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Treatment and prevention of cardiovascular disease

The potential of next generation omega-3 fatty acids

In 2019 approximately 17.3 million people died globally due to cardiovascular disease.

Treatment of cardiovascular disease and its complications continues to pose a substantial burden on healthcare systems around the world. The annual cost of cardiovascular disease in 2019 was officially estimated at $351bn in the US and €210bn a year in Europe.

Diabetes is a major public health problem which affects more than 415 million people worldwide with an estimated increase to 642 million by 2040. For individuals with diabetes, cardiovascular disease is the leading cause of morbidity and mortality. In the US alone there is an estimated $37.3bn in cardiovascular-related spending per year associated with diabetes.

Against this backdrop, the ability to treat both type 2 diabetes by improving blood glucose control and substantially improve cardiovascular outcomes in both diabetics and non-diabetics represents an important opportunity to address two major public health needs with a single compound.

Many advances in the treatment and prevention of cardiovascular disease have been made over the past few decades including
type 2 diabetes treatments, LDL cholesterol management with statins, blood pressure- lowering medications, antiplatelet agents and other treatments. However, tackling residual cardiovascular risk remains as a substantial public health challenge across the world.

It is becoming more common for individuals to have multiple risk factors leading to an increased risk of cardiovascular disease. Therefore, a large unmet need remains for the development of new therapeutics that will tackle these various risk factors.

Recent progress in primary and secondary prevention of cardiovascular events provides hope that new therapies targeting various modifiable cardiovascular risk factors including high triglycerides, inflammation and hyperglycaemia will produce additional benefits to current prevention strategies.

In this context, the recent resurgence in omega-3 fatty acid research and the clinical data that has been produced provide an avenue for the development of such multifaceted therapies. The next generation of omega-3 fatty acids may have the potential to address several facets of cardiovascular risk simultaneously by significantly improving on what has been achieved to date.

Cardiovascular disease treatment and prevention

One strategy that had been trialled repeatedly to address cardiovascular risk is omega-3 fatty acid treatment. After a number of recently failed cardiovascular outcome trials of omega-3 fatty acid mixtures, including the recent STRENGTH study, the REDUCE-IT trial (Reduction of Cardiovascular Events with Icosapent Ethyl- Intervention Trial) with a highly purified omega-3 fatty acid signalled a promising development in cardiovascular disease treatment and prevention.

REDUCE-IT demonstrated that a specific omega-3 fatty acid, eicosapentaenoic acid (EPA), significantly reduces the risk of ischaemic events, including death from cardiovascular causes, in patients with high triglycerides despite statin use.

REDUCE-IT showed that in the enrolled population of 8,179 high-risk patients, treatment with highly purified EPA significantly reduced first cardiovascular events by 25% and total (first plus subsequent) cardiovascular events by 32%.

These findings represented a potentially notable advance in cardiovascular disease prevention, after the advent of statins approximately thirty years ago. EPA treatment was adopted into all major treatment guidelines in both the US and Europe, even though this was before regulatory approval for icosapent ethyl has been gained in Europe.

By contrast, the recent STRENGTH trial (Statin Residual Risk Reduction with EpaNova in High Cardiovascular Risk Patients with Hypertriglyceridemia) ‘was terminated early due to interim analysis revealing low probability for benefit with omega-3 CA’, as reported by the American College of Cardiology on 15 November 2020.

STRENGTH was a cardiovascular outcome trial of a therapy containing an omega-3 mixture of EPA and DHA (Docosahexaenoic acid). The different outcomes between the REDUCE- IT and STRENGTH studies highlighted that not all omega-3 treatments are equal and focused the attention of researchers on high-purity EPA-axis treatment.

Changes in the omega 3 space

Since the publication of the REDUCE-IT results, a change in omega-3 fatty acid research and drug development has taken place, focusing on EPA and its metabolites and derivatives. After the accumulation of evidence regarding the actions of EPA, the utility of this therapeutic approach is evident and has brought this field of research back into the spotlight.

Afimmune, a company with a focus on the discovery and development of bioactive lipids, is working to bring novel next generation derivatives of EPA and its metabolites to patients. High purity EPA treatment has opened the door to a largely untapped therapeutic class. Epeleuton
is the company’s first next generation synthetic omega-3 compound to enter phase 2 clinical trials.

It appears to not only replicate the effects of EPA more potently and at a lower dose but also treats type 2 diabetes by improving glycaemic control. This is a novel additional property as EPA has not demonstrated any improvements in glycaemic control.

Epeleuton is a synthetic high-purity EPA- derived second-generation omega-3 fatty acid with a therapeutic profile that is distinct from
other omega-3 fatty acids. In a phase 2a study, it decreased triglycerides, improved glycaemic control and improved markers of inflammation.

The data indicates that this next generation derivative of EPA has potential for cardiovascular risk reduction by simultaneously targeting high triglycerides, type 2 diabetes, inflammation and other risk factors.

The speed of translation of the learnings from REDUCE-IT to further drug discovery and development shows a renewed interest in this space. Epeleuton is currently being studied in a phase 2b multinational trial in the US and Europe, with results expected before the end of 2021.

Beyond the efficacy results, EPA and its next generation derivatives show a good safety and tolerability profile compared to many of the current treatment options for cardiometabolic diseases.

The established and advantageous safety profile of this therapeutic class is suited to long-term treatment that could not only alleviate some of the substantial burden experienced by patients but will also encourage further research in this field.

Improving cardiometabolic disease treatment

Current cardiovascular risk strategies often require multiple treatments to address individual risk factors. Treatment of hypertriglyceridaemia, hyperglycaemia and inflammation have been individually shown to effectively reduce cardiovascular risk and the rate of ischaemic events.

While there is established and accumulating evidence that multiple strategies may delay the progression of atherosclerosis and reduce the incidence of ischaemic events, this comes with an added pill burden to patients and in many cases potentially problematic polypharmacy, itself a growing problem. Each treatment comes with its own individual safety concerns and considerations, and the often burdensome combinations present additional concerns.

The next generation omega-3 fatty acids currently in development have the potential to treat these multiple risk factors simultaneously, advancing on the established effects of EPA. The omega-3 story has just started with EPA which has laid the foundations for the platform.

The next generation compounds will build on this evidence base to provide greater efficacy and expanded therapeutic benefits with treatments that are safe, convenient for patients and ultimately improve their quality of life. This is an exciting time in cardiovascular research and innovation.

Moayed Hamza is Medical Director of Afimmune Ltd

29th December 2020

Moayed Hamza is Medical Director of Afimmune Ltd

29th December 2020

From: Healthcare

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