Assessment of Multiple-Dose Pharmacokinetics and Safety of the Co-administration of Galicaftor, Navocaftor and ABBV-576 and Potential of ABBV-576 for CYP3A Induction in Healthy Volunteers

Start Date20 Sep 2022

Sponsor / Collaborator

AbbVie, Inc.

NCT04853368

/ TerminatedPhase 2

A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

Cystic Fibrosis (CF) is a rare, life-threatening, genetic disease that affects the lungs and digestive system, significantly impairing the quality of life, with those affected having a median age of death at 40. The main objective of this study is to assess how safe and effective is the combination therapy of galicaftor/navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 in adult participants with CF who are homozygous or heterozygous for the F508del mutation in each arm.
Galicaftor/Navocaftor/ABBV-119 combination therapy and Galicaftor/Navocaftor/ABBV-576 is being developed as an investigational drug for the treatment of CF. Study doctors place participants in 1 of the 4 groups, called treatment arms. Each group receives a different treatment. Around 90 adult participants with a diagnosis of CF will be enrolled in the study around approximately 35 sites worldwide.
Participants in arm 1 will receive oral capsules of galicaftor/navocaftor dual combination for 28 days followed by galicaftor/navocaftor/ABBV-119 triple combination for 28 days. Participants in arms 2 and 3 will receive the galicaftor/navocaftor/ABBV-119 triple combination or placebo for 28 days. Participants in arm 4 will receive galicaftor/navocaftor/ABBV-576 triple combination therapy for 28 days. For all study arms, ABBV-576, galicaftor, navocaftor, will be given once daily and ABBV-119 twice a day.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Start Date20 Sep 2021

Sponsor / Collaborator

AbbVie, Inc.

100 Clinical Results associated with Galicaftor

100 Translational Medicine associated with Galicaftor

100 Patents (Medical) associated with Galicaftor

Literatures (Medical) associated with Galicaftor

01 Mar 2024·European journal of pharmacology

PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR

Article

Author: Lopes-Pacheco, Miquéias ; Ferreira, Filipa C ; Amaral, Margarida D ; Bacalhau, Mafalda

The deletion of a phenylalanine at position 508 (p.Phe508del) in the CFTR anion channel is the most prevalent variant in people with Cystic Fibrosis (CF). This variant impairs folding and stability of the CF transmembrane conductance regulator (CFTR) protein, resulting in its defective trafficking and premature degradation. Over the last years, therapeutic accomplishments have been attained in developing small molecules that partially correct p.Phe508del-CFTR defects; however, the mechanism of action (MoA) of these compounds has only started to be uncovered. In this study, we employed biochemical, fluorescence microscopy, and functional assays to examine the efficacy and properties of PTI-801, a newly developed p.Phe508del-CFTR corrector. To exploit its MoA, we assessed PTI-801 effects in combination with low temperature, genetic revertants of p.Phe508del-CFTR (the in cis p.Val510Asp, p.Gly550Glu, p.Arg1070Trp, and 4RK) and other correctors. Our results demonstrated that PTI-801 rescues p.Phe508del-CFTR processing, PM trafficking, and channel function (upon agonist stimulation) with greater correction effects in combination with ABBV-2222, FDL-169, VX-661, or VX-809, but not with VX-445. Although PTI-801 exhibited no potentiator activity on low temperature- and corrector-rescued p.Phe508del-CFTR, this compound displayed similar behavior to that of VX-445 on genetic revertants. Such evidence associated with the lack of additivity when PTI-801 and VX-445 were combined indicates that they share a common binding site to correct p.Phe508del-CFTR defects. Despite the high efficacy of PTI-801 in combination with ABBV-2222, FDL-169, VX-661, or VX-809, these dual corrector combinations only partially restored p.Phe508del-CFTR conformational stability, as shown by the lower half-life of the mutant protein compared to that of WT-CFTR. In summary, PTI-801 likely shares a common MoA with VX-445 in rescuing p.Phe508del-CFTR, thus being a feasible alternative for the development of novel corrector combinations with greater capacity to rescue mutant CFTR folding and stability.

15 Aug 2023·Biochemistry

Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs.

Article

Author: Mitchell, Alexis ; Johnson, Quentin R ; Girard, Christian ; Henager, Marissa E ; Ramsdell, Havanna ; Lester, Anna ; Dixon, Brandon ; Poulos, Jack ; Reber, Callista ; Evans, Claudia N ; Spinney, Allison ; Herring, Caitlin ; Sandman, Madeline ; Turlington, Mark

Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The recent development of a class of drugs called "correctors", which repair the structure and function of mutant CFTR, has greatly enhanced the life expectancy of CF patients. These correctors target the most common disease causing CFTR mutant F508del and are exemplified by the FDA-approved VX-809. While one binding site of VX-809 to CFTR was recently elucidated by cryo-electron microscopy, four additional binding sites have been proposed in the literature and it has been theorized that VX-809 and structurally similar correctors may engage multiple CFTR binding sites. To explore these five binding sites, ensemble docking was performed on wild-type CFTR and the F508del mutant using a large library of structurally similar corrector drugs, including VX-809 (lumacaftor), VX-661 (tezacaftor), ABBV-2222 (galicaftor), and a host of other structurally related molecules. For wild-type CFTR, we find that only one site, located in membrane spanning domain 1 (MSD1), binds favorably to our ligand library. While this MSD1 site also binds our ligand library for F508del-CFTR, the F508del mutation also opens a binding site in nucleotide binding domain 1 (NBD1), which enables strong binding of our ligand library to this site. This NBD1 site in F508del-CFTR exhibits the strongest overall binding affinity for our library of corrector drugs. This data may serve to better understand the structural changes induced by mutation of CFTR and how correctors bind to the protein. Additionally, it may aid in the design of new, more effective CFTR corrector drugs.

13 Oct 2021·Journal of biomolecular structure & dynamics

Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)

Article

Author: de Lima Menezes, Gabriela ; da Silva, Roosevelt Alves

Non-structural protein 1 (nsp1) is found in all Betacoronavirus genus, an important viral group that causes severe respiratory human diseases. This protein has significant role in pathogenesis and it is considered a probably major virulence factor. As it is absent in humans, it becomes an interesting target of study, especially when it comes to the rational search for drugs, since it increases the specificity of the target and reduces possible adverse effects that may be caused to the patient. Using approaches in silico we seek to study the behavior of nsp1 in solution to obtain its most stable conformation and find possible drugs with affinity to all of them. For this purpose, complete model of nsp1 of SARS-CoV-2 were predicted and its stability analyzed by molecular dynamics simulations in five different replicas. After main pocket validation using two control drugs and the main conformations of nsp1, molecular docking based on virtual screening were performed to identify novel potential inhibitors from DrugBank database. It has been found 16 molecules in common to all five nsp1 replica conformations. Three of them was ranked as the best compounds among them and showed better energy score than control molecules that have in vitro activity against nsp1 from SARS-CoV-2. The results pointed out here suggest new potential drugs for therapy to aid the rational drug search against COVID-19. Communicated by Ramaswamy H. Sarma.

News (Medical) associated with Galicaftor

09 Feb 2025

·medcitynews.com

Vertex Pharma Challenger Sionna Secures $191M in IPO Cash for Cystic Fibrosis Pipeline - MedCity News

Vertex Pharmaceuticals dominates the market for cystic fibrosis drugs, but Sionna Therapeutics contends the pharma company’s products still have efficacy and safety limitations. Sionna has mapped out a clinical trial strategy that could validate its different approach to the chronic respiratory disease. Now the biotech can execute those plans with $191 million from an upsized IPO. Sionna had planned to offer more than 8.8 million shares in the range of $16 and $18 each, which would have raised nearly $150 million at the pricing midpoint. The company was able to boost the deal size to more than 10.5 million shares offered at the top of the targeted price range. Sionna’s shares debuted on the Nasdaq Friday under the stock symbol “SION.” Strong investor interest in the new stock enabled Sionna’s shares to close their first day of trading at $25 apiece, up nearly 39% from the IPO price. In cystic fibrosis (CF), genetic mutations lead to faulty versions of CFTR, a protein key to moving ions in and out of cells. Improperly functioning CFTR leads to mucus buildup in the lungs of CF patients. Two types of drugs improve CFTR function. Correctors bind to the protein and help it fold into the proper shape. Potentiators open channels of the protein. Vertex’s drugs combine both mechanisms to improve CFTR function at the surface of a cell. Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech Waltham, Massachusetts-based Sionna is developing CF drugs that target NBD1, a domain on the CFTR protein. NBD1 has long been thought to be important for normalizing CFTR function because it’s the location of the F508del mutation — the most common mutation that causes CF. Sionna aims to succeed where others have fallen short developing drugs that stabilize this target. “Approximately 90% of people with CF carry at least one copy of the F508del genetic mutation,” Sionna said in the IPO filing. “We believe stabilizing NBD1 is central to unlocking dramatic improvements in clinical outcomes and quality of life for CF patients. 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.” Sionna expects NBD1 stabilization could be used as part of a dual combination therapy or as an add-on to standard CF therapies. The company has three NBD1 stabilizers in clinical development. SION-109, which targets NBD1’s interface with the CFTR intracellular loop 4 (ICL4) region, has completed Phase 1 testing in healthy volunteers. Sionna said results showed this molecule was well tolerated and achieved exposure in the body that could support its use as part of a combination with two other Sionna stabilizers, SION-719 and SION-451. These two NBD1 stabilizers began clinical testing last summer. Interim data as of mid-January indicate that both have been well tolerated by patients so far, the company said in the filing. Vertex’s twice-daily drug Trikafta, a combination of two correctors and one potentiator, has become a standard of care therapy for CF patients who have at least one F508del mutation in the CFTR gene. This drug, approved in 2019, has also become the company’s top-selling product. In the nine months ended Sept. 30, 2024, Trikafta (marketed as Kaftrio in Europe) accounted for $7.5 billion in sales, up 14% compared to the same period in 2023. This past December, the FDA approved Vertex’s Alyftrek, which offers the same drug combination in a once-daily pill. Neither Trikafta nor Alfytrek address NBD1. Exclusive Improving the Healthcare Financial Experience to Help Care Flow Zelis CEO Amanda Eisel shares her perspective on how the company is solving the problems of a fragmented health financial system to benefit all. By Stephanie Baum Despite Vertex’s dominance in CF, its drugs still leave unmet medical need, Sionna said in the filing. Patients treated with Vertex’s drugs can continue to experience reduced CFTR function and declining lung function over time. Also, safety and tolerability issues lead some patients to reduce their dosage or discontinue treatment. The labels of Trikafta and Alyftrek carry black box warnings for the risk of drug-induced liver injury and liver failure. “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,” Sionna said in the filing. Sionna was co-founded in 2019 by Greg Hurlbut and Mark Munson, two scientists who spent more than a decade at Sanofi researching ways to treat CF by targeting NBD1, according to the filing. The company’s NBD1 research was licensed from Sanofi. Last July, Sionna expanded its pipeline by licensing three clinical-stage CF drugs that AbbVie developed under a partnership with Galapagos. Sionna said these molecules, two correctors and one potentiator, could be combined with its NBD1 stabilizers. Prior to the IPO, Sionna said it had raised about $330 million from investors. The most recent financing was a $182 million Series C round announced last March. RA Capital Management is Sionna’s largest shareholder with a 22.9% post IPO stake, according to the filing. As of the end of 2024, the company said its cash position was about $168 million. Combining its existing capital with the IPO proceeds, Sionna plans to spend about $40 million on the ongoing Phase 1 tests of SION-719 and SION-451. After completing those studies, Sionna plans to select a lead NBD1 stabilizer, conduct a drug-drug interaction trial, and then proceed to a Phase 2a proof-of-concept study. This trial, enrolling CF patients who are stable on Vertex’s Trikafta, is expected to begin in the second half of 2025. Sionna also plans to advance the lead NBD1 stabilizer to multiple ascending dose trials in dual combinations with galicaftor (one of the in-licensed AbbVie drugs) and/or SION-109 in healthy volunteers. These studies, expected to start in the second half of this year, will inform the selection of one dual combination to advance to a Phase 2b dose-ranging study in CF patients. Sionna has budgeted $95 million to start this study and for manufacturing drug product for pivotal studies. The company expects its cash will last into 2028. Image: Jackie Niam, Getty Images

Phase 1Drug ApprovalClinical ResultIPO

07 Feb 2025

·endpts.com

Sionna inks $191M IPO for cystic fibrosis pipeline as Aardvark eyes $89M for its own listing

Cystic fibrosis biotech Sionna Therapeutics will raise $191 million in its upsized Nasdaq debut on Friday, and metabolic disease biotech Aardvark Therapeutics outlined plans for a potential $89 million IPO. Sionna will begin trading as $SION on Friday to help it fund the development of treatment candidates that it in-licensed from Sanofi and AbbVie for $1.5 million upfront in 2019 and $5 million upfront in 2024, respectively. The Boston-area biotech sold 10.58 million shares versus an original plan of 8.82 million shares. It priced at $18 apiece, the high end of the range it marketed this week. Aardvark, meanwhile, penciled in a price range of $16 to $18 per share for its proposed entry onto the Nasdaq as $AARD . If the metabolic disease biotech prices at the midpoint of that range and sells all 5.88 million of its marketed shares, it could garner about $89 million in net proceeds, according to a Thursday evening SEC filing . Sionna’s transition to a public company comes as the biotech plans to report topline Phase 1 data on its NBD1 stabilizers SION-719 and SION-451 — which derive from Sanofi — in the first half of this year. The drug developer will then select one of those for a Phase 2a in the second half of 2025, according to its IPO documents. It also has clinically tested assets from AbbVie , including a CFTR corrector called galicaftor and a CFTR potentiator known as navocaftor. Six-year-old Sionna isn’t in a funding crunch. Its $182 million Series C from last year was slated to fuel the company through 2026, CEO Mike Cloonan previously told Endpoints News . The company still had about $180 million at the end of September. But with multiple clinical programs underway in a condition that has been cornered by Vertex for two decades, and the public markets appearing to get a little bit warmer, Sionna decided to plow ahead with its IPO. Its Friday float follows last week’s Nasdaq launches from Metsera and Maze . More publicly traded hopefuls are on deck. One of them, immunology startup Odyssey Therapeutics, revealed its IPO ambitions the same day as Sionna last month. But Odyssey has yet to reveal the scope of its proposed offering, perhaps signaling that it’s running into challenges during the process. RA Capital, TPG Growth, Atlas Venture and OrbiMed were its largest financial backers. Sionna’s experimental small molecules target the most common genetic mutation for patients with cystic fibrosis: ΔF508, chief medical officer Charlotte McKee previously told Endpoints . “NBD1 is the domain in which that ΔF508 actually lives,” she said. “Vertex has very successfully, to this point, found drugs that bind around NBD1,” McKee said last July. She joined Sionna in 2021 after six years at Vertex, where she worked on CF clinical development. “The current modulators stabilize and bind around this domain, but they don’t directly stabilize, so you’ve still got this critical place where the thing that goes wrong is actually living. That still causes a significant amount of instability and dysfunction that’s being left on the table at this point with the current modulators.”

IPOPhase 1

03 Feb 2025

·endpts.com

Sionna seeks $135M IPO to fuel tests of cystic fibrosis drug candidates

Cystic fibrosis drug developer Sionna Therapeutics hopes to join the IPO wave started by Metsera and Maze Therapeutics last week. Sionna, which snagged some of its programs from AbbVie last year, hopes to garner net proceeds of $135 million from its proposed Nasdaq debut as $SION, according to an updated SEC filing on Monday morning. The biotech had revealed its IPO intentions at the same time as immunology drug developer Odyssey Therapeutics a day after the JP Morgan Healthcare Conference concluded last month. Odyssey has not yet revealed its IPO sizing. Sionna, Odyssey and a handful of other biotech startups seek to follow obesity-focused Metsera and kidney disease drug developer Maze. Metsera and Maze floated last Friday , raising about $275 million and $140 million, respectively. Metsera popped 47% $MTSR in its first day of trading, perhaps a sign of investors’ ongoing enthusiasm for new obesity medications. Maze, meanwhile, struggled to stay at its launch price, ending the first day down 0.31% $MAZE . After the listings from Sionna, Odyssey and other Nasdaq hopefuls Aardvark and Aurion, the IPO market will likely be quiet for a few weeks as companies digest year-end audits, Raymond James bankers wrote in a biotech market check on Sunday evening. Activity will then likely resume in early March. “A growing backlog of 10-15 biotechs are watching the market and could potentially launch in that window,” the Raymond James team wrote. “It is clear that launching an IPO in this market is not an obvious yes and we expect companies to be appropriately cautious.” In its updated IPO planning docs, Sionna outlined an offering of 8.82 million shares. It’s marketing the shares at $16 to $18 apiece. Last week, Metsera priced above its range, but sold fewer shares than initially planned. Maze, on the other hand, sold more shares than initially anticipated but priced at the midpoint of its marketed range. Metsera’s IPO was oversubscribed 14-fold, the Raymond James bankers said. “The majority of this early wave of IPOs this year needs to trade well in the aftermarket to have a functioning and constructive IPO market going forward,” the bankers wrote. Boston-based Sionna disclosed a $182 million Series C last year and shortly after disclosed an in-licensing deal for three experimental cystic fibrosis drugs from AbbVie. While the upfront payments were minimal — $5 million plus $8.6 million worth of common stock — AbbVie stands to receive up to $490 million in development, commercial and sales-based biobucks. Sionna plans for topline Phase 1 data on its NBD1 stabilizers SION-719 and SION-451 in the first half of this year. It will then select one of those for a Phase 2a in the second half of 2025, according to its IPO paperwork. The biotech also has clinically-tested assets galicaftor, a TMD1-directed CFTR corrector, and navocaftor, a CFTR potentiator. Galapagos had originally tested them before handing them to AbbVie . Founded in 2019, Sionna isn’t in dire need of cash. CEO Mike Cloonan, a former Sage and Biogen executive, told Endpoints News last year that the Series C would bankroll Sionna through 2026 . The company still had $180 million in cash, equivalents and marketable securities at the end of September, according to its S-1 filing. In the first nine months of 2024, it devoted $43 million to R&D. Its biggest investors include RA Capital, TPG Growth, Atlas Venture and OrbiMed. Odyssey, meanwhile, hopes to go public with a new chief financial officer announced just last month. Jason Haas joined after a three-year stint in the same post at Syros Pharmaceuticals . Prior to that, he was a longtime investment banker at Barclays, Deutsche Bank and Goldman Sachs.

Phase 1IPOLicense out/in

100 Deals associated with Galicaftor

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 2	Australia	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	Belgium	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	Czechia	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	Germany	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	Ireland	Galapagos NV	01 Jan 2017
Cystic Fibrosis	Phase 2	United Kingdom	Galapagos NV	01 Jan 2017

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04853368 (CTgov)	Phase 2	Cystic Fibrosis	48	ABBV-119+Galicaftor+Navocaftor (Cohort 1(Day 1 - 29) Triple Combination Galicaftor + Navocaftor + ABBV-119 for F508del Homozygous)	pezwtvgzaz(zxsjntxzph) = yxdgzzgrrd jelfyspbky (ophnzkhruo, 3.68) View more	-	16 Jul 2024
				ABBV-119+Galicaftor+Navocaftor (Cohort 2(Day 1 - 29) Triple Combination Galicaftor+ Navocaftor + ABBV-119 for F508del Heterozygous)	pezwtvgzaz(zxsjntxzph) = simyvowzvp jelfyspbky (ophnzkhruo, 5.62) View more
NCT03969888 (CTgov)	Phase 2	Cystic Fibrosis	78	Placebo ABBV-2222+ABBV-3067 (ABBV-3067 50 mg + Placebo for ABBV-2222)	qbujhohyqt(soqfetwnyv) = kqktdisnet uxdftlpfpq (mlwvvxactu, bxdcprgyzf - xkxpbvsepg) View more	-	28 Jun 2023
				Placebo ABBV-2222+ABBV-3067 (ABBV-3067 150 mg + Placebo for ABBV-2222)	qbujhohyqt(soqfetwnyv) = fqcbwdilwg uxdftlpfpq (mlwvvxactu, srxxvmrqgw - yiffermcnt) View more
NCT03119649 (FLAMINGO, Pubmed \| J Cyst Fibros) Manual	Phase 2	Cystic Fibrosis	59	GLPG2222	kloqmhldrj(ohufrxdelr) = yjvqmecyfy bnzbmxgymf (rdpikvduce )	Negative	01 Sep 2019
NCT03119649 (FLAMINGO, CTgov)	Phase 2	Cystic Fibrosis	59	Placebo+GLPG2222 100 mg (Cohort A: GLPG2222 100 mg QD)	edwhjpkqik = egkjxtxszf wdjqrexmdv (mhcmariwim, khmrxcsegq - uvoyheuvzg) View more	-	16 Nov 2018
				Placebo+GLPG2222 200 mg (Cohort B: GLPG2222 200 mg QD)	edwhjpkqik = yesuiycxbt wdjqrexmdv (mhcmariwim, kmosbtcmnp - cvrpofquuh) View more

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