Peptide Applications for Cardiovascular Therapies

Featured In: Industries | Cardiovascular | Health | Pharma | Peptide Services

Thursday, January 22, 2024

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By Gary Hu, Vice President, Sales & Marketing, American Peptide Company, Inc.

A recent report by market and technology research firm Frost & Sullivan projected that the global peptide therapeutics market will be valued at nearly $2 billion by 2010, with Europe contributing more than a third, or $605 million, in a rapid development to meet the increasing need for new therapeutic approaches with peptides as active pharmaceutical ingredients (APIs).

The peptide therapeutics market, according to Frost & Sullivan, is providing new commercial opportunities to life science industries. To cultivate these markets, biotechnology and pharmaceutical companies are actively pursuing the development of a variety of peptide-based technologies, peptide manufacturing technologies and drug delivery methods.

The specificity of peptides has tremendous clinical value and makes them attractive and lucrative therapeutics. Though previous development concentrated on oncology therapies, the current focus in the peptide market has broadened to include a wide range of treatments for such conditions as allergies, Parkinson’s, multiple sclerosis, and heart failure.

In fact, the Frost & Sullivan report indicates that more than 40 peptides are in the world market for clinical applications. More than 400 are in advanced preclinical phases worldwide.

The report also points out that entry of major pharmaceutical companies in the peptide market, including Roche and Merck, have been encouraging. Yet, promising developments also are occurring among biotech companies, like Nile Therapeutics Inc., San Francisco, Calif., and Capstone Therapeutics, formerly known as OrthoLogic Corp., Tempe, Ariz.

These two biotechnology firms are working with California-based American Peptide Co., a contract manufacturing organization (CMO) of peptides, to develop peptide-based therapies for cardiovascular ailments, including heart failure.

Nile’s CD-NP is a novel chimerical natriuretic peptide in clinical development for an initial indication of acute decompensated heart failure (ADHF), while Capstone’s thrombin peptide, Chrysalin, is a 23 amino acid peptide that in preclinical studies has shown that it can minimize cardiovascular tissue damage by initiating a series of anti-apoptotic events.

Heart failure, a growing public health problem affecting 5.3 million Americans, is a chronic condition in which the heart cannot effectively pump enough blood to the body’s other organs, either as a result of impaired contractility (systolic heart failure) or impaired relaxation and ventricular filling (diastolic heart failure). The most common cause of heart failure is left ventricular systolic dysfunction, in most cases as a result of end-stage coronary artery disease, either with a history of myocardial infarction (heart attack) or viable but chronically under-perfused myocardium.

Case History:
Nile’s CD-NP peptide

Designed by scientists at the Mayo Clinic’s cardio-renal research labs, CD-NP improves on current therapies for ADHF, including B-type natriuretic peptide or nesiritide, which has been associated with favorable pharmacologic effects, but also with increased risks of hypotension.

CD-NP was designed to preserve the favorable effects of current therapies, while preventing or attenuating the hypotensive response, and enhancing or preserving renal function. In development for ADHF, CD-NP, according to Nile, is poised to be a novel natriuretic peptide rationally designed to be favorably differentiated from small molecule therapies and other natriuretic peptides; a clinical/regulatory development path informed by precedent and published guidelines; a well recognized unmet medical need; and a commercial opportunity, which is “poorly served by current therapies.”

“The hypothesis of the peptide is that it’s designed to specifically to reduce pressure between the heart and the lungs and improve kidney function while having a minimal effect on systemic blood pressure,” says Daron Evans, CFO of Nile Therapeutics. “There is a tremendous unmet need in treating these patients and the current standard-of-care therapies were not even approved to treat this indication by the FDA.”

Nile, he says, is pursuing a targeted approval-enabling clinical development plan which will test the hypothesis of favorable hemodynamic and renal efficacy with the prevention or attenuation of hypotension, while enhancing or preserving renal function. Development timelines lead to an end-of-Phase-2 meeting with the FDA in the first half of 2010.

In addition to an initial indication for ADHF, CD-NP has potential utility in other indications, including preservation of cardiac function subsequent to acute myocardial infarction (AMI), and prevention of renal damage subsequent to cardiac surgery.

“If a patient comes to the hospital with shortness of breath, or dyspnea, signs of fluid volume overload and a history of heart failure, it is likely that there is an increase in the pressure between the heart and the lungs, causing fluid build-up in the lungs,” Evans says. “A doctor’s first tasks are to relieve the dyspnea and to reduce the amount of fluid in the body. CD-NP was designed to help reduce the cardiac pressure and increase kidney function while minimizing the risk of hypotension.”

Case History: Capstone’s- Chrysalin TP508 peptide

Chrysalin, or rusalatide acetate, is a 23-amino acid synthetic peptide representing a receptor-binding domain of human thrombin. Thrombin is a naturally occurring molecule in the body and is active in both blood-clotting and initiating cellular events for tissue repair.Drugs based on the Chrysalin peptide can be used to mimic the tissue repair aspect of thrombin activity without stimulating the events associated with blood clotting. Therefore, it has the potential to accelerate the natural cascade of healing events in a wide range of tissue injuries. Based on this ability, initial development efforts with Chrysalin were focused on speeding the healing process for bone fractures.

Studies to understand the mechanism of action of Chrysalin showed that upregulation of nitric oxide (NO) was important, and this finding suggested that the drug might be effective in cardiovascular conditions involving impaired NO production. Pre-clinical studies in hearts with chronic low blood flow demonstrated that Chrysalin improved blood flow, heart function and small artery function when compared to placebo. In studies with acute loss of blood flow, mimicking a sudden heart attack, the area of damaged muscle was profoundly reduced by Chrysalin treatment, even in animals with high blood cholesterol levels.

“Most current therapy for heart attack involves the use of clot busters, such as tissue plasminogen activator (TPA), that will dissolve the clot so blood can flow again through the heart,” says Roger S. Crowther, Sr. Director Pharmaceutical Development at Capstone. “The cells of the heart begin to die when the blood flow is cut off and this may continue even after blood flow has been restored. We have shown that Chrysalin can help prevent these cells from dying and in doing so limit the amount of tissue damage in the affected area of the heart.”

With a to-market target date of 2013, Crowther says that Capstone plans to develop Chrysalin into a therapy that may limit the damage to heart muscle caused by a heart attack, and this could increase the chance of surviving the initial attack as well as protecting cardiac function over time. If successful, this approach will represent a significant clinical advance in the treatment of this life-threatening condition.

“The peptide is a fragment of the human thrombin protein of the clotting cascade,” Crowther says. “Similar fragments are produced naturally as part of the wound healing process, so it’s something that the body is used to seeing, and testing has shown that the peptide has very low toxicity. This excellent safety profile will facilitate developing Chrysalin, and when used in conjunction with an existing clot buster we expect that Chrysalin will greatly improve the survivability of a heart attack.”

Conclusion

With more than 650,000 new cases diagnosed every year, the annual mortality for heart failure is 19 percent. Treatment generates annual costs of approximately $35 billion, of which approximately $3 billion is spent on drugs and $19 billion is spent in the acute hospital setting, according to the American Heart Association.

Patients frequently suffer acute episodes of ADHF, which require hospitalization. For Americans over 65 years of age, ADHF is the most frequent cause of hospital admission. In recent years, 2.4 million patients in the United States were hospitalized with a primary or secondary discharge code of ADHF and the average length of hospital stay is 4.3 days. This incidence of ADHF is almost double the number seen 25 years ago. Subsequent to a discharge for ADHF, the average time to re-admission is 3 months and mortality is high with 12 percent mortality at 30-days and 33 percent mortality at one year.

The use of peptides to treat ADHF represented one of the most significant advances in heart failure treatment in recent years. However, concerns regarding their effect on blood pressure and renal function have limited their use in clinical practice. Second generation peptides, like those in development by Nile and Capstone have been rationally designed to deliver optimal hemodynamic and renal effects and may fulfill the original promise of earlier peptide-based therapies.

About the Author

Gary Hu oversees all non-GMP and GMP business divisions for American Peptide Company. He spearheads the Total Peptide Management program, American Peptide's flagship initiative, designed to help the pharmaceutical and life sciences industries bring drugs to market faster. Hu has a B.S. in Business Administration and Aeronautical Engineering from San Jose State University, California.
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