Cardiac Care: Cornovus eyes heart failure remedy

One particular patient underscored Dr. Bruce Liang's mission to help people with advanced heart failure live longer.

The patient was a caretaker for several family members, despite being physically compromised with a heart functioning at half capacity. Liang kept the woman stable for seven years before, within about a year's time, her heart function significantly deteriorated. He called colleagues, searching for answers he might have missed. There were none.

She was in her 70s when she died, worried not about herself, but those she was leaving behind, Liang recalled.

Liang, a clinical cardiologist and researcher at UConn Health since 2002 and dean of the UConn School of Medicine since 2015, had been conceptualizing a potential new drug treatment for people with advanced heart failure before the woman died. He and Kenneth Jacobson, a chemist with whom he's collaborated for about 20 years, had already begun to develop a synthetic molecule they thought could help such patients, but the woman's death motivated Liang to accelerate the pace.

Her age and coexisting medical condition meant she couldn't be a candidate for a cardiac transplant or ventricular-assist device, an expensive piece of hardware to help a failing heart pump blood. “She wasn't a candidate, so we had nothing,” Liang said.

Jacobson, focused on the chemistry, and Liang on the biological application, co-invented a potential new medication that worked well on mice with similar heart failure conditions and later on dogs, where it also worked well.

The drug, derived from the synthetic molecule, apparently prevents heart muscle cells from dying.

“The heart has limited ability to regenerate itself, but also dies in the condition of heart failure,” Liang said. “If you have more … cells dying than you can regenerate, then the net effect is you have fewer, good viable contracting muscle cells and then [the]whole organ fails. We think our drug is preventing the death of heart muscle cells.”

Liang formed Cornovus Pharmaceuticals Inc. in 2011 to pursue a treatment for what he says is an unmet need for such heart-failure patients because there's no medication for them. The name represents “cor,” for heart, and “novus,” meaning new.

In August, Cornovus solidified the final piece of roughly $3.5 million in funding needed to do the additional preclinical testing Liang hopes will cement Cornovus' case for investigational new drug, or IND, approval from the Food and Drug Administration (FDA) in about 18 months. After that, human tests could begin. At that point, Cornovus would need to secure more funding from venture capitalists or work with a pharmaceutical partner to cover what could be a $20 million stage of human testing lasting another six or seven years.

But getting IND status reduces the risk by more than half for future investors, Liang said, increasing the odds Cornovus can land a deep-pocketed partner for human clinical trials.

The new medication is noteworthy, said Jacobson, director of the bio-organic chemistry lab at the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health outside Washington, D.C.

“It fills an unmet medical need and it would be a lifesaving treatment, so I think it's highly significant and there appear to be no serious adverse effects in animals, so quite likely it will prove to be safe,” Jacobson said.

The medication is a nucleotide derivative, he said, adding there are many drugs on the market that are from this class of compounds, nucleosides and nucleotides.

“So this is already a member of a well-validated class of medicines … ,” he said.

The initial market for the drug, for patients with advanced heart failure for whom transplants or ventricular-assist devices are not an option, is an estimated 500,000 to 600,000 patients in the U.S. and Europe, where Cornovus' patents are issued, Liang said.

But that's just the start. If Cornovus proves its drug works on those patients, it would seek to use it in patients who are less sick, but also have heart failure, to try to prevent their disease from progressing to a more advanced stage, Liang said. Patients in that category number around 6 million in the U.S. and 5 million to 6 million in Europe, “so then you're talking about 12 million patients at any given time could be benefiting from a medication like this.”

It's possible that such a medication, initially envisioned to be infused via a catheter in a vein or through something akin to an insulin pump, could replace the need for a ventricular-assist device, he said, expanding the patient universe even more. Those devices cost about $110,000, require maintenance, and can carry the risk of infection and clots, he said.

Key advantages

So what are the risks or challenges that could confront Cornovus?

There's always the possibility another new treatment could arise, but Liang isn't aware of anything similar with the kind of properties Cornovus' medication has.

Key to its medication is that it doesn't lower blood pressure in sick dogs that already have low blood pressure because of their heart failure, he said. That's an important feature since further lowering of blood pressure can be deadly.

“So that's a big advantage because that means if it's true in humans with end-stage heart failure, you could go ahead and give it without worrying about dropping their blood pressure, which is a big no-no because they could die from low blood pressure,” he said. “To our knowledge, there's not another drug out there in development that has this unique property.”

That's a feature attractive to investors, which included Connecticut Innovations ($1 million) and longtime UConn supporter Ray Neag ($2.5 million). Neag, a UConn alum after whom the Neag School of Education and The Carole and Ray Neag Comprehensive Cancer Center at UConn Health are named, was one of four founding members of Arrow International Inc., a Reading, Pa. manufacturer of cardiac and critical-care products.

Cornovus also is receiving help from NIH through its SMARTT program, Science Moving towArds Research Translation and Therapy.

SMARTT provides regulatory support, manufacturing and pharmacology/toxicology services to speed translation of research from the lab to submission of an IND application with the FDA, according to NIH's website. SMARTT gives Cornovus additional support to do some of the studies needed for making the compound in large scale under good manufacturing guidelines so that it can be put in patients.

CEO with chops

Dan Wagner, managing director-investments at CI and its point person with Cornovus, said the quasi-public venture firm invested $150,000 in the company four or five years ago to help get it off the ground, before its latest $1 million commitment.

CI's investment is based on more than the drug potential, but also the Cornovus team, Wagner said.

The hiring of CEO Glenn Mattes in December was important because he has the connections to execute Cornovus' business plan, Wagner said.

Mattes has more than 30 years of experience in the pharmaceutical industry in executive roles, including with Rhône-Poulenc Rorer (the pharmaceutical operations of which are now part of Sanofi); Centocor Biotech; Ortho-McNeil, Johnson & Johnson's largest operating company; and CEO at Arno Therapeutics. For the last five or six years, he's worked with smaller companies like Cornovus that are in the preclinical stages or with companies in early clinical development and has advised large private equity firms on healthcare acquisitions.

Mattes said he looks for companies that are founded by a quality person like Liang, with a strong medical school or academic relationship, “somebody who's got a great reputation in their specialty field and where they're working on a unique therapeutic product for unmet medical needs,” he said.

“So the biggest attraction, quite frankly, to Cornovus was Bruce, given his background, and also the product I think has an awful lot of promise,” Mattes said. “Of course, there's still a long way to go.”

But Mattes likes the company's chances of getting funding for clinical trials.

The idea is to hire staff locally as the company ramps up, said Mattes, who lives outside Philadelphia and will have an office locally as well. He spends about half his time now working for Cornovus, which is expected to increase. Cornovus is seeking office space in UConn's Technology Incubation Program, or TIP, at 400 Farmington Ave., Farmington.

UConn saw promise in Cornovus early on, investing in its patent portfolio and supporting Liang's endeavors with the company, said Rita Zangari, director of innovation programs and external relations in the Office of the Vice President for Research at UConn.

Wagner said the chemistry is licensed from NIH, where Jacobson is, and use of it in cardio therapy is licensed from UConn, with the two pieces together in-licensed to Cornovus. Wagner noted that CI is trying to support UConn and UConn technologies.

Yale University has a history of taking technologies and making them companies and getting them out the door, he said.

“UConn continues to build that and I think [Cornovus] is one of the better things that have come out of UConn in my time here,” Wagner said. “This could be a big-market drug.” 

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