By Ashleen Knutsen
For decades, cardiovascular disease has been the leading cause of death around the world, currently accounting for about one-third of global mortalities. Most patients don’t know they have this lifelong affliction until they suffer a heart attack. Yet despite the persistent chart-topping status and the seriousness of cardiovascular disease, drug discovery for cardiovascular conditions has lagged behind that for other types of illnesses.
Now, with a better understanding of the molecular mechanisms and genetics of cardiovascular diseases, as well as advancements in genetic and tissue engineering, developers are creating cardiovascular drugs that address some of the limitations of existing treatments. For example, the new drugs are more targeted, which means they can reduce side effects and improve patient adherence. Also, some of the new drugs can improve patient adherence by resolving, all at once, the root cause of a cardiovascular condition, removing the need for ongoing treatment.
Tackling heart disease at its source
Atherosclerotic cardiovascular disease (ASCVD), which affects about 8% of adults in the United States, is caused by long-term exposure to high levels of blood cholesterol, mainly low-density lipoprotein cholesterol (LDL-C). ASCVD is commonly treated by statin therapy, a drug that lowers blood cholesterol. However, only 39% of patients report sticking with their statin regimen in the year after a heart attack.
“This is a disease that, for many patients, can feel asymptomatic at times,” says Andrew Bellinger, MD, PhD, chief scientific officer and chief medical officer at Verve Therapeutics. “That’s a scenario where chronic therapy goes from bad to worse. That leads to desire on people’s part to not think about their disease, to not treat it. But their disease is progressing and getting worse, and they’re at an increased risk of bad outcomes.”
For this reason, Verve is taking a “one and done” approach to ASCVD treatment. Rather than develop drugs that must be taken by patients throughout their lives, the company is developing cutting-edge gene editing technology that can permanently lower the production of cholesterol.
The company’s lead product candidate, VERVE-101, uses a CRISPR base editor packaged in a lipid nanoparticle that travels to the liver, where the PCSK9 gene is expressed. The base editor then makes a single base change that inactivates the gene, permanently reducing LDL-C levels and, ultimately, reducing ASCVD risk.
In preclinical tests on 36 nonhuman primates, VERVE-101 resulted in a 60% reduction in LDL-C that was maintained for the six-month duration of the study, with no off-target editing.
Clinical trials are set to begin this year on patients with heterozygous familial hypercholesterolemia. This disease is caused by a genetic mutation that leads to the overproduction of LDL-C from birth, leading to earlier heart attacks. Though underdiagnosed, it is estimated to affect 1 in 250 to 1 in 500 people, and its identification is a result of the advancements this field has seen in recent years.
“What we’re seeing is that we can do a better job of identifying specific subtypes that are genetic diseases that put people at an increased risk. And those are treatable,” Bellinger asserts. “I think that’s something that’s going to make a big impact in the next decade: greater diagnosis with more targeted treatments.”
Identifying genetic causes
Contour Therapeutics is also taking advantage of recently discovered genetic connections to develop more targeted therapeutics for cardiovascular diseases. Founded at the end of 2020, Contour is a joint venture between Maze Therapeutics and BridgeBio Pharma that is applying the expertise of each parent company to develop efficient treatments and identify the patients who would most benefit from them.
Contour emerged from a discovery made with the Maze Compass platform, which combines human genetic data, functional genomic tools, and data science technology to map novel connections between known genes and their influence on susceptibility, timing of onset, and rate of disease progression. This platform helps Maze locate genes that either increase or decrease the risk of disease.
“[The platform can help us] find situations where there may be different variants within the same gene—some of which provide an increased risk and some of which provide protection,” says Eric Green, MD, PhD, senior vice president of research and translational sciences at Maze. Genes for which both risk-enhancing and risk-reducing variants exist are the ones that most interest Maze. “They really give us confidence that [they are] involved in the disease,” Green stresses. “And that’s the kind of association that we found here.”
Using the Compass platform, Maze identified a certain gene that, depending on which variant is present, can either cause or prevent heart disease. (As of the publication of this article, Contour is unable to disclose which gene or heart disease it is targeting.)
BridgeBio, which specializes in cardiac drug discovery and the clinical development of cardiac drugs, is helping translate these genetic insights into therapeutics. For this application, the company’s preferred approach is to develop small-molecule drugs.
These pharmaceuticals are designed to bind to a specific target, such as the protein of a certain gene, and affect the target’s function. Contour, which is still in the drug discovery phase, is currently developing a molecule that can be used to reshape a mutated protein and give it a healthy configuration.
At the same time, the company is using its genetic background to choose the best patient population. “Because we’re guided by genetics, it gives us some strong ideas about who might be the patients who are going to most benefit from this therapy,” Green explains. Determining how to screen patients is an important step when developing more targeted solutions. And as new genetic diseases and patient populations are identified, the modality of treatment must be chosen to suit the disease.
Choosing the best treatment
To address the need for different treatment modalities, Tenaya Therapeutics is developing medicines across a number of platforms, including gene therapy, precision medicine, and cellular regeneration platforms, while finding ways to improve more conventional technologies.
Gene therapy is used to treat illnesses that are caused by mutated genes. For its gene therapies, Tenaya uses adeno-associated viruses (AAVs) to replace mutated genes with healthy copies. Typically, a potential limitation with AAV gene therapy is that a high dose is required to eventually reach a sufficient number of the desired target cells. Tenaya has screened over one billion AAV variants to discover novel AAV capsids that selectively target the different types of cells in the heart.
“We inject the AAVs into nonhuman primates and then isolate the heart and other organs to identify the variants that have better heart tropism and decreased tropism for other organs,” says Timothy Hoey, PhD, chief scientific officer at Tenaya. “The idea is to get better efficacy at a lower dose through the engineering of the AAV capsid. This can be really enabling for cardiac gene therapy in general, to be able to deliver a payload to the heart more effectively.”
Tenaya has also used its AAVs to make large strides in the field of cardiovascular cellular regeneration, a therapy that would create new heart cells after some are lost during events such as heart attacks.
Traditional methods in which stem cells or cardiomyocytes are injected into the injured heart often fail. Many of the injected cells are not retained or integrated into the heart’s function. Tenaya is taking a different approach by modifying the technology that creates induced pluripotent stem cells (iPSC), cells that have been reprogrammed to the embryonic-like pluripotent state.
“Our approach is analogous, but instead of going to an undifferentiated stem cell, we are reprogramming cells to a different differentiated cell type,” Hoey details. “We are converting existing cardiac fibroblasts to new cardiomyocytes through the expression of cardiomyocyte-specifying factors.
“This has been shown to work very robustly in vitro, and we see wholesale changes in gene expression. We have also demonstrated efficacy with this approach in a pig model with a human sized heart.”
Tenaya has a number of therapies under development, all in either the discovery phase or the preclinical phase. The company plans on beginning clinical trials after submitting INDs in the second half of 2022.
Better preclinical models
Compared to drugs for other disease areas, drugs that target cardiovascular diseases have a much lower probability of success during clinical development. The researchers at Tara Biosystems believe this is in part due to inadequate preclinical models. Unlike heart cells, many other cell types can be grown in the laboratory, providing the opportunity for more studies and a better understanding of the disease.
“Part of what we think is a big challenge and why there’s been a lot of failures is an overreliance on animal models that inadequately reflect human disease,” says Misti Ushio, PhD, CEO of Tara. Even cardiomyocytes derived from human iPSCs don’t function like real hearts. “What TARA does,” Ushio points out, “is take these human iPSC cardiomyocytes and put them into our systems, which turn [the cells] into cardiac tissue that beats and functions like our hearts.”
The three-dimensional tissue, created through electrical and mechanical stimulation, consists of about 100,000 heart cells that contract and relax like a beating human heart. For diseases that involve errors in this essential pumping mechanism, such as cardiomyopathies, this technology can provide insight into the disease itself as well as the effects that drugs may have on it.
Having validated a healthy heart model against existing patient data, as well as cardiomyocytes and large animals, Tara is now working with a number of pharmaceutical companies to develop heart tissues that replicate genetic and acquired heart diseases.
“Because there have been so many failures in cardiac drug discovery, the risk appetite for companies is really low relative to the unmet need,” Ushio explains. “I hope that the Tara technology lowers the bar for people to pursue cardiovascular drug development by mitigating risk. I believe Tara’s cardiac models enable faster and less expensive innovation with an increased probability of success.”