CEO and Board Member, Cereno Scientific
Pulmonary arterial hypertension kills most patients within seven years of diagnosis. The vasodilators that have defined PAH treatment for decades have extended median survival—but they have not stopped the disease.
Cereno Scientific is betting that epigenetic modulation of key pathophysiological pathways can do what vasodilation cannot: slow, halt, and potentially reverse the vascular remodeling that drives PAH’s relentless progression. The company’s lead asset, CS1—a reformulated, patent-protected version of valproic acid—recently completed a Phase IIa trial that moved 43% of patients to a lower REVEAL risk score category in just three months, translating to a nearly 23% reduction in mortality. Cereno is entering Phase IIb, a multi-continent pivotal trial designed with regulatory approval squarely in view. CEO and board member Sten R. Sörensen, with Chief Medical Officer Rahul Agarwal, explains the science, the strategy, and what the data might mean for patients who have run out of options.
Moe: What key characteristics of epigenetic modulation and HDAC inhibition convinced you it was the right approach for PAH?
Sten R. Sörensen: The company was founded in 2012 by Professor Sverker Jern, whose interest was in developing a drug that wouldn’t carry the high bleeding risk that all current agents have—including the new ones being pursued. His approach was epigenetic: increasing the synthesis, storage, and release capacity of a fibrinolytic protein called TPA, stored in the vessel wall. All patients with depleted TPA storage are at elevated risk of thrombosis—it’s our self-defense mechanism, dissolving clots before they become occlusive.
I joined the board in 2014 and became CEO in 2015. I’d done two drug repurposing efforts with success before—beta blockers and MR antagonists—improving survival by more than 30% in left heart failure, published in the New England Journal of Medicine. When I met this team, I saw tremendous potential in bringing HDAC inhibition into cardiology and eventually pulmonology.
The real turning point came when I reconnected with Professor Bertram Pitt at the University of Michigan—Professor Emeritus, recipient of the gold medal for his lifetime achievement in aldosterone and MR antagonist research, and the principal investigator on that earlier heart failure trial. When I described what we were doing at Cereno, he asked me to come meet him immediately. That was December 13th, 2018. He said what we had was really, really big. There were more than 600 published articles providing proof-of-concept for HDAC inhibition—most of them on VPA, with highly translatable models across vital organs including kidney, liver, heart, vessels, and lungs.
We brought him to the board, reviewed all the literature, and asked where to bring this potential first. We landed on PAH. The characteristics of HDAC inhibition fit the pathological process in these patients precisely: it’s antiproliferative, reverses vascular remodeling, anti-inflammatory, anti-fibrotic, it reduces pulmonary and systemic pressure, and it’s antithrombotic. PAH patients have all of those disease processes running simultaneously, including micro-thrombotic incidents. The pulmonary artery undergoes this rapid pathological process—inflammation, fibrosis, proliferation of pulmonary vascular wall cells—that then afflicts the right heart, which has a narrowing, less elastic tube to pump blood through, hypertrophies, loses elasticity and contractility, and eventually fails. These patients die of right heart failure. That’s why we chose PAH, but the decision was really triggered by that conversation with Dr. Pitt.
Moe: Why position CS1 as an add-on to standard of care rather than pursuing standalone from the outset?
Sten R. Sörensen: Cardiology doesn’t work the way oncology does—it’s not a matter of hitting one receptor and taking out the disease. It’s a much more holistic approach, especially when you’re dealing with conditions that progress to left or right heart failure. There are multiple signal pathways driving disease deterioration.
In left heart failure, we spent years working with pump-and-plumbing approaches—inotropic agents and loop diuretics. That didn’t stop progression. The breakthrough came when we took a more holistic approach and targeted the hormonal cascades: the RAAS system with ACE inhibitors and AT1 receptor blockers, and the adrenergic drive with beta blockers. Both worked. Today you have seven or eight agents used in parallel for optimal left heart failure management. PAH is well behind that kind of thinking but slowly catching up.
Currently in PAH, vasodilators relax the pulmonary artery and reduce pressure—but they don’t stop the disease process. What we’re offering is something that can slow down, halt, and possibly reverse the pathological process, or at least get patients into remission. Why not do that alone? Because by the time most patients are diagnosed—typically already in NYHA functional class 2 or even 3—you want something that reduces pressure immediately. Vasodilators are smart to use for that. But you don’t stop the process with vasodilators alone. What you’d like to add is what we’re developing.
The thinking is: the vasodilator gets the pressure down; you add a drug like ours that impacts multiple pathways and stops the pathological process. With both working together, you get the pressure down and stop the progression. You could probably take the vasodilator out of the therapy eventually. This is also consistent with what Professor Marc Humbert—our Phase IIb study steering committee chairman, one of the absolute top experts in PH, and one of the leaders of the sotatercept development—has said publicly. When he was asked why he wanted to work with us, he said his life’s goal is to get patients into remission, and that maybe this could do it. He doesn’t know yet, of course—nor do we. But in preclinical work, two published studies show that if you introduce the drug early, you can prevent PH buildup, right heart hypertrophy, and increased right heart mass. If you introduce it later, when PH is more established, you can reverse vascular and cardiac remodeling. That’s the model we’re applying into the clinical setting.
“They have seven, seven and a half years to live from diagnosis. With vasodilators you have expanded the life expectancy from 2.8 years to 7 and a half years, but that’s it. You run into a wall.”
Moe: How does CS1 demonstrate reversal of vascular remodeling without an established non-invasive endpoint for capturing it?
Chief Medical Officer and Head of R&D, Cereno Scientific
Rahul Agarwal: In preclinical work you can biopsy and examine the animals directly—but with patients we have to make do with indirect signals. One of the most reliable is right ventricular function, because what PAH patients die of is right heart failure. What we want to see is either stabilization or, in the best cases, improvement in right ventricular function.
We’ve already seen very promising signals in our Phase IIa trial. One parameter we look at through echocardiography—which every patient receives anyway—is global longitudinal strain, or GLS, which is considered one of the most powerful early indicators of improved right heart function.
The primary endpoint in Phase IIb, as required by the regulatory bodies, is pulmonary vascular resistance, which is measured invasively through right heart catheterization. But as secondary endpoints—alongside the six-minute walk test—we will be looking at right ventricular function, quality of life, and biomarkers among others, so that we have a comprehensive view without requiring invasive procedures. If all of those signals point in the same direction, that’s a strong indication.
Sten R. Sörensen: I’d add that Lancet Respiratory published an article about a year ago on what should be done for PAH patients—reverse remodeling as the goal of future therapeutic approaches. It came out of the CVCT Cardiovascular Clinical Trial Forum in Washington. The founders of that group, Professor Bertram Pitt and Professor Faiez Zannad, are both on our scientific advisory board. Faiez Zannad, Marc Humbert, and Sandeep Sahay (co-chair of our clinical steering committee) co-authored the article with the FDA and other thought leaders in PAH, defining what clinical trials should look like going forward. We’ve followed that article, and those FDA discussions, in designing the trial Rahul is describing.
There are a couple of other things worth noting. The FDA is pushing for rare disease drugs to reach patients as quickly as possible—they’ve moved to one pivotal trial generally before acceptance, and they’re pushing for a more holistic review prior to approval. We think we are running a very strong Phase IIb trial relative to what they’re asking for. If we have really good data, we think we’ll be in a position to discuss conditional approval. One reason for that is that this molecule has been in humans for 60 years at much higher dosages—the safety and tolerability profile is very well understood. We’re using much lower dosages. Regulatory authorities weigh two things: risk and efficacy. If the risk is low and you have an effective Phase IIb trial, especially in a fast-progressing, deadly disease, you want to bring it to patients as quickly as possible.
Moe: How does the current M&A wave in PAH change your strategic thinking heading into Phase IIb?
Sten R. Sörensen: Pharma today originates about 70–75% of all innovative drugs from biotech and launches about 80% of all new drugs. The deals happen in between. And right now, Pharma is facing a $200–$350 billion patent cliff running out between 2028 and 2032. They need to fill that gap, essentially by moving through the biotech innovation sphere. What are they looking for? Primarily small molecules, repeatable biology—what people call a pipeline in a drug—and something that doesn’t carry late-stage failure risk. Ideally, they come in at mid-to-late clinical stage unless they’re buying a large platform.
What does Cereno have? We have repeatable biology—a mode of action that can be moved into various indications that share similar driving pathology: inflammation, fibrosis, thrombosis, and so on. We have small molecules. We’ve de-risked the molecules considerably, given that the compound has been in man for a long time. I think we’re in a very good position for that kind of approach.
We know Merck bought Acceleron for $11.5 billion four and a half years ago and acquired the assets from Acceleron for $7 billion. We’re currently valued at around $200 million. Analysts put fair value around $700 million, with a projected $4 billion market penetration for the first asset in PAH, and expectations of a deal north of $2 billion after a successful Phase IIb. For us, the question isn’t really if a deal happens—it’s when. We would expect a deal to happen more competitively after a successful Phase IIb readout. We’re in conversations now, but it has to be the right thing.
Moe: Why does this matter for patients—what does it actually mean for someone living with PAH?
Sten R. Sörensen: At our capital markets day in February, we had on stage a patient who has survived twenty years with this disease—a remarkable and very rare achievement. He’s part of PH Europe, the patient organization. He, like Professor Humbert, wants to see this disease go into remission.
I’ve been fortunate to do this twice before—with MR antagonists and beta blockers, I helped prolong life and increase life expectancy by more than 30% in left heart failure by taking existing drugs into new usage. I think we can do it in this disease too.
One of the first patients in our trial was a woman in her early fifties, diagnosed three years earlier and on triple vasodilator therapy. She received our drug on top of standard of care for three months. Her investigator called our principal investigator and said she couldn’t believe her eyes—her patient had moved from symptomatic NYHA class 2 to class 1. They’d normalized her cardiac output. They’d reduced her pulmonary vascular resistance by 44%. The investigator wanted to write an abstract for the American Heart Association. We pulled it at the time because we wanted to inform our shareholders first. We call her the remarkable patient. She was the first patient where we said: this seems to work. But she was one patient.
Then we did the top-line analysis, and then the full Phase IIa data. Forty-three percent of patients reduced their REVEAL risk score by more than one point over three months—translating to reducing mortality by almost 23%. We improved NYHA functional class in one third of patients. We reduced pulmonary pressure in two thirds. We improved quality of life between 73 and 85% across the full cohort. And we saw a statistically significant improvement in cardiac contractility in the right heart—a very strong prognostic factor, despite the small size of the study and shorter duration of 12 weeks.
So if a patient is reading this: let’s cross our fingers that we see the same kind of data in Phase IIb that we saw in Phase IIa. If that’s the case, I think this drug will be approved within a year of the data coming out. But we have to hope it works. When I was young, I thought everything had already been discovered—I’ve learned that’s not the case. I think we might be onto something here.
Rahul Agarwal: We also have a patient representative on our clinical steering committee. The drug is once daily, oral, and combinable—well tolerated relative to many of the current options, which have side effects that are genuinely unpleasant. These patients will be taking this medication for the rest of their lives, so we want to make sure it’s something they can actually live with.
“One of our first patients was a lady, 51, 52 years old, on triple vasodilator therapy. The investigator called up and said, ‘I can’t believe my eyes. We’ve normalized her cardiac output. We’ve reduced her pulmonary vascular resistance with 44%.’”
Sten R. Sörensen is CEO and board member of Cereno Scientific, a Swedish biopharmaceutical company developing epigenetic therapies for cardiopulmonary diseases. Rahul Agarwal is Chief Medical Officer and Head of R&D.
Moe Alsumidaie, MBA, MSF, is founder and Chief Editor of Vanguard Publications, which publishes Clinical Trial Vanguard, Pharma Vanguard and BullScope, and Head of Research at CliniBiz. He has two decades in clinical trial operations and data science, with earlier roles at Genentech, Abbott Vascular and Stanford University Medical Center, and is a guest lecturer in clinical trial sciences at Rutgers University.
