Progress of PCSK9 inhibitors displays power of human genetics in finding future therapies

An update on PCSK9 inhibitors presented at the annual Cardiometabolic Health Congress showcased the rapid development of the agents, from gene to antibody, and examined where the field is moving in applying the therapies.

“This has been a remarkably short period from discovery to actually having a therapeutic,” Jay Horton, MD, chief of the division of digestive and liver diseases at UT Southwestern Medical Center, said during the presentation. “It highlights the importance of human genetics.”

Horton noted that the role human genetics has played in accelerating the progress of PCSK9 inhibitors illustrates that this kind of knowledge is an asset in guiding targeted therapy.

Brief history, background

The history of the PCSK9 inhibitors is brief: Discovery in 2003 by a company conducting screenings for genes involved in cholesterol synthesis and fast forward drug approval in 2015.

During the keynote session, Horton discussed early findings on transcription factors SREBP-1 and SREBP-2, respectively regulating fat synthesis and activating all enzymes involved in the creation of a cholesterol molecule, and experiments in animal models that led to gene identification.

Formally proprotein convertase subtilisin/kexin type 9 serine protease, PCSK9 is actually the ninth member of its family.

“Like all other family members, it cleaves itself. This is an important part of its biology,” Horton said.

But the big breakthrough in learning about its function happened in France, where researchers found mutations in the PCSK9 gene associated with hypercholesterolemia — suggesting they were functional mutations.

Upon realizing LDL was being affected, Horton said research was relatively straightforward. Many investigators took approaches looking at PCSK9 expression in relation to LDL in the liver. “When PSCK9 was deleted, the LDL receptor protein went up by two-and-a-half to threefold.”

Horton highlighted findings in humans from the population-based Dallas Heart Study involving 3,557 individuals who provided DNA and blood measurements including LDL. Researchers reported two mutations that were loss-of-function mutations, he said. “In individuals who lacked one functional allele of PCSK9, their plasma cholesterol levels were significantly lower.”

But Horton said the “most important” study was the Atheroscelerosis Risk in Communities (ARIC) study, which examined loss of function in 15,000 individuals and the incidence of CV events.

The ARIC study “really established PCSK9 as a solid therapeutic target,” he said. “In essence, this was a genetic outcomes trial that showed that inhibiting this protein — in this case by deleting the gene — had a positive effect on cardiovascular events.”

Research has since focused on how and where the protein worked. Horton said investigations have shown that after being secreted, PCSK9 binds directly to the LDL receptor, crystallizes and leads to its degradation.

Other LDL-lowering agents

Considering the mechanisms, Horton examined the potential means by which it is possible to block the activity of PCSK9 and in particular whether there is a need other agents.

“Most people here would agree with the assumption there could be some room for the additional development of drugs to lower LDL.” He underscored a clear need in patients with familial hypercholesterolemia, for example, as well as those who are statin intolerant.

Horton covered four therapeutic approaches to inhibit PCSK9 action.

“The cleanest way … is to block the enzymatic activity.” This might entail blocking the processing of PCSK9 with a small molecule, but Horton said it is a “big task” because it requires great specificity.

Blocking the movement of PCSK9 to the Golgi would be a second approach. Horton said researchers have gleaned more information about how this occurs, but specificity would again be a challenge.

Horton highlighted a third method that involves inhibiting PCSK9 synthesis, with two technologies — RNAi and anti-sense RNA — already in development. “Both of these approaches degrade RNA; if you degrade the RNA, the PCSK9 protein would not be present.”

The fourth approach, receiving the most traction and leading to therapies now available for clinical use, involves disrupting the PCSK9-LDLR interaction, Horton explained.

“Theoretically, this could be done with peptides or small molecules,” he said. “The ones that we’re familiar with are the antibodies.”

Current state, future

Clinical trials on two antibodies — alirocumab (Praluent, Regeneron/Sanofi) and evolocumab (Repatha, Amgen) — led to FDA approval this year. Yet to receive approval, Pfizer is also in the process of developing bococizumab.

Overall, Horton said the literature on genetic variants points to CVD being a “lifetime disease … and it is a lifelong lowering of LDL” that results in a marked benefit. He said genetics has taught us not only about metabolism and the function of proteins and cholesterol regulation, but also offers direction.

“The genetics also helps provide us with additional hints as to where we should probably go in the future,”