Atherosclerosis
- Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of plaque within arteries. The leading cause of death globally, atherosclerosis accounts for over 40% of all deaths worldwide.
- Currently, the cholesterol-lowering drugs prescribed to tackle atherosclerosis do not address the underlying cause of the disease, or reverse the atherosclerotic plaques already formed. As the burden of atherosclerosis related diseases continues to grow, novel solutions for treatment are becoming necessary.
- Cyclarity is developing genuine “disease-modifying” solutions to address age related diseases, such as atherosclerosis, by repairing an underlying cause common to many of them: the inevitable accumulation of toxic biomolecules inside cells over time.
- Cyclarity’s primary candidate, UDP-003 is a specially-engineered beta-cyclodextrin designed to target and remove toxic, oxidized cholesterol – a key driver of atherosclerosis.
- Without doubt, Cyclarity’s approach to true disease medication, and therefore reversal of age-related disease, offers a great deal of promise for investors, healthcare systems in the US and globally, and, most of all, for those affected by atherosclerosis-related disease.
Cardiovascular disease and atherosclerosis: the silent killer
Cardiovascular disease (CVD) is the #1 cause of death globally and encompasses a broad set of over a dozen disorders that compromise the function of the heart and blood vessels. The major cause of CVD by far, however, is the pathological process of atherosclerosis (CDC, 2022). Like the accumulation of rust within pipes, atherosclerosis involves the gradual build up of plaque within arteries which compromises the flow of blood and oxygen in the body. Strikingly, atherosclerosis is responsible for more than 40% of all deaths worldwide, and 80% of those deaths are in individuals 65 years and older. This includes mortality from devastating pathologies that are among the leading causes of death like coronary artery disease, chronic obstructive pulmonary disorder and stroke (Pahwa, 2022).
Unbeknownst to many, the process of atherosclerosis begins during early childhood. As we age, plaque builds up extensively and eventually ruptures, inducing blood clots that completely block blood flow through arteries (Goldman, 2018). Often undiagnosed, the consequences of atherosclerosis can be sudden and fatal cardiovascular events that traumatize families and exhaust healthcare systems around the world. Due to its gradual and insidious nature, a significant percentage of individuals are unaware they have cardiovascular disease until they have a heart attack. Further, it is estimated that 45% of heart attacks are silent; individuals do not notice any symptoms, yet the damage is done. Heart attacks drastically increase the risk of sudden cardiac arrest (SCA) and 90% of SCAs that happen outside hospital settings end in fatality. This has earned heart disease the notorious title – “the silent killer” (Virani, 2021).
The Center for Disease Control and Prevention estimates that the US spends $219B each year on improving metabolic health and managing symptoms of heart disease in the hopes of dethroning humankind’s most infamous killer; this alone makes it the most expensive disease to treat in the US. [Current drug treatments focus solely upon (a) lipid management, and (b) management (BP med, blood thinner) to help prevent major cardiac events.]
The conventional approach: disease management
The development of therapeutics to combat atherosclerotic CVD forms a significant part of humankind’s battle against chronic disease. The basic pathological process of atherosclerosis has been characterized for over a century (Figure 2). Despite its multifaceted nature, the major clinical focus for treatment of atherosclerosis has involved targeting cholesterol metabolism to reduce the rate of plaque accumulation within blood vessels or improving recovery after a cardiovascular event (Table 1). Of all therapeutic interventions, cholesterol-lowering statins dominate the CVD market. In fact, statins are the most commonly-prescribed drug in the world (Finnegan, 2018). In essence, the field of CVD therapeutics has adopted a strategy of slowing the rate of disease progression and reducing the risk of complications from disease (i.e. cardiovascular events, like heart attacks). Although this strategy has played a role in the significant increase in average human lifespan over the past century, it is essentially a disease management approach that has failed to erase CVD from the list of humanity’s most prolific killers.
| Class | Goal | Therapeutic Interventions |
|---|---|---|
| Cholesterol lowering drug | Slow down disease progression, reduce cardiovascular events | Statins, CETP inhibitors, PCSK9 inhibitors |
| BP lowering drugs | Slow down disease progression, reduce cardiovascular events | ACE inhibitors, Diuretics, Beta blockers, Angiotensin II receptor blockers |
| Cardiovascular trauma recovery | Cardiovascular event recovery | Stents, Bypass surgery, Angioplasty, Clot busters, Anti-platelet drugs |
| Plaque removal, Immunotherapy | Reverse atherosclerosis | Engineered cyclodextrins |
Table 1 – Classes of CVD therapeutics: Standard of care includes therapeutics that improve metabolic health (cholesterol and blood pressure lowering drugs as well as interventions for recovery from cardiovascular trauma. Cholesterol and BP lowering drugs are targeted towards slowing down CVD progression and reducing cardiovascular events. Cardiovascular trauma recovery involves stents and clot busters that treat symptoms of disease. Cyclarity’s lead candidate is a “first of its kind” drug for plaque removal and immune cell rejuvenation. It is the only intervention of its class that has potential to reverse atherosclerosis progression and reboot the cardiovascular system to a youthful state.
Top 3 leading causes of death in the US
Chart shows number of deaths (Y axis) plotted against the year (X axis)
Figure 1 – Leading cause of death from 2001-2019 and statin use: Despite statin use nearly doubling in the past 20 years, cardiovascular disease remains the leading cause of death. Cardiovascular disease continues to kill nearly 200,000 more people than the number 2 leading cause of death, cancer. The incidence of CVD mortality has been steadily rising since 2011 (ironically, since statin use nearly doubled) and is the highest it has been in several decades (Roser, 2022)
In spite of incredible biomedical advances and hundreds of billions of dollars of investment in developing drugs that target cholesterol metabolism, atherosclerosis continues to kill more humans than anything else. (Figure 1). This includes infectious disease, cancer, and diabetes. This trend shows no signs of slowing down, as the incidence of atherosclerosis and cardiovascular disease has been steadily increasing for the past three decades (Roser, 2022). It is time for the field of cardiovascular therapeutics to reevaluate its approach and reduce its fixation on disease management and to consider the possibility of genuine disease modification – but what would an approach like this even look like?
Figure 2 – Atherosclerosis Master Figure: Graphic illustrating the multi-faceted, pathological process of atherosclerosis. Standard of care either targets too early/upstream (only to slow the disease progression) or intervenes too downstream (to facilitate recovery post cardiovascular event). Cyclarity’s drug UDP-003 works in the “Goldilocks” zone, targeting the root cause and leading to disease reversal. 1) Cholesterol flowing through healthy blood vessel. 2) Cholesterol gets into walls of blood vessel. 3) Cholesterol gets damaged/oxidized within walls of blood vessel, making it toxic. (ROOT CAUSE) 4) Macrophages (immune cells) engulf oxidized cholesterol, but can not degrade it, transforming them into pathological foam cells/plaque. Undamaged cholesterol is easily degraded by macrophages. 5) Foam cells secrete inflammatory factors that drive inflammaging and accelerate plaque accumulation (COMPOUNDING EFFECT) creating a vicious cycle of disease progression. 6) Plaque ruptures and blocks blood flow through vessel, leading to cardiovascular event.
Cyclarity’s approach: disease modification
While high cholesterol levels in the blood is clearly a significant contributor and risk factor for CVD, clinical research within the past two decades is revealing that it is far from the complete picture. This is because there are several downstream events that transform this essential metabolite into a toxic waste product. Most importantly, the development of atherosclerosis is contingent upon cholesterol penetrating blood vessels and becoming oxidized – making it non-degradable and toxic.
This corrupted form of cholesterol ultimately drives an insidious cycle of low level chronic inflammation (inflammaging), macrophage dysfunction, and plaque accumulation (Figure 2) (He, 2022). There is a rapid body of evidence amassing in support of inflammaging as a key, unifying driver of several age-related diseases and, indeed, the process of aging itself. In this sense, atherosclerosis may be more accurately described as “a smoldering inflammatory condition that is aggravated by cholesterol” (Tsoupras, 2018). A true disease modification approach requires targeting and remedying these pathological features of atherosclerosis, an endeavor that no company to date has successfully demonstrated.
Cyclarity Therapeutics is an innovative biopharmaceutical company that seeks to address age-related diseases by repairing an underlying cause common to many of them: the accumulation of toxic biomolecules inside of cells. Cyclarity’s initial focus is restoring cardiovascular health through removing the cellular trash that gives rise to immune cell dysfunction, inflammation, and plaque accumulation within blood vessels. This is in stark contrast to the conventional focus on disease management through slowing plaque accumulation or reducing the risk of cardiovascular events. At its roots, atherosclerosis is a disease that begins within cells – not in the plasma. Adopting an engineering approach to remove damage and repair cells, Cyclarity seeks to offer the first genuinely disease-modifying drug for atherosclerosis. Cyclarity’s ground-breaking therapeutic, a drug called UDP-003, holds promise to radically reduce the trillion-dollar burden of this condition and save countless lives (Garth, 2022).
Redefining the treatment paradigm for atherosclerosis
Since atherosclerosis was first characterized in the early 20th century, the field of cardiovascular therapeutics has operated with a rigid, ameliorative strategy for addressing cardiovascular pathology; the development and gradual improvement of interventions focused on slowing down the process of atherosclerosis, reducing cardiovascular events, and supporting event recovery (Minelli, 2020).
Cyclarity Therapeutics works instead to rehabilitate the cardiovascular system’s own, natural self-repair mechanism, removing the toxic byproducts that cause macrophage dysfunction and restoring their natural ability to manage and reduce plaque. This is a “first in class” therapy that could redefine the treatment paradigm for atherosclerosis, paving a path for a new class of disease-modifying therapeutics. For the first time in the history of mankind’s fight against chronic disease, the possibility of disease reversal has been enabled.
There are several pivotal factors that lend great promise to Cyclarity’s lead candidate UDP-003:
- Unique biological properties: UDP–003 belongs to a class of compounds known as cyclodextrins. Cyclodextrins have special chemical properties that give them powerful fat/cholesterol binding capabilities (Szente, 2016).
- Robust safety profile: Cyclodextrins are a well known class of compounds used in common household and food products, as well as a pharmaceutical ingredient used to enhance the delivery of dozens of FDA approved drugs (American Chemical Society, 2015).
- Precision engineered: Cyclarity uses its novel computational platform technology to engineer cyclodextrins to enhance target specificity, safety, and efficacy relative to generic cyclodextrins.
- UDP-003 clears away plaque (refer to Figure 1): UDP-003 is designed to precisely bind and clear a toxic form of oxidized cholesterol, 7-ketocholesterol (7-KC), that builds up in immune cells (macrophages), transforming them into foam cells – the root cause of plaque formation.
- UDP-003 is an immunotherapy that restores the cardiovascular system’s natural self-repair system (refer to Figure 1): The transformation of macrophages into foam cells is the critical transition point that drives plaque formation. The factors foam cells secrete drive inflammaging, a central mediator and compounding factor of atherosclerosis. By clearing out oxidized cholesterol from foam cells, UDP-003 has been shown to restore macrophages back to their functional state (National Institute of Aging, 2021).
Winning Strategy
Beyond UDP-003, there are several key features to Cyclarity’s strategy that set it up for success as a biopharmaceutical trailblazer within a challenging disease market:
- Disruptive platform technology: Cyclarity’s platform technology designs, predicts, builds, and tests the ability of cyclodextrins to bind target molecules. This saves significant money, time, and resources by simulating and anticipating results before synthesis, benchwork, and clinical testing. Further, it facilitates iteration and evolution of Cyclarity’s pipeline to target other cellular waste products and indications.
- Strong regulatory advantage: In recognition of its groundbreaking therapeutic strategy and promising preclinical results for UDP-003, Cyclarity was recently awarded an Innovation Passport under the United Kingdom’s Innovative Licensing and Access Pathway (ILAP). This has the potential to significantly accelerate progression and reduce costs of the clinical trial process, one of the biggest hurdles for up and coming biopharma companies (Garth, 2022).
- Complementary combinatorial potential (constructive disruption): Due to its unique mechanism of action, UDP-003 should be complementary with standard of care therapeutics. Using a complementary approach may allow Cyclarity to “constructively disrupt” the CVD market by adding more effective and cost-reducing treatments without the need to immediately challenge standard of care.
- World class team: Cyclarity is headed up by leaders in the longevity field supported by critical partnerships with the premier engineers of custom cyclodextrins and the world’s leading specialists in the development of cyclodextrin-specific simulations. Currently, Cyclarity is the only company that is engineering cyclodextrins to improve their precision, efficacy, and applicability for targeting age-related diseases. Their experienced in-house team and exceptional external partnerships promises to keep them ahead of their competition.
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