Research Focus

Cardiovascular Diseases

PL3994 Natriuretic Peptide Receptor Exploratory Program

PL3994 is an NPR-A agonist and synthetic mimetic of the endogenous neuropeptide
hormone atrial natriuretic peptide (“ANP”). PL3994 activates NPR-A, a receptor
known to play a role in cardiovascular homeostasis. Consistent with being an NPR-A
agonist, PL3994 increases plasma cyclic guanosine monophosphate (“cGMP”) levels,
a pharmacological response consistent with the effects of endogenous natriuretic
peptides on cardiovascular function and smooth muscle relaxation. PL3994 also
decreases activity of the renin-angiotensin-aldosterone system (“RAAS”), a hormone
system that regulates blood pressure and fluid balance. The RAAS system is
frequently over-activated in heart failure patients, leading to worsening of
cardiovascular function.

In conjunction with clinicians at a major research institution, PL3994 is entering a
Phase 2A clinical trial supported by a grant from the American Heart Association in
2020. We have conducted Phase 1 safety studies with PL3994, with no serious or
severe adverse events. Consistent with the PL3994 mechanism of action, elevations
in plasma cGMP levels, increased diuresis and increased natriuresis were all
observed for several hours after single subcutaneous doses.

PL5028 for Cardiovascular and Fibrotic Disease

PL5028, a dual NPR-A and NPR-C agonist we developed, is in preclinical
development for cardiovascular and fibrotic diseases, including reducing cardiac
hypertrophy and fibrosis. We have ongoing academic collaborations with several
institutions with PL5028.