- Chronic PB1046 treatment shown to ameliorate Duchenne muscular dystrophy myopathies, slow cardiac deterioration in mice
- Compound protected skeletal muscle, decreased fibrosis
- Data to be presented in emerging science poster session at the American Academy of Neurology Annual Meeting
Malvern, PA, April 22, 2015 – PhaseBio Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company and leader in the field of biopolymer-based drugs focused on developing treatments for metabolic and specialty cardiopulmonary disorders, announced that positive pre-clinical data on its compound PB1046 in Duchenne muscular dystrophy (DMD) models will be presented today in the emerging science poster session at the 67th American Academy of Neurology (AAN) Annual Meeting being held at the Walter E. Washington Convention Center in Washington, DC. The poster “Chronic treatment with PB1046, a stable and long-acting vasoactive intestinal peptide receptor agonist, improves cardiac and skeletal muscle function in mouse models of Duchenne Muscular Dystrophy” is based on a study conducted by QTest Labs (Columbus, OH) in collaboration with Nationwide Children’s Hospital and Ohio State College of Veterinary Medicine.
In MDX (dystrophin deficient) mice, a pre-clinical model extensively used to evaluate potential therapies for DMD, chronic treatment with PB1046 was shown to ameliorate DMD myopathies, slow cardiac deterioration and protect skeletal muscle by reducing fibrosis.
“Patients with DMD are living longer primarily due to improvements in pulmonary support and as a result these patients are ultimately dying of heart failure. Current heart failure therapies have not been shown to normalize cardiac function in these patients. These data generated with chronic administration of PB1046 show the drug may be effective at slowing cardiac deterioration and protecting against contraction-induced damage, which could provide a valuable new therapeutic avenue for DMD and Becker muscular dystrophy,” said Pradeep Mammen, M.D., FACC, FAHA, Medical Director of the Neuromuscular Cardiomyopathy Clinic and Director of Translational Research for the Advanced Heart Failure Program at the University of Texas Southwestern Medical Center.
Summary of pre-clinical data supporting PB1046 for the prevention and treatment of cardiomyopathy secondary to DMD / Becker muscular dystrophy (BMD)
The study demonstrated that chronic administration of PB1046 slowed cardiac deterioration in MDX mice, providing valuable insight into a clinical development strategy. The fractional area shortening (an index of systolic function) was preserved over the duration of the study. In MDX mice, PB1046 tended to have shorter QRS intervals (preserved ventricular conduction) versus placebo-treated animals. Similar results were noted in DKO (double knockout) (dystrophin/utrophin deficient) mice, with PB1046 treatment appearing to blunt the QRS prolongation.
In vivo analysis demonstrated improved cardiac contractility (elevated maximal rate of pressure rise dp/dtmax – an index of systolic function) and relaxation (Tau constant of relaxation) with PB1046 treatment. During skeletal muscle evaluation, PB1046 protected against contraction-induced damage on isolated extensor digitorium longus (EDL) muscles in MDX mice. Moreover, PB1046 significantly decreased gastrocnemius collagen content (an indicator of fibrosis) in the MDX mice. Additionally, there was a favorable reduction in collagen content in MDX heart muscle.
“Results of this pre-clinical study support the continued advancement of PB1046 into clinical trials for cardiomyopathy in DMD and BMD patients,” said Jonathan Mow, Chief Executive Officer of PhaseBio. “Moreover, this novel approach might serve as a complementary therapy to other DMD compounds in clinical development.”
About cardiac and skeletal muscular dysfunction in Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy, affecting 1 in 3,500 live male births. This rare disease is caused by mutations in the dystrophin gene, resulting in the absence or defect of the dystrophin protein. Children with DMD suffer from progressive loss of muscle strength resulting in complete loss of ambulation by the age of 12. Respiratory and cardiac muscles are also severely affected by the disease causing most patients to die in early adulthood due to cardiac failure.
PB1046 is based on Vasoactive Intestinal Peptide (VIP), a naturally occurring neuropeptide that exerts its physiological effects through activation of G protein-coupled receptors – VPAC1 and VPAC2 that are widely distributed throughout the cardiovascular, pulmonary and immune systems. The extremely short in vivo half-life of VIP has precluded its therapeutic use. Utilizing Elastin-Like Polypeptide (ELP) technology, PhaseBio has overcome these limitations, demonstrating prolonged circulatory drug exposure in humans. PB1046 has been shown to be highly effective in pre-clinical studies of hypertension, pulmonary arterial hypertension and in multiple heart failure models, with positive cardiac inotropic (contractility) and lusitropic (relaxation) effects without an increase in myocardial oxygen demand. Furthermore, proof of concept was established on the safety, pharmacokinetics and hemodynamic activity measured directly by means of changes in blood pressure as a surrogate following single subcutaneous and intravenous administration of PB1046 in two clinical trials conducted in volunteers with essential hypertension.
PhaseBio Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing novel drugs to treat diabetes and cardiovascular dysfunction in patients suffering from rare diseases. The Company’s proprietary discovery platform technology uses recombinant ELP biopolymers to control the half-life, bioavailability and physical characteristics of molecules for ease of administration. The resulting compounds are tuned for a specific rate of absorption, thereby increasing efficacy and reducing side effects. The Company’s lead development candidates are PE0139, a novel basal insulin ELP-fusion with the potential for weekly dosing; and PB1046, a weekly VIP agonist for treatment of acute and chronic heart failure and Duchenne muscular dystrophy-associated cardiomyopathy. PhaseBio is privately owned, with headquarters and research laboratories in Malvern, PA.