CS1 – an HDACi with epigenetic effects

CS1 is an innovative formulation of valproic acid (VPA) and is an HDAC inhibitor that has received orphan drug designation (ODD) for the treatment of PAH. CS1's active substance VPA works through epigenetic modulation with a multifold efficacy profile that is pressure-reducing, "reverse-remodeling" and has anti-fibrotic, anti-inflammatory, and anti-thrombotic properties. CS1 has the potential to offer an effective, safe and disease-modifying PAH treatment through epigenetic modulation and thus be able to offer improved quality of life and increased survival. CS1, therefore, offers the possibility to impact the underlying pathophysiology of the disease.

The documentation of CS1's properties has been demonstrated through in vitro models, animal models, human physiological data, independent epidemiological studies and a successfully completed Phase I study. In preclinical studies and clinical studies of the anti-thrombotic effect, CS1 showed an improvement of the endogenous fibrinolytic system by supporting local thrombolysis with impending occlusive thrombosis through the effect on local release of t-PA and reduction of the blood levels of PAI-1. With the Phase I clinical trial, CS1 demonstrated good safety and tolerability, robust reduction of PAI-1 and no problems with bleeding.

Overall, CS1 shows promising potential with a multifold efficacy profile with properties such as:

  • Pressure reducing
  • “Reverse-remodeling”
  • Anti-thrombotic
  • Anti-inflammatory
  • Anti-fibrotic

Phase II study in PAH

CS1's unique efficacy profile has been shown to be a good match with the pathogenetic mechanisms of the rare disease PAH and is believed to have potential as a disease-modifying treatment in the future.

The development program for CS1 in PAH is an­chored in the Orphan Drug Designation (ODD) grant­ed by the US FDA in March 2020. The FDA grants national orphan drug designation to encourage the development of drugs intended for the treatment of rare diseases in the US. Several incentives are as­sociated with orphan drug status to facilitate drug development and they include, among other things, seven years of market exclusivity in the US from ap­proval, assistance from the FDA in the design of clin­ical studies, and tax credits for qualified study costs. Through the granted orphan drug status, the FDA has also indicated that they believe that CS1 has the potential to offer patients with PAH a significantly improved treatment.

A Phase II clinical trial is ongoing to confirm CS1's safety, tolerability and efficacy in patients with PAH. A collaboration agreement with the global healthcare company Abbott is the basis for Cereno to be able to use Abbott's pioneering technology, the CardioMEMS HF System, in the study. The technology will be used to daily monitor pulmonary pressure and other cardiopulmonary function in patients in the Phase II study. The primary objective of the study is to evaluate the safety and tolerability of the drug candidate CS1. All relevant standard endpoints used in previous PAH studies for this patient group will also be evaluated and a validated estimate of risk is calculated and various biomarkers, quality of life and various aspects of cardiac function are evaluated. Cereno expects that the optimal dose for later clinical trials will be possible to be determined from the study.


Remarkable Patient Case Study data

A patient case study performed on the first patient having completed the study at a specific clinic showed remarkable efficacy data. In 12 weeks of treatment with CS1, the patient showed a 30% reduction in pulmonary pressure and a 20% increase in cardiac output. The patient’s overall functional status was changed from NYHA/WHO functional class II to I at the end of the treatment period, meaning that the patient had next to normal functional physical capacity with CS1 added to stable conventional therapy.


Positive findings from the Data Quality Control Review

In October 2023, a Data Quality Control Review (DQCR), of data obtained by the CardioMEMS HF System from the first 16 patients, was concluded with positive findings. The data quality of the CardioMEMS measurements was found satisfactory with adherence to study protocol and with timely data transfers from the patient's home to the clinic. Efficacy findings showed a clinically meaningful reduction of pulmonary pressure in several patients, included in the data quality control, of a similar or greater magnitude as in the Patient Case.

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 Expanded Access Program (EAP) will provide Cereno with the opportunity to, under a formal FDA-approved protocol, collect safety and efficacy data from long-term exposure to CS1 in patients with PAH. This initiative not only extends support to those suffering from PAH but will also allow Cereno to gather further documentation of CS1 use in patients suffering from PAH, which will help in discussions with regulatory authorities and support the design of our Phase IIb/III pivotal study with CS1.