The Cardiovascular Program aims to deliver a single pill for the treatment of high cholesterol. This is via a small molecule PCSK9 inhibitor that can be taken with or without a statin, thus enabling patients to reach their safe target cholesterol level, and lower their risk of cardiovascular disease.
Nyrada’s lead drug candidate, NYX-PCSK9i is suitable for once-per-day, oral dosing, matching the convenience of statin drugs. It also aims to replace injectable PCSK9 inhibitors, which are expensive and inconvenient for patients.
A Phase I first-in-human study will measure the safety, tolerability, and pharmacokinetics of NYX-PCSK9i and is anticipated to commence in H1 CY2023. An exploratory objective will be to evaluate NYX-PCSK9i’s efficacy by measuring changes in LDL-cholesterol levels in the blood, thus providing a first insight at efficacy in humans.
Incidence of Cardiovascular Disease
Cardiovascular disease is the leading cause of death globally. In the US, more than 600,000 people die each year from cardiovascular disease, accounting for 1 in 4 deaths. In 2016, there were an estimated 17.9 million deaths globally, of which 85% or 15.2 million were due to heart attack or stroke.
When the body has too much LDL (“bad”) cholesterol, the LDL cholesterol can build up on the walls of blood vessels. This build-up is called “plaque.” As blood vessels build up plaque over time, the insides of the vessels narrow, and this blocks blood flow to and from the heart and other organs. This condition is called atherosclerotic cardiovascular disease (ASCVD), sometimes referred to as “hardening of the arteries”. When blood flow to the heart is blocked, it can cause angina (chest pain) or a heart attack. When blood flow is blocked in the arteries supplying the brain, it can cause a stroke.
PCSK9 is a blood protein that serves a normal purpose in holding LDL in the blood. This means that high PCSK9 levels result in high blood LDL, which causes further build up of plaques in blood vessels. Thus, it is favourable to reduce your PCSK9 protein levels as this increases the LDL receptors on the surface of liver cells and these help to clear LDL from the blood stream.
Current standard of care
Current standard of care for hypercholesterolaemia is treatment with once daily, oral statins. Statins are inexpensive and typically lower LDL cholesterol levels by between 30-55%. However, up to 50% of patients fail to achieve a 50% reduction in LDL cholesterol. In 2017, estimated global sales of statins were US$19 billion.
Another approach to lower LDL cholesterol levels is via the inhibition of PCSK9. Although several strategies have been tried for inhibiting PCSK9, the most successful approach is the injection of monoclonal antibodies (mAb) that interfere with the function of PCSK9 thereby increasing the rate at which LDL is removed from the bloodstream. There are currently two marketed mAb PCSK9 inhibitors, both launched in 2015, evolocumab (Repatha: Amgen) and alirocumab (Praluent: Sanofi and Regeneron). The use of these mAb drugs to block the ability of PCSK9 to bind to the LDL receptor has proved to be the most effective approach to date in inhibiting PCSK9 function and in reducing LDL cholesterol levels. These mAb drugs typically can reduce LDL cholesterol levels up to 60% greater than statins alone. PCSK9 mAb drugs have few adverse side-effects, and none are considered life-threatening. However, they come with a high cost (approx. US$5K per year) and the self-injecting needles are not user friendly. To date, no orally bioavailable small-molecule PCSK9 inhibitor drug has advanced to the clinic.
Nyrada is seeking to fill this void in the market by developing a small-molecule oral PCSK9 inhibitor. A small molecule has several advantages including ease of synthesis and simple formulation for oral dosing. Being oral, it will be more user friendly than the current injectable PCSK9 inhibitors. It will be more cost effective than current monoclonal PCSK9 inhibitors, which due to their manufacturing, cannot be mass produced and have a limit to how cheaply they can be produced.