FDL169
/ Flatley Discovery Lab
- LARVOL DELTA
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September 04, 2024
Partial rescue of p.Phe08del-CFTR trafficking and stability defects by dual and triple corrector combinations
(NACFC 2024)
- "The additive correction of PTI-801 to type I (ABBV-2222, FDL-169, VX-661, VX-809), type II (Corr-4a), and type III (VX-445) correctors was also assessed. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue p.Phe508del-CFTR. Nevertheless, despite the higher level of functional rescue by dual- and triple-corrector combinations, p.Phe508del-CFTR still presents instability and accelerated degradation."
CFTR
March 22, 2024
Partial Rescue of p.Phe08del-CFTR Trafficking and Stability Defects by Dual and Triple Corrector Combinations
(ECFS 2024)
- "The additive correction of PTI-801 to type I (ABBV-2222, FDL-169, VX-661, VX-809), type II (Corr-4a) and type III (VX-445) was also assessed. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue p.Phe508del-CFTR. Nevertheless, despite the higher level of functional rescue by dual and triple corrector combinations, p.Phe508del-CFTR still presents instability and accelerated degradation."
CFTR
February 10, 2024
PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR.
(PubMed, Eur J Pharmacol)
- "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."
Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases
November 20, 2023
Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).
(PubMed, Cochrane Database Syst Rev)
- "There is insufficient evidence of clinically important effects from corrector monotherapy in pwCF with F508del/F508del. Additional data in this review reduced the evidence for efficacy of dual therapy; these agents can no longer be considered as standard therapy. Their use may be appropriate in exceptional circumstances (e.g. if triple therapy is not tolerated or due to age). Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar small improvements in QoL and respiratory function with lower pulmonary exacerbation rates. While the effect sizes for QoL and FEV still favour treatment, they have reduced compared to our previous findings. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population,..."
Journal • Review • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR
October 19, 2023
Allosteric pathways of CFTR activation reveal mechanistic insights into modulator-resistant variants
(NACFC 2023)
- "Finally, I507del folding (mature band C) was unresponsive to correctors C18 and C4a at 37°C or with galicaftor or FDL-169 at 27°C...Likewise, I507del single-channel activity was observed in 10 of 71 (14%) membrane patches but only after low-temperature incubation (27°C for >25 days) when combined with elexacaftor-tezacaftor-ivacaftor (1–3 days)... Structural and functional analyses suggest that a subset of variants that are poorly responsive to current modulators disrupt a key allosteric hub that coordinates CFTR activity. Attaining clinically relevant levels of function for CFTR I507del and others in this region will require a new series of correctors, possibly compounds that stabilize NBD1 folding directly."
October 19, 2023
Systematic review of corrector modulator therapy for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del)
(NACFC 2023)
- " Thirty-four RCTs were included (4,781 participants): eight monotherapy RCTs (4PBA, CPX, lumacaftor, cavosonstat, FDL 169), 15 dual-therapy RCTs (lumacaftor-ivacaftor or tezacaftor-ivacaftor), and 11 triple-therapy RCTs (elexacaftor-tezacaftor-ivacaftor [ETI], VX-659-teza-caftor-ivacaftor, VX-440-tezacaftor-ivacaftor, VX-152-tezacaftor-ivacaftor). There is no evidence to support monotherapy and limited evidence to support dual therapy for PwCF who have a class II CFTR gene variant. Clinically relevant differences were found in key outcomes in the triple therapy studies, and these demonstrated a better safety profile than lumacaftor-ivacaftor. There appears to be additional benefit of changing to triple therapy for PwCF already established on ivacaftor."
Review • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR
February 28, 2023
Partial correction of F508del-CFTR trafficking and stability defects by the combination of PTI-801 with ABBV-2222 or FDL-169
(ECFS 2023)
- "To shed light on the MoA of PTI-801, its additive effects to correctors (VX-445, VX-661, ABBV-2222, FLD-169, and Corr-4a), genetic revertants of F508del-CFTR (G550E, R1070W, and 4RK) and the traffic-null variant DD/AA were assessed. The maximal rescue of F508del-CFTR processing and function by PTI-801 was achieved at 3 µM concentration. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue F508del-CFTR."
CFTR
November 15, 2022
Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del)
(BTS WM 2022)
- "Two authors then independently extracted data, assessed risk of bias and evidence quality (GRADE).Results A total of 34 RCTs were included (1754 participants); eight monotherapy RCTs (4PBA, CPX, lumacaftor, cavosonstat and FDL 169), fifteen dual-therapy RCTs (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and eleven triple-therapy RCTs (elexacaftor-tezacaftor-ivacaftor, VX-659- tezacaftor-ivacaftor, VX-440-tezacaftor-ivacaftor and VX-152-tezacaftor-ivacaftor). There were significant and clinically relevant differences found across outcomes in the triple therapy studies, with improved safety profile. More research is needed into assessing these therapies in paediatric patients and the longer-term safety profiles of these new therapies, but these early results suggest this will be a transformational intervention for pwCF with class 2 CFTR gene variants."
Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR
April 14, 2022
Characterisation of F508del-CFTR rescue by corrector PTI-801
(ECFS 2022)
- "PTI-801 demonstrated additivity to the genetic revertants G550E, R1070W and 4RK, but was unable to rescue DD/AA trafficking. In summary, these preliminary findings suggest that PTI-801 acts as a pharmacological chaperone and may have different binding sites compared to other correctors, namely VX-661, VX-809, ABBV-2222 and FDL-169."
December 19, 2020
Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).
(PubMed, Cochrane Database Syst Rev)
- "There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple..."
Journal • Review • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR
June 27, 2018
Safety, tolerability and pharmacokinetics of the CFTR potentiator FDL176
(ECFS Belgrade 2018)
- "In combination with CFTR corrector FDL169, it has similar in vitro efficacy to lumacaftor/ivacaftor under acute conditions and higher under chronic conditions. FDL176 is well tolerated and demonstrated a favorable safety profile in healthy subjects. Safety and PK profile support further development of FDL176."
Clinical • PK/PD data • Biosimilar • Dermatology • Immunology
April 12, 2018
A Study to Evaluate Safety, PK and PD of FDL169 in Cystic Fibrosis Subjects
(clinicaltrials.gov)
- P1; N=27; Completed; Sponsor: Flatley Discovery Lab LLC; Recruiting ➔ Completed
Trial completion • Biosimilar • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology
February 05, 2020
A DDI Study of FDL169 and FDL176 in Healthy Subjects
(clinicaltrials.gov)
- P1/2; N=78; Suspended; Sponsor: Flatley Discovery Lab LLC; Recruiting ➔ Suspended
Clinical • Trial suspension
August 01, 2019
A DDI Study of FDL169 and FDL176 in Healthy Subjects
(clinicaltrials.gov)
- P1/2; N=78; Recruiting; Sponsor: Flatley Discovery Lab LLC; Phase classification: P1 ➔ P1/2; N=32 ➔ 78; Trial completion date: Mar 2019 ➔ Feb 2020; Trial primary completion date: Mar 2019 ➔ Feb 2020
Clinical • Enrollment change • Phase classification • Trial completion date • Trial primary completion date
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