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Pharmaceutical Manufacture: Peptide Applications for Cardiovascular Therapies
November 13, 2009 | By GARY HU, AMERICAN PEPTIDE COMPANY
Gary Hu, American Peptide Company, VP Sales & Marketing
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 very 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. (
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
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
“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.”
“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
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.”
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
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