Cereno Scientific’s cardiovascular disease drug candidate CS1 has shown potential for clinical benefit both in preclinical studies as well as in the ongoing phase II study in Pulmonary Arterial Hypertension (PAH), as underlined by the FDA’s recent approval of CS1 for “Compassionate Use” in patients that have completed the PAH study. To build on this progress, Cereno is strengthening its management team with the recruitment of Dr Rahul Agrawal as Chief Medical Officer and Head of R&D. BioStock contacted Dr Agrawal to learn more about his new role.

Cardiovascular disease (CVD) is the number one killer in the world, in majority due to thrombotic complications e.g. stroke and myocardial infarction (MI). Currently, available CVD treatments for prevention and treatment represent a significant unmet medical need. The Gothenburg-based biopharma company Cereno Scientific is dedicated to addressing this gap by developing innovative treatments for common and rare cardiovascular disease with novel disease-modifying capacity.

Cereno has three drug programmes in development: CS1, CS014 and CS585. Lead asset CS1 is currently in phase II for the treatment of the rare CVD pulmonary arterial hypertension (PAH). In PAH, the blood pressure in the arteries that go from the heart to the lungs is higher than normal due primarily to vascular changes leading to high resistance for the blood. This causes the right heart to work excessively, eventually leading to heart failure and death. Thus, PAH is a devastating disease with impaired quality of life and poor survival.

A paradigm shift in PAH

The company is driving a potential paradigm shift in PAH by developing CS1 with a multi-fold mechanism of action; its primary effect is on the pathological remodelling of the blood vessels, so called reverse remodelling. The concept, based on epigenetic modulation, involves restructuring the vessels to reverse disease progression, reduce resistance and lower the pulmonary arterial blood pressure.

CS1 is a reformulation of the histone deacetylase inhibitor (HDACi) valproic acid (VPA). While the VPA is well known for its positive effects in primarily in epilepsy, the HDAC inhibitory approach which VPA exerts is a novel treatment approach in the CVD field.

The range of potential benefits of CS1 (VPA) has been extensively studied by Cereno. According to the company, the approach has also, beyond the remodelling capability, shown antifibrotic, anti-inflammatory, pressure-reducing as well as antithrombotic properties – all important for tackling the underlying PAH pathology. Additionally, clinical studies run on CS1 thus far give the candidate a strong safety profile. Based on all these drug candidate characteristics, CS1 has a promising potential to significantly change the treatment landscape for PAH patients.

Positive findings from phase II trial

Last summer, Cereno announced exciting positive results from a patient case study in the phase II trial with CS1. Data from a 51-year-old female patient who had been suffering from PAH for three years showed that after a 12-week treatment period with CS1 when added on top of her current triple drug therapy, her mean pulmonary arterial pressure (mPAP) was reduced by 30 per cent and almost normalised, and her cardiac output (CO) was improved by 20 per cent and also almost normalised. In addition, the patient’s pulmonary vascular resistance (PVR) was reduced by close to 50 per cent.

According to Dr Raymond Benza – Principal Investigator of the study and part of Cereno’s Scientific Advisory Board – these results are the goal for normalising the affected part of the heart in PAH. Moreover, the patient’s status improved from NYHA/WHO functional class II to functional class I at the end of the treatment period – meaning that the functional physical capacity of the patient was next-to-normal after the addition of CS1 to stable conventional triple therapy.

At Cereno’s 2023 Capital Markets Day, Benza commented on the results:

»Our effect on resistance was much more than what would be expected just with the change in cardiac output. That means that this vessel is actually remodelling, and the resistance is coming down through a change in architecture of the vessel. That is really exciting to me.«

The CardioMEMS HF System – a cutting-edge arterial pressure sensor technology provided by the global healthcare company Abbott is implanted in all patients taking part in the study. In October, a Data Quality Control Review (DQCR) initiative was conducted to verify the utility of the CardioMEMS measurements. The review was positive, thus supporting that CS1 has had a clinical meaningful reduction of pulmonary pressure in several patients – in line with the patient case previously presented.

Compassionate Use strengthens the case for CS1

After receiving a request in November last year from an investigator in the ongoing phase II study, Cereno applied for and subsequently was granted Expanded Access, also known as “Compassionate Use,” for CS1 from the FDA. This provision gives the clinical investigators permission to continue administering CS1 to patients post the conclusion of the study, if deemed beneficial by the investigator, and the patient is willing to continue CS1.

The Expanded Access program (EAP) will allow Cereno to gather further documentation of CS1 use in patients suffering from PAH beyond documentation obtained through the original ongoing clinical phase II study. This additional information will help in upcoming discussions with regulatory authorities, and it will further support the design of a phase IIb/III pivotal study with CS1.

Cereno’s new CMO and Head of R&D in the spotlight

With the phase II study progressing steadily towards completion estimated Q3 this year, Cereno has been taking steps to ensure it has the right competence and expertise to support its clinical development with expected pivotal studies on CS1 and with drug candidate CS014 soon entering the clinic. The company has announced changes to its Executive Management Team, most recently the recruitment of Dr Rahul Agrawal as CMO and Head of R&D. Dr Agrawal brings extensive experience in CVD, including leading and/or co-designing nearly 30 clinical trials involving over 200,000 patients. He will play a key part in advancing the continued development of CS1, as well as the rest of the company’s portfolio.

BioStock caught up with Dr Rahul Agrawal to learn more about his new role.

Dr Agrawal, why are you a good fit for Cereno Scientific and what compelled you to accept the position?

– Cereno is on a very exciting journey and working in fields of high unmet medical need. The vision of Cereno resonates with me and I feel that my previous experience could help in bringing Cereno to the next step. The speed at which Cereno has developed from pre-clinical, to investigating compounds in patients, is very inspiring and it is apparent that Cereno is on the cusp of making an important difference in patients’ lives.

In previous roles, you have been involved in the development and commercialisation of PAH drugs. Given such experience, could you tell us how CS1 fits into the current PAH treatment landscape?

– While a lot has been happening in the PAH field, most of the drugs have addressed vasodilation. I believe that CS1 with its cardiovascular remodelling properties is unique here and could be very complimentary to other drugs already in use as it will offer a possibility to impact the disease underlying pathophysiology in contrast to the currently available drugs.

What is your strategy for advancing the development of CS1 into a pivotal clinical study?

– We will carefully evaluate the results of the ongoing study with its unique aspects. We are continuously obtaining haemodynamic parameters with the Cardio-MEMS HF System from Abbott; we are using imaging techniques like MRI and Echo to document signs of remodelling. With this information we are in a remarkable position to document the benefits obtained from CS1 in patients suffering from PAH.

Could you tell us more about why the FDA’s Expanded Access, or “Compassionate Use,” is so important?

– As you know Expanded Access, also called “Compassionate Use,” provides a pathway for patients to gain access to investigational drugs. What this means is, first and foremost, that if the investigators and patients feel the drug is doing them good, they would like to continue using it and under this Expanded Access Program they are allowed by regulatory authorities to continue using CS1. We are getting encouraging feedback here, with investigators indicating that close to two-thirds of the patients, having completed the study or are currently on therapy, have been judged to be applicable for continued access to CS1 following study completion. Further, it gives us an opportunity to obtain “Real-World Data,” of the usage of CS1 in these patients with PAH disease which will help further inform the design of our phase IIb/III pivotal study with CS1.

Dr Benza talks about structural remodelling in PAH patients. What does that mean exactly?

– Dr Benza is referring to the fact that there are publications showing that in PAH, there is an upregulation of HDAC, which contributes to pathological changes in the pulmonary vasculature. We believe that inhibition of the HDAC pathway could alleviate pulmonary arterial remodelling and therewith PAH. We believe with CS1 we are targeting the underlying pathophysiological mechanism of this rare debilitating disease.

Is this a feature that can be translated to other CVD indications?

– Structural remodelling does play a role in other CV and pulmonary diseases; we will explore various possibilities as we can gain further insights into the effects of CS1.

In your capacity as Head of R&D, what goals have you set for Cereno beyond the CS1 project?

– Besides CS1 we have two other compounds with promising properties which we are developing further; CS014 being developed as a future treatment to effectively prevent thrombosis without increasing the risk of bleeding. CS585 has not yet been assigned a specific indication for clinical development as evaluation in the preclinical programme is still ongoing. However, so far CS585 has shown exciting data in prevention of thrombosis without increasing the risk of bleeding which was recently published in the top peer review journal Blood. We at Cereno have shown that we can develop drugs and bring them into the clinical stage with a very focused strategy and approach, and we are always on the lookout for other promising compounds that fit with our skill set.

Finally, Dr Björn Dahlöf previously filled the roles of both CMO, CSO and Head of Clinical Development at Cereno, and he will now put all his efforts in the CSO role. How will the two of you work together?

– Dr Björn Dahlöf, who with Sten R Sörensen, our CEO, has been instrumental in bringing Cereno this far, and I complement each other very well and I will be working closely with Björn and Sten in leading Cereno to the next step on our exciting journey.

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