– Data provide additional evidence supporting development of praliciguat as a potential treatment for diabetic nephropathy and for heart failure with preserved ejection fraction –
Building on previously announced top-line data from the Phase IIa randomized, placebo-controlled, 14-day study, which showed that treatment with praliciguat led to reductions in blood pressure, fasting plasma glucose, cholesterol levels and triglycerides in patients on a stable regimen of medicines to manage their disease, the newly reported findings also suggested that praliciguat improved insulin sensitivity. Insulin resistance is a hallmark of diabetes1 and often linked to hypertension2. In addition, the data suggested that praliciguat decreased levels of apolipoprotein B (ApoB), a key lipid parameter that – when elevated – is associated with increased cardiac events3. The effect of praliciguat on ApoB in this Phase IIa study was shown within the context of broader lipid effects, including a reduction in total cholesterol and low-density lipoprotein (LDL) cholesterol, the component of total cholesterol associated with long-term cardiovascular risk.
“In this study, praliciguat demonstrated a positive impact across
critical biomarkers of metabolic and cardiovascular disease – including
blood pressure, lipids, and glucose – providing a strong rationale for
praliciguat as a potential treatment for diabetic nephropathy and for
The newly disclosed data presented at the ADA Scientific Sessions were as follows:
- Improvement in insulin sensitivity: In patients treated with praliciguat who were not taking concomitant insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score – a measure of insulin resistance – declined by an average of 36% from baseline to day 15, following completion of the study treatment regimen, compared to a decrease of 13% in patients taking placebo, representing a 23% greater reduction with praliciguat compared to placebo.
- Decline in ApoB: Patients treated with praliciguat showed a mean decrease in ApoB of 170 mcg/ml from baseline to day 15, compared to a decrease of 51 mcg/ml in patients taking placebo, a 119 mcg/ml greater reduction with praliciguat compared to placebo.
The Phase IIa exploratory study was designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of praliciguat in diabetic patients with hypertension, and included a number of exploratory biomarkers related to diabetes and cardiovascular disease. The study included two active dosing regimens: (1) 40 mg once-daily for days 1 to 14, and (2) 20 mg twice daily for days 1 to 7 followed by 40 mg once daily for days 8 to 14. Overall, results were similar for both dosing regimens, and data were combined for analysis.
The study was not designed or powered to assess efficacy, but the data yielded clear and consistent trends indicating a positive effect of praliciguat on blood pressure, metabolic parameters and endothelial function biomarkers. These improvements were seen in patients who were taking a stable regimen of therapies to manage their disease; all participating patients were taking at least one medication to manage their hypertension and at least one medication to manage their diabetes, and a majority were also taking additional medications to manage their cholesterol and serum lipid levels. The study also confirmed a pharmacokinetic profile of praliciguat supporting once-daily dosing and suggested broad distribution to relevant tissues, offering the potential to maximize anti-inflammatory, anti-fibrotic and metabolic effects.
Praliciguat was generally well-tolerated. Nausea was the only adverse event (AE) present in the praliciguat group at a greater incidence rate than placebo. There was a single serious AE, an upper gastrointestinal hemorrhage in a participant with erosive esophagitis receiving praliciguat. Across all five clinical studies of praliciguat to date, praliciguat was found not to impair platelet function or blood clotting, either on its own or when co-administered with aspirin. No other serious bleeding episodes have been observed. All other AEs in this Phase IIa study were characterized as mild.
Praliciguat (IW-1973), an oral, once-daily soluble guanylate cyclase (sGC) stimulator, is being studied in patients with diabetic nephropathy and in patients with heart failure with preserved ejection fraction (HFpEF). Diabetic nephropathy affects an estimated eight million Americans and 20 to 40 percent of all diabetic patients worldwide. It is the leading cause of end-stage renal disease. Currently available products do not treat the underlying pathophysiology of the disease or fully address the needs of this patient population. HFpEF affects an estimated three million Americans and 40 to 70 percent of heart failure patients worldwide. It is a highly symptomatic condition with high rates of morbidity and mortality that can cause insufficient delivery of oxygen to the tissues, fluid in the lungs and edema of the extremities, causing patients to be short of breath and have compromised exercise tolerance. There are no approved therapies to treat HFpEF.
Currently in Phase II development for diabetic nephropathy and for HFpEF, praliciguat has the potential to address the underlying causes of these devastating diseases by improving nitric oxide (NO) signaling, which may improve vascular and metabolic function and decrease the inflammatory and fibrotic consequences associated with these diseases.
About Ironwood's sGC Program
As a pioneering expert in cyclic GMP (cGMP), Ironwood is building on its success with linaclotide, which stimulates guanylate cyclase-C in the intestine, to develop a pipeline of soluble guanylate cyclase (sGC) stimulators. sGC plays an important role in regulating diverse physiological processes; dysregulation of sGC may play a role in multiple serious diseases. Ironwood's sGC stimulators are believed to harness the nitric oxide (NO)/sGC/cGMP pathway by working synergistically with NO to improve blood flow and metabolism and decrease inflammation and fibrosis.
Ironwood is advancing praliciguat (IW-1973) for the potential treatment of diabetic nephropathy and of heart failure with preserved ejection fraction (HFpEF). Olinciguat (IW-1701) is being developed for the potential treatment of achalasia and of sickle cell disease. In addition, Ironwood has a pipeline of other sGC stimulators in pre-clinical development.
This press release contains forward-looking statements. Investors are
cautioned not to place undue reliance on these forward-looking
statements, including statements about Ironwood's sGC program and the
clinical program for praliciguat; the assessment of the data from the
clinical trials of praliciguat; the mechanism of action of praliciguat;
prevalence and unmet need; the development, regulatory and
commercialization plans for praliciguat; and praliciguat as a potential
treatment for diabetic nephropathy and HFpEF. Each forward‐looking
statement is subject to risks and uncertainties that could cause actual
results to differ materially from those expressed or implied in such
statement. Applicable risks and uncertainties include those related to
preclinical and clinical development, manufacturing and formulation
development; the risk that future clinical studies need to be
discontinued for any reason, including safety, tolerability, enrollment,
manufacturing or economic reasons; the risk that findings from our
completed nonclinical and clinical studies may not be replicated in
later studies; efficacy, safety and tolerability of praliciguat; the
risk that the therapeutic opportunities for praliciguat are not as we
expect; decisions by regulatory authorities; the risk that we may never
get sufficient patent protection for praliciguat or that we are not able
to successfully protect such patents; the outcomes in legal proceedings
to protect or enforce the patents relating to praliciguat; developments
in the intellectual property landscape; challenges from and rights of
competitors or potential competitors; the risk that our planned
investments do not have the anticipated effect on our business or the
praliciguat program; and those risks listed under the heading "Risk
Factors" and elsewhere in Ironwood's Quarterly Report on Form 10-Q for
the quarter ended
1 “Insulin Sensitivity.” Diabetes.co.uk. https://www.diabetes.co.uk/insulin/insulin-sensitivity.html.
2 Salvetti A, Brogi G,
3 Walldius, G., & Junger, I. (2004). Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy.
Media and Investors:
Meredith Kaya, 617-374-5082
Vice President, Investor Relations and Corporate Communications
Jessi Rennekamp, 617-374-5404
Associate Director, Corporate Communications