Bellerophon Therapeutics Inc (BLPH)

We are a clinical-stage biotherapeutics company focused on developing innovative products at the intersection of drugs and devices that address significant unmet medical needs in the treatment of cardiopulmonary diseases. We are currently developing three product candidates under our INOpulse platform, a proprietary pulsatile nitric oxide device system.  The first is for the treatment of pulmonary arterial hypertension (PAH) , which is currently in Phase 3 clinical testing.  The other two product candidates are for the treatment of pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF) which are both in Phase 2 development.

The INOpulse platform is an extension of the technology that is used in hospitals to deliver continuous-flow inhaled nitric oxide. Use of inhaled nitric oxide is approved by the U.S. Food and Drug Administration (FDA) and other regulatory authorities across the world to treat persistent pulmonary hypertension of the newborn. An investigational new drug application, or IND, for INOpulse for the treatment of patients with PAH, which is a form of pulmonary hypertension that is closely related to persistent pulmonary hypertension of the newborn was filed in 2010.  A second IND for INOpulse for the treatment of patients with pulmonary hypertension associated with chronic obstructive pulmonary disease, or PH-COPD was filed in 2012. Bellerophon has exclusive worldwide rights to the ongoing INOpulse programs and related intellectual property.

Jonathan Peacock // Chairman

Jonathan Peacock serves as the Chairman of our Board of Directors. Previously, Mr. Peacock served as both President and Chief Executive Officer as well as Chairman of our Board of Directors. Prior to joining us, Mr. Peacock served as the Chief Financial Officer of Amgen from August 2010 to January 2014. From 2005 to 2010, he served as Chief Financial and Administrative Officer of Novartis Pharmaceuticals AG, the Pharmaceutical and Biotechnology Division of Novartis AG. Mr. Peacock was also a partner at McKinsey and Co, the strategy consulting firm from 1998 to 2005 and a partner at Price Waterhouse from 1993 to 1998.

Mr. Peacock received an M.A. degree in economics from the University of St. Andrews.

Fabian Tenenbaum // Chief Executive Officer

Mr. Tenenbaum serves as our Chief Executive Officer. Previously, Mr. Tenenbaum served as our Chief Financial Officer and Chief Business Officer. Prior to joining Bellerophon, Mr. Tenenbaum served as Chief Financial Officer and Chief Business Officer of Anterios, Inc., a clinical-stage biopharmaceutical company, from 2014 to 2016. Prior to that, Mr. Tenenbaum served as Chief Executive Officer with Syneron Beauty from 2011 to 2014, and Chief Financial Officer and Executive Vice President of Syneron Medical from 2007 to 2011. Prior to Syneron Medical, Mr. Tenenbaum was Vice President Americas for Radiancy, Inc., from 2002 to 2006, and Director, Commercial Operations and Corporate Development at Sunlight Medical, Inc. from 1999 to 2002.

Mr. Tenenbaum holds a Bachelor in Medicine (B.Md.) from Ben Gurion University, Israel and an MBA from Columbia Business School.

Deborah A. Quinn, M.D. // Chief Medical Officer

Deborah A. Quinn, M.D. has served as our Vice President and Medical Lead for the INOpulse programs since January 2015 prior to being appointed Chief Medical Officer in September 2015. Prior to joining us, Dr. Quinn held several positions at Novartis Pharmaceuticals AG from December 2006 to January 2015, most recently as medical director for both pulmonary arterial hypertension and heart failure programs. Previously, Dr. Quinn worked at the Massachusetts General Hospital from 1998 to 2011 where she was an Instructor in Medicine from 1998 to 2006 and a Clinical Assistant Professor in Medicine at Harvard Medical School from 2006 to 2011.

Dr. Quinn received her postdoctoral training in Medicine and Pulmonary and Critical Care Fellowship at Massachusetts General Hospital. She received an M.D. from the University of Massachusetts Medical School.

Peter Fernandes // Chief Regulatory and Safety Officer

Peter Fernandes has been our Chief Regulatory and Safety Officer since May 2015. Prior to joining Bellerophon, Mr. Fernandes was Vice President of Global Regulatory Affairs at Ikaria Inc., from October 2012 to May 2015, and in this capacity also led Bellerophon’s regulatory group since its inception in February of 2014. Previously, he led Regulatory Affairs and Quality Assurance for OptiNose, Inc., was Vice President US Drug Regulatory Affairs Respiratory and US DRA Respiratory Franchise Head for Novartis Pharmaceuticals. He has also served as the Head of US Development Site and Vice President of Regulatory Affairs and Quality Assurance at Altana Pharma, a subsidiary of Nycomed Inc., and led the US Respiratory and GI Drug Regulatory Affairs group at Boehringer Ingelheim.

Peter has an M. Pharm. from the Grant Medical College and a B. Pharm. from the K.M. K College of Pharmacy, both at the University of Bombay in India.

Parag Shah, Ph.D. // Vice President, Project Management and Distribution

Parag Shah, Ph.D. has served as our Vice President, Project Management and Distribution since April 2016 with responsibilities for Project Management, Supply Distribution, Pre-Clinical and Business Development activities.  Prior to joining Bellerophon, Dr. Shah was Principal Scientist at Pfizer from 2004 through 2010 where he was responsible for leading multiple parenteral and liquid formulation development teams.  In addition, Dr. Shah was a member of multiple Limited Duration Teams including serving as Pfizer’s Team Lead for the Nanoparticle Network responsible for internal and external evaluation of nanoparticle technologies.  Dr. Shah joined Ikaria as Parenteral Development Lead in 2010 and assumed additional responsibilities in 2012 as Director, Pharmaceutical Science, covering both Pharmaceutical Development and Clinical Supply Management. 

Dr. Shah received his Bachelor’s degree from Carnegie Mellon and his Ph.D. in Chemical Engineering from The University of Texas at Austin.

Martin Dekker // Vice President, Engineering and Manufacturing

Martin Dekker has served as our Vice President, Engineering and Manufacturing since January 2015. Prior to joining us, Mr. Dekker held several positions at Spacelabs Healthcare, a company that develops and manufacturers medical devices, from November 1998 to January 2015, most recently as Director of Global Operations Engineering. During his time at Spacelabs Healthcare, Mr. Dekker led and co-designed new products, developed and launched transformative manufacturing technologies and championed cross-functional quality/engineering projects. He is a member of the Institute of Electrical and Electronic Engineers.

Mr. Dekker received a B.S. in electronics from Noordelijke Hogeschool Leeuwarden, the Netherlands.

Amy Edmonds // Vice President, Clinical Operations and Administration

Amy Edmonds has served as our Vice President of Clinical Operations and Administration since September 2015 with responsibilities for Clinical Operations, Contracts & Outsourcing, Human Resources and Information Technology. Ms. Edmonds has over twenty years of global Clinical Operations and Training experience. Prior to Bellerophon, Ms. Edmonds was responsible for Ikaria’s Clinical Operations and Contracts & Outsourcing departments and held several positions of increasing responsibility at Celgene from November 2002 through October 2012. During her time at Celgene, Ms. Edmonds served as Global Clinical Operations Lead for the Americas for multiple therapeutic programs, the Head of North America Monitoring, and the Head of Clinical Operations Training. Ms. Edmonds has also worked in Clinical Operations and Training for Pfizer, Knoll Pharmaceuticals and ICON Clinical Research.

Ms. Edmonds holds a Bachelor’s degree from the University of Richmond.

Pipeline

Our goal is to become a leader in developing and commercializing innovative products at the intersection of drugs and devices that address significant unmet medical needs in the treatment of cardiopulmonary diseases. The key elements of our strategy to achieve this goal include executing on our INOpulse programs which we are evaluating for the treatment of pulmonary arterial hypertension (PAH),  pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD), and pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF).

The active substance in our INOpulse product candidate is pharmaceutical-grade nitric oxide. Nitric oxide is a molecule naturally produced in the endothelial lining of blood vessels that plays a significant role in vasodilation, or opening of the arteries, including arteries in the lung. When given to a patient with pulmonary hypertension (PH) who has constricted blood vessels in his or her lungs, it is anticipated that inhaled nitric oxide may be absorbed by the smooth muscles and, through a series of reactions, may help relax these muscles, which causes the blood vessels in the affected area to dilate or open. This is expected to reduce blood pressure in the lungs and therefore reduce the strain on the right ventricle of the patient’s heart and allow blood circulation to become more normal. Since inhaled nitric oxide is quickly inactivated after contact with blood, the product should act locally with minimal potential for systemic effects—an important safety consideration.

Inhaled nitric oxide (iNO), administered to ventilated patients by a dedicated in-hospital device, is marketed in many countries worldwide. We are now testing whether nitric oxide works in conditions where patients also have some form of pulmonary hypertension, such as pulmonary arterial hypertension (PAH), PH associated with chronic obstructive pulmonary disease (PH-COPD) and PH associated with idiopathic pulmonary fibrosis (PH-IPF).

The INOpulse device is designed to be portable for use by ambulatory patients on a daily basis inside or outside their homes. The device is programmed to automatically adjust based on a patient’s breathing pattern to deliver a constant and appropriate dose of the inhaled nitric oxide over time, independent of the patient’s activity level, thus ensuring more consistent dosing in the alveoli of the lungs. In addition, we have developed a proprietary triple-lumen nasal cannula which enables more accurate delivery of the dose to the patient. The INOpulse device is also compatible with many long-term oxygen therapy systems that operate via a nasal cannula. Our newest generation INOpulse device has approximately the same dimensions as a paperback book and weighs approximately 2.5 pounds. It has a simple and intuitive user interface and a battery life of approximately 16 hours when recharged, which takes approximately four hours and can be done while the patient sleeps.

FOR PAH

Bellerophon Therapeutics is developing the INOpulse delivery system for the treatment of patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH).

Mechanism of Action

Nitric oxide (NO) is normally produced in the blood vessel endothelium linings, working on the smooth muscle of the blood vessels to dilate or open the arteries. When nitric oxide enters the smooth muscle cells, it directly activates a chemical called soluble guanylate cyclase (sGC) in these cells. sGC produces another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP then causes the smooth muscle cells to relax, which in turn causes the blood vessels (arteries) to widen or dilate.

Since blood vessels in the lungs of PAH patients are narrowed and because PAH patients sometimes have impaired release of naturally produced nitric oxide in their lungs, researchers have proposed the potential benefit of chronic administration of inhaled nitric oxide to PAH patients. Small studies published in medical literature support this potential, but larger definitive studies are needed.

Disease Overview

PAH is a rare, chronic, and currently incurable disease that causes the walls of the arteries of the lungs to tighten and stiffen. Estimates suggest that there are about 15,000 patients diagnosed with PAH in the United States and about 20,000 patients in Europe. In someone with PAH, the right side of the heart has to work harder to pump blood through narrowed arteries in the lungs, which can decrease blood flow through the body. Eventually, the extra stress causes the heart to enlarge and become less flexible, further compromising its ability to pump blood out of the heart, through the lungs, and into the rest of the body. Patients with PAH have symptoms ranging from dizziness and fainting to shortness of breath during exercise. This range of symptoms, combined with the rare nature of the condition, often makes diagnosis difficult, and many PAH patients are not diagnosed until the disease has progressed.

To learn more about this condition, visit the Pulmonary Hypertension Association.

Clinical Need

Although current therapies for PAH provide some benefit, there remains no cure, and some approved therapies can have significant systemic side effects, such as hypotension, hepatic dysfunction, and nausea. Despite the availability of approved medications, mortality remains a significant concern.

The INOpulse delivery system was designed specifically to continuously administer nitric oxide to spontaneously breathing ambulatory patients using a carefully controlled, fixed dose over time that is independent of changes in respiratory rate during exercise or sleep. The device delivers a pulsed dose of nitric oxide to ensure a constant dose over time in micrograms per kilogram of ideal body weight per hour (mcg/kg/IBW/hr). The INOpulse is configured to be highly portable and compatible with many available modes of oxygen delivery.

Clinical Trials

In October 2014, we completed a randomized, placebo-controlled, double-blind Phase 2 clinical trial of INOpulse for PAH. This was a Phase 2, placebo-controlled, double-blind, randomized, clinical study to determine safety, tolerability, and efficacy of pulsed iNO versus placebo as add-on therapy in symptomatic subjects with PAH.  The phase 2 data have shown the optimal benefit of INOpulse is in combination with long-term oxygen therapy (LTOT).  Based on the results of the Phase 2 trial, we have finalized our clinical development plans including phase 3 trial design in agreement with FDA and European Medicines Agency (EMA).  We initiated our Phase 3 clinical program for INOpulse for PAH in 2016.

Find out more about this trial at clinicaltrials.gov.

FOR PH-COPD

 

Bellerophon Therapeutics is developing the INOpulse delivery system for the treatment of patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD).

Mechanism of Action

Nitric oxide (NO) is normally produced in the blood vessel endothelium linings, working on the smooth muscle of the blood vessels to dilate or open the arteries. When nitric oxide enters the smooth muscle cells, it directly activates a chemical called soluble guanylate cyclase (sGC) in these cells. sGC produces another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP then causes the smooth muscle cells to relax, which in turn causes the blood vessels (arteries) to widen or dilate.

COPD patients with advanced disease often have low blood oxygen levels, a condition known as hypoxemia. When parts of the lungs are not well ventilated, as is often the case in COPD, a protective mechanism known as protective hypoxic vasoconstriction can occur. This condition, where the body narrows certain blood vessels in poorly ventilated parts of the lung to send blood to better functioning parts of the lung, is the body’s mechanism to increase the amount of oxygen transferred to the blood. However, when this happens, the narrow arteries can put extra pressure on the heart. In addition, COPD patients often have depressed production of the natural nitric oxide in the blood vessels of their lungs, which also causes them to narrow.

Researchers have suggested that inhaled nitric oxide could help open or dilate the blood vessels in the lungs of these patients. Further, they proposed that dosing as a small pulse early in the patient’s breath could reduce the potential for adverse effects.

Disease Overview

COPD is a chronic progressive disease caused by chronic inflammation and destruction of the airways and lung tissue. While COPD is primarily a respiratory disease, the chronic exposure to toxins in tobacco smoke and resulting lack of oxygen may cause changes in the pulmonary circulation, resulting in chronic pulmonary vasoconstriction and pulmonary hypertension. Pulmonary hypertension, or PH, is a common complication in patients with late-stage COPD. PH-COPD has also shown to be associated with poorer clinical outcomes in patients with this condition when compared to similar patients without PH. However, a causal link between higher pulmonary pressures and worsened health outcomes has not yet been proven.

To learn more about this condition, visit the COPD Foundation.

Clinical Need

There is a significant and common unmet medical need for patients with PH associated with COPD that may be overlooked in everyday clinical practice because of the lack of available approved therapy. Also, drugs that are currently used to reduce pulmonary hypertension in PAH patients have been shown to potentially cause other problems, such as worsening hypoxemia, when used on patients with PH-COPD. This may be because these drugs act across a wide portion of the lungs’ blood vessels and can reverse the body’s protective mechanism of hypoxic vasoconstriction.

The INOpulse delivery system was designed to deliver nitric oxide in a targeted fashion allowing it to act primarily on the well-functioning part of the lung. The theory behind this delivery is that because inhaled nitric oxide is very short-acting and is deactivated quickly when it contacts blood, delivering it to well-ventilated parts of the lung will allow it to open up the blood vessels where good gas exchange is possible, while not reversing the body’s protective mechanism in other parts of the lung.

This concept has shown benefit in an open-label randomized control study in a small number of subjects. We are now evaluating this in a larger clinical trial using a new device and dosing regimen and plan to conduct additional studies with the goal of getting this drug-device combination approved, by health regulatory agencies around the world, for use by patients with PH-COPD on long-term oxygen therapy.

Clinical Trials

A Phase 2, randomized, controlled, open-label, comparative study in 32 subjects with PH associated with COPD was conducted in Austria and sponsored by Messer Austria GmbH. Subjects were randomized to receive either oxygen alone (17 subjects) or oxygen with pulsed inhaled nitric oxide (15 subjects) for 3 months. Pulsed delivery of nitric oxide showed no treatment-limiting long-term effects on lung function, methemoglobin levels, or incidence of adverse events after 3 months of therapy. Importantly, there were reductions in pulmonary arterial pressures and improvements in cardiac output. We have obtained an exclusive license to this data and have incorporated the findings into our clinical development program.

We completed a Phase 2 acute dose ranging trial with the INOpulse DS device in July 2014. Given the nature of the condition, we required that all participants in the trial be on long-term oxygen therapy (LTOT).

Find out more about this trial at clinicaltrials.gov.

We have initiated a chronic use clinical trial in PH-COPD evaluating the effect on exercise capacity.

Reference

Vonbank K, Ziesche R, Higenbottam TW, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax. 2003;58(4):289-293.

FOR PH-IPF

Mechanism of Action

Nitric oxide is normally produced in the blood vessel endothelium linings, working on the smooth muscle of the blood vessels to dilate or open the arteries. When nitric oxide enters the smooth muscle cells, it directly activates a chemical called soluble guanylate cyclase (sGC) in these cells. sGC produces another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP then causes the smooth muscle cells to relax, which in turn causes the blood vessels (arteries) to widen or dilate.

IPF patients have low blood oxygen levels, a condition known as hypoxemia. When parts of the lungs are not well ventilated, as is often the case in PH-IPF, a protective mechanism known as protective hypoxic vasoconstriction can occur. This condition, where the body narrows certain blood vessels in poorly ventilated parts of the lung to send blood to better functioning parts of the lung, is the body’s mechanism to increase the amount of oxygen transferred to the blood. However, when this happens, the narrow arteries can put extra pressure on the heart. In addition, PH-IPF patients often have depressed production of the natural nitric oxide in the blood vessels of their lungs, which also causes them to narrow.

Research has suggested that inhaled nitric oxide may help open or dilate the blood vessels in the lungs of these patients. Dosing as a small pulse early in the patient’s breath may reduce the potential for adverse effects.

Disease Overview

IPF is a chronic progressive disease of destruction of the airways and lung tissue. This results in scarring, thickening of the lung tissue causing insufficient ability for the lungs to oxygenate blood to be delivered to the body, caused by imbalance in mediators and chronic inflammation. While IPF is primarily a respiratory disease, it can also affect the pulmonary blood circulation, resulting in chronic pulmonary vasoconstriction and pulmonary hypertension. Pulmonary hypertension (PH) is a common complication in patients with late-stage IPF. PH-IPF has also shown to be associated with poor clinical outcomes when compared to similar IPF patients without PH.

To learn more about this condition, visit the IPF Foundation

Clinical Need

There is a significant and common unmet medical need for patients with PH associated with IPF that may be overlooked in everyday clinical practice because of the lack of available approved therapy. Also, drugs that are currently used to reduce pulmonary hypertension in PAH patients have been shown to potentially cause other problems, such as worsening hypoxemia, when used on patients with PH-IPF. This may be because these drugs act across a wide portion of the lungs’ blood vessels and can reverse the body’s protective mechanism of hypoxic vasoconstriction. Patients have a life expectancy of only 3-5 years after diagnosis. There is no cure, and extremely few, or specific therapies to treat IPF.

The INOpulse delivery system was designed to deliver nitric oxide in a targeted fashion allowing it to act primarily on the well-functioning part of the lung. The theory behind this delivery is that because inhaled nitric oxide is very short-acting and is deactivated quickly when it contacts blood, delivering it to well-ventilated parts of the lung will allow it to open up the blood vessels where good gas exchange is possible, while not reversing the body’s protective mechanism in other parts of the lung.

Clinical Trials

We hypothesize inhaled nitric oxide reduces pulmonary vascular resistance without disturbing ventilation/perfusion of the lungs. Previous studies of inhaled nitric oxide in IPF patients have supported the hypothesis.

In a previous study by Yoshida et al., PH-IPF patients (10 subjects) were monitored with Right Heart Catheterization (PHC) for hemodynamic changes. Each patient was monitored for 10 minutes each on room air, room air with nitric oxide, oxygen alone, and nitric oxide with oxygen. The results showed a significant decrease in pulmonary pressure and a significant increase in oxygenation for the combination of nitric oxide and oxygen when compared to oxygen alone.

In another study by Blanco et al., PH-IPF patients (7 subjects) received inhaled nitric oxide both at rest and during exercise for 20 minutes. During both rest and exercise, hemodynamic measurements showed a significant decrease in pulmonary artery pressure on inhaled nitric oxide compared to air, with greater vasodilation during exercise than at rest.

We have initiated a clinical trial to evaluate both acute and chronic inhaled nitric oxide therapy in PH-IPF patients.

Find out more at clinicaltrials.gov.

INVESTORS