CS1

CS1 – an HDACi with epigenetic effects Phase IIa trial in PAH Expanded Access Program for CS1 in PAH

CS1 – an HDACi with epigenetic effects

Drug candidate CS1 is an innovative formulation of valproic acid (VPA) and is an HDAC inhibitor that works through epigenetic modulation, being developed as a treatment for the rare disease PAH. CS1 holds the potential to be an effective, safe and disease-modifying drug, targeting the root cause of the disease by reverse remodeling.

In preclinical cardiovascular disease models, HDAC inhibitors have shown disease-modifying potential through reverse pathological remodeling, as well as anti-fibrotic, anti-inflammatory, pulmonary pressure-reducing, and anti-thrombotic effects. CS1’s unique efficacy profile aligns well with the underlying mechanisms of PAH, positioning it to address the critical unmet need for more effective treatment options. The goal of CS1's development is to improve quality of life and extend survival for patients with PAH.

CS1 is part of Cereno’s HDACi portfolio, untapping the potential of epigenetic modulation in CVD.

The development program for CS1 in PAH is further supported by the Orphan Drug Designation (ODD) granted by the US FDA in March 2020, and the Orphan Medicinal Product Designation (OMPD) granted by the European Commission (by recommendation of the European Medicines Agency, EMA) in August 2024. Through the granted ODD/OMPD, the FDA and EMA indicate that they believe that CS1 has the potential to offer patients with PAH a significantly improved treatment.

Phase IIa trial in PAH

CS1-003 is a Phase IIa trial evaluating the safety, tolerability, pharmacokinetics, and exploratory efficacy of CS1 on top of standard-of-care in patients with PAH. The study, which was performed at 10 clinical sites in the US, randomized 25 patients to CS1 treatment,
out of which 21 patients completed the treatment without protocol deviations. Topline results were presented in Q3 2024.

CS1 – Phase IIa safety data – Primary endpoint of safety and tolerability met successfully
The primary endpoint of safety and tolerability was met successfully:

  • No CS1-related serious adverse events, including hospitalizations/mortality
  • No changes in liver lab values or clinically significant drug-related platelets decrease or bleedings, were seen in the study
  • CS1 was well tolerated.

 

CS1 Phase IIa – Compelling positive impact on exploratory clinical efficacy parameters

Efficacy data from the three doses were pooled together due to therapeutic drug exposure (i.e. plasma concentration) also in the low dose group.

CS1 showed compelling positive impact on exploratory clinical parameters already over a 12-week treatment period:

  • REVEAL risk score:
    • 43% (9/21) of the patients improved risk score
    • 71% 15/21) of the patients improved or had a stable risk score
  • Functional Class:
    • 33% (7/21) of the patients improved functional class
    • 86% (18/21) of the patients improved or had a stable functional class
  • Mean pulmonary arterial pressure (mPAP, AUC):
    • 67% (14/21) of the patients had sustained pressure reduction

 

CS1 phase II a study clinical data, together with preclinical information, is consistent with reversing pathological remodeling
An in-depth analysis made on a subgroup of patients with a remarkable response showed:

  • 25% (5/21) of patients responded to CS1 with remarkably large reductions in pulmonary vascular resistance (PVR reduced by >30%, range 35–51%, mean 45%) consistent with the proposed reverse vascular-remodeling mechanism of action.
  • These large reductions in PVR were strongly associated with robust increases in right ventricular stroke volume.
  • Findings suggest the lower dose range in the trial (480–960mg) as optimal.

 

The data from the CS1-003 trial, together with recently announced preclinical data from our HDAC inhibitor program, directly demonstrating our HDAC-inhibitor program’s dose-dependent positive impact on reverse vascular remodeling in small lung arteries, provide a basis for assuming that CS1 may act with a disease-modifying capacity in PAH.

Expanded Access Program for CS1 in PAH

Since January 30th 2024, CS1 is approved by the FDA for Expanded Access, or "Compassionate Use", as an extension of the ongoing Phase II trial evaluating CS1 in pulmonary arterial hypertension (PAH). The EAP allows Cereno to, under a formal FDA-approved protocol, collect safety and efficacy data from long-term exposure to CS1 in patients with PAH. As such, this initiative not only supports the treatment of PAH patients but also enables Cereno to gather additional CS1 usage documentation for regulatory discussions and Phase IIb/III pivotal study design planning.