Heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure, accounts for roughly half of all heart failure cases worldwide. The condition, which occurs when the ventricles do not relax as they fill with blood following heart muscle contractions, is especially common in elderly women, striking up to 10% of those over 80. Now stem cell biotech firm Novoheart Holdings Inc., of Vancouver, British Columbia, is partnering with Astrazeneca plc, of Cambridge, U.K., to co-develop a human-specific in vitro, functional model of HFpEF. The goal is to give drug researchers critical clues of a drug candidate’s efficacy before it is tested in patients.
Preclinical testing of drugs for HFpEF is currently hampered by a lack of effective humanized models. The collaboration aims to bridge the gap from animal to human studies using Novoheart’s 3D human ventricular cardiac organoid chamber (hvCOC) technology, also known as “human heart-in-a-jar,” which reproduces key phenotypic characteristics of HFpEF.
HvCOC, part of Novoheart’s Myheart platform for drug discovery and development, is a bioengineered miniature human heart pump, about 5 mm in diameter, built with human heart muscle cells derived from human stem cells. The human stem cells are produced by reprogramming cells from an individual and then are guided into differentiating human heart muscle cells using Novoheart’s proprietary methods.
10 million heart cells
“We use 10 million heart muscle cells in a hydrogel mix to make each hvCOC, inside a proprietary bioreactor, and the hvCOC takes the shape of a small hollow chamber or balloon that can pump on its own,” Gabriel Wong, Novoheart’s vice president of scientific development, told BioWorld.
The goal of the collaboration is to develop the HFpEF model using the hvCOC technology so that candidate therapeutics for the disease can be prescreened on it, providing valuable insights on how a drug will perform when tested in humans. Since the model functions exactly like the human heart, cardiologists can assess or monitor parameters they would study in patients, such as ejection fraction, cardiac output and stroke volume.
“There are significant unmet treatment needs in patients with heart failure with preserved ejection fraction. By combining Novoheart’s proprietary hvCOC model with our expertise in heart failure, we aim to create the first in vitro model reproducing phenotypic characteristics of heart failure with preserved ejection fraction,” said Regina Fritsche Danielson, senior vice president and head of research and early development of cardiovascular, renal and metabolism, biopharmaceuticals R&D at Astrazeneca. “This could bridge the gap between in vivo animal models and clinical trials to help accelerate the drug discovery process by providing human-specific preclinical trials.”
Alternative to animal testing
Novoheart claims that its hvCOC is the only engineered human heart model on the market that can offer this type of measurement, which traditionally has relied on animal testing. “The limitations of using these animal models are that due to their differences in physiology from humans, they cannot completely accurately predict how the human heart behaves in response to pharmaceuticals or therapeutics, nor can they mimic all human pathologies,” Wong said.
With human heart-in-a-jar, “investigators have access for the first time [to] a human heart model that can closely mimic the native human heart inside healthy or diseased people,” he added. “They can tell how treatments may benefit or adversely affect the human heart, no matter healthy or sick.” The tool can be used to test multiple doses of a single drug, as well as multiple drugs simultaneously or sequentially to observe potential interactions.
Under the agreement, Novoheart will hold exclusive intellectual property rights to the HFpEF hvCOC model and will be able to license it to other companies.
Novoheart previously partnered with New York-based Pfizer Inc. to create stem cell-based models of cardiac dysfunction in Friedreich’s ataxia. In research described in the July 2019 issue of Stem Cell Research and Therapy, Novoheart’s human heart-in-a-jar model for Friedreich’s ataxia captured electrical and mechanical heart defects seen in patients with the neuromuscular degenerative disease.
In a separate blinded study using cardiac cells derived from healthy donors, published in the August 2019 issue of Clinical Pharmacology & Therapeutics, the company’s human ventricular cardiac tissue strips and hvCOC showed strong predictive capabilities, correctly classifying 90% of drugs provided by Pfizer.
The company also has an agreement with Global Pharmapartners Inc., of Springfield, Mo., to design a customized, high-throughput hardware and software system for measuring human heart tissues engineered by Novoheart. Wong said that additional partnerships may be announced in the future.
Novoheart reported revenue of CA172,812 (US$128,784) and cost of sales of $71,963 for the three months ended Sept. 30. The company cited stepped up pursuit of commercial agreements.
Earlier this year, Novoheart acquired Xellera Therapeutics Ltd., of San Diego, a development and manufacturer of gene- and cell-based therapies. The move gives Novoheart another avenue for improving patients’ lives.
While the hvCOC is currently being used to preclinically assess potentially promising new therapies, it could find a niche in precision medicine. “In the future, there is a possibility of using personalized models [ones made with stems cells originating from individual patients’ own blood cells] to help make clinical decisions about what therapies may be most effective for individual patients,” Wong said.