Pipeline
At PhaseBio, we are committed to bringing innovation to the cardiovascular community, as exemplified by our pipeline of unique medicines.
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Despite a declining trend over several decades, mortality rates for cardiovascular disease have been creeping up in recent years. The demographics of the patient population have also changed – rates of obesity and diabetes continue to rise, and now more women, non-smokers and younger individuals are presenting with cardiovascular disease. This makes the need for innovation that much more pressing.
Our novel cardiovascular therapeutic candidates may help meet this growing need. These include bentracimab (PB2452), an agent for the reversal of ticagrelor’s antiplatelet activity in major bleeding or to enable urgent surgery; pemziviptadil (PB1046), a once-weekly VPAC2-selective agonist for pulmonary arterial hypertension (PAH) and PB6440, an oral selective aldosterone synthase inhibitor for treatment-resistant hypertension.
Bentracimab (PB2452)
Reversal of the Antiplatelet Activity of Ticagrelor
Pemziviptadil (PB1046)
Pulmonary Arterial Hypertension (PAH)
PB6440
Treatment-resistant Hypertension
GLP2-ELP
Short Bowel Syndrome
CNP-ELP
Achondroplasia
Early Programs
PROPRIETARY LONG ACTING INJECTABLE RECOMBINANT BIOPOLYMERS
(Elastin-like Polypeptides – ELPs)
BENTRACIMAB (PB2452)
A novel ticagrelor-reversal agent
Bentracimab (PB2452) is a novel recombinant human monoclonal antibody antigen-binding fragment, designed to reverse the antiplatelet activity of ticagrelor in the event of major bleeding or when urgent surgery is required. Ticagrelor is an antiplatelet therapy widely prescribed to reduce the rates of death, heart attack and stroke in patients with acute coronary syndrome (ACS), or who have previously experienced a heart attack. More recently, the FDA has approved a new indication for ticagrelor in patients with acute ischemic stroke or high-risk transient ischemic attack (TIA). The American College of Cardiology and American Heart Association guidelines recognize ticagrelor as the preferred antiplatelet therapy for ACS.
Ticagrelor binds to platelets to prevent them from forming blood clots that could restrict blood flow. As with other antiplatelet agents, patients on ticagrelor have an elevated risk of spontaneous bleeding. In addition, patients on ticagrelor who need urgent surgery cannot wait the recommended five days for the effects of ticagrelor to dissipate, meaning they are at increased risk of major bleeding during and after surgery. There are currently no other specific reversal agents approved or in clinical development for ticagrelor or any other antiplatelet drugs.
Bentracimab (PB2452) binds to ticagrelor with high affinity and specificity to reverse the antiplatelet activity of ticagrelor, as illustrated by data from the Phase 1 and Phase 2a clinical trials. We are currently conducting additional clinical trials to evaluate the safety and efficacy of bentracimab (PB2452).
For more information about our current clinical trials investigating bentracimab (PB2452), please visit our Clinical Trials page.
Pemziviptadil (PB1046)
A long-acting VIP analogue for pulmonary arterial hypertension
Pemziviptadil (PB1046) is a VPAC2 receptor-selective agonist we are investigating for treatment of pulmonary arterial hypertension (PAH). Based on our ELP platform technology, pemziviptadil (PB1046) is a novel, once-weekly subcutaneously-injected, sustained release analogue of the native human peptide vasoactive intestinal peptide (VIP) fused to our ELP biopolymer. VIP is a neurohormone that lowers blood pressure and has anti-inflammatory and anti-fibrotic activity, as well as having direct, positive effects on cardiac function. Native VIP exerts its function in the body by binding to two distinct receptors: VPAC1 is found in the gastrointestinal tract, while VPAC2 is found in the cardiopulmonary system, including the myocardial wall and pulmonary arteries.
Native VIP is rapidly degraded and, when injected into the body, is eliminated within minutes — severely limiting its therapeutic effect. We have used our ELP technology to extend the effective half-life of VIP in pemziviptadil (PB1046) to approximately 60 hours. In addition, we designed pemziviptadil (PB1046) to be active predominantly on VPAC2 rather than VPAC1 in order to preferentially affect the lung and cardiac tissue and reduce the potential for gastrointestinal side effects associated with VPAC1 activation.
PhaseBio is developing pemziviptadil (PB1046) for the treatment of PAH, a progressive and life-threatening orphan disease with no known cure that is caused by abnormal constriction and adverse remodeling of the pulmonary arteries and is characterized by high blood pressure in the pulmonary arteries. We have received an Orphan Drug Designation for pemziviptadil (PB1046) for the treatment of PAH from the Food and Drug Administration.
Listen to Harold Palevsky, MD, pulmonary critical care physician and professor of medicine at the University of Pennsylvania, provide more information on PAH and the current need that exists for patients today.
Potential applications of pemziviptadil (PB1046) in other indications
The biological activities associated with VIP have the potential to provide therapeutic benefit to patients with other diseases. We believe that pemziviptadil (PB1046) provides an opportunity to bring these VIP-based therapies forward in the following indications:
DMD-associated Cardiomyopathy
Cardiac dysfunction is a very common manifestation of DMD and a common cause of death for individuals with this condition. The ability of PB1046 to increase contractibility of cardiac muscles presents the possibility that it could provide therapeutic benefit to these patients. We observed that PB1046 slowed deterioration in cardiac function and preserved skeletal muscle function in a mouse model of DMD. In addition to direct effects on cardiac function, we believe decreased fibrosis also contributed to the positive effects of PB1046 on both cardiac and skeletal muscle in this model.
Cystic Fibrosis
VIP has been shown to stimulate the processing of cystic fibrosis transmembrane regulator (CFTR), the protein defective in patients with cystic fibrosis (CF). In mice lacking the gene for VIP, CFTR is not located at the cell surface, where it is required to function properly, but accumulates within the cell. These mice have lung abnormalities that resemble CF, and treatment with VIP peptide restored CFTR to the cell surface and corrected the lung tissue abnormalities. Treatment with PB1046 of human epithelial cells containing the most common CFTR mutation found in patients with CF, F508del, has been observed to increase CFTR activity, providing further support that PB1046 may have potential as a treatment for patients with CF.
For more information about our clinical trials investigating pemziviptadil (PB1046), please visit our Clinical Trials page.
PB6440
An oral selective aldosterone synthase inhibitor for treatment of resistant hypertension
PB6440 is a novel selective aldosterone synthase inhibitor being developed for treatment-resistant hypertension. Despite the broad range of currently available antihypertensive therapies, approximately 10 million (20%) of drug-treated hypertension patients in the United States have not achieved target blood-pressure lowering while on three or more antihypertensive medications. These patients with treatment-resistant hypertension are at a significantly greater risk for major adverse cardiovascular events, including heart attack, stroke and heart failure, as well as peripheral artery disease and kidney failure.
The mineralocorticoid aldosterone is a critical regulator of fluid and electrolyte balance in the body and, as such, can play an important role in the development of high blood pressure or hypertension. Elevated aldosterone levels are associated with resistant hypertension, congestive heart failure and chronic kidney disease. Agents that block the action of mineralocorticoids at the receptor level, such as spironolactone, have been shown to lower blood pressure, including in patients with resistant hypertension.
However, use of these agents is limited by adverse side effects. Inhibition of the production of aldosterone through inhibition of the enzyme responsible for its synthesis, aldosterone synthase (CYP11B2), is an alternative approach to treatment of hypertension. However, development of aldosterone synthase inhibitors is challenging because of a closely related enzyme steroid 11β-hydroxylase (CYP11B1), which many potential compounds also inhibit. PB6440 has been shown to be a highly potent and selective inhibitor of aldosterone synthase and demonstrated a dose-dependent aldosterone reduction without a significant increase in 11-deoxycorticosterone or deoxycortisol in both rodent and primate models. The oral bioavailability and pharmacokinetic profiles appear suitable for once-daily dosing in humans. To date, no evidence of toxicity has been observed in either in vitro toxicity studies or in preclinical models.
We plan to submit an Investigational New Drug Application (“IND�?) and initiate the first-in-human clinical trial in 2022.
Additional Discovery Programs
PhaseBio is leveraging our ELP biopolymer technology to evaluate additional preclinical and discovery-stage candidates. Our focus is on proteins and peptides that are scientifically or clinically validated, but where a suboptimal half-life, stability and delivery limit their potential therapeutic applications.
C-type natriuretic peptide
C-type natriuretic peptide (CNP) is a regulator of bone growth and can rescue defects in fibroblast growth factor 3 that cause achondroplasia resulting in dwarfism. Native CNP has a half-life of less than three minutes, limiting its use as a direct therapeutic. We are developing our CNP-ELP product candidate to deliver therapeutic levels of CNP with once weekly subcutaneous injections. In a mouse model, we observed a statistically significant effect on linear growth when our CNP-ELP product candidate was injected once every four days.
Glucagon-like peptide-2
Glucagon-like peptide-2 (GLP-2) stimulates growth of intestinal villi, increasing their ability to absorb nutrients. GLP-2 is a potential treatment for patients with short bowel syndrome, Crohn’s disease or mucositis in patients undergoing cancer treatment. Teduglutide, currently marketed under the brand name Gattex, is an FDA-approved therapy based on GLP-2 that requires daily injections. In animal models, our GLP-2-ELP product candidate provided sustained levels of GLP-2, resulting in greater efficacy than teduglutide with less frequent dosing.
Publications
Bentracimab (PB2452)/MEDI2452
Bhatt et al. 2021. Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery. New England Journal of Medicine Evidence.
Bhatt et al. 2021. Effect of Bentracimab on Platelet Inhibition and Hemostasis in Patients on Ticagrelor with Major Bleeding or Requiring Urgent Procedures. Poster presentation at the American Heart Association’s (AHA) Scientific Sessions 2021.
Kong et al. 2021. All-Cause and Bleeding Costs of Patients Initiating P2Y12 Inhibitors, FXa Inhibitors, and Dabigatran. Poster presentation at the International Society for Pharmacoeconomic and Outcomes Research (ISPOR) Virtual 2021 Conference.
Kong et al. 2021. Bleeding and Procedure Rates Among Patients Treated With P2Y12 Inhibitors Compared with Factor Xa Inhibitors. Poster Presentation at the American College of Cardiology (ACC) 2021 Virtual Conference.
Bhatt et al. 2019. Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers. New England Journal of Medicine.
Sandige et al. 2018. Quantification of unbound concentration of ticagrelor in plasma as a proof of mechanism biomarker of the reversal agent, MEDI2452. PLoS ONE.
Pehrsson et al. 2017. Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin. Journal of Thrombosis and Haemostasis.
Almquist et al. 2016 Unraveling the pharmacokinetic interaction of ticagrelor and MEDI2452 (ticagrelor antidote) by mathematical modeling. CPT Pharmacometrics & Systems Pharmacology.
Buchanan et al. 2015. Structural and functional characterization of a specific antidote for ticagrelor. Blood.
Erlinge 2015. The first specific antiplatelet antidote. Blood.
Pemziviptadil (PB1046)
Vasoactive Intestinal Peptide