Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SPL84 in Patients With Cystic Fibrosis

Cohort 1-3:

Inclusion criteria

• Diagnosis of CF and two CF causing mutations; 3849+10 Kb C->T mutation on one allele in the CF transmembrane conductance regulator (CFTR) gene (homozygote or compound heterozygote). Source documentation from a certified genetic laboratory is required.
• Body mass index (BMI) of ≥ 17 kg/m2.
• FEV1 40-90% predicted at screening.
• Non-smokers or vapers for at least 180 days (6 months) prior to screening, per participant report.

Exclusion criteria

• Use of Kalydeco, Orkambi, Symdeko/Symkevi or Trikafta/Kaftrio within 30 days of first dose with study intervention.
• Use of any investigational drug (other than SPL84) or device within 30 days of first dose with study intervention.
• Use of systemic steroids over 3 consecutive months in the last 6 months prior to screening, or use of systemic steroids in the last month prior to screening. Use of inhaled steroids above 1 mg.
• Use of CF medications, e.g. inhaled antibiotics, dornase alfa (Pulmozyme), hypertonic saline and physiotherapy should be on stable regimen for the period 28 days prior to screening; those participants taking inhaled antibiotics for prophylaxis must be on a stable regimen of these drugs for at least 90 days prior to first dose with study intervention.
• Any acute infection including acute upper respiratory or lower respiratory infections, pulmonary exacerbation, changes in therapy for pulmonary disease, or any non CF-related illness which results in the initiation of any new therapy within 14 days prior to first dose with study intervention.
• Hemoptysis of greater than 30 mL within 90 days prior to Day 1, or hospitalization for hemoptysis within 6 months of first dose with study intervention.
• Liver disease characterized by clinically significant cirrhosis and/or documented portal hypertension.
• History of any organ transplantation.
• Documented coronavirus disease (COVID-19) infection within 4 weeks prior to dosing.

Cohort 4:

Inclusion criteria

• Diagnosis of CF and two CF causing mutations; 3849+10 Kb C->T mutation on one allele in the CF transmembrane conductance regulator (CFTR) gene (homozygote or compound heterozygote). Source documentation from a certified genetic laboratory is required.
• Body mass index (BMI) of ≥ 17 kg/m2.
• FEV1 40-80% predicted at screening.
• Non-smokers or vapers for at least 180 days (6 months) prior to screening, per participant report.
• Stable adherence to standard use of Trikafta/Kaftio or Alyftrek for at least 3 months, or Alyftrek for 1 month after switching from Trikafta/Kaftio, according to prescribing information.

Exclusion criteria

• Previous participation in active arm of SPL84-002 study (Cohort 1-3)
• Use of any investigational drug (other than SPL84) or device within 30 days of first dose with study intervention.
• Use of systemic steroids over 3 consecutive months in the last 6 months prior to screening, or use of systemic steroids in the last month prior to screening. Use of inhaled steroids above 1 mg.
• Use of CF medications, e.g. inhaled antibiotics, dornase alfa (Pulmozyme), hypertonic saline and physiotherapy should be on stable regimen for the period 28 days prior to screening; those participants taking inhaled antibiotics for prophylaxis must be on a stable regimen of these drugs for at least 90 days prior to first dose with study intervention.
• Any acute infection including acute upper respiratory or lower respiratory infections, pulmonary exacerbation, changes in therapy for pulmonary disease, or any non CF-related illness which results in the initiation of any new therapy within 14 days prior to first dose with study intervention.
• Hemoptysis of greater than 30 mL within 90 days prior to Day 1, or hospitalization for hemoptysis within 6 months of first dose with study intervention.
• Liver disease characterized by clinically significant cirrhosis and/or documented portal hypertension.
• History of any organ transplantation.
• Documented coronavirus disease (COVID-19) infection within 4 weeks prior to dosing.