Regenerative Therapy: Stem Cells Generate More Interest

We’re all developmental products of stem cells. Apart from the billions of cells generated after sperm meets egg, each of us also has an elegant “rescue” system of stem cells circulating in the blood and residing in our organs. A better understanding of this system is already leading to enhanced repair processes locally after injury.

However, the research is going well beyond using stem cells or genes to activate the body’s native repair function to facilitate the repair or recovery of any damaged or dysfunctional organs, tissues, or vessels. Down the road, these efforts may lead to the regeneration or repair of whole hearts or other organs (see this issue’s cover story). Where we currently are on this particular research highway might surprise you.

Cell therapy remains the biggest and fastest-growing segment of the regenerative medicine industry. More than $5 billion has been invested, so far, with more than 2,500 regenerative medicine clinical trials in progress (Frost & Sullivan, 2015). Globally, the stem cell therapy market is expected to be worth $40 billion by 2020 and $180 billion by 2030.

Some investigators have moved from academia to industry, partly because industry—including big pharma—has become expanding their regenerative medicine investment, including Pfizer, Novartis, Cellectis (France), Celgene, Teva Pharma, and Johnson & Johnson. Not all are focusing on cardiovascular applications, of course, although Teva is a major partner in the Chronic Congestive Heart Failure program (phase III trials) and J&J is investing up to $325 million (depending on milestone attainment) in a stem cell therapy for cardiovascular disease (phase II trials scheduled).

Leslie Miller, MD, has been chair of the Department of Cardiovascular Medicine at the University of Minnesota, Minneapolis, MN, and was most recently at the University of South Florida (USF), Tampa, FL, where he directed the cardiovascular clinical research program. He has also been director of cardiology at Washington Hospital Center, Georgetown University Hospital, and Georgetown University School of Medicine.

Today, he is the chief science officer of Okyanos Cell Therapy and his focus is now entirely on regenerative medicine and the use of adult stem cells to repair and recover heart function. He is one of four editors responsible for the new textbook (September 2015), Stem Cell and Gene Therapy for Cardiovascular Disease.¹

Turning the Corner?

You may be more familiar with the failures—let’s call them setbacks—in this field in recent years, but the reality is far more positive. The goal of using stem cell and gene therapy to enhance tissue repair of acute and chronic disease and create new treatments to reduce the significant morbidity and mortality from cardiovascular disease (CVD) has come a long way in the last decade. The field of regenerative medicine is an excellent example of the bidirectional flow of translational medicine between the basic and clinical sciences. Shortcomings in clinical trials have driven a good deal of basic research, which has led to further understanding of important mechanisms, such as cell homing and viability.

Here’s a good example: the National Institutes of Health FOCUS trial of 92 patients with stable ischemic heart failure (HF; a median left ventricular ejection fraction [LVEF] of 27%) randomized 2:1 to autologous bone marrow cells or placebo. About 100 million cells were delivered in the active therapy arm via endocardial cell delivery (the NOGA catheter). There was no change in various parameters until they looked at one variable: age. Patients older than 62 years had 0% change in LVEF, while those who were younger had a 4.7% increase in LVEF.

It turns out that one major limitation is that human stem cells become dysfunctional with age. They become less able or even unable to replicate and the age at which this happens appears to be around 60 years. Similarly, the number and effectiveness of bone marrow-derived and circulating stem cells are also reduced in patients with severe disease or many risk factors for CVD. Therefore, notwithstanding its elegance, the human rescue system of stem cells is often unable to repair damaged hearts in those for whom repair is most often needed.

Not too long ago, it was thought that any allogenic (read: foreign) cell was thought to require long-term immunosuppression. It turns out that mesenchymal stem cells seem to be “immune privileged,” meaning minimal alloimmune (antibody) response. Other cells have also been found to be as effective as autologous cells, meaning it may be possible to develop off-the-shelf therapy for any age, or need using, for example, mesenchymal stem cells from youthful donors to treat aging individuals with CVD. These cells may not be immunologically rejected when taken from one person (who is younger) and transplanted into another (much older individual).

These cells can be found in bone marrow, myocardium, or adipose tissue (the latter of which, you have to admit, is a lot easier to collect than the other two). So far, the largest experience certainly has been using bone-marrow derived cells, while human embryos are almost no longer being used at all as a stem cell source. The cell source with real growth potential right now is adipose tissue given the realization that it contains 100- to possibly 1,000-fold more stem cells per gram of tissue than bone marrow.

In one study, such cells from a healthy young donor were injected transendocardially into patients with ischemic or nonischemic cardiomyopathy. Among those receiving the highest cell dose, they demonstrated improved LV function and improved coronary blood flow as well as what appeared to be substantially reduced rates of death, slower disease progression, and fewer hospital readmissions for HF.²

Finding the right cell also is critically important. Makes sense, but getting there (to the best cells) took a lot of studies that most certainly did not work. An example of choosing wisely is one study conducted by Dr. Miller and others. The ReACT (Refractory Angina Cell Therapy) trial evaluated a cell population of promonocytes that promotes angiogenesis in refractory angina patients. In the summer of 2015, the investigators published an update showing long-term sustained efficacy and cost effectiveness.³

The ReACT phase IIA/B noncontrolled, open-label, clinical trial enrolled 14 patients with refractory angina and viable ischemic myocardium, without ventricular dysfunction, who were not suitable for myocardial revascularization. The procedure consisted of direct myocardial injection of a specific mononuclear cell formulation, with a certain percentage of promonocytes, in a single series of multiple injections (24 to 90; 0.2 ml each) into specific areas of the LV.

Primary endpoints were Canadian Cardiovascular Society Angina Classification (CCSAC) improvement at the 12-month follow-up and ischemic area reduction (scintigraphic analysis) at 12-month follow-up. A recovery index (for patients with more than 1-year follow-up) was created to evaluate CCSAC over time. Almost all patients presented progressive improvement in CCSAC beginning at 3 months post-procedure (p = 0.002), which was sustained at 12-month follow-up (p = 0.002), as well as objective myocardium ischemic area reduction at 6 months (decrease of 15%; p < 0.024) and 12 months (decrease of 100%; p < 0.004). QOL per SF-36 questionnaire improved significantly in almost all domains.

Cost-effectiveness analysis showed decreases in angina-related direct costs. Refractory angina patients presented a sustained long-term improvement in CCSAC and myocardium ischemic areas after the procedure. Thus, the authors concluded: “Promonocytes may play a key role in myocardial neoangiogenesis. ReACT dramatically decreased direct costs.”

Tissue Engineering

One of the limitations of current approaches to stem cell therapy is the short retention time (days to maybe a few weeks). It is only during this time that cells remain in the target tissue after transplantation. A great deal of progress has been made in the field of tissue engineering to design new methods to increase cell retention. These include what Dr. Miller calls “remarkable work” on the development of scaffolds using both natural and synthetic materials, including extracellular matrix to hold either stem cells or genes for slow and programmed release. In addition, scaffolds are being developed with cells implanted for delivery to the target tissue.

One of the most exciting approaches to tissue engineering is the concept of organogenesis or creation of whole organs that might potentially be used for elective, off-the-shelf transplantation. Research in this area has demonstrated both the complexity of individual tissues and cells within each organ, the challenging requirements of creating equipment to sustain and test these constructs, as well as which cell to use given the astounding plasticity of transplanted cells.

According to Dr. Miller and colleagues, in the introduction to their new book, “We believe we are on the threshold of a new era of regenerative medicine taking advantage of the lessons learned in the past decade and the strategies moving into clinical trials.”

References:

1. Perin EC, Miller LW, Taylor D, Willerson JT. Stem Cell and Gene Therapy for Cardiovascular Disease. 1st edition. Waltham, MA: Academic Press, 2015. ISBN: 978-0128018880.
2. Perin EC, Borow KM, Silva GV, et al. Circ Res. 2015;117:576-84.
3. Hossne NA, Cruz E, Buffolo E, et al. Cell Transplant. 2015;24:955-70.

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Lipid Therapy 2016: The ‘Doughnut’ Hole and PCSK9 Sticker Shock

We have recent cholesterol guidelines,¹ multiple studies confirming that the guidelines got it right (putting to rest much of the original criticism), and new agents recently approved that can dramatically lower LDL-C levels in patients, including those already on statin therapy. Thus, nothing left to discuss here, right?
Well, not so fast: there are still a few issues.

The Doughnut Hole

C. Noel Bairey Merz, MD, FACC, director of the Barbra Streisand Women’s Heart Center and director of the Preventive Cardiac Center at Cedars-Sinai Heart Institute, Los Angeles, CA, recently addressed the doughnut hole in the guidelines. As a member of the expert panel, she said they were charged by the National Heart, Lung, and Blood Institute to develop new cholesterol guidelines and told to evaluate only higher-quality randomized controlled trial (RCT) data. No need to reiterate the value of RCT data here, but that leaves a narrow field of data that misses huge swaths of the population.

Let’s face it, there is limited generalizability of the available data for the unstudied, including those younger than age 40 or older than age 75. For example, in these two broad age groups, there is wholly underpowered subgroup data in women and non-whites, limiting guidelines for these dominant groups. (Women comprise a total of 52% of the population, while non-white individuals are projected to make up more than half of the population by 2020.)

Sure, there have been subgroup analyses, but Dr. Bairey Merz is pointing to the challenge of making clinical decisions based on limited data from studies of inadequate sample size, low event rates, and limited trial durations, thus limiting precision, accuracy, and relevance of trial subgroup analyses. Consensus is that subgroups should be treated according to trial evidence of risk and benefit until proven otherwise.

Having acknowledged that, Dr. Bairey Merz asked: Can the guidelines be based only on clinical trials?

• How confident are we that statins do not save lives in subgroups (age, sex, ethnicity)?
• What do we value? For example, is reduction in revascularization and angina hospitalization—which both impact morbidity and cost—provide justification for the use of statins for primary prevention?
• Why are underpowered data sufficient to make treatment decisions on subpopulations (women and non-whites)?
• Is it time to stop comparing women to men and fund an adequately powered primary prevention women-only trial?

Familial Hyperglycemia

Over the past decade, John J.P. Kastelein, MD, PhD, of the Academic Medical Center/University of Amsterdam, notes that we have witnessed the unparalleled success of statins to treat dyslipidemia. Target identification by Mendelian randomization, human monoclonal antibodies, gene therapy, RNA-based targets, and atherogenic lipoproteins other than LDL-C have fueled intense development efforts that may bear fruit, providing new treatment options, in the very near future.²

However, right now—as noted earlier in this issue of ACCEL—there are two new PCSK9 inhibitors, which, Dr. Kastelein said, has converted familial hypercholesterolemia (FH) from a lethal disorder to a manageable dyslipidemia. Given strong evidence that lower LDL-C is better in these individuals, now one of the challenges is finding them, preferably before their first myocardial infarction brings them to medical attention.

Just how many patients will likely be put on these new monoclonal antibodies to PCSK9? Assuming that the early use will be limited to FH patients and for very high-risk patients with documented statin intolerance, Dr. Bairey Merz estimates that, for the foreseeable future, use of PCSK9 inhibitors will be limited to roughly 10% or less of the CVD population.

Ouch – and No Thank You

That may seem like a small percentage of patients given that these drugs are more powerful than statins. Cost is definitely a consideration, given that PCSK9 pricing levels are now known, running a little over $14,000 per year in the U.S. That’s well above earlier analyst estimates and on another planet from a Sept. 2015 draft report from the U.S. Institute for Clinical Economic Review (ICER), suggesting that the drugs should cost approximately 85% less than priced. (Which would reduce the price to about $175 a month.) In case you’re wondering, the annual cost of ezetimibe is $2,828, based on wholesale acquisition cost.

Wow, what do you think the final report will say? Let’s look, because it was published Nov. 24, 2015.3 After various analyses, including cost effectiveness and number needed to treat, the draft ICER value-based price benchmark for each of the new PCSK9 inhibitor drugs was $2,177. As the report states, “This figure represents an 85% discount from the full wholesale acquisition cost assumed in our analysis ($14,350).”

The ICER study authors did use a budget impact model to estimate what would happen if both the FH and cardiovascular disease (CVD) populations were treated based on certain uptake pattern assumptions. They estimate that 527,000 individuals will receive PCSK9 therapy in the first year. After 1 year of PCSK9 treatment, cost offsets due to reduced cardiovascular adverse events were estimated to range from $592 per patient with FH to $1,010 per patient for patients with CVD who are statin-intolerant. Including this cost offset, their estimated 1-year budget impact is still high: approximately $7.2 billion for all patient populations.

The TABLE demonstrates that, compared with statin therapy, incremental treatment with ezetimibe would avert 115,900 Major Adverse Cardiac Events (MACE) over the lifetime horizon and produce 250,600 additional QALYs with an incremental cost-effectiveness ratio of $135,000/QALY vs. current (statin) treatment. Adding PCSK9 inhibitors to current treatment would avert 324,200 MACE and produce 665,200 additional QALYs, producing an incremental cost-effectiveness ratio of $290,000/QALY. This higher ICER for PCSK9 inhibitors is driven largely by differences in the drug costs noted above.

Here are a few more numbers: As uptake of new PCSK9 inhibitors is estimated to increase over the first 5 years of use, the ICER report estimates that approximately 2.6 million persons will receive PCSK9 inhibitor therapy for 1 or more years by the end of that period. Total budgetary impact over 5 years is estimated at approximately $19 billion, $15 billion, and $74 billion for the FH, CVD statin-intolerant, and CVD not at LDL-C target subpopulations, respectively.

Finally, what’s happening in the real world as decisions are made about these newly approved agents? On Nov. 24, 2015, CVS announced that only evolocumab will be offered in the U.S. in the CVS/Caremark commercial formularies. In a press release, the company said the decision came after a thorough evaluation of the two new PCSK9 inhibitor therapies. “We have determined that choosing a single PCSK9 inhibitor for our commercial formularies allows us to get the best price possible,” according to Troyen A. Brennan, MD, MPH, executive vice president and chief medical officer, CVS Health.

That’s the opposite of what happened a few days earlier when the UK’s National Institute for Health and Care Excellence (NICE) published draft guidance not recommending evolocumab as an option for people with primary hypercholesterolemia—heterozygous-familial and non-familial—and mixed dyslipidemia. The UK price was too much for the regulators to stomach: annually, it is the British pound equivalent of $6,763.49 for 140 mg every 2 weeks and $9,310.10 for 420 mg/month.

It is doubtful we have heard the last of the PCSK9 cost debate.

References:

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. J Am Coll Cardiol. 2014;63:2889-934.
2. Kastelein JJ. Nat Rev Cardiol. 2014;11:629-31.
3. Tice JA, Ollendorf DA, Cunningham C, et al. for the Institute for Clinical and Economic Review. PCSK9 Inhibitors for Treatment of High Cholesterol: Effectiveness, Value, and Value-Based Price Benchmarks. 2015 Nov. 24: 1-113. Available online: cepac.icer-review.org/adaptations/cholesterol/.

Keywords: CardioSource WorldNews, Cell- and Tissue-Based Therapy, Cholesterol, Regeneration, Regenerative Medicine, Spermatozoa, Stem Cells, Wound Healing

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