Peter Couroux1, Paulina Farias2, Leena Rizvi3, Katherine Griffin3, Christie Hudson2, Timothy Crowder4, Robert Tarran5, Elizabeth Tullis6. 1. Inflamax Research Limited, Mississauga, Ontario, Canada. 2. Spyryx Biosciences, Inc, Durham, NC, USA. 3. Toronto Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, Ontario, Canada. 4. Spyryx Biosciences, Inc, Durham, NC, USA. Electronic address: tcrowder@spyryxbio.com. 5. Marsico Lung Institute, Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA. 6. Toronto Adult Cystic Fibrosis Centre, St. Michael's Hospital, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Canada.
Abstract
BACKGROUND: ENaC inhibition has been investigated as a CF treatment; however, small molecule inhibitors of ENaC lack efficacy and/or have shown dose-limiting hyperkalemia. SPX-101 is a novel, investigational small peptide (SPLUNC1 mimetic) that regulates ENaC density with the potential for efficacy without systemic effects. METHODS: Two trials are presented: The first was a Phase 1, 2-part, randomized, double-blind, placebo-controlled, ascending-dose study of nebulized SPX-101 in healthy adults. Part 1 evaluated 4 single doses of SPX-101 ranging from 20 to 240 mg. Part 2 evaluated a 14-day regimen of SPX-101 at 4 doses of SPX-101 ranging from 10 to 120 mg BID. Pharmacokinetics, adverse events, spirometry, vital signs, electrocardiograms, pulse oximetry, and clinical laboratory values were assessed. The second trial was a tolerability-confirming, Phase 1b, open-label study conducted in 5 adult subjects with CF. Ascending doses of SPX-101 inhalation solution (10 mg-120 mg BID) were administered for 7 days. Safety was assessed as described above. RESULTS: All 64 healthy volunteers (32 in each Part) completed the single and multiple dose study. SPX-101 was well tolerated with little/no systemic exposure and with no hyperkalemia. Adverse events were generally mild with reported respiratory events associated with the purported pharmacological activity of SPX-101. Tolerability of SPX-101 was similarly observed in adults with CF; all 5 subjects treated with SPX-101 completed the study. CONCLUSIONS:SPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF. CLINICALTRIAL. GOV REGISTRATION: NCT03056989.
RCT Entities:
BACKGROUND:ENaC inhibition has been investigated as a CF treatment; however, small molecule inhibitors of ENaC lack efficacy and/or have shown dose-limiting hyperkalemia. SPX-101 is a novel, investigational small peptide (SPLUNC1 mimetic) that regulates ENaC density with the potential for efficacy without systemic effects. METHODS: Two trials are presented: The first was a Phase 1, 2-part, randomized, double-blind, placebo-controlled, ascending-dose study of nebulized SPX-101 in healthy adults. Part 1 evaluated 4 single doses of SPX-101 ranging from 20 to 240 mg. Part 2 evaluated a 14-day regimen of SPX-101 at 4 doses of SPX-101 ranging from 10 to 120 mg BID. Pharmacokinetics, adverse events, spirometry, vital signs, electrocardiograms, pulse oximetry, and clinical laboratory values were assessed. The second trial was a tolerability-confirming, Phase 1b, open-label study conducted in 5 adult subjects with CF. Ascending doses of SPX-101 inhalation solution (10 mg-120 mg BID) were administered for 7 days. Safety was assessed as described above. RESULTS: All 64 healthy volunteers (32 in each Part) completed the single and multiple dose study. SPX-101 was well tolerated with little/no systemic exposure and with no hyperkalemia. Adverse events were generally mild with reported respiratory events associated with the purported pharmacological activity of SPX-101. Tolerability of SPX-101 was similarly observed in adults with CF; all 5 subjects treated with SPX-101 completed the study. CONCLUSIONS:SPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF. CLINICALTRIAL. GOV REGISTRATION: NCT03056989.
Authors: Joe A Wrennall; Saira Ahmad; Erin N Worthington; Tongde Wu; Alexandra S Goriounova; Alexis S Voeller; Ian E Stewart; Arunava Ghosh; Krzysztof Krajewski; Steven L Tilley; Anthony J Hickey; M Flori Sassano; Robert Tarran Journal: Am J Respir Cell Mol Biol Date: 2022-03 Impact factor: 6.914
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