PDE9 inhibitors for treating sickle cell disease
Inventors
CALAMAI, Edward George • DOBBINS, Deborah Lynn Leithead • DeHart, Michael Paul • McArthur, James • FOO, Shi Yin
Assignees
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Publication Number
US-12213975-B2
Publication Date
2025-02-04
Expiration Date
Abstract
The present disclosure relates to PDE9 inhibitors, pharmaceutical compositions comprising the PDE9 inhibitors, and methods of using the PDE9 pharmaceutical compositions for the treatment of sickle cell disease (SCD).
Core Innovation
The document describes PDE9 inhibition as a treatment for sickle cell disease (SCD) using PDE9 inhibitors, including Compound 1, which is defined as an imidazo[1,5-a]pyrazin-8-one derivative. The rationale focuses on targeting PDE9 and cGMP signaling to increase fetal hemoglobin (HbF), and it also describes reducing neutrophil adhesion and inflammation in the context of SCD.
The described approach links PDE9 targeting of cGMP signaling with downstream effects including reduced soluble E-selectin (sE-Sel) and adhesion/integrin markers such as CD11a, CD11b, and CD18. The document also references sickle cell anemia (SCA) and discusses HbF relative to HbS and HBB within the SCD context.
The document further describes an oral tablet composition for Compound 1. The formulation concepts include microcrystalline cellulose (MCC), colloidal silicon dioxide, and magnesium stearate, with optional additional components such as hydroxypropyl cellulose, and film coating with Opadry II.
Claims Coverage
The partial content provides two independent claims directed to an oral tablet composition that includes Compound 1 and defined excipient components, with one independent claim further requiring lactose as part of one or more solid carriers. Across the independent claims, the inventive features include specific drug identity and quantitative-by-weight excipient constraints.
Oral tablet composition defined by Compound 1 and specified excipient levels
An oral tablet composition comprising 50 mg of Compound 1 and microcrystalline cellulose (MCC) at about 20%, about 30%, or about 40% by weight, about 1% by weight colloidal silicon dioxide, and about 0.8% by weight magnesium stearate.
Oral tablet composition requiring lactose-containing solid carriers
An oral tablet composition comprising 50 mg of Compound 1, microcrystalline cellulose (MCC) at about 20% or about 30% by weight, about 1% by weight colloidal silicon dioxide, about 0.8% by weight magnesium stearate, and one or more solid carriers comprising lactose.
Both independent claims focus on oral tablet compositions containing Compound 1 and specified excipient components with quantitative-by-weight constraints, with one independent claim further requiring solid carriers comprising lactose.
Stated Advantages
Increase fetal hemoglobin (HbF) in sickle cell disease (SCD).
Reduce neutrophil adhesion and inflammation, including reduction of soluble E-selectin (sE-Sel) and adhesion/integrin markers such as CD11a, CD11b, and CD18.
Documented Applications
Treatment of sickle cell disease (SCD) using PDE9 inhibitors, including Compound 1.
Reduction of neutrophil adhesion and inflammation in the context of sickle cell disease (SCD), with effects described using soluble E-selectin (sE-Sel) and adhesion/integrin markers.
A Phase 2a randomized double-blind placebo-controlled study is described as a clinical bridging example in relation to the treatment approach.
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