Renova Targets Prevalent Diseases with Gene Therapy

While many gene therapy developers target genetic causes of disease, Renova Therapeutics is developing gene therapies for prevalent diseases—specifically heart failure and type 2 diabetes. 

A small company with big plans, Renova’s lead therapeutic RT-100 is a potential first-in-class single administration gene therapy candidate designed to improve heart function in patients with congestive heart failure by targeting the AC6 enzyme (a protein). Recent data from a phase 2 trial demonstrated that it could work to increase heart function and reduce heart failure hospitalization.

Why gene therapy for heart failure? 

“Well, there are a couple of reasons there,” says H. Kirk Hammond, a cardiologist and scientific founder of Renova who has been seeking new methods to treat heart failure for more than 25 years. “Even now, all these years later, the success rate for pharmacological and device treatment for heart failure with reduced ejection fraction remains dismal so that the five year survival is around 50 percent. Once you've been hospitalized for heart failure, the survival is much lower than 50%. There is a vacuum in that area for effective therapies.”

Hammond had worked on a gene transfer for heart failure focused on the protein AC6, funded by three NIH Program Project grants, and acquired compelling data from animal models.  This led to the founding of Renova in 2009 to advance the candidate into clinical trials.

AC6 is the dominant isoform of adenylyl cyclase in the heart. Hammond and colleagues’ data from animals showed that you could dramatically improve the function of heart cells (cardiac myocytes) in normal and diseased hearts in animal models by increasing the expression of this important effector molecule. AC6 resides on the plasma membrane and converts ATP to cyclic AMP, which drives contractile function. Increasing AC6 content was relatively unresponsive to basal β-adrenergic receptor stimulation in the basal state but responded only when recruited by physiological needs. 

“For example, in transgenic mice with cardiac-directed expression of AC6, AC6 has recruitable increase in heart rate and function, but no increase in activity in the basal state.  These mice have life-long normal and responsive hearts,” says Hammond. “However, mice with cardiac-directed β-adrenergic receptor expression or expression of Gs (a transducing protein in β-adrenergic signaling) initially have high heart rates and increased contractile force even at rest.  This eventually leads to heart failure. So, the over stimulation of the heart can be dangerous. In contrast, AC6, which does not increase heart rate of heart function in the basal state, circumvents this toxic effect. But this is really a unique effector molecule as a gene therapy agent.” 

For the phase 2 clinical trial, 56 patients with heart failure with reduced ejection fraction, which comprises about 50 to 60 percent of all heart failure in the United States, were enrolled. They had symptomatic heart failure but were not bedridden and not on the transplant list. An adenovirus encoding human AC6 was delivered into all three coronary arteries as a one-time treatment. Patients were followed for a year with evidence that there was a treatment effect. Subsequent analysis indicated that the effect was better in patients that had nonischemic rather than ischemic-based heart failure.  The therapy was safe and effective with no inflammation from the gene therapy delivery. 

Renova’s next step will be a phase 2b/3 study in about 200 patients who will undergo a cardiac MRI to measure end-systolic volume. Renova is poised for a clinical trial for its RT-100 in the UK, which has awarded Renova with an Innovation Passport designation for RT-100 by the British regulatory agency, MHRA. 

The company has been working to raise money to fund the trial and to engage with manufacturers and potential partners. “We’re looking for at least $10 million to initiate the process for one of our single therapy programs and then more capital before we start conducting the clinical trials,” says Renova CEO Vijay Mahant. 

Renova joined the Bioneex drug candidates marketplace platform as a provider looking for fundraising and/or partnering opportunities. “What I liked was the uniqueness of the platform. It's a marketplace. So, I registered the two products that we have in November 2023,” said Mahant. “I thought it was a great opportunity to bring it to the market. 

Renova’s second pipeline candidate RT-200 is a first-of-its-kind single-dose investigational gene transfer of urocortin 2 peptide to improve outcomes for patients with type 2 diabetes. Hammond and colleagues, while working in other animal models, serendipitously discovered that animals receiving urocortin 2 gene transfer had reduced blood sugars. 

They then ran trials in five preclinical models of diabetes and subsequently published a series of papers that showed it worked very well. And there again, one injection had an effect on hyperglycemia and glucose flux that persisted for many months. When treating heart disease associated with advance age, they showed that the increase in urocortin 2 persisted for 2-years after a single injection. A small study in African green monkeys showed persistent urocortin 2 expression for the length of the 10-month study, and improved glucose disposal. These data showed that the approach should be tested in clinical diabetes. 

Hammond also wondered if it would work in type 1 diabetes and published data that showed that it not only restored normal glucose metabolism despite the fact that these animals had a 90 percent reduction in endogenous insulin, but it also markedly improved survival and prevented diabetic retinopathy and visual impairment. RT-200, in preclinical development, is also a potential first-in-class gene therapy that uses an AAV vector that targets the liver for one-time delivery of the gene encoding for urocortin 2. Urocortin 2 is an AMPK activator, which is a major switch for metabolic function and it increases Glut4 translocation to the plasma membrane, which is the initial part of glucose entry into the cell. This is in skeletal muscle and it's dependent on the corticotropin releasing hormone receptor 2, which is the cognate receptor for urocortin 2. 

“These data have been so consistent in different preclinical models of diabetes that I am hopeful that it may have a similar effect in patients with diabetes” Hammond stated. 

RT-200 has also received an Innovation Passport from the UK MHRA for the treatment of type 2 diabetes and Renova is currently planning a phase 2 clinical study of the urocortin 2 gene transfer. 

Of course, Renova will need significant capital to conduct these trials, which are planned for the UK and U.S, and the company has recently launched a new funding round looking to raise $25 million in new equity. 

“It's a new class of preferred stock that we're offering,” says Bill Davidson, a director that oversees business development. “The valuation pre-money is in the $125 million range. We're looking to raise up to $25 million and we have quite a detailed use of proceeds plan. Of course, the primary purpose is to launch the clinical trials for the RT-100 heart failure therapy first and to begin the preparations for the RT-200 diabetes drug. We have a very robust roadmap for different geographies and therapies.” 

Manufacturing will be a challenge and Mahant is working with more than half a dozen manufacturers and has begun to receive proposals. But the future is promising for Renova given the potential of its therapies and the huge market that they address.