Multiple-Ascending-Dose Study of the Soluble Guanylate Cyclase Stimulator, IW-1701, in Healthy Subjects

Background: Nitric oxide (NO), a key regulator of vascular health, modulates smooth muscle tone and blood pressure, inhibits vascular smooth muscle proliferation, and suppresses inflammation and platelet activation. These protective functions are mediated by soluble guanylate cyclase (sGC), a signaling enzyme that catalyzes the formation of cyclic guanosine monophosphate (cGMP) in response to NO binding. The compromised vascular health characteristic of the hemoglobinopathies may in part be due to deficient NO bioavailability and inadequate sGC-cGMP signaling. IW-1701 is an orally available sGC stimulator that binds to sGC and enhances NO-sGC-cGMP signaling.

Methods: A Phase 1b placebo-controlled, randomized, multiple-ascending-dose study was conducted to assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (blood pressure, heart rate, platelet function, and plasma cGMP) of IW-1701 in healthy subjects. Five successive cohorts of 11 subjects each (8 active and 3 placebo) were randomized. The first 3 cohorts received 7 days of repeated once-daily (QD) doses of 1-, 2- or 5-mg IW-1701 respectively, and the last 2 cohorts received 7 days of lead-in QD doses of 3 mg followed by 7 days of up-titrated QD doses of 5 or 6 mg, respectively.

Results: IW-1701 doses ranging from 1 to 6 mg were tolerated and no safety concerns were identified. There were no serious adverse events (SAEs), severe adverse events (AEs), or withdrawals due to AEs. All AEs were mild or moderate, most resolved on the day of onset. Among the 40 subjects who received IW-1701 for 7 consecutive days, the most common AEs were tachycardia and headache (each reported in 7 subjects), and hypotension and nausea (each reported in 3 subjects). Among the 16 subjects who received an up-titrated dose of IW-1701 for 7 additional days, headache was the only AE reported in >1 subject (2 subjects). IW-1701 was rapidly absorbed, with median T_max achieved from 2 to 4 hours postdose. Systemic exposure to IW-1701 was less than dose proportional after a single dose (C_max slope, 0.701 [90% CI, 0.578-0.824] and AUC_tau slope, 0.833 [90% CI, 0.726-0.939]) and was dose proportional after 7 days of QD dosing (C_max slope, 1.01 [90% CI, 0.873-1.14] and AUC_tau slope, 1.03 [90% CI, 0.892-1.17]). Intersubject variability in PK was low to moderate (AUC_tau %CV range, 10.6-39.1%). The accumulation ratio (based on R_AUC) ranged from 1.95 to 2.63 across doses of 1-, 2-, 3-, and 5-mg IW-1701 after 7 days of QD dosing. Mean CL/F (apparent total body clearance) and V_z/F (apparent volume of distribution) ranged from 1080 to 1520 mL/h and 49.4 to 58.9 L, respectively. Mean terminal t_1/2 was 30 hours, which is consistent with a QD dosing regimen. After 7 days of QD dosing, least squares mean changes from baseline in 24-hour ambulatory systolic blood pressure (±SE) (in cohort order) were -1.17±1.24 (placebo), -2.98±1.80 (1 mg), -5.37±1.71 (2 mg), -6.67±1.69 (5 mg), -6.55±1.95 (3 mg), and -4.98±1.68 mmHg (3 mg). After 14 days of QD dosing in the 2 cohorts that received up-titrated doses, the least squares mean changes from baseline in 24-hour ambulatory systolic blood pressure (±SE) were -1.51±2.42 (placebo), -6.85±2.03 (5 mg), and -8.64±2.08 mmHg (6 mg). Plasma cGMP levels were highly variable; in general, mean plasma cGMP levels were increased from baseline at dose levels ≥3 mg IW-1701. There were no clinically meaningful changes from baseline in platelet function assessment by PFA-100^® at any dose level.

Conclusion: IW-1701 was tolerated in healthy subjects with only mild and moderate AEs. Common AEs were consistent with the effects of sGC stimulation. Lead-in dosing with a lower dose (3 mg) appeared to improve the tolerability of higher doses (5 and 6 mg). The PK of repeat IW-1701 dosing was dose proportional with low-to-moderate intersubject variability and half-life consistent with QD dosing. Pharmacodynamic results, including blood pressure and plasma cGMP levels, demonstrated target engagement. Clinical evaluation of IW-1701 in diseases associated with NO deficiency, including sickle cell disease and achalasia, are planned or ongoing.

-- The authors gratefully acknowledge the early contributions of Bernard J. Lavins. --