Canada leads the world’s first epigenetics treatment trial for pulmonary arterial hypertension
““As researchers begin to understand the underlying causes of PAH, it opens the door to testing new treatments, of which apabetalone is only one.””
In the last few decades, we’ve learned that there are many factors that influence how genes are expressed, including epigenetic changes.1 Epigenetic changes can control which parts of our genome are “read” and expressed into proteins not by altering our genes, but by altering how genes are packaged. Often, epigenetic changes can affect the expression of many genes and genetic pathways at once, and sometimes, the changes promote disease.1 However, the changes are not permanent and have the potential to be reversed. Thus, treatments that aim to reverse epigenetic changes that cause disease have the potential to “silence” entire disease-promoting genetic pathways to restore a healthy balance.
Recent clinical trials of epigenetic treatments have shown some benefit for treating cancer.2 This bodes well for patients with a rare and incurable disease called pulmonary arterial hypertension (PAH), as it is similar to cancer in many ways.3,4 PAH affects the lungs and the heart. The cells in the arteries of the lungs, called pulmonary arteries, multiply rapidly similar to cancerous cells. This uncontrolled cell growth narrows the pulmonary arteries, making it difficult for patients to breathe. The narrowing also causes high blood pressure in the pulmonary arteries, which can put a lot of stress on the right side of the heart and lead to right heart failure.
Researchers now agree that there are key epigenetic changes associated with PAH.5 While current treatments can reduce symptoms and extend patients’ lives, they are not a cure. Thus, the hope is that combining epigenetic treatments with existing interventions may help stop progression of the disease.5
In 2006, Resverlogix, a Canadian company based in Calgary, Alberta, created an epigenetic treatment called apabetalone. Apabetalone affects several genetic pathways, reducing the expression of cancer-promoting genes. So far, apabetalone has undergone several clinical trials, mainly in patients with cardiovascular related diseases, with some promising results.6
In August 2019, Canada began the world’s first trial of apabetalone in PAH patients. The early phase I clinical trial (APPRoAcH-p) is funded by Resverlogix. Its goal is to evaluate the safety of apabetalone in PAH patients with the hope of conducting a phase 2 trial soon after to determine whether apabetalone could benefit PAH patients. The APPRoAcH-p trial is being led by the co-founders of the PAH Research Group: Dr. Steeve Provencher, a respirologist and researcher at the Quebec Heart and Lung University Institute (IUCPQ), and Dr. Sebastien Bonnet, a researcher and Canadian Research Chair in Translational Research in Pulmonary Vascular Disease.
Both Drs. Bonnet and Provencher have studied the epigenetics of PAH. In a 2015 study, they found high levels of a protein called bromodomain-containing protein 4 (BRD4) in the pulmonary arteries of PAH patients.7 “BRD4 is what we call an epigenetic reader,” explained Dr. Provencher in a recent phone interview. “Essentially, BRD4 influences how genes are going to be selected and produced into proteins.” BRD4 accomplishes this by “reading” chemical modifications made to histones (DNA binding proteins).1 BRD4 is over activated in cancer10,11,12,13,14 and helps cancerous cells survive and multiply by promoting the expression of cancer-causing oncogenes.15 Drs. Bonnet and Provencher found that BRD4 is upregulated in the pulmonary artery tissue of PAH patients, just like it is in cancer. “This leads to the overexpression of several pathways that are involved in disease progression, where cells proliferate and become resistant to death. That proliferation leads to the progressive obliteration and narrowing of the pulmonary arteries,” said Dr. Provencher.
But there is some good news. In the lab, treating human PAH lung cells with BRD4 inhibitors that blocked BRD4 expression reduced the levels of cancer-promoting genes and slowed cell growth, essentially reversing the disease.7 Next, the researchers moved to animal models of the disease. “We show that in those animal models, BRD4 was also involved in PAH progression, and when we blocked BRD4, we were able to at least partly reverse the PAH in those animals,” said Dr. Provencher. These results emphasized the key role that BRD4 plays in the disease and suggested that BRD4 inhibition may be useful for treating PAH.7
Moreover, patients with PAH are about 4 times more likely to get coronary artery disease (CAD) compared to the general population.16,17 In a follow-up study, Bonnet and Provencher examined the coronary arteries of PAH patients and found that, compared to healthy people, the patients had thicker coronary arteries with more signs of DNA damage and inflammation, including high levels of BRD4 expression.8 The researchers also demonstrated that inflammation triggers BRD4 expression by treating coronary artery cells collected from PAH patients with pro-inflammatory proteins. The pro-inflammatory proteins increased DNA damage and BRD4 expression, consistent with previous reports.18 Conversely, treating the coronary artery cells with a BRD4 inhibitor that blocked BRD4 expression reduced their uncontrolled growth. Overall, the results from these studies suggest that BRD4 inhibitors could help treat PAH, as well as CAD seen in these patients.7,8
This is where the medication apabetalone comes in. Apabetalone is a BRD4 inhibitor derived from resveratrol,15 a natural substance commonly found in berries. Apabetalone binds to BRD4 and prevents it from “reading” the modifications made to histones (DNA binding proteins) and promoting the expression of cancer-promoting genes.15 Thus by impairing BRD4, apabetalone lowers the expression of cancer-promoting genes that help cells multiply quickly19 and lowers the expression of pro-inflammatory genes that otherwise contribute to a cancer-promoting state.18
A few months prior to the start of the APPRoAcH-p study, the results of a multi-center pre-clinical trial were published that showed that using apabetalone in combination with traditional PAH treatments (tadalafil and macitentan) was safe and effective for treating PAH in a rat model of the disease.9 “We performed the first ever multi-center pre-clinical PAH study, where we tested apabetalone in several animal models in several research centers to make sure we observed the same improvements in all of the animals at the different centers,” said Dr. Provencher. And they did. The combined therapy (tadalafil and macitentan plus apabetalone) produced significant positive results compared to tadalafil and macitentan alone, including reduced pulmonary blood pressure, decreased pulmonary artery thickness, and less scarring in the blood vessel wall,9 further supporting that apabetalone could benefit PAH patients.
The early phase I APPRoAcH-p trial is currently being conducted from two locations: Calgary, Alberta, and Québec City, Québec. Patients from a wide age range (18 to 75 years old) who have been stable on PAH therapy for more than 4 months are eligible for the study. During the trial, patients will receive apabetalone for 16 weeks and will be monitored for changes in pulmonary blood pressure, heart function, blood oxygen saturation, quality of life, and various other biomarkers. Although the primary goal is to assess the safety of treating PAH patients with apabetalone, doctors will collect patient samples at the start of the trial and at 8 weeks and 16 weeks from the start date to assess the effect of apabetalone on gene expression.
Although initially expected to be completed by December 2020, the ongoing COVID-19 pandemic has currently halted all patient recruitment for clinical trials, and it is now likely that the APPRoAcH-p trial will not be completed until 2021. In terms of a phase 2 trial, Dr. Provencher indicated that “many centers have already been identified worldwide to complete the [phase 2] trial. We also have the funding to do it, and we expected it to be launched by the end of 2020. Now, it’s more likely to be the first half of 2021.”
Existing PAH therapies do not cure the disease. But as researchers begin to understand the un¬¬derlying causes of PAH, it opens the door to testing new treatments, of which apabetalone is only one. As evidence shows that PAH is a complex disease with epigenetic dysregulations, it may be that a combination of treatments that can target many contributing disease pathways is what will bring us closer to a cure.
Works Cited:
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Cite This Article:
Bergeret M. Canada leads the world’s first epigenetics treatment trial for pulmonary arterial hypertension. Illustrated by J. Tamura. Rare Disease Review. April 2020. DOI:10.13140/RG.2.2.24411.31523.
