CS1, a controlled-release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial.
Raymond L BenzaPhilip B AdamsonDeepak L BhattFredrik FrickGunnar OlssonNiklas BerghBjörn DahlöfPublished in: Pulmonary circulation (2024)
Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled-release formulation of valproic acid, which exhibits a multi-targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti-inflammatory, anti-fibrotic, and anti-thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open-label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS™ HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6-min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1.
Keyphrases
- pulmonary arterial hypertension
- open label
- pulmonary artery
- pulmonary hypertension
- clinical trial
- phase iii
- phase ii
- double blind
- study protocol
- patient reported outcomes
- magnetic resonance imaging
- placebo controlled
- phase ii study
- coronary artery
- genome wide
- computed tomography
- anti inflammatory
- risk assessment
- drug delivery
- atrial fibrillation
- randomized controlled trial
- cancer therapy
- polycyclic aromatic hydrocarbons
- adipose tissue
- free survival
- magnetic resonance
- systemic sclerosis
- smoking cessation
- squamous cell carcinoma
- idiopathic pulmonary fibrosis
- replacement therapy
- metabolic syndrome