Breaking New Ground in Cardiovascular Health: Innovative Approaches in Clinical Trial Design

John Kastelein, MD

While many big pharma companies have shied away from the cardiovascular space, and even fewer smaller biotechs are venturing into it, NewAmsterdam Pharma stands as a notable exception. In this interview, John Kastelein, MD, founder and chief scientific officer, delves deep into the challenges and opportunities within the cardiovascular field, exploring the current landscape for lipid-lowering therapies and the unique potential advantages of CETP inhibitors. The conversation covers various aspects of clinical trial design, emphasizes the importance of diversity and inclusion in trial enrollment, and reflects on lessons learned from the COVID-19 pandemic. Additionally, Kastelein shares his perspective on why the company has chosen to invest in its own Phase III trials instead of pursuing acquisition.

Moe Alsumidaie: Given the global concern for cardiovascular health and the crisis driven by factors like obesity, why are relatively few biopharmaceutical companies working in this space?

John Kastelein: The rising rates of cardiovascular disease and death in the US can be partly attributed to therapeutic inertia, where patients and doctors struggle to adhere to and implement guidelines. Expensive new drugs, such as monoclonal antibodies to PCSK9, and inexpensive but less potent generics like ezetimibe have left little room for new development. Also, companies find it difficult to introduce drugs that offer significant benefits over existing generics to justify payers to cover the costs.

MA: Can the success seen in the diabetes space, with many new medications and no therapeutic inertia, be replicated for blood pressure and lipid management?

JK: Yes, it should be possible for blood pressure and lipid management, but we still need to see that happen. We believe that obicetrapib, our CETP inhibitor, has the potential to partly address some of the questions in the lipid space.

MA: With your extensive experience in cardiovascular studies, can you explain how trial designs have evolved to generate better outcomes compared to the past?

JK:. The major change is that new drugs must be tested on top of statin therapy. However, some mistakes have been made in the past that can be corrected now. For instance, cardiovascular outcomes trials need to last at least four years for lipid lowering to see significant changes in endpoints.

MA: What barriers do you face as a small company trying to enter the cardiovascular space?

JK: One of the main challenges for investors and small companies is the cost of clinical trials. FDA requires large Phase III lipid programs and outcomes trials, making the costs quite significant. However, we are committed to approving our drug. We believe our current cash balance will be sufficient to fund our operations through the expected completion of our ongoing trials and demonstrate that our drug lowers cholesterol and reduces heart attacks and strokes.

MA: Smaller pharma companies usually pursue acquisition rather than investing in their own Phase III trials. Why did you choose the latter?

JK: We chose to invest in our own Phase III trials because we believe the true value of our compound will only become apparent after the completion of the two lipid-lowering Phase III trials. We believe our drug has unique properties, with potential benefits in diabetes, Alzheimer's, and other conditions, along with its potent LDL-lowering capability. We think that the full potential of our drug can only be appreciated after large-scale trials that demonstrate its efficacy and safety. Our management team has extensive experience in this area, which gives us confidence in our ability to successfully execute the trials ourselves and maximize the value of our compound.

MA: Considering the current landscape for lipid-lowering therapies, what unique benefits does the CETP inhibitor offer that would justify its inclusion in payer formularies and differentiate itself from existing therapies in the market like the SGLT2 inhibitors?

JK: Our CETP inhibitor is very potent at a low dose of 10 milligrams, making it appealing for our target demographic with a mean age of 70. Additionally, our drug has been generally well tolerated in clinical trials to date, is cost-effective to produce, and is designed to be taken as a small tablet once a day. We have learned from past challenges in trial design and have taken great care in designing our Phase III program and our cardiovascular outcomes trial differently, hopefully ensuring its success.

MA: What unique benefits does the CETP inhibitor offer compared to existing therapies like SGLT2 inhibitors?

JK: Our CETP inhibitor has several advantages. It is very potent at a low dose of 10 milligrams. In our ROSE Phase IIb trial, patients receiving our CETP inhibitor at 10 mg showed a median reduction of LDL-C of 51% versus baseline in patients who were on a high-intensity statin therapy. When given the CETP inhibitor at 10 mg in combination with ezetimibe in the ROSE2 trial, we saw even greater reductions in that population. These data are appealing for our target demographic, who are mainly elderly people. The small pill is convenient for daily use and can be taken with or without food. Additionally, the drug is inexpensive to produce, which allows for flexible pricing attractive to payers. Furthermore, we plan to study the CETP inhibitor’s protective effects against diabetes and possibly also against Alzheimer’s disease. This range of potential benefits makes it a promising option for patients.

MA: How have you ensured your clinical trials last long enough and target high-risk patients? How has the COVID-19 pandemic influenced your trial designs?

JK: We have stipulated that our outcomes trials should last at least 2.5 years after the last patient enrolls, totaling about 4 years. To enrich our trials, we have selected patients with conditions such as elevated triglycerides, diabetes, and recent coronary disease. During the pandemic, we were also able to address underrepresented communities, such as African Americans and other demographics in our trials, achieving our intended diversity goals. Conducting cardiovascular outcomes trials during the pandemic was challenging for the industry, but fortunately, the bulk of NewAmsterdam’s ongoing outcomes trial has taken place after the worst of the pandemic.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and regular contributor to Applied Clinical Trials.