DUBLIN – Compared to other indication areas, gene therapy for cardiac disease is still at the “caveman” stage, according to Dinaqor AG CEO and Chairman Johannes Holzmeister. The Pfäffikon, Switzerland-based firm aims to drag it into the modern era by applying a novel locoregional delivery system to its adeno-associated virus 9 (AAV9) vector technology, in order to achieve high levels of transduction and high levels of selective transgene expression in cardiac cells.
The company recently entered a strategic collaboration with Basel-based CDMO Lonza AG on gene therapy process and analytical development, which will underpin its entry into clinical development for cardiac myosin-binding protein-C (MyBPC3) cardiomyopathies. “We are in an IND-enabling process,” Holzmeister told BioWorld. A clinical trial start is imminent. “In the best-case scenario, very, very soon,” he said. The company plans to conduct clinical trials in the U.S. and Europe.
Dinaqor was established in April 2019 by a team of founders with deep roots in cardiology, gene therapy and molecular medicine. Several of the senior management team double up at Zug, Switzerland-based Cardiorentis AG, where Holzmeister, a board-certified cardiologist, has spent almost a decade at the helm. Reto Wittwer fulfills the chief financial officer roles at each firm, while Dinaqor’s chief technology officer and head of global supply Hanns Erle fulfills a similar function at Cardiorentis. The latter firm has, however, been dormant on the news front since the failure several years ago of its lead drug, the vasodilatory peptide ularitide, to demonstrate a mortality benefit in a phase III trial in acute heart failure.
Dinaqor is very much focused on the same organ, but on a wholly different pathology and a wholly different therapeutic modality. The gene encoding cardiac MyBP-C protein is mutated in about 40% of monogenic hypertrophic cardiomyopathy (HCM) cases, which leads to impaired contraction of the heart. Neonatal patients with the severe form of the condition develop heart failure and generally die during their first year of life unless they undergo heart transplant.
Its lead program, Dina-001, is based on preclinical research led by Lucie Carrier of the University Medical-Center Hamburg Eppendorf, who published in 2014 preclinical proof of concept of an AAV9-based gene therapy in a mouse model of HCM. Carrier and colleagues – including Thomas Voit, now Dinaqor’s chief scientific officer – reported, in the Dec. 2, 2014, issue of Nature Communications, that a single systemic administration of AAV9 encoding Mybpc3 in 1-day-old knock-in mice prevented the development of cardiac hypertrophy and dysfunction over a 34-week observation period, while Mybpc3 mRNA and cMyBP-C protein levels increased in a dose-dependent fashion.
Dinaqor’s goal is to recapitulate those effects in neonatal human patients with a systemically delivered therapy. It is also developing a version for adult patients, who have later disease onset, which will involve a locoregional delivery system currently in development. The heart has proved to be a difficult organ for cell and gene therapy developers, because it is literally a moving target. High levels of vector washout can stymie efforts to obtain efficient delivery and functional expression. “This has never been demonstrated,” Holzmeister said. The company is collaborating with the German Heart Center Berlin on the development of its delivery device. “If we master the technology – get functional expression – we can build a highway to the human heart,” Holzmeister said. Key data on that system are due in the coming year. “If that works the way we think it works, then we could cut the amount of viral vector needed by a factor of ten,” he said. Dinaqor is also employing a human troponin T promoter to ensure cardiac-specific gene expression.
‘An open landscape’
Dinaqor’s lead indication involves the same gene that was targeted by Shoukhrat Mitalipov, of Oregon Health and Science University, in his controversial gene experiments on human embryos that employed CRISPR/Cas9 to replace a mutated gene with a healthy copy. “Gene editing is obviously on our radar,” said Holzmeister. “If our locoregional approach works, then we can think about bringing Cas9 into the human heart.” Myokardia Inc. is developing small-molecule-drug approaches for treating HCM. It is in phase III with mavacamten, which reversibly binds myosin and reduces the excessive contractility associated with the condition. It is also in phase I with MYK-224, which has a similar mechanism but a shorter half-life. “I think our approach is complementary,” Holzmeister said.
Companies involved in gene therapy for cardiovascular indications are few and far between. But one noteworthy comparator is New-York-based Rocket Pharmaceuticals Inc., which has built up a market capitalization topping $1.2 billion on the basis of several clinical-stage gene therapy programs in rare diseases, including Danon disease, a fatal X-linked condition characterized by hypertrophic cardiomyopathy, myopathy and intellectual disability. Like Dinaqor, Rocket is also employing an AAV9 vector in that indication – given its tropism for cardiac tissue – and is currently recruiting patients onto a phase I trial.
Philadelphia-based Xylocor Therapeutics Inc. raised $17 million in series A funding 12 months ago to take forward an adenovirus-based vector encoding VEGF for patients with refractory angina who have exhausted other treatment options. A phase I start is imminent. But compared with other areas of medicine, such as ophthalmology or neurology, the heart is still “an open landscape,” said Holzmeister. Positive data could quickly change that situation.