Introduction
Phosphodiesterase-1 (PDE-1) hydrolyzes cyclic adenosine monophosphate and cyclic guanosine
monophosphate, key second messenger molecules in cardiac and vascular tissue. Selective
PDE-1 inhibition with ITI-214 resulted in systemic vasodilation and positive inotropic
effects (inodilator) in a canine heart failure (HF) model with minimal effects on
blood pressure.
Hypothesis
The specific PDE-1 inhibitor, ITI-214, confers inodilator effects in humans with HF
with reduced ejection fraction.
Methods
ITI-214-104 was a Phase Ib/IIa, multi center, double-blind, randomized, placebo-controlled
single ascending dose cohort study of ITI-214 in patients with stable chronic systolic
HF (NYHA Class II-III, LVEF ≤ 35%) (NCT03387215). Participants were randomized 9:3
to receive either ITI-214 10, 30, or 90 mg or placebo, with transthoracic echocardiography
obtained just before and 120 min after dosing. Safety outcomes included supine and
orthostatic BP and HR, telemetry events and blood laboratories. Hemodynamic outcomes
included mean LV power index (primary outcome), as well as exploratory outcomes: cardiac
output, LV volumes, LVEF, effective arterial elastance (Ea), and estimated systemic
vascular resistance (SVR).
Results
Patient mean age was 54 yr, 57% male and 57% Black with mean LVEF 25% (31% had ischemic
HF). Cmax occurred at 90 - 120 min, with area under curve increasing with dose escalation.
ITI-214 30 mg increased mean LV power index and cardiac output while SVR and MAP decreased
at 30 and 90 mg doses at 120 minutes post dose compared to placebo (Figure). Total
LV afterload (Ea) followed the same pattern as SVR change. There were 3 orthostatic
hypotension and 3 hypotension adverse events, both mild to moderate. There was no
change in arrhythmia on continuous telemetry monitoring and no serious adverse events.
Conclusion
Single-dose ITI-214 confers inodilator effects in humans with systolic HF. These data
confirm our previous findings in the canine HF model. Further investigation of acute
and chronic PDE-1 inhibition in HF should be considered.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Cardiac FailureAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
Article info
Identification
Copyright
© 2020 Published by Elsevier Inc.
