Genes and the Heart
How do you price a cure?

Cover Story | By Debra L. Beck

Why treat the symptoms of a disease or contend with a failing organ system if a cure is an option? The staid, technical term would be “disease-modifying agent.” The dreamier term is “cure.” With heart failure (HF) prevalence and incidence still rising and outcomes still dismal, gene therapy promises not just another treatment for HF and other cardiovascular diseases, but something—well, if not a complete cure, then a fix that can last years and then be fixed again. At this stage, it’s still only a promise, but one encompassing both crash-and-burn failures and encouraging successes.

Until recently, any talk of a ‘cure’ for HF required a serious physical and financial commitment: namely, heart transplantation. Hardly a simple undertaking or a practical solution for the millions of individuals who suffer from chronic HF. But this rather large problem may be resolved with a small solution: gene therapy, which may be the David to HF’s Goliath by offering another opportunity to reverse the damage done to the heart by disease.

But gene therapy poses one of the greatest technical challenges in modern medicine. All of the components must be right: the right target, the right vector, the right delivery mode; transduction has to be adequate, immune response controlled, and results lasting; then it must get approved and be commercially viable. There are good reasons why so many biotech companies in the gene therapy space fail.

Getting the therapy right might be almost as complicated as heart transplantation or it might not work at all; however, if it can be made to work right, the possibilities are unreal. And the price for such a cure? That’s not simple either, as you’ll see later in this article.

Gene Therapy Made… Simpler

Gene therapy seeks to add or replace a nonfunctional gene or to disrupt or silence a detrimental gene that is causing disease. There are basically three components of a successful gene therapy: 1) an appropriate therapeutic gene; 2) a dependable delivery mechanism (the vector) that will transport the gene to its target location; and 3) a level of uptake of the gene in the target cells to ensure efficient transduction or transfection to cardiomyocytes.1

There is always more than one way to skin a cat and multiple strategies have been tried using gene therapy to aid in the repair or recovery of a damaged heart. These include overriding cell cycle checkpoints, improving angiogenic mechanisms within the heart, and enhancing the contractile potential of remaining cardiomyocytes, among others.

Once an optimized gene of interest has been found, it has to be delivered and accepted into the target cells. Options include direct intramuscular injection, antegrade and retrograde infusions during bypass grafting, and catheter-based techniques, including direct intracoronary infusion.

Typically, gene therapy uses a vector to deliver the gene to the target cells. Both engineered viral or non-viral vectors have been tested for gene delivery, along with nucleases and gene silencing techniques. Many gene therapy trials have relied on retroviruses or adenoviruses to deliver the desired genes. Others, like the CUPID (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) trials, use adeno-associated viruses (AAVs). As you may recall, these little sweethearts infect humans but are not known to actually cause disease.

Off to a Slow Start

The first gene therapy was tested in humans in the 1990s. In 1999, 18-year-old American Jesse Gelsinger died after receiving an experimental gene therapy, which doctors think caused an overwhelming inflammatory reaction. Around the same time, two cases of leukemia were reported in a trial and research in this area slowed for several years.

In the early 2000s, novel methods were developed to minimize immune response and success was seen in primarily monogenic diseases and some cancers. The first gene therapy ever approved was Gendicine, developed by SiBiono GeneTech, which entered the market in 2003 in China. Gendicine is designed to treat head and neck squamous cell carcinoma tumors that have mutated p53 genes.

To date, only one gene therapy product is approved in the West and that’s Glybera, which received EU approval in Nov. 2012 after being rejected three times.

Glybera (alipogene tiparvovec) is a gene therapy treatment for patients with lipoprotein lipase (LPL) deficiency, a rare disorder that can cause severe pancreatitis leading to serial hospitalizations. It consists of an intact copy of the human LPL gene, encoded by an adeno-associated virus serotype 1 (AAV1) viral vector, administered through a series of intramuscular injections (Figure 1). 

As part of the approval, European regulators required Glybera’s maker, Amsterdam-based uniQure, to provide 6 years of follow-up data on the 19 trial patients. The results, released in June 2014, showed that bouts of pancreatitis and hospitalization rates were reduced by about half. While not published, the results were reported in June 2014.2 UniQure has not submitted for U.S. approval.

Glybera has the unique distinction of being the single most expensive medication that exists, set to go on sale in Germany in 2016 at a cost close to $1 million per treatment.4 UniQure points out that orphan drugs targeting rare diseases cost, on average, about $250,000 a year. Given the 6-year success in their study above, that makes the $1 million price equivalent to about $166,666 a year. In addition, the therapy can limit hospital stays and long-term complications, such as heart disease and diabetes.

Again, this is a rare disease with only 150 to 200 patients eligible for treatment across Europe, with a similar number in the United States, should the therapy ultimately receive U.S. Food and Drug Administration approval.5 (As of Dec. 1, 2015, it was reported that the company is no longer pushing for U.S. approval of Glybera, probably not surprising given the frustrating path the drug took in Europe and what is referred to by one analyst as a “disappointing EU launch.” Nevertheless, 3 days later, it was reported that UniCure has begun manufacturing runs at a new plant in Massachusetts.) Not sure what this particular optimism is based on, but in a Bloomberg Business article, Gbola Amusa, MD, CFA, the head of health care research at Chardan Capital Markets in New York, NY, suggested that the cost of Glybera “is likely to be far above the price of future gene therapies.”6

Gene therapy treatments are in development for a wide array of illnesses, including a dozen or more products in late-stage clinical development for the treatment of cancer, ocular, and cardiovascular disorders. One therapy that may soon get EU approval is from GSK and treats patients with adenosine deaminase for severe combined immunodeficiency syndrome. A recent market research report identified a total of 483 gene therapy molecules in the market or clinical pipeline, most in early development. There are a handful of gene therapies approved for use in China, Russia, and the Philippines.

How Can You Mend a Broken Heart?

Optimal heart function is dependent on, among other things, healthy cardiomyocytes. Progressive changes in cardiomyocyte phenotype are a central feature in chronically stressed and failing hearts, as is cell death.

Damage to the cardiomyocyte population comes in several forms. The human left ventricle has 2 to 4 billion cardiomyocytes, 25% of which can be wiped out with a single myocardial infarction.7 Cardiomyocyte hypertrophy is also seen in physiologic settings: 20 million are lost yearly due to aging, for example, and pregnancy and athletic challenges may result in cell loss, too. But it’s the chronic stress and overload conditions seen in HF and its predecessors that really cause problems. Regenerating or repairing damaged myocytes has been an important theme in cardiovascular research.

Unfortunately, the heart is one of the least regenerative organs in the body. Traditionally, the heart has been thought of as a terminally differentiated postmitotic organ in which the number of cardiomyocytes is established at or near birth. Researchers now know that cardiac stem cells reside in the heart and have the ability to differentiate into cardiomyocytes, allowing for some—albeit limited and slow—regeneration.8

Cell therapy relies on the administration of live whole cells or maturation of a specific cell population to repopulate areas of damaged myocardium. Despite extensive efforts, no cell therapy has been conclusively shown to be effective.9

Gene therapy, on the other hand, focuses not on replacing lost cardiomyocytes but rather on improving the function of existing myocytes by altering or influencing the expression of specific genes. Some approaches try to introduce a new gene into the body to help fight a disease.

Sometimes a combined approach works best, making it hard to categorize an approach as clearly cell or gene therapy. In May, phase II results were presented at Heart Failure 2015 showing the potential of a novel non-viral gene therapy that expresses stromal cell-derived factor-1 (SDF-1), a naturally occurring signaling protein that repairs damage by recruiting circulating stem cells to the site of injury.

The therapy, called JVS-100 (Juventas Therapeutics, Cleveland, OH), is a deoxyribonucleic acid plasmid designed to be delivered directly to the site of injured tissue. The trial, called STOP-HF, showed that a single treatment of 15 mg or 30 mg SDF-1 (delivered to the heart as 15 injections using an endocardial injection catheter) did not significantly improve the composite endpoint of 6-minute walk distance and quality of life compared to placebo (the primary endpoint), but at its highest dose and in the sickest patients (left ventricular ejection fraction [LVEF] < 26%), it did significantly increase LVEF compared to placebo at 1 year. The therapy appeared safe and the development of JVS-100 continues.

Squeeze and Release

Calcium cycling is central to cardiomyocyte function and a popular target for gene therapy. During each heartbeat, calcium (Ca2+) is taken up and then released from the sarcoplasmic reticulum (SR). Calcium handling in HF-damaged cardiomyocytes is impaired, producing a weak contractile force. Also, impaired calcium uptake to the SR results in incomplete myocyte relaxation after contraction. Calcium cycling is a popular gene therapy target for HF and the focus of two of the companies profiled below: Celladon and Renova.

The field is an interesting mix of traditional academic research and Silicon Valley-type start-ups with bubbly valuations, news-making partnerships, and loads of entrepreneurial spirit. But the level of expertise needed to develop a successful product—expertise not only in gene therapy but also in product development and product registration—makes for a field that demands high performers, generous funding, and the possibility of abject failure.


When biotech companies fall, they fall hard. Unrealistic valuations help, as do politicians trying to score points with voters. But the real issue for these companies is that they often have no sales or revenue and only one or two drugs in the pipeline. If a key compound fails to meet an endpoint in a phase II or III clinical trial, stock prices commonly drop 50% or more.

Not long ago San Diego-based Celladon was a biotech darling in the gene therapy space. Its targeted therapy, called Mydicar, was designed to enhance the contractile potential of remaining cardiomyocytes in individuals with HF.

We noted above that deficient SR calcium uptake has been identified in failing hearts. The sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase (SERCA2a) enzyme causes muscle relaxation by lowering levels of cytosolic calcium and restoring calcium reserves in the SR. A decrease in SERCA2a activity has been shown to be responsible for abnormal calcium homeostasis in failing hearts. Conversely, overexpression of SERCA2a boosts contractility.

The concept behind Mydicar was that overexpression of the SERCA2a gene in the myocardium would restore SERCA2a enzyme production in the cardiomyocytes, which would then power the SR, improving contraction and relaxation of remaining cardiomyocytes.

In preclinical models of HF, increasing the expression of SERCA2a in cardiomyocytes by gene transfer restored normal calcium cycling and resulted in improved cardiac function and myocardial energetics. The early phase II CUPID trial confirmed SERCA2a as an important target in HF and showed that its pairing with an AAV1 and administration as a one-time antegrade epicardial infusion was both safe in humans with advanced HF and very likely clinically beneficial at the highest dose tested (FigurE 2).10 Just the fact that a gene therapy for HF made it successfully through a phase II trial was considered “by no means a minor achievement.”11 At this point, stock prices were looking pretty healthy for Celladon…

Unfortunately, the phase IIb CUPID 2 trial didn’t go so well. The trial enrolled 250 patients in 56 clinical sites and randomized them to Mydicar or placebo in equal numbers. All patients were prescreened for the presence of AAV neutralizing antibodies.

The novel treatment failed to meet any of its primary or secondary endpoints. Mydicar did not reduce HF hospitalizations, all-cause death, or the need for a mechanical circulatory device or heart transplantation (Figure 3). Celladon stock collapsed on the news.

When Celladon went public in early 2014, its stock traded at $8/share. The month before the CUPID 2 trial results were released (in April 2015), the stock hit a high of about $28, falling to $13.68 the day before the results were revealed, and then tanking at $2 when the bad news was confirmed. In Nov. 2015, Celladon Corporation and Eiger BioPharmaceuticals, Inc., a privately-held firm, announced that they have entered into a definitive merger agreement.

Renova Therapeutics

Renova Therapeutics is another hot gene therapy start-up based in San Diego, CA, but of a very different flavor than Celladon and, obviously, hopeful of a different future. The company is supported by a group of high-net-worth individuals and has not taken any venture capital money—as of yet. This nonpublic route is by design, according to Renova CEO, Jack W. Reich, PhD.

“When you’ve got individual investors, it’s quite different than venture capital investors who are purely financial investors,” explained Dr. Reich in an interview with CSWN. “We’re not sort of forced to go public or something like that because we have investors that want to get liquid. Our investors and our management are on the same side of the table.”

They have partnered with the National Institutes of Health (NIH) to run both an extensive preclinical program on their target gene therapy product and to conduct clinical trials through a public-private partnership between the NIH and Renova Therapeutics.

Renova’s scientific founder is Kirk H. Hammond, MD, from the University of California San Diego. Dr. Hammond was the first to discover that adenylyl cyclase type 6 (AC6) was downregulated in patients with HF of any etiology and that regulating AC6 could have a positive effect on said patients.

AC6 is a protein found in cardiomyocytes that catalyzed conversion of adenosine triphosphate to cyclic AMP (cAMP) and, thus, is a central regulator of calcium cycling. As it happens, AC6 also improves the affinity of SERCA2a for calcium by activating a cAMP-dependent protein kinase of phospholamban, placing it upstream from SERCA2a and possibly explaining its greater efficacy (at least at this point in the development cycle).

“[SERCA2a] does not have the effect of normalizing heart function,” said Dr. Reich about SERCA2a. “They thought that it would improve calcium handling, but the results speak for themselves.” He also questioned whether AAV1 was the optimal vector for this therapy, noting that Renova’s adenovirus vector when delivered by catheter directly into the coronary arteries “causes the heart to take up the gene therapy like a sponge.”

“You get extraordinarily high yield gene transfer and, as a result, you get extraordinary production of the protein the gene produces and then the effects that we have now demonstrated in the clinic.”

RT-100 is designed to upregulate AC6 content and restore heart function. In extensive preclinical study, a single dose improved myocardial function and reversed HF-induced remodeling of the heart. These early results supported the phase II trial conducted at seven U.S. centers and presented by Dr. Hammond during a Clinical Trial Update session at the 2015 European Society of Cardiology meeting in London.

In the study, 56 patients with HF with reduced ejection fraction (HFrEF) were randomly assigned to one of six dose groups of RT-100. During the 1-year trial, there were no differences in HF hospitalization or death between groups. AC6 gene transfer was not associated with myocarditis or liver inflammation, or an increase in implantable cardioverter-defibrillator events.

In terms of efficacy, RT-100 given at the two highest doses increased EF significantly at 4 weeks, but because of an insignificant but substantial increase in the placebo group at 4 weeks, the between-group difference was not significant at 12 weeks. When the investigators looked at EF change > 5 units, eight of 21 individuals who received the two highest doses of RT-100 showed at least a 5-unit increase in EF at 12 weeks, while none of the 13 placebo patients did (p = 0.013).

When response was categorized by HF etiology, nonischemic HF patients were the only patients who showed improved EF with the therapy. The ischemic subjects did not improve at all. The investigators also saw a signal that a dose higher than the highest they tested might be beneficial.

In terms of left ventricular -dP/dt, which is a direct measure of the heart’s ability to relax and one of the trial’s primary endpoints, a significant difference was noted favoring RT-100 over placebo (p = 0.03). Findings for LV +dP/dt—also listed as a primary endpoint—were not presented.

And while symptoms improved significantly after RT-100, a large placebo effect was noted such that the between-group difference was not significant at 4 or 12 weeks. “The placebo subjects had an amazing 17% improvement in time on a treadmill and we were not able to do better than that with treatment,” explained Dr. Hammond.

Renova plans to meet with health authorities in the U.S. and Europe in early 2016 to discuss further clinical trials, which will support registration of RT-100. There are no trials ongoing presently. Dr. Reich, who has vast experience in getting products registered, explained the importance of stepping in sync with regulatory bodies.

“It’s much smarter to get input from the regulators, and then you go out and do exactly what you said you were going to do and submit the results. Then you’ve got a chance of getting a registration. If you do anything different than that you’re shooting yourself in the foot,” he said.

He should know. Dr. Reich’s record is impressive. He was a co-founder of the first gene therapy company in 1987, Viagene, which was acquired by Chiron in 1995. His last company, Collateral Therapeutics, was the first gene therapy company focused on cardiovascular disease and was sold to Schering AG in 2009. Dr. Reich came out of retirement to lead Renova.

How Do You Price a Cure?

All this science is fascinating, but let’s get down to business: what do you charge for a cure?

The concept is simple: a single treatment to cure an otherwise chronic and usually progressive lifelong illness. How much should that cost? With pharmaceutical and biotechnology stocks taking a beating these days over concerns about drug pricing, it’s hardly a simple answer. Heath care professionals and politicians alike continue to weigh in on the topic but often disagree on how to rein in prices that are much higher in the U.S. compared with the rest of the world.

Merck CEO Kenneth Frazier, JD, recently discussed the issue in a meeting with U.S. President Barack Obama and said that Merck for one has “tried to approach pricing from the perspective of value.” Indeed, value-based pricing is a popular concept: the common sense idea of paying for drugs according to how well they work. Another way to look at pricing is according to overall savings afforded by the treatment.

So, thinking about value and overall savings, how do you price a one-time therapy that offers a “cure” for HF? Is it of equal value to a lifetime of polypharmacy that only offers symptom management? Is it more valuable?

It’s a topic that Dr. Reich from Renova Therapeutics is already thinking seriously about. When asked in an interview by CSWN Executive Editor Rick McGuire how the company might price RT-100, the single-dose therapy designed to restore heart function in HF patients, he said that Renova is motivated first and foremost to save the health care system money and ensure the treatment is accessible to patients.

To inform the company and the pubic of the potential impact of RT-100, Renova is working with the nonprofit RAND Health Advisory Services to do an independent analysis that will reflect the health care patterns of multiple advanced HF patients over a 5-year period. Results of the modeling experiment are expected to be published in three separate articles in major journals in the first half of 2016.

“We’re not interested in how much we could charge or how much we defend,” said Dr. Reich in the interview. “What we are interested in is to set a price that people can afford. And demonstrate to the health care system that the price could be multiple times higher, but we’re not trying to extract the last dime. We’re trying to get the medicine truly available to these patients that have this disease.”

Renova plans to take a similar approach with the other therapy in their pipeline—a second-generation product for type 2 diabetes.

According to a blog post on Bioentrepreneur, a Nature Biotechnology portal for scientists interested in commercializing their research, pricing gene therapies will likely follow one of three general schemes: the classic up-front, one-time payment; an annuity model that spreads that payment over a number of years to lessen the cost-density burden on payers (think of it as a subscription to life); and a pay-for-performance, risk-sharing model that tracks patient outcomes and rewards manufacturers for maintaining patients’ health over a period of time.

Said blogger Chris Morrison,4 from Yardley, PA, “All gene therapies are unlikely to be deemed equal in the eyes of payers.[…] But curative products that are safe and have meaningful cost offsets, particularly in rare diseases, are likely to command record prices in the not-too-distant future.”

Without a doubt, millions of HF patients are hoping this theoretical issue becomes a real one very soon.


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  3. van der Loo JC, Wright JF. Hum Mol Genet. 2015 Oct 30. pii: ddv451 [Epub ahead of print]
  4. Morrison C. Nat Biotechnol. 2015;33:217-8.
  5. Ylä-Herttuala S. Mol Ther. 2015;23:217-8.
  6. M Kitamura. “World’s most expensive medicine: Is it worth the price?” Bloomberg Business. May 21, 2015.
  7. Laflamme MA, Murry CE. Nature. 2011 May 19;473(7347):326-35.
  8. Leri A, et al. Chapter 3. Cellular basis for myocardial regeneration and repair. Heart Failure: A companion to Braunwald’s Heart Disease. 3rd edition. 2016. Mann DL and Felker GM, editors. (and) Bergmann O et al. Science. 2009; 324:98-102.
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Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant

Keywords: CardioSource WorldNews, Biotechnology, Genetic Therapy, Heart Failure, Heart Transplantation, Physical Examination, Prevalence

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