Therapeutic areas in focus
CARDIOVASCULAR & METABOLIC
Addressing inequalities in access to medicines in a post-COVID world: the challenge of cardiovascular disease
Dan Ionescu from Daiichi Sankyo Europe talks to Pharmafile about the company’s role in improving access to cardiovascular treatments and preventing cardiovascular disease
What are the major health system challenges that you would like to tackle?
My biggest priority is to partner with health systems and payers to improve access to Daiichi Sankyo medicines, so people living with cardiovascular disease (CVD) have a better chance of living healthier lives. In my role, I am committed to ensuring that those who could potentially benefit from our treatments, are able to do so.
When I started my career as a neurologist, I was working in the National Stroke Institute in Bucharest and, every day, I saw first-hand the difficulties that access barriers have on treating and managing patients. That experience had quite an impact on me as a young doctor, and it motivates me to this day.
Since I started working in the pharmaceutical industry, I have worked to help efforts to address the unmet clinical needs of many patients with CVD. The disease burden is significant: in 2020 alone, 60 million people were living with the disease in Europe.
Our understanding of the needs of CVD patients is growing, particularly for those with complex medical needs or who are at high-risk for cardiovascular events. We see this reflected in the expanding scope covered within European guidelines, which are now advising that more powerful and effective therapies are needed to manage certain patient groups.
We know, however, that these come at a cost to the healthcare systems where generic medicines can be seen to be more financially favourable.
This is not a small challenge to overcome, and it requires a collective, collaborative approach between system partners to deliver improved outcomes for patients.
How does Daiichi Sankyo support discussions around medicine access in CVD?
Given the increasingly difficult economic situation we’re facing in Europe, which has been worsened by the COVID-19 pandemic, I feel it has become even more important to ensure that people have the opportunity to get the treatments that might help them the most.
I think some payer bodies perceive CVD as a low health priority and, in an effort to restrict budgets, are faced with difficult decisions about which therapy areas to prioritise. As CVD is Europe’s leading cause of death, I would argue that it requires appropriate prioritisation by health systems, payers and policy makers alike.
Especially since we know that 80% of premature deaths due to heart attacks and stroke are preventable.
Now more than ever, it is important that payer bodies recognise the health and budgetary advantages of improving access to novel therapies for CVD. There is great value in adopting a longer-term focus in all health-economic conversations. At Daiichi Sankyo we are keen to work with payer bodies to demonstrate efficiencies and savings by investing in medicines that can help prevent costly CVD events later on.
Such preventative measures and early therapeutic interventions can have significant benefits for healthcare systems in the long term.
Key to this is making use of our extensive data and working with payer bodies to identify which patient populations respond best to these treatments. From my experience, we truly see the positive impact of this approach in key markets across Europe.
Why is this an important time to focus on improving access to cardiovascular health?
CVD has an enormous societal and economic impact, costing healthcare systems in Europe €210bn a year.
Given the fast-growing and ageing population, combined with late-stage CVD diagnoses during the COVID-19 pandemic, patient numbers and the financial implications of CVD are only going to rise over the coming years.
As if that was not enough, the pandemic has had an even larger impact on CVD than some other conditions.
report we commissioned found that an infection with COVID-19 can actually induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism.
In addition, the findings showed that people with CVD who are infected with COVID-19 are far more likely to experience severe symptoms of that infection, or even lose their life to it.
While we can’t predict the evolving needs of CVD patients affected by COVID-19 in the long term, we do know that its lasting impact is going to put further strain on healthcare systems. We can expect more people to be living with a higher risk for cardiovascular events and more patients with advanced stages of CVD – that is why more effective treatments with longterm effects will play an important role in managing this situation.
What is the role that Daiichi Sankyo Europe and the wider industry play in helping to lessen the impact of CVD in Europe?
Given the vast scale of CVD in Europe, the opportunity to help people is enormous. When a treatment becomes reimbursed and thus widely accessible, it could potentially have an impact for hundreds of thousands of patients, and their families and loved ones, who are affected by the disease.
That is why we shouldn’t stop driving awareness about CVD, its prevention and risk factors across Europe, and work with relevant stakeholders to bring new treatments to patients who so urgently need them.
I’m convinced that what we are doing is making a real difference in people’s lives – and this is what motivates me in my role. That being said, addressing the impact of CVD in Europe goes beyond the provision of medicines. The pharmaceutical industry can play a key role in supporting holistic care and advancing scientific understanding of CVD. At Daiichi Sankyo in Europe we are truly passionate about this aspect of care. Through our medical studies, but also broader initiatives such as the
report, we intend to advance and share knowledge about the scale and impact of CVD that can help inspire the future of care.
As we’ve seen in the wake of the pandemic, this is so important, now more than ever.
November 2022 DSC/22/0174
This content has been commissioned by Daiichi Sankyo Europe and has been reviewed for compliance with the ABPI Code of Practice.
European Society of Cardiology. Fighting cardiovascular disease – a blueprint for EU action. (2020) Available at:
https://www. escardio.org/static-file/Escardio/Advocacy/ Documents/2020%20ESC-EHN-blueprint_ digital%20edition.pdf Last accessed November 2022.
Taskforce for cardiovascular disease prevention. (2021) ‘ESC Guidelines on cardiovascular disease prevention in clinical practice’, Eur. Heart J. 42(34); 3227–3337.
The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). (2020) ‘ESC/EAS guidelines for the management of dyslipidaemia’, Eur. Heart J. 2020 1;41(1):111–188.
Albrecht, M, et al. (2015) Value of generic medicines: an health economics study. Journal of Pharm. Policy and Practice. 8; 15.
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Timmis A, et al. (2020) European Society of Cardiology: Cardiovascular Disease Statistics 2019. Eur. Heart J. 41(1):12–85.
Cardiovascular Disease in Europe. A Call to Action 2019-2024. MedTech Europe. Available at:
https://www.medtecheurope. org/wp-content/uploads/2019/10/MedTech- Europe-Cardiovascular-Disease-in-Europe- Call-to-Action-August2020.pdf Last accessed November 2022.
European Commission. Ageing Europe: Looking at the lives of older people in the EU. Available at:
https://ec.europa.eu/ eurostat/documents/3217494/11478057/ KS-02-20-655-EN-N.pdf/9b09606c-d4e8- 4c33-63d2-3b20d5c19c91 Last accessed November 2022.
Economist Impact. Links between COVID-19 and cardiovascular disease: Seeing the warning signs and preparing for a healthier future. Available at:
https://impact. economist.com/perspectives/healthcare/ covid-and-cardiovascular-disease Last accessed November 2022.
is Vice- President, Head of Value and Access, Speciality Medicines at Daiichi Sankyo Europe
CARDIOVASCULAR & METABOLIC
Diuretic-resistant congestion – ‘The road less travelled’ in novel treatments for chronic heart failure
Ian Crosbie, CEO at Sequana Medical, explores treatments for chronic heart failure and the challenges facing their development
Congestion is a key challenge in heart failure
The problem of heart failure (HF) is well recognised, with The American Heart Association estimating that 6.5 million adults in the US are affected by HF, and that number is expected to rise to 8 million adults by 2030. Overall chronic heart failure (CHF) death rates remain significantly high, with up to half of patients dying within five years of a HF diagnosis. Although there have been tremendous advances in both drug and device approaches in recent years, they have generally focused on improving the function of the failing heart whilst failing to address the key issue of congestion. While HF is generally regarded as the inability of the heart to pump sufficient blood, on a population level, congestion (aka, hypervolemia/volume overload) is the primary driver of morbidity and hospitalisation. Symptoms and signs of volume overload directly result from the mechanical consequences of fluid (water) retention. However, the primary pathophysiologic driver of water accumulation is actually sodium retention, with fluid largely passively following the retained salt.
Diuretics – limitations and resistance
Diuretics and, in particular, loop diuretics (LD) – drugs that force the kidneys to remove excessive salt/water from the
body – are the standard of care for this patient group, but there is well-described toxicity and resistance is a major problem.
Notably, some degree of diuretic resistance is essentially the rule in HF, with the average diuretic response being approximately 10% of the normal response to LD. Once patients become
significantly diuretic-resistant or are at risk of severe renal damage, there are limited clinical alternatives to combat congestion, and the majority of these are of limited effectiveness.
It is well documented in both animal and human studies that there is adverse structural remodelling of the kidney that occurs with chronic exposure to LD.
Furthermore, the escalating doses required to maintain fluid balance are acknowledged as a double-edged sword (i.e., ‘save the heart or save the kidneys’). In addition, LD strongly activates the neurohormonal system, which not only increases the retention of sodium (and thereby fluid overload) but also acts contrary to the mainstays of HF therapy, such as ARBs, MRAs, betablockers and ACE-inhibitors, which seek to block the neurohormonal system.
HF is the leading cause of hospitalisations in patients over 65 in the US and, of these 1 million hospitalisations for HF patients each year in the US, 90% are due to fluid overload. The ADHERE registry highlights that ~50% of patients are discharged with no clinically relevant loss of weight and one in four acutely decompensated HF patients are readmitted within 30 days of discharge. There are an estimated 400,000 HF patients in the US and Europe that are chronically decompensated or congested (the ‘frequent flyers’) and they have few clinical options due to their poor response/inability to tolerate diuretic therapy. These patients have repeated hospitalisations per year, as well as poor clinical outcomes. There is no apparent new drug nor any successor to LD in development for HF patients, and the cost of HF hospitalisations in the US is over $14.5 billion annually.
Novel approach to address this key driver of heart failure
Direct Sodium Removal (DSR), a drug therapy currently in development by Sequana Medical, has the potential to improve the clinical outcomes for this large and growing body of HF patients. DSR therapy works in partnership with the kidneys to safely, rapidly and effectively remove the fluid overload, improve cardio-renal status and restore the ability of the kidney to manage the body’s fluid balance naturally. DSR therapy removes excess sodium from the body, prompting the body to eliminate excess fluid. Removing the need for LD for the duration of DSR therapy allows the cardiorenal system to ‘reset’, restoring the natural ability to manage fluid and sodium for an extended period.
The procedure involves administration of the sodium-free DSR solution into the peritoneal cavity and allowing it to dwell for a pre-defined period of time. During this period, sodium diffuses from the body down a steep gradient into the DSR solution with the circulation keeping the effective blood sodium concentration high. The DSR solution and the extracted sodium are then removed from the body, resulting in a significant elimination of sodium. The body responds to restore the concentration of sodium in the body by eliminating the excess fluid via urination and osmotic ultrafiltration, the movement of water and sodium from the bloodstream to the peritoneal cavity, resulting in reduced fluid overload. No clinically relevant electrolyte imbalances have been observed during clinical studies.
With an estimated 400,000 HF patients in the US and Europe suffering every day from diuretic-resistant fluid overload, there is a desperate need for disease-modifying therapies to address this forgotten driver of heart failure, improve clinical outcomes, transform patient quality of life and reduce the huge costs for healthcare systems.
has served as Chief Executive Officer of Sequana Medical since 2016 and has been a member of the Board of Directors since 2019. Ian has over 25 years of experience in the healthcare sector, both in-house at medical device and pharmaceutical companies, and as an investment banker at leading global firms. He has extensive expertise in implantable medical devices and a strong track record in capital markets, licensing and strategic transactions.
CARDIOVASCULAR & METABOLIC
How RNA-based therapeutics improve care and benefit patients
RNA-based therapeutics could herald a new era in metabolic care, but how do we ensure patients will actually benefit at scale?
In recent years, advances in the discovery and development of RNA-based therapeutics have been incredible.
The momentum of medicines targeting or harnessing RNA mechanisms has been growing rapidly for approximately five years, when data raised excitement at global medical congresses. However, if you had asked a person on the street, unfortunately few would have been interested. While not unusual, it leaves those with a belief in the potential of this science wanting others to see it too.
The COVID-19 pandemic resulted in monumental changes across the globe, including in this area of medicine. It facilitated the rapid rise of RNA therapeutics in scientific discussion, which became one of the most prominent scientific areas in decades, and arguably is becoming a common term.
The development of RNA-based medicines is a vast field. The first wave of COVID-19 vaccines from Pfizer-BioNTech and Moderna demonstrated how science could quickly develop vaccines with high specificity, without compromising on safety or efficacy. This gives us a glimpse of the therapeutic potential that can be developed when focusing on RNA-based medicines.
Current developments are still only the tip of the iceberg. While vaccines may have stolen the show, the same technology is also showing promise in the prevention and treatment of numerous other diseases. It could even play a role in managing the health of entire populations.
What role might RNAi play in this journey?
One approach within the field of RNA therapy is RNA interference (RNAi) – a process that blocks the production of disease-causing proteins in a highly selective way. RNAi was recognised in 2006 with the Nobel Prize in Physiology or Medicine, and is a rapidly advancing frontier in biology and drug development today. Since then, a number of RNAi therapies have been approved in certain countries across the world, primarily for the treatment of rare diseases.
As RNAi therapies are highly specific to messenger RNA (mRNA) targets, these medicines have the potential to treat any condition caused by the production of a faulty or disease-causing protein. With our understanding of the human genome ever-expanding, and collaboration across industry and research institutes becoming more commonplace, we now have significant opportunities to explore novel approaches to treating some of society’s biggest health challenges.
Unleashing RNAi’s full potential with the UK Biobank
So, the big question now is: ‘What does the future hold for RNA-therapeutics?’ Could they hold the key to treating diseases that affect more than a few thousand individuals ‒ maybe even millions?
A barrier to overcome in order to answer these questions is finding new targets; the root causes of diseases, hidden deep in the genome. In 2018, stakeholders across the industry set out to equip ourselves with that information by entering an agreement with the UK Biobank to form and fund the UK Biobank Exome Sequencing Consortium (UKB-ESC). This funding enabled the sequencing of the exomes (the protein-coding parts of a genome) of half a million UK participants ‒ for whom in-depth medical histories were available ‒ to potentially unravel long-standing health mysteries. Using this information, research has already revealed unparalleled findings and identified new therapeutic targets in areas of unmet need.
From Biobank to breakthrough in metabolic disease
For a while now, evidence has shown a link between patterns of fat distribution and metabolic conditions, including type 2 diabetes, hypertension and heart attack risk. However, there was limited knowledge of the genetic connections between them.
Drawing from the information generated by the Biobank, the human genetics teams leveraged data from over 360,000 individuals, looking specifically at these factors. Through this, they found loss-of-function variants in the INHBE gene that are associated with protection against abdominal obesity and metabolic syndrome. Specifically, these gene variants were found in 1 in 587 individuals who had a lower waist-to-hip ratio adjusted for body mass index (WHRadjBMI), which is a surrogate for abdominal fat, compared to those who did not have these variants. As well as the lower WHRadjBMI, these individuals had decreased triglycerides, increased
high-density lipoprotein cholesterol and decreased fasting glucose – all indicating a favourable metabolic profile.
The results of this study have given us fresh insight into the mechanisms that contribute to body fat distribution and its disease sequelae, helping to refine the blueprint for potential therapeutics targeting INHBE. With metabolic syndrome affecting an estimated one in three adults aged 50 or over in the UK, confirming whether targeting INHBE could have a beneficial effect on this condition is extremely important.
This hypothesis is already being tested. Given the INHBE variants result in partial loss of expression of the gene and the expertise we have at Alnylam, we can almost immediately start synthesising drug candidates and testing their potential in
cell models. Ultimately, this means it may be possible to go from identifying potential targets for our therapies to starting clinical trials in drug candidates in as little as 18 months.
The data sequenced by the UK Biobank has been invaluable and something we are continuing to research in the hope of identifying further gene mutations to transform outcomes for people across the world. But the work does not stop there. We are also supporting the Our Future Health research programme, which has the ambitious goal of capturing the genetic and health data of over 5 million adult volunteers across the UK. The goal is to gather a remarkably detailed picture that truly reflects the whole population, offering the potential to unlock transformative discoveries in health, while those whose health information is used in the programme can also benefit from the findings.
Watching the science of RNAi develop has been an eye-opening experience, and the prospect of bringing forward a new technology to modify risk factors in major diseases is hugely exciting. But it has also raised important questions around access, particularly in Health Technology Assessment-based health systems. RNA therapies present the potential to transform long-term health outcomes in major health conditions, but only if they are fully accessible to the patients that need them. This raises questions about how we will be able to reliably predict these long-term outcomes and agree access solutions that are sustainable for both industry and health services.
This will not be without difficulties. Population health is a huge operation, and being able to forecast outcomes for such numbers in the general population will require new approaches as to how we research, assess and pay for medicines. With the ever-changing nature of the world – from population growth to the increased prevalence of preventable diseases – it is important that we adopt a holistic approach and aim to prevent illness and improve health outcomes on a larger scale.
In the last few years, the NHS has pioneered new mechanisms to validate research behind population health, including its first population health agreement (announced in September 2021), aiming to treat up to 300,000 people with high cholesterol. Alongside the goals set out in the NHS Long Term Plan, and the ambitions of the UK Government, MHRA and NICE to expedite patient access to life-changing treatments, the UK has a great opportunity to continue to lead in population health if we continue to collaborate effectively.
Together, we are breaking new boundaries in healthcare and, with the steady emergence of RNA therapies, we are harnessing a revolution in biology for human health. As an industry moving forward in researching and developing medicines for the masses, it will be critical that we continue to engage early and openly, address challenges head-on, and consider that agreements may need to be as innovative as the treatments they encompass.
PhD, is Vice-President, Discovery and Translational Research, Alnylam Pharmaceuticals. His work covers new drug target identification and validation, biomarkers and preclinical drug discovery programmes.
is Senior Vice President, Commercial Innovation Lead, Alnylam Pharmaceuticals. Brendan joined Alnylam in 2016 as one of the company’s first Europe-based employees and has helped to build and establish its presence in the region.