How Genetic Validation Helped Innovate Medicine for Patients with High Cholesterol

For people who have suffered a heart attack or other cardiovascular events correlated with high levels of LDL cholesterol, the development of PCSK9-inhibiting medicines has been one of the most exciting advances in cardiovascular medicine in recent years. In August 2022, Circulation published Amgen’s FOURIER OLE study of Repatha, which demonstrated that long-term use of Repatha meaningfully and sustainably reduced LDL-C and was associated with lower rates of cardiovascular events such as heart attack and stroke.¹

Cardiovascular disease and lowering bad cholesterol: The journey

PCSK9 inhibitors were among the first medicines developed through a relatively new process called genetic validation, in which scientists identify a genetic target in humans associated with a disease, leading to the development of a medicine that will interact with that target to achieve a specific health goal.²

It was important to apply the most precise tools available to reducing cholesterol because high cholesterol (specifically high LDL cholesterol, or LDL-C) is among the most well-established risk factors for cardiovascular disease, the leading cause of morbidity worldwide.^3,4 In 2020, about 19.1 million deaths were attributed to cardiovascular diseases globally.⁵ It is estimated that more than four out of five of these deaths are from heart attacks and strokes, and about one third occur prematurely in those under 70 years old.⁶

Prior to the development of PCSK9 inhibitors, statins and ezetimibe were the only effective medicines available to help lower LDL-C⁷. However, not all patients are able to achieve sufficiently low LDL levels with statins and ezetimibe.²

From genetic insight to investigational medicine

The path to bringing PCSK9 inhibitors to patients began with scientists in France who were studying multiple generations of a single family that exhibited unusually high levels of LDL-C.⁸ In the journal Nature Genetics, the scientists proposed that the family’s history of heart disease and high LDL-C was correlated with a particular mutation in a gene called proprotein convertase subtilisin/kexin type 9 (PCSK9).⁸

Independently, a group of researchers from Dallas Heart Study found that different mutations of PCSK9 could be correlated with lower LDL-C.⁹ “That showed both sides of the penny had been proven,” says Simon Jackson, Amgen’s executive director of research for Cardiometabolic Disorders. “By 2006, they found that people with these variants were less likely to develop cardiovascular disease.”⁹

Capturing this insight was incredibly meaningful but scientists were still a long way off from taking this insight and turning it into a cholesterol-lowering medicine.

Amgen’s own PCSK9 research program began in 2005, and the scientists on Jackson’s team were able to identify how these variants in the PCSK9 gene were impacting cholesterol levels. They discovered that PCSK9 binds directly to LDL receptors on the liver, which results in the breakdown of the LDL receptor. This prevents the liver from clearing LDL-C from the blood. Once this was understood, Amgen’s efforts focused on ways to inhibit PCSK9 protein binding to LDL receptors, so that LDL-C clearance by the liver could be increased.

“We showed that the PCSK9 protein and the LDL receptor protein came together,” Jackson explains. “That launched the whole idea of creating an antibody that would bind PCSK9 circulating in the blood, and therefore stop it from binding to the LDL receptor.” Jackson’s team accomplished this through a process called immunoprecipitation, a technique for isolating a protein antigen out of a solution, along with any proteins bound to it.

“That was the 'aha' moment for our team, leading to the hypothesis that an antibody that binds PCSK9 might be useful as a therapeutic. We launched our antibody program in 2006,” Jackson says. “We did our first proof of concept in 2007, showing for the first time that our antibody candidate could lower cholesterol levels, and at the end of 2007, we nominated AMG 145 as the clinical candidate.”

Bringing first-in-class medicine to patients

First-in-human trials for AMG 145 started in 2009.¹⁰ Subsequent trials showed AMG 145 significantly reduced LDL-C among at-risk subjects and demonstrated a consistent safety profile.¹¹ By 2013, Amgen launched the cardiovascular outcomes study, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER).¹²

In the following year, the U.S. Food and Drug Administration (FDA) had accepted Amgen's Biologics License Application (BLA) for the medicine, now called Repatha.¹³ Over the next two years, Repatha earned several global approvals, becoming the first PCSK9 inhibitor available to help reduce LDL-C in at-risk patients:¹⁴

• July 21, 2015: The European Commission approved Repatha as a treatment of patients with uncontrolled cholesterol who require additional intensive LDL-C reduction¹⁵
• August 27, 2015: FDA approved Repatha to treat patients with high cholesterol¹⁶
• September 10, 2015: Health Canada approves Repatha¹⁷
• January 21, 2016: The Japanese Ministry of Health, Labour and Welfare approved Repatha as the first PCSK9 inhibitor in Japan¹⁸
• July 11, 2016: FDA approves Repatha Pushtronex as the first and only single monthly injection for a PCSK9 inhibitor¹⁹

The FOURIER trial was completed in November 2016 and demonstrated that patients with cardiovascular disease treated with Repatha had a significant reduction in major cardiovascular events like heart attack and stroke.²⁰

“Amgen continued to study the long-term safety of Repatha among FOURIER trial subjects by launching two extension studies (FOURIER OLE) that enabled patients completing FOURIER to receive Repatha for up to five years,” explains Narimon Honarpour, vice president of Global Development for Amgen’s General Medicine therapeutic area.²¹

The FOURIER-OLE trial started in March 2017 and completed in February 2022. The results were presented at the 2022 ESC conference.²² Completed and ongoing Repatha studies make Amgen’s research the longest-running data set for any PCSK9 inhibitor currently available to patients.²³

In August 2022, Circulation published Amgen’s FOURIER OLE study of Repatha, which demonstrated that long-term use of Repatha significantly reduced LDL-C and was associated with lower rates of cardiovascular events such as heart attack and stroke.¹

Amgen has continued to expand the treatment paradigm for Repatha, with the FDA approving Repatha for pediatric patients aged 10 years and older with familial hypercholesterolemia, an inherited disorder that results in extremely high cholesterol starting at birth.²³

“Today, Amgen is dedicated to improving the lives of patients with cardiovascular disease. Since launch, more than 1 million patients worldwide have received Repatha to reduce LDL-C,” Honarpour says.²⁴ “However, cardiovascular disease remains the leading cause of morbidity worldwide.²⁵ This is partly because there are additional risks beyond LDL-C that contribute to cardiovascular illness.²⁵ Addressing the remaining risk is an important motivator for Amgen in its mission to serve patients with serious unmet medical need.”

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References:

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