Bellerophon Therapeutics, Inc., based in Warren, NJ, is developing innovative therapies at the intersection of drugs and devices for patients with severe cardiopulmonary and cardiac diseases.
Bellerophon’s lead product is the novel, patented and proprietary INOpulse®, a portable nitric oxide delivery system being developed for two lead indications -- pulmonary arterial hypertension (PAH), now entering Phase 3 trials, and pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (PH-COPD), in Phase 2. Currently, there are no FDA-approved nitric oxide-based therapies for the treatment of PAH or therapies to treat PH associated with COPD. The company is also planning to begin testing of INOpulse for PH associated with idiopathic pulmonary fibrosis (PH-IPF), among others.
Most of us are unaware of the critical role that nitric oxide plays in our daily lives and how important it is to people with any type of PH-related condition. This molecule is naturally produced in the endothelial lining of blood vessels and helps to open the blood vessels, including those in the lung, which are narrowed in people with PAH and PH-COPD.
Leveraging a Well-Understood Therapeutic Agent
The original technology behind INOpulse was developed by Bellerophon’s predecessor company, Ikaria, Inc. (now part of Mallinckrodt). Ikaria received FDA approval in 1999 to market its flagship product, INOMAX®, a continuous-flow inhaled nitric oxide delivery system used in hospitals for treatment of newborns with hypoxic respiratory failure associated with pulmonary hypertension. INOMAX has proven to be a vital therapy for these vulnerable patients and has been embraced by the medical community in the U.S. and abroad (where it has also received regulatory approval in several countries) for its ability to improve patient outcomes. According to Ikaria, more than 450,000 patients have been treated with INOMAX therapy to date.
Building off of this success, Ikaria began expanding the indications for the technology, initiating clinical programs in PAH and PH-COPD. In 2014, Ikaria transferred certain of its R&D programs to Bellerophon Therapeutics and then spun out Bellerophon as a private company. Bellerophon completed its IPO in February 2015.
Targeting Patients with Few Treatment Options
PH is a rare and debilitating lung disorder in which the arteries that carry blood from the heart to the lungs become dangerously narrowed. Blood pressure in the pulmonary arteries then rises far above normal levels, straining the right ventricle of the heart causing it to expand in size. Overworked and enlarged, the right ventricle gradually becomes weaker and loses its ability to pump enough blood to the lungs, which eventually leads to heart failure.
Bellerophon’s lead indication -- PAH -- is a rare, chronic disease in which the arterial walls of the lungs tighten and stiffen over time forcing the right side of the heart to work harder to pump blood through narrowed arteries in the lungs. There is no ‘cure’ other than lung transplantation, which comes with its own risks and is not an available option for every patient. Median survival after diagnosis with PAH is less than five years. Bellerophon currently estimates that approximately 20,000 patients have severe to very severe PAH and are treated with multiple therapies, including long-term oxygen therapy. According to a 2013 CVS Caremark Specialty Analytics report, the annual per patient cost for many existing treatments in the U.S. is approximately $100,000 - $150,000. Non-specific symptoms including dizziness, fainting and shortness of breath during exercise, and when combined with the rare nature of the condition, can affect diagnosis such that many patients are not identified until the disease has progressed.
The daily lives of many patients with PAH are spent just trying to catch one’s breath. Routine activities such as climbing stairs, walking a few steps or a few blocks, going to work or school, are often difficult or impossible. PAH occurs in both children and adults, but most often affects women between the ages of 30 and 60 according to the REVEAL registry.
While current therapies provide benefits, many also have significant side effects. Industry research and Bellerophon’s preliminary clinical data have shown that patients on long-term oxygen therapy may benefit materially from treatment with inhaled, pulsed nitric oxide, which relaxes the smooth muscles, reduces blood pressure in the lungs and reduces strain on the right ventricle of the heart -- giving weight to the potential value for INOpulse therapy to this patient population.
COPD, another chronic progressive disease, is caused by inflammation and destruction of the airways and lung tissue, and occurs chiefly among smokers. Chronic exposure to toxins in tobacco smoke and a resulting lack of oxygen can cause changes in pulmonary circulation, leading to development of PH, especially in patients with late-stage COPD. These patients, who tend to be older in age and chiefly male, have high hospitalization rates as well increased risk of death, with median life expectancy of four years.
There are currently no approved therapies for treating PH-COPD, and the only generally accepted treatments are oxygen therapy, pulmonary rehabilitation or a lung transplant. Certain drugs used to reduce PH can cause other conditions, most notably a worsening of low blood oxygen levels. This may be because certain of these drugs act across a wide portion of the lungs’ blood vessels and can reverse the body’s natural protective mechanism against areas of low oxygen in the lungs. In contrast, the INOpulse system has the potential to offer a safer alternative since it delivers nitric oxide in a targeted fashion.
Therapeutic Benefit + Convenience = Enhanced Quality of Life
In addition to its potential therapeutic benefits, the portability of INOpulse is what makes it most unique. Intended for daily use by ambulatory patients, INOpulse allows patients to go about their daily activities while receiving the benefits of the therapy. The device is programmed to adjust automatically based on individual breathing patterns, thereby delivering a constant and accurate pulsed dose of inhaled nitric oxide over time, regardless of activity level.
Bellerophon’s team has recently completed development of its second generation INOpulse device, the Mark2. The Mark2 is as small as a paperback book, weighs only about 2.5 pounds, has a simpler and more intuitive user interface and a battery life of approximately 16 hours when recharged, which can be done in around four hours while sleeping. Because these patients must ‘take’ their therapy (which can include an oxygen tank) with them wherever they go, the Mark2’s small size directly addresses patient needs, providing therapeutic relief as well as convenience. The Mark2, which can be carried in a small bag, will be utilized in all of Bellerophon’s upcoming trials, and if approved, for the commercial market.
Moving Ahead with Clinical Trials
After data from a Phase 2 trial in PAH showed a sustainability of benefit to patients on long-term oxygen therapy whose disease was progressing despite taking one or more existing PAH therapies, Bellerophon finalized the protocol with the FDA for the Phase 3 trial through a Special Protocol Assessment. Under the Special Protocol Assessment, the primary endpoint of the trial is a statistically significant improvement in the distance walked by patients in six minutes after 16 weeks for patients receiving inhaled nitric oxide therapy compared to those receiving placebo. This protocol for approval of the therapy has also been agreed to with the European Medicines Agency through their Scientific Advice Working Party process. The Phase 3 program will include a total of 450 patients in two confirmatory clinical trials and Bellerophon intends to enroll the first patient by the end of 2015.
In PH-COPD, Bellerophon completed acute, dose-confirmation Phase 2a testing of INOpulse for PH-COPD in July 2014. Phase 2 testing to demonstrate the potential benefit of reducing PH on improving exercise capacity in these patients is planned for 2016. In September 2015, an oral presentation of late-breaking data from a clinical trial sponsored by Bellerophon and presented at the European Respiratory Society International Congress 2015 in Amsterdam, showed that INOpulse improved vasodilation in patients with PH-COPD. Looking ahead, management also plans to begin clinical testing with patients suffering with PH-IPF.
In September 2015, Bellerophon made several key changes to its leadership team to align with its strategic focus. Notably, Dr. Deborah Quinn, former medical director of Novartis Pharmaceutical’s PAH and heart failure programs and Instructor in Medicine at Massachusetts General Hospital, was named Bellerophon’s Chief Medical Officer. Martin Dekker, now Head of Device Engineering and Supply, comes with 20 years of experience in the design and manufacture of electro mechanical medical devices at Spacelabs Healthcare. Peter Fernandes, Chief Regulatory and Safety Officer, has 25 years’ experience in working with the FDA and European Medicines Agency in respiratory medicine.
“Our objective in developing and commercializing INOpulse is to bring clinically meaningful improvements in quality of life to those suffering from these chronic, progressive and debilitating diseases, and through this to improve clinical outcomes for these patient populations. Guided by our experienced and expert team, we are progressing our INOpulse platform and intend to actively explore opportunities to acquire or invest in new activities that will broaden our portfolio and leverage the team's strong capabilities,” stated Jon Peacock, Chairman and Chief Executive Officer of Bellerophon Therapeutics.
For more information about Bellerophon Therapeutics, Inc., please visit: www.Bellerophon.com
The company paid consideration to SNN or its affiliates for this article.
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