First clinical trials of novel ENaC targeting therapy, SPX-101, in healthy volunteers and adults with cystic fibrosis

Pulm Pharmacol Ther. 2019 Oct;58:101819. doi: 10.1016/j.pupt.2019.101819. Epub 2019 Jul 11.


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.

Keywords: Cystic fibrosis; ENaC inhibitor; ENaC modulator; SPLUNC1; SPX-101.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adult
  • Cystic Fibrosis / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Epithelial Sodium Channel Blockers / adverse effects
  • Epithelial Sodium Channel Blockers / pharmacokinetics*
  • Epithelial Sodium Channel Blockers / therapeutic use*
  • Epithelial Sodium Channels
  • Female
  • Glycoproteins / metabolism
  • Healthy Volunteers
  • Humans
  • Male
  • Middle Aged
  • Phosphoproteins / metabolism


  • BPIFA1 protein, human
  • Epithelial Sodium Channel Blockers
  • Epithelial Sodium Channels
  • Glycoproteins
  • Phosphoproteins

Associated data