Cash for Cardiovascular: Who Might Be Next?

by: Michael Becker

By Michael D. Becker, Jeffrey Martini, Ph.D., and Janet L. Dally

In January 2007, Amgen, Inc. (NASDAQ:AMGN) obtained an option from Cytokinetics, Inc. (NASDAQ:CYTK) to commercialize a novel small-molecule therapeutic product candidate that activates cardiac myosin with potential applications in the treatment of heart failure. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction.

Although the compound, known as omecamtiv mecarbil (previously CK-1827452), had just completed Phase 1 clinical trials at that time, Amgen paid Cytokinetics approximately $75 million upfront, comprised of a license and technology access fee of $42 million along with a $33 million equity investment whereby Amgen purchased 3.5 million Cytokinetics common shares at $9.47. During the initial two year research term, Cytokinetics would continue to pay for development of omecamtiv mecarbil.

If the product met pre-defined criteria in Phase 2a clinical trials, Amgen would be able to exercise its option to commercialize omecamtiv mecarbil, prompting an additional $50 million exercise fee payment to Cytokinetics. Amgen would then be responsible for the costs of developing the compound and any related products. In addition, Cytokinetics may be eligible to receive pre-commercialization and commercialization milestone payments of up to $600 million as well as royalties that escalate based on increasing levels of annual net sales of products commercialized under the collaboration.

On May 26, 2009, the companies announced that Amgen exercised its option to obtain an exclusive worldwide license [excluding Japan]. Shortly thereafter, data from Phase 2a clinical trials were presented at the 2009 Heart Failure Congress of the European Society of Cardiology. Based on clinical results to date, Cytokinetics and Amgen have agreed to proceed with a modified-release oral formulation of omecamtiv mecarbil in the planned Phase 2b clinical trials. Shares of Cytokinetics, which were trading around $2 prior to these positive events, recently rallied to around $3 per share – still less than one-third the price Amgen paid back in 2007.

Amgen isn’t the first company looking beyond its internal R&D efforts for new products or expanding into a new therapeutic class or disease setting. Beyond such licensing transactions, there have been some high profile acquisitions in the area of cardiovascular disease. Consider the following:

  • Johnson & Johnson (NYSE:JNJ) acquired Scios, Inc. for approximately $2.4 billion in 2003
  • Gilead Sciences, Inc. (NASDAQ:GILD) acquired Myogen, Inc. for approximately $2.5 billion in 2006 and more recently CV Therapeutics, Inc. for approximately $1.4 billion in 2009
  • Merck & Co., Inc. (NYSE:MRK) acquired privately-held NovaCardia, Inc. for $350 million in 2007

With this in mind, we offer a brief review of one specific segment of the cardiovascular space – ischemic heart disease – and some of the remaining biotechnology companies focusing on this area.

Ischemic Heart Disease

Ischemic heart disease or heart failure [HF] is the leading cause of death worldwide, causing about 1 in every 5 deaths in the United States [US]. HF, which affects over 5.7 million people in the US, is caused by a lack of oxygenated blood flow through the coronary arteries to heart muscle cells [cardiomyocytes] causing cell death. This process is known as a myocardial infarction [MI] or heart attack.

Cardiomyocytes are responsible for the synchronized contraction and blood pumping action of the heart. Importantly, the number of cardiomyocytes in the heart is a relatively fixed number, as these cells are unable to divide [see note at the end of this article]. If a patient suffers an MI in which blood flow is blocked to 30% of the heart resulting in death of 30% of the cardiomyocytes, the heart only has about 70% of the cardiomyocytes remaining that need to do the work the original 100% normally do. That is why cardiac function is often severely depressed after MI; some patients become tired after walking a short distance because their heart function is unable to meet the demands of the body. In addition, this puts a severe strain on the remaining cells – creating a vicious cycle of more cell death.

Current medications to treat patients with HF include b-adrenergic receptor blocker [beta blockers, or BB], angiotensin-II receptor blockers [ARBs], and diuretics. Patients taking these pharmacological modifiers have increased survival yet they are far from ideal. Many of these drugs were discovered and developed quite a few years ago and their mechanism of action is limited to cell surface receptor modulation [table 1]. Importantly, the incidence of HF is increasing in the US and the 5-year prognosis of patients diagnosed with HF is not improving.

Table 1.

Drug Class



Year Discovered

ACE Inhibitors Captopril, Lisinopril Enzyme inhibitor 1979
ARB Valsartan, Losartan Receptor antagonist 1977
Beta Blockers Metoprolol, Carvedilol Receptor antagonist 1958
Aldosterone Antagonists Spironolactone Receptor antagonist 1953
Vasodilators Minoxidil K+ Channel modulator 1956
Diruretics Furosemide Membrane transport proteins 18th Century

Over the past 10 years, significant progress has been made in understanding the molecular mechanisms of HF. As a result, new molecular targets and therapeutic strategies are in clinical development to treat patients suffering from HF. Several of these approaches, including gene therapy and stem cell therapy, are making significant progress in the preclinical and clinical space.

Small Molecule and Peptide Approaches

In addition to Cytokinetics’ aforementioned cardiac myosin activator, other companies are also developing small molecule and peptide approaches to treat HF. Several of these companies are large biopharmaceutical companies developing drugs that are line extensions or reformulations of FDA approved drugs. Herein, we have highlighted select companies with unique compounds or technology.

For example, shares of Palatin Technologies, Inc. (NYSEMKT:PTN) have doubled since the announcement of Amgen’s option for the Cytokinetics compound. Although quite dissimilar from omecamtiv mecarbil, Palatin’s PL-3994 is a synthetic molecule acting as an atrial natriuretic peptide mimetic for the treatment of HF. PL-3994 may have several advantages versus traditional peptides, such as Natrecor [Nesiritide], the recombinant DNA produced intact natriuretic hormone from Scios/Johnson & Johnson. These advantages include an extended half-life and reduced affinity for natriuretic peptide clearance receptors reducing enzymatic digestion. In addition, PL-3394 can be administered subcutaneously compared to IV delivery for other peptides or biologics. Preclinical data demonstrated the prevention of cardiac hypertrophy and other indicators of HF. Importantly, the clinical trials demonstrated safety in combination with other anti-hypertensive therapies. Together, PL-3994 may offer improved pharmacokinetic and pharmacodynamic properties for patients with significant cardiac decompensation.

Cardioxyl Pharmaceuticals, Inc. is a privately-held company focused on the discovery and development of nitroxyl therapeutics for the treatment of cardiovascular diseases. The company’s lead program, CXL-1020, is a novel, proprietary nitroxyl donor currently in Phase 1 development as a potential therapy for acute decompensated heart failure.

Another privately-held company, Cordex Pharmaceutical, Inc. is developing CDP-1050, which is expected to enter a Phase 2 clinical study in 2009. CDP-1050 is designed to correct nitric oxide and redox imbalance in the failing heart and improve cardiovascular function. The drug has a dual mechanism of action; it inhibits the production of tissue-damaging reactive oxygen radicals and restores nitric oxide to physiologic levels. The principal therapeutic target of the drug is the ryanodine receptor, a key calcium-ion channel in the heart that supplies the calcium necessary for the heart to contract.

RegeneRx Biopharmaceuticals, Inc. (RGN) is developing RGN-352, an injectable naturally occurring peptide in solution, for the treatment of cardiac tissue damage post MI. RGN-352 has demonstrated both myocardial salvage and angiogenic properties in at-risk myocardial tissue. More specifically, preclinical studies have identified Tβ4’s ability to promote cell migration, anti-apoptosis, anti-inflammation and myocardial stem cell differentiation in the heart.

Stem Cell Therapies

In the scientific and investment community there is much excitement over cardiac regeneration therapies through stem cells or progenitor cells. Stem cell therapy offers the promise of replacing many of the dead cardiomyocytes with functional cells. There is, however, no consensus on the best approach to achieve optimal results. As such, the field of cardiac regeneration is relatively new with many more questions than answers. However, numerous biotechnology companies, both public and private, are developing cardiac stem cell therapy approaches:

  • Bioheart, Inc. (OTCPK:BHRT) is developing MyoCell, a clinical stage cardiac stem cell therapy for patients who have suffered an MI. MyoCell uses a patient’s myoblasts that are directly injected into the cardiac ventricles. Bioheart has demonstrated that the myoblasts are able to differentiate and begin to contract. The company is set to begin a 330-patient, multicenter Phase II/III trial of MyoCell in North America and Europe.
  • Aastrom Biosciences, Inc. (ASTM) is developing Cardiac Repair Cells [CRCs] that are based on their patented Tissue Repair Technology, with the goal of repairing and regenerating damaged heart tissue in patients with dilated cardiomyopathy [DCM]. The company is currently recruiting patients for their phase 2 trial.
  • Geron Corporation (NASDAQ:GERN) has a stem cell therapy in preclinical development using human cardiomyocytes derived from hESCs [GRNCM1] through a process that can be scaled for clinical production. GRNCM1 cells have normal contractile function and respond appropriately to cardiac drugs. The company plans to continue preclinical development of GRNCM1 in 2009.
  • Aldagen, Inc., a privately-held company, has completed enrollment for the phase 1 study of its ALD-201 product candidate. ALD-201 is a population of stem cells collected and isolated from a patient’s bone marrow receiving the therapy. Aldagen isolates a population of cells expressing a conserved enzyme expressed by their target cells allowing for isolation of a heterogeneous population of cells needed for repair.
  • Angioblast Systems, Inc., also a privately-held company, recently announced positive interim results from their Phase 2 study of Revascor, an “off the shelf” adult stem cell product for HF. The interim data showed improved cardiac function with the lowest dose of Revascor along with an excellent safety profile.
  • Last, privately-held Amorcyte, Inc. is developing AMR–001, a bone marrow-derived, CD 34 positive selected stem cell. Amorcyte plans to begin enrollment of their phase 2 trial in 2009.

Gene and Recombinant Therapy

Gene therapy is another new approach being taken by biotechnology companies for the treatment of HF. Gene therapy is the introduction of DNA into the cell aimed at targeting a specific cellular pathway that may not be achievable through small molecules.

Celladon Corporation is a privately-held company developing MYDICAR, an Adeno Associated Virus [AAV] delivered enzyme replacement therapy for patients at end stage HF that are eligible for heart transplantation. MYDICAR therapy is designed to restore levels of SERCA2a, an enzyme known to play a key role in the progression of heart failure. In early stage human clinical trials, MYDICAR has been shown to be safe and improved cardiac function as well as exercise performance.

Cardiome Pharma Corp (NASDAQ:CRME) is developing GED-aPC, an engineered analog of recombinant human activated Protein C [aPC] with enhanced anti-inflammatory, anti-thrombotic and strong binding to endothelial protein C receptor properties. Cardiome intends to initially develop GED-aPC in cardiogenic shock, a life-threatening form of acute circulatory failure due to cardiac dysfunction, which is a leading cause of death for patients hospitalized following a heart attack.

Who Might Be Next?

Despite the promise and significant upside associated with cardiac regeneration through gene therapy or stem cell therapy, Amgen chose Cytokinetics’ relatively lower-risk small molecule as their investment for the future of HF. Other potential acquirers may do the same, as small molecules are advantageous for a variety of reasons, including:

  • Dosing and Delivery: Drug delivery with small molecules is much less of a concern, so these technologies clearly have an advantage over gene and stem cell approaches. Gene and stem cell technologies will most likely be administered only at specialized treatment centers while small molecules will have faster market penetration.
  • Clear Regulatory Path: The regulatory path is a major hurdle to cross for any new drug entering the market. Small molecules have an advantage because the FDA is much more familiar with small molecule approval. The FDA is less familiar with stem cell therapy and gene therapy products. In fact, gene therapy products go through an additional review by the Recombinant DNA Advisory Committee [RAC], adding to the complexity of FDA approval.
  • Safety: There are less safety concerns associated with small molecules compared to the potential long-term effects of progenitor cells and cardiac regeneration. Several groups are concerned with off target differentiation, but the only ways to truly know the risks are through clinical trials and new product monitoring. Although gene therapy has made significant strides since the death of Jesse Gelsinger in 1999, the potential risks associated with gene therapy are immune response, low transduction, and off target gene production.
  • Manufacturing: Small molecule and peptide manufacturing will also be an advantage, as these products can be produced efficiently and at a relatively low cost. While the manufacturing of AAV for Celladon should not be a major hurdle, a specialized GMP manufacturing facility will be needed. Like other biologics, the manufacturing process will be significantly more complex and costlier compared with small molecules. Some of the stem cell therapies will not have to manufacture their product, but isolation of the precursor cells will require a physician specialist.

The fact that Amgen chose a small molecule over cardiac regeneration through stem cell or gene therapy may underscore the uncertainty of these emerging technologies. Stem cell and gene therapies have more therapeutic potential by addressing the underlying pathophysiology of HF, but significant work may be required before investors or large biopharmaceutical partners enter the space. However, in view of the high profile acquisitions in the area of cardiovascular disease, many biopharmaceutical companies may be keeping a close eye on the progress of these new therapeutic approaches and will be poised to pounce as a winner emerges.

Note: There is much debate about endogenous progenitor cells within the heart. Some scientists say the number of cardiomyocytes is fixed while others say there is very slow regeneration. Regardless, the regeneration would never come close to being able to replace the massive cell death associated with MI. Some labs are looking to activate these endogenous progenitor cells, but this technology is still in academic research. For an excellent review on cardiac regeneration, please see “Curr Treat Options Cardiovasc Med. 2009 Aug;11(4):316-27”.

Disclosure: No positions

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