'How Do You Feel?': Designing A Cardiac Trial With A Patient-Reported Primary Endpoint

A conversation between Imbria Pharmaceuticals Chief Medical Officer Albert Kim, MD, Ph.D., and Clinical Leader Executive Editor Abby Proch

For people living with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM), improving clinical measures is only part of the equation. How patients feel and function in their daily lives matters, too.

That thinking helped shape Imbria Pharmaceuticals’ Phase 2b FORTITUDE-HCM clinical trial, which is evaluating ninerafaxstat, an investigational therapy designed to improve cardiac energetics, in patients with symptomatic nHCM. The trial uses the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) as its primary endpoint, alongside secondary measures of symptom burden and functional capacity. Because that’s the goal — to understand whether treatment can meaningfully improve the symptoms and limitations that affect patients’ daily lives.

In this conversation, Clinical Leader Executive Editor Abby Proch speaks with Albert Kim, M.D., Ph.D., CMO of Imbria, about the thinking behind FORTITUDE-HCM and the operational choices that shaped it.

Their discussion covers how Imbria designed its trial to have low patient burden, balance patient-reported outcomes and functional testing, and engage patients globally with clear communication.

Clinical Leader: Your trial design might differ from broader cardiovascular trials. How so?

Albert Kim: Your typical cardiovascular trial would include some very objective endpoints. You measure somebody's blood pressure, it's a number. You measure somebody's serum cholesterol, that's also a number. We're doing numbers in our trial, too. But for our patients with symptomatic nHCM, our primary endpoint uses the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, or KCCQ-CSS, to assess patients’ symptoms and limitations – their overall health status. A key secondary endpoint uses cardiopulmonary exercise testing, or CPET, to assess functional capacity. So, we're not just taking a blood sample or taking a single measurement. We're trying to assess how our therapy improves how people feel and how they function.

Did you have to check with regulators before deciding on patient-reported and functional endpoints?

Typically, companies develop drugs for three reasons: to help patients feel, function, or survive better. Cardiovascular trials are well known for evaluating hard clinical endpoints such as stroke, heart attack, and death. In this Phase 2b trial, we’re focused on shorter-term endpoints: how people feel and function. This approach is well aligned with the health authorities both in the U.S. and in Europe. We didn’t invent this path, in fact, there have been several precedents for trials and agents using the KCCQ-CSS and CPET.

Speaking of patients, how much of a niche condition is this, and what were some of the recruitment challenges, if any?

The population that we're recruiting, patients with symptomatic nHCM, is considered an orphan population, and the FDA recently granted Orphan Drug Designation to ninerafaxstat for the treatment of symptomatic nHCM.

That being said, within the broader community of people with hypertrophic cardiomyopathy, the population is underdiagnosed and very much underserved. At this time, there are no therapies specifically approved for symptomatic nHCM.

As we’ve seen in other cardiovascular diseases, greater awareness and new treatment options can lead to increased diagnosis. As the nHCM landscape evolves, we may gain a better understanding of the true size of this patient population.

You're in the middle of enrollment right now. How have insights from patients and the HCM community informed the trial design and eligibility criteria?

We've come to realize that the hypertrophic cardiomyopathy community is very well connected. The cutting edge of research is very quickly communicated and disseminated among the patients and patient organizations over the internet and social media.

Because of that, we better understand the priorities of patients and their organizations and what they want to see in a clinical trial design. I can't really point to one or two inclusion or exclusion criteria that have made the difference, but a lot of sponsors like us are now using the KCCQ-CSS as key endpoints.

The KCCQ-CSS ranges from zero to 100, with higher scores reflecting better health status and fewer symptoms. In FORTITUDE-HCM, we use a score of 80 or less as an eligibility criterion to help identify patients with meaningful symptom burden.

Determining that threshold requires careful consideration. If you set the number too low, you may significantly limit the number of patients who are eligible for the trial. If you set it too high, you may enroll patients who are less symptomatic and therefore have less room to demonstrate meaningful improvement. By talking with patients and patient organizations, we learned a lot about how to set the bar in a way that is both clinically meaningful and realistic for enrollment.

In the process of identifying the sites, what did you need to know from a trial site before activating it?

This question is the make or break of a clinical trial. We designed the trial with an overall low patient burden. There are only six visits, but each visit is high touch. We asked sites whether this would be feasible for them. There were some questions you would ask any clinical site, such as, “Have you done this before?” But also, “Do you have infrastructure and staff to support this kind of clinical trial? Do you have a good echocardiography lab that can take ultrasounds? Do you have a good cardiopulmonary exercise test machine and staff that can do the assessment the way we want to?” It was a dual-pronged feasibility assessment to determine their generic capabilities and their fit for our protocol.

What about trials across various geographies? How does that impact your design or recruitment?

We try to make it as seamless a clinical trial experience as possible so people can feel the consistency of the trial protocol. We have a fairly large footprint across 11 countries. And, yes, we needed to be aware of the differences in healthcare systems, regulatory environments, and local practices across the countries where we’re conducting the trial.

There is a lot of operational influence and local expertise needed to successfully enter those countries in an efficient way. Even simply translating documents is a big deal to make sure that you have consistency between the different versions of documents. But that's the tip of the iceberg. We're fortunate to have good local partners helping us navigate all the paperwork.

Translating the questionnaire is one thing, and it’s likely straightforward. But what about interpreting patients’ answers? What are the nuances by region or country?

This is something we’ve talked about explicitly in our design meetings, investigator meetings, and our conversations with the sites. In some cultures, there can be a particularly high-trust relationship between patients and their physicians. A patient may worry that reporting that they feel poorly somehow reflects negatively on their physician. It’s important to make clear that it doesn’t. We want patients to accurately describe how they’re feeling. Cultural awareness matters both for the patient experience and the integrity of the trial data.

What lessons have you learned over the course of FORTITUDE-HCM that you can share with readers?

It’s always hard to give widely generalized advice, but one lesson for me is that communication really matters. Whether written or spoken, being clear about what you’re trying to accomplish in a clinical trial  is fundamental to success. That applies to everything we’ve discussed today — whether it's translating a document, understanding cultural differences, or understanding how a patients feel about their illness. All of that hinges on good, clear, direct, and authentic communication at every level, from informed consent and the trial protocol to patient questionnaires and investigator meetings. That’s been a particular focus for us at Imbria.

Editor’s note: This transcript has been edited for clarity.

About The Expert:

Albert M. Kim, MD, Ph.D., FACC, FHRS, is a physician-scientist with over two decades of experience in cardiovascular disease, novel therapeutic product development, translational science, and clinical medicine. He currently serves as Chief Medical Officer of Imbria Pharmaceuticals.

Prior to Imbria, Dr. Kim was a venture partner at RA Ventures (Raven), CMO of the Raven Blackbird Development Team, and as CMO of Cytel. He has held senior leadership roles at Novartis and Pfizer, where he oversaw early- and late-stage clinical development programs. At Pfizer, Dr. Kim served as vice president, clinical research head for the internal medicine research unit.

He is a fellow of the American College of Cardiology and the Heart Rhythm Society. Dr. Kim earned his undergraduate degree in biomedical engineering from Harvard University, his MD and Ph.D. from the University of California, Los Angeles, and trained at Brigham and Women’s Hospital, Massachusetts General Hospital, and the University of California, San Francisco.