Beating the Odds: The Development of New Drugs for Cardiovascular Disease

The Development of New Drugs for Cardiovascular Disease
The Development of New Drugs for Cardiovascular Disease

Heart disease causes 1 in 5 deaths per year in the U.S. alone, as estimated by the Centers for Disease Control and Prevention (CDC). While genetics can contribute to the onset of heart disease, there is significant data showing that it is also attributed to poor lifestyle and habits, which makes it one of the top preventable causes of death.

Cardiovascular conditions are not modern medical concerns, though – even Egyptians from 3,500 years ago showed evidence of cardiovascular disease (such as atherosclerosis, the narrowing of arteries). However, modern medicine has been developing new drugs for cardiovascular disease, including those that are genetic or rare.

Cardiovascular Disease Research in History

William Heberden first described the condition of angina – tightness in the chest preceding ischemic heart disease – in 1768. He called it a “disorder of the breast marked with strong and peculiar symptoms, considerable for the kind of danger belonging to it” and then named it angina pectoris.

Following that, William Osler worked to further characterize angina in the late 1800s and was the first to indicate it was a syndrome instead of a disease in itself.

Research into heart disease began expanding in the 1900s, with the formation of the American Heart Association in 1924. Doctors began exploring coronary arteries with catheters, giving them the ability to evaluate and diagnose coronary artery disease. These diagnoses became more accurate with F. Mason Sones’ technique for capturing high-quality diagnostic images in 1958.

By the 1940s, researchers initiated the Framingham Heart Study, the first major medical study investigating heart disease. Then, in the early 1950s, John Gofman identified different cholesterol types, which led to a further understanding of atherosclerosis. Doctors began advising the general population to be more mindful of their diets, particularly of foods high in saturated fats.

Over the next decades, doctors and scientists would invent treatments such as bypass surgery, angioplasty, and the use of stents, and blood tests to predict the risks of heart attack.

Modern medicine has developed new drugs for cardiovascular diseases, such as coronary artery disease and other cardiovascular conditions, greatly improving the quality of life for many people. Many of these treatments include new drugs that target or mitigate various underlying symptoms.

Understanding Drug Development for Cardiovascular Disease

During drug discovery, clinical researchers test active compounds to see whether they have the predicted therapeutic effects on the target disease. From there, they determine dosage and delivery, then test for safety and efficacy.

Drug discovery can take 10 years or more, with only a handful of medications ultimately earning FDA approval. There are several stages of drug discovery, but they can be condensed into 4 categories.

1. Discovery

Researchers begin by identifying an unmet medical need, which can come from new insights into disease onset and progression, or undesirable side effects from existing treatments. From there, the researchers pinpoint the gene or protein playing a key role in disease manifestation. They will begin screening compounds and molecules for potential therapeutic effects to treat or counter that gene or protein.

Through rigorous screening, researchers will aim to identify several “hits” – compounds that produce the desired effect on the gene or protein. Following that, researchers will assess the way these compounds interacts with and affects the disease and the human body. They will then generate the “lead” compound, which is the primary compound to be developed into a drug.

Once the lead compound has been identified, researchers will begin addressing potential risks and safety concerns in an appropriate animal model. They will investigate aspects such as efficacy, potency, toxicity, stability, and bioavailability.

2. Preclinical testing

After the lead molecule has been determined, researchers begin refining, optimizing, and testing it to understand the pharmacodynamics at a granular level. They also begin formulation, where they convert the lead compound into an orally-available pill, a consumable liquid, or intravenous solution. While many preclinical trials still use animal testing, there have been efforts to regulate and limit these methods.

Alternatives to animal testing include biosimulation, computational modeling, cell models, and organism testing (such as on flies and zebrafish).

The preclinical phase allows researchers to determine facets such as:

  • Absorption, metabolization, and excretion routes
  • Potential benefits
  • Dosage and delivery route
  • Side effects
  • Interactions with other drugs and foods
  • Preliminary effectiveness

3. Clinical trials

Once the preclinical testing phase has revealed promising results and an Investigational New Drug (IND) application is approved, researchers move on to intensive drug development through in-human clinical trials and volunteer studies. Clinical trials involve controlled studies across diverse populations, in order to ensure the drug is safe and works as intended.

Clinical trials have four phases, from tolerance and safety tests to dosage tests. Phase I studies usually involves a small pool of participants to generate initial safety data while Phase II, III, and IV studies increase the number of participants and begin delineating the efficacy of the novel treatment.

4. FDA approval

From 5,000–10,000 drug candidates, only 250 will make it to preclinical testing. Due to the rigorous screening and testing processes, there are even fewer drugs making it to the stage of regulatory approval.

Following the success of each clinical trial, the researchers will collect and analyze all the relevant data. They then submit this data alongside the proper documentation to the appropriate regulatory body for review. No drug or vaccine can be sold commercially without approval from a national regulatory authority and ethics committees such as the U.S. Food and Drug Administration (FDA).

New Drugs for Cardiovascular Disease

The identification of new cardiovascular drug targets has led to advancements in drug development over recent years. These emerging medications have transformed the landscape of cardiovascular treatments by addressing unmet medical needs or supporting existing therapies. Below we list a few of the advancement of new drugs for cardiovascular disease.

1. Inclisiran

The U.K. National Health Service and the National Institute for Health and Care Excellence (NICE) collaborated in 2020 with pharmaceutical company Novartis to test the drug inclisiran, as a treatment to lower cholesterol. Early results from previous trials suggested that out of 300,000 patients taking inclisiran annually, the treatment could prevent 55,000 heart attacks and strokes.

The U.S. FDA approved inclisiran (Leqvio) in 2021.

Inclisiran is a bi-annual injection that lowers low-density lipoprotein cholesterol (LDL or “bad cholesterol”) with 2 doses a year. It improves the liver’s natural ability to mitigate the production of a protein that maintains high levels of circulating cholesterol. It is intended for use alongside proper diet and maximally tolerated statin therapy.

2. Icosapent ethyl

In 2021, the E.U. approved the use of icosapent ethyl (Vazkepa) as a medication to reduce the risk of cardiovascular events such as heart attacks and strokes. It is intended as a tandem treatment to statin medicine for adults with high levels of triglycerides in their blood.

Icosapent ethyl can be taken by patients who either have a cardiovascular disease or have other comorbidities that increase the risk of a cardiovascular event.

Vazkepa is prescribed as a capsule with 998mg of icosapent ethyl, taken twice daily with or after meals. The active compound has an anti-inflammatory effect, reduces harmful triglyceride-rich proteins, and incites a protective antioxidant effect.

3. Mavacamten

In late 2020, Bristol-Myers Squibb acquired the heart drug company MyoKardia, which specializes in small molecule therapies for patients with genetic heart disease. MyoKardia focuses on diseases such as hypertrophic cardiomyopathy (thickening of heart walls) and dilated cardiomyopathy (weakening of heart walls).

MyoKardia’s biggest asset is the compound mavacamten, a “potentially revolutionary” medicine for treating obstructive hypertrophic cardiomyopathy (HCM). This chronic heart disease has a high morbidity rate and is most prevalent in people aged 40–50 years old.

The drug company uses its proprietary drug discovery platform to combine cardiovascular genomics and heart muscle biology to target heart conditions at the genetic level.

In 2022, Bristol-Myers Squibb announced that the U.S. FDA had approved mavacamten (Camzyos) for treatment.

The Future of Drug Development for Cardiovascular Disease

So what does the future look like for new drugs for cardiovascular disease? The American Heart Association predicts that by 2030, approximately 40.5% of the U.S. population will have a form of cardiovascular disease. This includes conditions such as hypertension, coronary heart disease, heart failure, and stroke.

However, in terms of clinical research, there is increasing emphasis on the need for improvements in public health, a larger focus on diverse populations, and more engagement with communities. Cardiovascular research needs to “do more” – that is, explore new directions and move beyond studies of existing treatments.

The necessity of equal and equitable access to cardiovascular treatment is of particular significance. Select socioeconomic, racial, and ethnic groups in the U.S., for example, have higher rates of cardiovascular disease risk factors, incidence, and mortality.

Major contributors to these disparities can include implicit bias and socioeconomic stereotyping. Both affect health promotion, disease prevention, and access to cardiovascular care. Future developments in drug and treatment development need to focus on accessibility and diversity to level the field for cardiovascular epidemiology.

In another aspect, research should take advantage of technological innovations such as biosensors and wearables. These provide a substantial window of valuable clinical data, which patients and doctors can use for diagnosis and treatment. These sensors and wearables collect metrics such as heart rate and rhythm, blood pressure, weight, physical activity, and oxygen levels – all relevant to cardiovascular health.

Lastly, advances in the Human Genome Project and related initiatives have expanded our scientific ability to measure biomarkers and characterize genetic profiles (among other factors). An understanding of genomics is becoming crucial to cardiovascular epidemiology since we can now identify genetic variants (both rare and common), alongside the use of genetic markers in clinical trials.

The Role of CROs in Cardiovascular Drug Development

As more clinical researchers involve themselves in the development of new drugs for cardiovascular disease, more treatments and potential cures for conditions are discovered. However, drug development is no easy feat, taking years to complete at the cost of millions of dollars. Sponsors looking to run cardiology clinical trials will benefit from partnerships with clinical research organizations (CROs) in order to execute the different stages of drug development, making the processes more efficient and leading to more productive results.

Vial is a next-generation CRO powered by technology with specializations in different therapeutic areas, including cardiology. Our experienced team of ClinOps and technology experts help us reimagine the landscape of clinical trials and empower scientists to find treatments and cures for human diseases.

Reach out to us for a proposal today!

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