Designing Trials For Disease Modification: Cereno Scientific's Approach To Pulmonary Arterial Hypertension

Sometimes the call for faster clinical trials has to go unanswered, because speed can’t take precedent over scientific rigor, especially in studying a novel therapy for pulmonary arterial hypertension (PAH) and when disease modification is the goal.

In this Q&A, Cereno Scientific’s Rahul Agrawal discusses the scientific and strategic rationale behind extending the company’s Phase 2b study duration. He also shares how patient input, regulatory guidance, and earlier-phase data shaped a design intended to generate more meaningful and durable insights in a complex, heterogeneous disease.

Clinical Leader: Cereno Scientific is embarking on a Phase 2b trial for CS1 for the treatment of pulmonary arterial hypertension. How does it break away from a traditional trial design, and why?

Rahul Agrawal: The design reflects, first and foremost, the scientific rigor we bring to this program but also a pragmatic understanding of the realities of PAH drug development. Rather than relying solely on traditional short-term endpoints, as most vasodilating drugs have done, we've designed this study to better capture the broader potentially disease-modifying effects of CS1.

PAH is a progressive, highly heterogeneous disease. It's not just one patient type, so we wanted a design that reflects meaningful clinical benefit while also being operationally feasible. If a study is too complex, sites and patients simply won't participate.

The trial involves approximately 126 patients across two active dose groups plus a placebo arm, all on top of standard of care. What makes it particularly unique is what happens after the 36-week primary endpoint period. At that point, half the patients in each active dose group (roughly 21 or 22 patients) are switched to placebo, while the other half remain on CS1.

This allows us to assess whether the treatment effect is sustained after the drug is stopped. If CS1 is truly disease-modifying, we should see a durable effect even in patients who are no longer taking it. To our knowledge, no other PAH program has done this before.

Meanwhile, the placebo group from the first 36 weeks crosses over to receive CS1 on top of standard of care, so every participant ultimately has the opportunity to receive the investigational drug.

From a regulatory and commercial standpoint, the longitudinal depth of this data set will be substantial. Having nine months of data, not the typical six, provides a much richer picture of the drug's potential. And the once-daily oral tablet formulation makes a real difference for compliance and patient quality of life. Several existing PAH therapies involve subcutaneous injections or inhalation, and some carry significant safety risks. CS1 doesn't have those complications.

In Phase 2b, you'll be extending the trial timeline from 24 to 36 weeks. What fueled your decision to extend the trial by those 12 weeks?

The extension to 36 weeks, or nine months, was driven by both a strategic and a data-informed assessment of how best to characterize the therapeutic potential of CS1, given that we're pursuing disease modification not vasodilation.

Vasodilating drugs work quickly; you may see an effect within days. Disease modification is fundamentally different. The biology we're targeting requires more time to manifest meaningfully. We needed to allow sufficient duration for the full treatment dynamics to emerge and, critically, to observe the durability of the response.

Most historical PAH trials were designed at 24 weeks, which was appropriate for vasodilators. But CS1 has a different mechanism of action, and we took that seriously in the design. We felt that three additional months would allow us to better observe clinically relevant treatment effects and, importantly, to strengthen the overall value of the data set for regulatory discussions, for commercial partnering conversations, and for market differentiation.

The primary endpoint remains pulmonary vascular resistance, or PVR, measured via right heart catheterization, the invasive gold standard that both the FDA and EMA require, because PVR is part of the very definition of the disease. But alongside that, we're capturing secondary endpoints around right heart function and biomarkers. The extended timeline makes all of that data more meaningful.

How did emerging interim data, whether efficacy signals, variability, or safety observations, influence the decision to lengthen the study?

Several things fed into that decision. First and foremost, the Phase 2a trial reinforced our confidence in CS1's favorable safety and tolerability profile. Having that reassurance meant we could think more ambitiously about optimizing the study design. A drug with safety concerns doesn't give you the same freedom to extend.

The Phase 2a was a three-month trial conducted across 10 sites in the U.S., with the primary objective of assessing safety and tolerability, though we were also looking to capture early efficacy signals. And we know there is huge variability across PAH patients in disease severity, in background therapy, and in response. That complexity reinforced the argument for a longer observation window.

What was particularly compelling was the patient-level feedback from investigators during Phase 2a. Some sites saw what they described as really meaningful changes in their patients, and on the basis of that, a number of investigators requested an expanded access program. Ten patients from the final Phase 2a evaluation went on to receive CS1 for an additional year under an FDA-approved expanded access arrangement. That gave us solid safety and tolerability data at the doses we're using, over a longer horizon, in real PAH patients. It was a small group, too small to draw efficacy conclusions, but it was an important signal that the drug was well tolerated over time, which gave us confidence to design the Phase 2b with a nine-month active treatment period.

Did feedback from regulators play a role in extending the trial?

Very much so. We had a constructive Type C meeting with the FDA — the formal scientific advice pathway — and the discussion was highly productive. The FDA had already encountered CS1 through the Phase 2a work, so there was a degree of familiarity with the program.

What came through clearly was the FDA's expectation that if you're claiming disease modification, you need to demonstrate that the effect persists after treatment is stopped. That's a key part of what informed the post-36-week withdrawal sub-study. And they endorsed the overall design.

We'll also be seeking input from the EMA in the coming months. Our first interactions have been U.S.-focused because that's where Phase 2a was conducted, but we're committed to aligning with both regulators. The FDA's engagement was encouraging, and we believe the quality and longitudinal depth of data we're generating will serve us well in those forthcoming European discussions, too.

The primary endpoint readout is targeted for end of 2028, assuming no major disruptions, geopolitical or otherwise.

How has, or how do you anticipate, the timeline will affect patient recruitment, enrollment, and retention?

Any extension of trial duration has to be carefully considered in terms of the burden on patients and on sites. We take that seriously. But our honest assessment is that the extended timeline is unlikely to be a significant barrier, and there are several reasons for that.

The first is the drug itself. CS1 is a once-daily oral tablet that is well tolerated and combinable with existing standard-of-care therapies. Patients on this trial don't face the burden of injections or inhalation devices, and they're not experiencing the kind of safety concerns such as bleeding risk, thrombocyte monitoring, or cardiac effects that are associated with some existing PAH treatments. That makes a meaningful difference in day-to-day life during the trial.

In terms of site visits, patients attend approximately nine or 10 visits over the course of the year. The schedule is more intensive early on, then it spaces out to every two to three months. For a disease where patients are already engaged with regular medical follow-up, this isn't an extraordinary ask.

Equally important is what CS1 is offering. PAH patients enter trials because they're looking for something new, something that might genuinely change the trajectory of their disease. When you can tell them you're not just targeting symptoms but potentially modifying the disease itself, that resonates. There is currently no approved disease-modifying therapy for PAH, not even the newer agents. We believe that message will be compelling for patients who have already exhausted or are managing existing therapies.

We've also taken an important step in involving Hall Skaara, a patient representative from the patient organization PHA Europe & Global, directly on our clinical steering committee. He reviewed the study design and provided feedback before we finalized it. That kind of co-design process matters; it means the trial has been stress-tested from a patient perspective, not just a scientific one.

Patients, their advocates, and even industry experts are calling for faster and simpler trials. But that might not fit every drug and every patient population. Why doesn't scaling back work for CS1?

Everyone supports smarter, more efficient clinical development. But simplification and speed should never come at the expense of understanding the true value of a therapy, especially in a disease as complex as PAH.

In PAH, disease progression is multifactorial. Patients are heterogeneous and are already on background therapy. Short or overly simplified trials may simply fail to capture clinically meaningful changes, particularly when what you're looking for is disease modification. A vasodilator that works within days can be adequately evaluated in a 24-week trial. A drug that aims to slow or reverse disease progression cannot.

There is no approved disease-modifying therapy for PAH. Not a single one. That's the space we're trying to enter. To establish that credibly for regulators, for physicians, for payers, and for future commercial partners, we need data that goes beyond demonstrating safety. We need to demonstrate durable, clinically meaningful efficacy. And we need enough time in the study to show it.

The commercial reality also matters here. If a drug doesn't reach the market, it helps no one. Generating a high-quality, differentiated data set now means that when we approach potential partners or when we engage with payers, we have something genuinely compelling to offer. That's not a compromise of patient centricity, it's an enabler of it.

Decentralized and remote trial elements have a real place in clinical development, and we're certainly not opposed to them in principle. But some endpoints in PAH, particularly right heart catheterization for PVR measurement, simply cannot be decentralized. The regulatory requirement for invasive measurement is there precisely because the disease definition depends on it.

What advice do you have for those trying to achieve a balance of speed, efficacy, and safety?

My core advice is to remain patient-focused while being disciplined in strategic decision-making. Those two things are not in conflict; they're mutually reinforcing. Speed is important, and I understand why patients and advocates push for it. People are waiting for therapies that could extend or improve their lives. But speed alone should not drive development choices.

The most valuable clinical programs are those that generate a high level of confidence in the data they produce — data that can support regulatory success, clinical adoption, and commercial value creation. Cutting corners on study duration or design may get you to a readout faster, but it may not get you to a meaningful readout.

The best balance, in my view, comes from designing trials that are scientifically meaningful, operationally feasible, and aligned with long-term value creation. I don't shy away from the commercial dimension; I've worked on both the R&D and commercial sides of this industry, and I've seen too many promising drugs fail to reach patients not because of the science but because of how the development program was structured. If a drug never reaches the market, it cannot help anyone.

Surround yourself with the right expertise. Our steering committee at Cereno includes some of the world's leading PAH specialists — investigators from France, the U.S., Sweden, and South America, including representatives on both American and European guideline committees. We also include a world-class cardiologist. That international, multidisciplinary perspective has shaped how we think about the trial design, the patient population, and the regulatory strategy. And listen to patients. Include them in the design process, not as an afterthought but as genuine partners. If your trial works for patients, if it's tolerable, comprehensible, and aligned with what they actually care about, recruitment and retention follow naturally. The science and the patient experience don't have to be at odds.

About The Expert:

Rahul Agrawal, MD, is CMO and head of R&D at Cereno Scientific. He is a senior executive leader with a diverse background spanning Big Pharma and biotech. His expertise encompasses the entire value chain, including R&D, medical affairs, commercial, and strategy experience across various therapeutic areas, such as cardiovascular, renal, respiratory, and rare/orphan drugs, and he has launched seven drugs globally. Previous roles include CMO at Cardior, VP and global medicines leader at AstraZeneca, and global director of medical affairs and clinical development at Bayer HealthCare. Dr. Agrawal has an MD from the Free University of Berlin, Germany, and Cornell University, New York, and is board-certified in cardiology, internal medicine, and emergency medicine. Additionally, he holds an MBA from Buckinghamshire New University, U.K.