricing methodologies.
+Added: As proposed, GLOBE would begin a five year performance period on October 1, 2026 and GUARD would begin its performance period in 2027.
+Added: These proposals will likely be subject to legal challenges that could delay their implementation or modify their impact
+Added: on manufacturer pricing and revenue.
+Added: Additionally, in November 2025, CMS introduced the GENErating cost Reductions fOr U.S.
+Added: Medicaid (“GENEROUS”) Model, a voluntary MFN framework for manufacturers participating in the Medicaid Drug Rebate Program.
+Added: Although it is voluntary, the GENEROUS Model could also impact the drug pricing landscape for manufacturers.
+Added: Individual states have also been increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
+Added: In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.
+Added: We expect that additional state and federal healthcare reform measures will be adopted in the future, particularly in light of the new presidential administration, any of which could limit the amounts that federal and state governments will pay for healthcare products and services.
Healthcare reform efforts have been and may continue to be subject to scrutiny and legal challenge.
16 unchanged sentences
In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted.
−Removed: As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the product in that country.
+Added: As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price negotiations that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the product in that country.
Adverse pricing limitations may hinder our ability to recoup our investment in one or more product candidates, even if our product candidates obtain marketing approval.
1 unchanged sentence
Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.
−Removed: Coverage and reimbursement by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is:
+Added: Coverage and reimbursement
+Added: by a third-party payor may depend upon a number of factors, including the third-party payor’s determination that use of a product is:
• a covered benefit under its health plan;
24 unchanged sentences
The requirements governing drug pricing vary widely from country to country.
−Removed: For example, the
−Removed: European Union provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.
+Added: For example, the European Union provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.
To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently available therapies.
−Removed: A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.
+Added: A Member State may approve a specific price for the medicinal product or it may instead
+Added: adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.
Historically, products launched in the European Union do not follow price structures of the U.S.
4 unchanged sentences
Numerous state, federal and foreign laws, regulations, and standards govern the collection, use, access to, confidentiality and security of health-related and other personal information and could apply now or in the future to our operations or the operations of our partners.
−Removed: In the U.S., numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure, and protection of health-related and other personal information.
−Removed: In addition, certain foreign laws govern the privacy and security of personal data, including health-related data.
−Removed: Privacy and security laws, regulations and other obligations are constantly evolving, may conflict with each other to complicate compliance.
+Added: In the U.S., such laws and regulations include data breach notification laws, consumer privacy laws, health information privacy and security laws and consumer protection laws.
+Added: Privacy and security laws, regulations and other obligations are constantly evolving and may conflict with each other to complicate compliance.
+Added: The federal government and several states have also recently taken steps to restrict data transactions involving countries outside the U.S.
+Added: For example, the Department of Justice’s January 8, 2025, Rule on Preventing Access to U.S.
+Added: Sensitive Personal Data and Government-Related Data by Countries of Concern or Covered Persons, prohibits transfers of certain types of data, including health data, genetic data, and biospecimens, to countries of concern, including China.
+Added: Actual or alleged violations of these laws and regulations may be punishable by criminal and/or civil sanctions.
Employees and Human Capital Resources
−Removed: As of March 1, 2025, we had 41 full-time employees, of which 13 had M.D.
−Removed: Within our workforce, 22 employees were engaged in research and development and 19 were engaged in business development, finance, legal and general management and administration as of March 1, 2025.
+Added: As of February 15, 2026, we had 59 full-time employees, of which 15 had M.D.
+Added: Within our workforce, 31 employees were engaged in research and development and 28 were engaged in general and administrative activities, including business development, finance, legal and corporate administration as of February 15, 2026.
None of our employees are represented by labor unions or covered by collective bargaining agreements.
1 unchanged sentence
Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and new employees, advisors and consultants.
−Removed: The principal purposes of our equity incentive plans are to attract, retain and reward personnel through the granting of equity-based compensation awards in order to increase shareholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.
+Added: The principal purposes of our equity incentive plans are to attract, retain and reward personnel through the granting of equity-based compensation awards in order to increase shareholder value and support the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.
We believe that our future success largely depends upon our continued ability to attract and retain highly skilled employees.
−Removed: We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, development programs that enable continued learning and growth and a robust employment package that promotes well-being across all aspects of their lives, including health care, retirement planning and paid time off.
−Removed: We believe that much of our success is rooted in the diversity of our teams and our commitment to inclusion.
−Removed: We value diversity at all levels and focus on extending our diversity and inclusion initiatives across our entire workforce.
+Added: We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, professional development programs that enable continued learning and growth and a robust employment package that promotes well-being across multiple aspects of employees' lives, including health care, retirement planning and paid time off.
Corporate Information
We were incorporated under the laws of the State of Delaware in August 2019 under the name Sling Therapeutics, Inc., and changed our name to Sionna Therapeutics, Inc.
−Removed: in July 2021.
+Added: in November 2021.
Our principal executive offices are located at 21 Hickory Drive, Suite 500, Waltham, MA 02451, and our telephone number is (617) 819-2020.
4 unchanged sentences
We have included our website address in this Annual Report solely as an inactive textual reference.
−Removed: Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and 15(d) of the Securities Exchange Act of 1934, as amended, are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (the "SEC").
+Added: Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and
+Added: 15(d) of the Securities Exchange Act of 1934, as amended, are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (the "SEC").
Information on our website is not part of this Annual Report or any of our other securities filings unless specifically incorporated herein by reference.
5 unchanged sentences
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.