Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction

Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction: a Safety and Efficacy Phase 2 Randomized Clinical Study (SP9In-HFpEF)

This study is to evaluate whether 16 weeks of treatment with IMR-687 is a safe and effective treatment for patients with Heart Failure with Preserved Ejection Fraction (HFpEF). The primary objective is to evaluate whether IMR-687 reduces NT-proBNP compared to placebo in these patients.

Inclusion Criteria:

• Males or females ≥45 years

• Weight 60 to 160 kg, inclusive

• LVEF ≥45% by echo within 6 months prior to Screening Visit

• Symptoms of HFpEF requiring treatment with a diuretic(s) for at least 30 days prior to Screening

• NYHA class II to IV at the time of Screening

• LV hypertrophy, by echo within 6 months of screening, defined by either LV mass/BSA >95 g/m² for females and 115 g/m² for males or LV mass/m² for males >44 g/m2.7 for females and 48 g/m2.7 for males

• NT-proBNP criteria either ≥300 pg/mL if in sinus rhythm or ≥700 pg/mL if in atrial fibrillation at screening

• Elevated LV filling pressure criteria are defined as ONE OR MORE of the following:

  1. HF hospitalization within 12 months prior to screening
  2. LA enlargement (LA width (diameter) ≥3.8 cm, LA length ≥5.0 cm, LA area ≥20 cm² , LA volume ≥55 mL, or LA volume index >29 mL/m²) within 6 months of screening for a participant in sinus rhythm
  3. Cardiac catheterization with at least one of the following in the 12 months prior to screening: rest LVEDP or PCWP ≥15 mm Hg, exercise PCWP ≥25 mm Hg, or fluid challenge PCWP ≥18 mm Hg
  4. Echocardiogram criteria of one or more within 6 months of screening for a participant in sinus rhythm: E/e' (mean of lateral and septal) >13, E/e' lateral >12, or E/e' septal >14; or for a participant in atrial fibrillation: E/e' septal >11

• For WOCBP: Two negative pregnancy tests and the use of highly effective contraception up to 3 months following end of study

Exclusion Criteria:

• Any prior echocardiographic imaging measurement of LVEF <40%
• Six-minute walk test (6MWT) distance <100 m or >450 m at Screening Visit
• Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of >80
• Major cardiovascular surgery, or urgent percutaneous coronary intervention (PCI) within the 3 months prior to Screening Visit, or an elective PCI within 30 days prior to Screening Visit
• Any clinical event within 6 months prior to Screening Visit that could have reduced the LVEF (eg, myocardial infarction, coronary artery bypass graft) unless an echocardiographic measurement was performed at least 1 month after the event confirming the LVEF to be ≥45%