GLPG1837 / Galapagos, AbbVie - LARVOL DELTA

Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy. (PubMed, Biomedicines) - "Objective/ We synthesized a new set of LSO-24 structure-based compounds, screened their effects on p.Arg334Trp-CFTR activity, and assessed the additivity of hit compounds to VX-770, ABBV-974, ABBV-3067, and apigenin. Our data suggest that these new potentiators might share a common mechanism with apigenin, which is conceivably distinct from that of VX-770 and ABBV-3067. The additive rescue of p.Arg334Trp-, p.Ser549Arg-, p.Gly551Asp-, and p.Ser945Leu-CFTR also indicates that these variants could benefit from the development of a co-potentiator therapy."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector. (PubMed, J Med Chem) - "Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity."

Combination therapy • Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

X316761: a new highly efficacious potentiator of wild-type and mutant CFTR channels (NACFC 2023) - "We have previously reported that potentiators VX-770 and GLPG1837 have produced similar gating effects across a wide range of mutants by sharing a common mechanism of action and binding to the same target site. We hereby propose a similar mechanism for X316761 and a common binding site as VX-770 and GLPG1837. Cryogenic electron microscopy data supporting this proposition will be presented."

CFTR

CFTR function, pathology and pharmacology at single-molecule resolution. (PubMed, Nature) - "The potentiators ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while NBDs are dimerized. Disease-causing substitutions proximal (G551D) or distal (L927P) to the ATPase site both reduce the efficiency of NBD dimerization. These findings collectively enable the framing of a gating mechanism that informs on the search for more efficacious clinical therapies."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Triple potentiator-mediated activation of cystic fibrosis transmembrane conductance regulator mutants with gating defects is independent of channel phosphorylation and nucleotide binding domain dimerization (NACFC 2022) - "In this study, we investigated whether addition ofpreviously identified co-potentiators [3] to the VX-770+VX-445 combin-ation would further enhance mutant channel activity and interrogatedwhich steps of channel gating are required for the potentiator action.Combinatorial profiling and cluster analysis of R352Q-, S549N-,S549R, W1282X-, and N1303K-cystic fibrosis transmembrane conductanceregulator (CFTR) showed additivity of VX-445 to class I [4] (VX-770, ABBV-974) and class II [4] potentiators (apigenin, bDMC). The results suggest that triple potentiator –mediated CFTR activation is independent of channel phosphorylation and NBD1-2dimerization, but structural rearrangement of intracellular loops 2 and 4leading to tetrahelix bundle formation are required to support potentiator-mediated channel opening. Introduction of a third potentiator with distinctmechanism of action in addition to VX-770 + VX-445 further increaseschannel function, which may be particularly beneficial..."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

In vitro rescue of the bile acid transport function of some ABCB11 variants by CFTR potentiators: a targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2 (EASL-ILC 2022) - "Tritiated taurocholate ([3H]TC) transport activity and the effect of Ivacaftor (VX-770, Kalydeco®), a clinically approved cystic fibrosis (CF) treatment, GLPG1837 in phase 2 CF clinical trials as well as SBC040 and SBC219, known as potentiators of CFTR were studied in Madin-Darby canine kidney (MDCK) clones co-expressing Abcb11 and the rat sodium taurocholate co-transporting polypeptide (Ntcp/ Slc10A1). Potentiator drugs could increase the pharmacopoeia available for patients with ABCB11 deficiency due to missense variations affecting the transport function and may delay or even suppress the need for liver transplantation in these patients."

Preclinical • Cholestasis • Cystic Fibrosis • Fibrosis • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation • ABCB1

Molecular Dynamics and Theratyping in Airway and Gut Organoids Reveal R352Q-CFTR Conductance Defect. (PubMed, Am J Respir Cell Mol Biol) - "CFTR potentiators (VX-770, GLPG1837 and VX-445) and correctors (VX-809, VX-445 +/- VX-661) were tested. The combination approach of in vitro patient-derived cell models and in silico MD simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

[VIRTUAL] Effects of VX-445 on CFTR channel function and stability (NACFC-I 2021) - "Background : The CFTR modulator elexacaftor (VX-445) is one of 3 components of the FDA-approved drug elexacaftor/tezacaftor/ivacaftor and is the first of the next-generation correctors that is predicted to improve F508del CFTR thermal stability [1]. Based on our results, we conclude that VX-445 restores the thermal stability of F508del CFTR but cannot be considered as a gating potentiator."

[VIRTUAL] Role of KCNQ and 2-pore potassium channels in Cl− secretion across primary human bronchial epithelial cells (NACFC-I 2021) - "Similarly, following correction of F508del CFTR with C18, the forskolin+VX-770- stimulated Cl− Ieq was blocked by XE991 and bupivacaine, indicating a role of KCNQ and K2P channels in the Cl− secretory response...The F508del-CFTR results were confirmed using cells from a second donor and a chemically distinct potentiator (GLPG1837) and reversing the order of K+ channel inhibitors in a total of 112 filters. Finally, we assessed the role of these KCNQ/K2P blockers following correction of F508del CFTR with VX 445+VX-661... In summary, our results demonstrate that functional KCNQ and K2P channels are expressed in the basolateral membrane in WT, G551D, and S549N CFTR HBCEs. In contrast, in F508del CFTR HBECs, functional KCNQ and K2P channels are localized to the apical membrane, indicating an unrecognized phenotype in F508del CFTR CF HBECs. This apical localiza tion will hyperpolarize apical membrane voltage while resulting in net KCl secretion."

CFTR

Novel Correctors and Potentiators Enhance Functional Rescue of CFTR Nonsense Mutation Translational Readthrough. (PubMed, Am J Respir Cell Mol Biol) - "Novel correctors GLPG2222 (C1), GLPG3221 (C2), and potentiator GLPG1837 compare favorably to lumacaftor and ivacaftor in vitro. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin induced swelling (FIS) was observed with G418+GLPG1837+C1a+C2a although GLPG1837+C1a+C2a alone was sufficient to improve FIS in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Nanomolar-potency 'co-potentiator' therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants. (PubMed, Sci Rep) - "Increased CFTR chloride conductance by up to 8-fold was observed when a co-potentiator (termed 'Class II potentiator') was used with a classical potentiator ('Class I potentiator') such as VX-770 or GLPG1837. Co-potentiator efficacy was confirmed in primary human bronchial epithelial cell cultures generated from a N1303K homozygous CF subject. The Class II potentiators identified here may have clinical benefit for CF caused by mutations in the NBD2 domain of CFTR."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

1-BENZYLSPIRO[PIPERIDINE-4,1’-PYRIDO[3,4-b]indole] ’co-potentiators’ for minimal function CFTR mutants. (PubMed, Eur J Med Chem) - "We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants...Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1). (PubMed, J Cyst Fibros) - P2a | "Patient willingness to participate in the study suggests that the need for a short period of ivacaftor withdrawal may not be a barrier to development of novel potentiators, such as GLPG1837. A one-week ivacaftor washout was generally well tolerated, but resulted in a decline in lung function, which was reversed with GLPG1837 treatment to pre-washout levels. Combined with the concentration-dependent decrease in sweat chloride concentration, results show that GLPG1837 increases CFTR activity in G551D-CF patients. FUND: This work was supported by Galapagos NV."

Clinical • Journal • P2a data • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

[VIRTUAL] CFTR MODULATOR THERAPY FOR CYSTIC FIBROSIS CAUSED BY THE RARE C.3700A>G MUTATION (NACFC 2020) - "However, I1234del-CFTR showed much reduced activity, with modest activation seen with potentiators VX-770 and GLPG1837, correctors VX-809, VX-661 and VX-445, or low-temperature incubation...In primary cultures of human airway epithelial cells from nasal brushings on one homozygous c.3700A G subject, however, little CFTR current was seen without or with multiple correctors and potentiators/co-potentiators, including the combination VX-661/VX-445, with or without the CFTR amplifier PTI-428. To further clarify the potential utility of CFTR modulators, two limited N-of-1 studies were done, testing the efficacy of elexacaftor/tezacaftor/ivacaftor (ETI) in homozygous c.3700A G subjects. One subject showed a 30 mM decrease in sweat chloride and symptomatic improvement on ETI. These results suggest the potential benefit of CFTR modulators, including co-potentiators, for CF caused by the c.3700A G mutation."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770. (PubMed, J Gen Physiol) - "Collectively, these data identify two potential binding sites for GLPG1837 and VX-770 in CFTR. We discuss the pros and cons of evidence for these two loci and the implications for future drug design."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

[VIRTUAL] Amino Acids Regulate Defective CFTR Trafficking and Gating in Primary Human F508del-Bronchial Epithelial Cells Similar to Cystic Fibrosis Correctors and Potentiators (ATS-I 2020) - "Here, we compare the efficiency or additive efficiency of our AA to treatment with VX809/VX770 or VX661/VX770 alone in trafficking defective CFTR and increasing chloride secretion in primary human bronchial epithelial cells with homozygous F508del (HBEC-F508del)...After blocking ENaC with benzamil, chloride secretion was stimulated using GLPG1837 (VX770-analogue) with or without forskolin... A proprietary AA mixture increases apical anion secretion similar to correctors and potentiators rendering these AA a potential additive or stand-alone treatment option in CF patients following additional preclinical and clinical studies."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

CFTR modulator therapy for cystic fibrosis caused by the rare c.3700A>G mutation. (PubMed, J Cyst Fibros) - "These results support the potential benefit of CFTR modulators, including co-potentiators, for CF caused by the c.3700A>G mutation."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Structural identification of a hotspot on CFTR for potentiation. (PubMed, Science) - "Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Amino Acids Regulate Defective CFTR Trafficking and Gating in Primary Human F508del-Bronchial Epithelial Cells Similar to Cystic Fibrosis Correctors and Potentiators (ATS 2020) - "Here, we compare the efficiency or additive efficiency of our AA to treatment with VX809/VX770 or VX661/VX770 alone in trafficking defective CFTR and increasing chloride secretion in primary human bronchial epithelial cells with homozygous F508del (HBEC-F508del)...After blocking ENaC with benzamil, chloride secretion was stimulated using GLPG1837 (VX770-analogue) with or without forskolin... A proprietary AA mixture increases apical anion secretion similar to correctors and potentiators rendering these AA a potential additive or stand-alone treatment option in CF patients following additional preclinical and clinical studies."

CFTR

GLPG1837: Expiry of patents related to composition-of-matter and methods of treatment in US/ex-US, EU and China in 2034 (Galapagos) - Annual Report 2019

Patent

Physiological and pharmacological characterization of the N1303K mutant CFTR. (PubMed, J Cyst Fibros) - "N1303K has a severe gating defect, reduced ATP-dependence and aberrant response to ATP analogs. These results suggest a defective function of the NBDs in N1303K-CFTR. An improvement of channel function by GLPG1837 or VX-770 and an increase of Band C protein by VX-809 or VX-661 support a therapeutic strategy of combining CFTR potentiator and corrector for patients carrying the N1303K mutation."

Journal

Positional effects of premature termination codons on the biochemical and biophysical properties of CFTR. (PubMed, J Physiol) - "Biochemical and biophysical characterizations of three nonsense mutations of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) associated with severe form of cystic fibrosis (CF) reveal the importance and heterogenous effects of the position of the premature termination codon (PTC) on the CFTR protein function. Electrophysiological studies of W1282X-CFTR, whose PTC is closer to the C-terminus of CFTR, suggest the presence of both C-terminus truncated CFTR proteins that are poorly functional and read-through, full-length products. For G542X- and E60X-CFTR, the only mechanism capable of generating functional proteins is the read-through, but the outcome of read-through products is highly variable depending on the interplay between the missense mutation caused by the read-through and the structural context of the protein. Pharmacological studies of these three PTCs with various CFTR modulators suggest position-dependent therapeutic strategies for these..."

Journal