About Bellerophon Therapeutics

Bellerophon Therapeutics, Inc. operates as a clinical-stage therapeutics company. The company focuses on developing innovative products that address significant unmet medical needs in the treatment of cardiopulmonary diseases. Its focus is the continued development of its nitric oxide therapy for patients with or at risk of pulmonary hypertension, or PH, using its proprietary pulsatile nitric oxide delivery platform, INOpulse. In 2016, the company began developing INOpulse for the treatment of pulmonary hypertension associated with fibrotic interstitial lung disease (fILD), which includes PH associated with idiopathic pulmonary fibrosis (PH-IPF), as well as other pulmonary fibrosing diseases. During May 2017, the company announced the completion of its Phase 2 clinical trial using INOpulse therapy to treat PH-IPF. During August 2017, the company announced acceptance by the U.S. Food and Drug Administration (the FDA) of its Investigational New Drug (IND) application for its Phase 2b (iNO-PF) clinical trial using INOpulse therapy in a broad population of patients with pulmonary fibrosis, or PF, at both low and intermediate/high risk of PH. In January 2019, the company announced top-line results from cohort 1 of its iNO-PF trial. In April 2019, the company announced that it reached an agreement with the FDA on modifying the ongoing Phase 2b trial into a seamless Phase 2/3 trial, with cohort 3 serving as the pivotal study, as well as an agreement on the primary endpoint in cohort 3 of change in moderate to vigorous activity (MVPA) from baseline to month 4, measured by Actigraphy. Actigraphy (medical wearable continuous activity monitoring) has the potential to provide highly sensitive objective real-world physical activity data that the company expects to correlate with clinically meaningful patient functional abilities and health outcomes. In December 2019, the company announced top-line results from cohort 2 of the iNO-PF trial. In March 2020, the company announced that in consultation with the FDA, it had finalized some of the key elements of its planned pivotal Phase 3 study for fILD, including the use of MVPA as the primary endpoint for approval, the patient population of pulmonary fibrosis subjects at risk of PH, as well as the dose of iNO45. In December 2020, the company announced the first patient enrollment in this Phase 3 study called REBUILD. During January 2023, the company completed enrollment of the REBUILD study with a total of 145 patients enrolled. It expects to report pivotal top-line data results in mid-2023. In 2018, the company initiated an ancillary Phase 2 open-label intra-patient dose escalation study that utilizes right heart catheterization to assess the hemodynamic effect of INOpulse from a dose of iNO 30 to iNO 125 in PH-PF subjects. In February 2020, the company announced the completion of the study and that the top-line results demonstrated that INOpulse achieved clinically and statistically meaningful cardiopulmonary improvements in pulmonary vascular resistance and mean pulmonary arterial pressure. In 2018, the company also initiated development of INOpulse for the treatment of PH associated with Sarcoidosis (PH-Sarc). In December 2021, the company announced the completion of the acute dose escalation phase of the study and that the top-line results demonstrated that INOpulse provided clinically meaningful improvements in pulmonary vascular resistance. Supported by the results from this study, on June 21, 2022, the company submitted to the FDA an exploratory Phase 2 double-blinded placebo-controlled study to investigate the safety and efficacy of inhaled nitric oxide/INOpulse dosed chronically for six months in patients with PH-Sarc. Subsequently, on July 28, 2022, the company received an FDA letter indicating that the FDA completed its review of its study protocol, with a minor recommendation to include safety stopping rules. The company has agreed to incorporate this recommendation into its periodic safety reviews. The company is positioned to initiate this Phase 2 study and is assessing the next steps for the study. The company completed a randomized, placebo-controlled, double-blind, dose-confirmation Phase 2 clinical trial of INOpulse for pulmonary hypertension associated with chronic obstructive pulmonary disease, or PH-COPD, in July 2014. The results from this trial showed that iNO 30 was a potentially safe and effective dose for the treatment of PH-COPD. Based on the results of this trial, the company completed further Phase 2 testing to assess the targeted vasodilation provided by INOpulse in this patient population. The company presented the results of this trial in September 2015 at the European Respiratory Society International Congress 2015 in Amsterdam. The data showed that INOpulse improved vasodilation in patients with PH-COPD. On March 19, 2020, the FDA granted emergency expanded access (EA) to allow for the company's INOpulse system to immediately be used as supportive treatment for a patient with COVID-19 under the care and supervision of the patient's physician. In November 2020, the company announced that the independent Data Monitoring Committee (DMC) had completed its pre-specified interim analysis from the first 100 patients. Based on the finding of futility, the company placed the COViNOX study on a clinical hold. In May 2021, the company submitted notification of withdrawal of the COViNOX Investigational New Drug (IND) to the FDA. Development Program INOpulse The company's INOpulse program is an extension of the technology used in hospitals to deliver continuous-flow inhaled nitric oxide. Use of inhaled nitric oxide is approved by the FDA and certain other regulatory authorities to treat persistent PH of the newborn. Ikaria has marketed continuous-flow inhaled nitric oxide as INOmax for hospital use in this indication since FDA approval in 1999. In October 2013, Ikaria transferred to the company's exclusive worldwide, royalty-free rights to develop and commercialize pulsed nitric oxide in PAH, PH associated with chronic obstructive pulmonary disease, or PH-COPD, and PH associated with idiopathic pulmonary fibrosis, or PH-IPF. In July 2015, the company expanded the scope of its license to allow it to develop its INOpulse program for the treatment of chronic thromboembolic PH (CTEPH), PH-Sarc and PH associated with pulmonary edema from high altitude sickness with a royalty equal to 5% of net sales of any commercial products for these three additional indications. In November 2015, the company entered into an amendment to its exclusive cross-license, technology transfer and regulatory matters agreement with Ikaria that included a royalty equal to 3% of net sales of any commercial products for PAH. In April 2018, the company expanded the scope of its license from PH-IPF to PH in patients with Pulmonary Fibrosis (PH-PF), which includes idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, occupational and environmental lung disease. The company's INOpulse program is built on scientific and technical expertise developed for the therapeutic delivery of inhaled nitric oxide. In 2010 and 2012, respectively, Ikaria submitted INDs for INOpulse for the treatment of patients with PAH and PH-COPD. PAH is a form of PH that is closely related to persistent PH of the newborn. These INDs were included in the assets that were transferred to the company by Ikaria. The company has designed its INOpulse device, which is the means by which inhaled nitric oxide is delivered to the patient, to be portable, which enables use by ambulatory patients on a daily basis inside or outside their homes. The company's INOpulse device has a proprietary mechanism that delivers brief, targeted pulses of nitric oxide timed to occur at the beginning of a breath for delivery to the well-ventilated alveoli of the lungs, which minimizes the amount of drug required for treatment. The company estimates that this, and the higher concentration of nitric oxide it uses, reduces the volume of drug delivered to approximately 5% of the volume required for equivalent alveolar absorption using standard continuous flow delivery systems, and also reduces the amount of nitric oxide, as well as its by-product nitrogen dioxide, that is exhaled and released into the patient's environment. INOpulse is designed to automatically adjust nitric oxide delivery 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 of the nitric oxide to the alveoli of the lungs. In its previous Phase 2 INOpulse clinical trials, the company used the first generation INOpulse device, which it refers to as the INOpulse DS device. Beginning with its Phase 3 trial of INOpulse for PAH in 2016, the company began using its second generation device, which it refers to as the INOpulse device. The INOpulse device has approximately the same dimensions as a paperback book and weighs approximately 2.5 pounds. The INOpulse device 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. Based on the doses the company has evaluated in its clinical trials, it expects that most patients will use one or two cartridges a day. The INOpulse device incorporates the company's proprietary triple-lumen nasal cannula, safety systems and proprietary software algorithms. The triple-lumen nasal cannula enables more accurate dosing of nitric oxide and minimizes infiltration of oxygen, which can react with nitric oxide to form nitrogen dioxide. The company's triple-lumen nasal cannula consists of a thin, plastic tube that is divided into three channels from end-to-end, including at the prongs that are placed in the patient's nostrils, with one channel delivering inhaled nitric oxide, a second for breath detection and a third available for oxygen delivery. INOpulse is configured to be highly portable and compatible with long-term oxygen therapy, or LTOT, systems via nasal cannula delivery. INOpulse device has been well received by patients in the usability research the company has conducted. In addition to the baseline testing on the original INOpulse DS device, the company has conducted two rounds of testing with COPD and PAH patients to evaluate the user interface, loading mechanism, size, carrying bag and other features. In the usability research conducted, all eight patients who were experienced with the use of the INOpulse DS device responded positively to the modifications in the INOpulse device. The company conducted two studies to assess the environmental and the expiratory concentration of nitrogen dioxide associated with use of the INOpulse delivery system. Both studies found that the nitrogen dioxide levels were below the National Ambient Air Quality Standards. The company's technology is based in part on patents it has exclusively licensed from Ikaria for the treatment of PAH, PH-COPD, PH-PF, CTEPH, PH-Sarc and PH associated with pulmonary edema from high altitude sickness which, collectively, it refers to as the Bellerophon indications. The licensed patents from Ikaria include patents with respect to the pulsed delivery of nitric oxide to ensure a consistent dose over time, which expire as late as 2027 in the United States and as late as 2026 in certain other countries, as well as with respect to the special triple-lumen cannula that allows for safer and more accurate dosing of pulsed nitric oxide, which expires in 2033 in the United States and abroad. The company has licensed several other patent applications from Ikaria for certain of the innovations included in the INOpulse device, and certain of the resulting patents, if issued, would expire as late as 2030 in the United States. The company has expanded its patent portfolio by filing several Company-owned provisional and non-provisional patent applications relating to the use of nitric oxide that if pursued and issued would expire as late as 2043. During January 2016, the European Patent Office issued a Notice of Intention to Grant a European Patent that provides protection for the company's INOpulse program. The patent, entitled 'System of Administering a Pharmaceutical Gas to a Patient', covers the ability to provide a known amount of pharmaceutical gas to a patient regardless of the patient inspiration rate or volume and distinguishes the INOpulse delivery system from others on the market. This patent was granted by the European Patent Office on March 30, 2016, and was subsequently validated in 30 European countries. Also during January 2016, the company received European Conformity, or EC, Certification for its proprietary new, INOpulse drug-device delivery system. This EC Certification grants CE marking on the INOpulse product, which confirms INOpulse compliance with the essential requirements of the relevant European health, safety and environment protection legislation of the European Union, or the EU. This certification covers the design, development and manufacture of inhaled pulsatile nitric oxide drug delivery systems, including its triple-lumen cannula and application software. INOpulse for fILD The company is developing INOpulse for the treatment of patients with fibrotic interstitial lung disease (fILD) at a risk for pulmonary hypertension, which includes PH associated with idiopathic pulmonary fibrosis, as well as other pulmonary fibrosing diseases. INOpulse for PH-Sarcoidosis In 2018, the company also initiated development of INOpulse for the treatment of PH associated with Sarcoidosis (PH-Sarc). The study was a Phase 2 open-label dose escalation design that utilized right heart catheterization to assess the acute hemodynamic effect of INOpulse from a dose of iNO 30 to iNO 125 in PH-Sarc subjects. In December 2021, the company announced the completion of the acute dose escalation phase of the study and that the top-line results demonstrated that INOpulse provided clinically meaningful improvements in pulmonary vascular resistance. INOpulse for PH-COPD The company is also developing INOpulse for the treatment of PH-COPD. The data from an initial three-month, open-label chronic-use Phase 2 trial conducted by a third party, which the company in-licensed, showed that pulsed inhaled nitric oxide significantly reduced pulmonary arterial pressures in PH-COPD patients on LTOT and did so without causing hypoxemia, which is a significant concern for these patients. In order to confirm the dose with its proprietary INOpulse device, the company conducted a Phase 2 acute dose ranging randomized placebo-controlled trial in 159 patients with the INOpulse DS device, with doses ranging from iNO 3 to iNO 75. This trial, which the company completed in July 2014, identified a dose range that showed similar reduction in pulmonary arterial pressure versus baseline when compared to the initial acute effects of pulsed inhaled nitric oxide in the original chronic-use trial. In addition, in the company's confirmatory trial, none of the INOpulse doses tested had an adverse effect on hypoxemia relative to placebo. In September 2015, an oral presentation of late-breaking data from a clinical trial that the company sponsored was presented at the European Respiratory Society International Congress 2015 in Amsterdam. The data showed that INOpulse improved vasodilation in patients with PH-COPD. In July 2016, the results were published in the International Journal of COPD in an article titled 'Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension'. Building upon this and other subsequent work with acute testing, the company initiated additional Phase 2 testing for the use of the INOpulse device for PH-COPD patients to evaluate the potential benefit of chronic use on exercise capacity, and enrolled the first patient in October 2016. During September 2017, the company shared the results of its Phase 2a PH-COPD trial that was designed to evaluate the acute effects of iNO on vasodilation, as well as the chronic effect on hemodynamics and exercise tolerance. In May 2018, the company announced that the FDA concurred with the design of its planned Phase 2b trial of INOpulse for the treatment of PH-COPD. The study will assess the effect of INOpulse on various parameters, including exercise capacity, right ventricular function and oxygen saturation, as well as other composite endpoints. The company is evaluating alternatives for the funding and timing of this program. Strategy The key elements of the company's strategy are to advance the clinical development of INOpulse; leverage its historical core competencies to expand its pipeline; and build commercial infrastructure in select markets. Manufacturing INOpulse Drug Product In February 2014, the company and a subsidiary of Ikaria entered into a drug supply agreement which was subsequently amended in November 2015. Under this agreement, Ikaria has agreed to use commercially reasonable efforts to supply inhaled nitric oxide for the company in its clinical trials, and it has agreed to purchase its clinical supply of inhaled nitric oxide from Ikaria. The company has also granted Ikaria a right of first negotiation in the event that it desires to enter into a commercial supply agreement with a third party for supply of nitric oxide for inhalation. The company has a license from Ikaria to use this fill process technology to work with additional companies, as needed, to produce the final cartridge. For its clinical trials, Ikaria can supply and ship product from the Port Allen site and the cartridges have a shelf life of at least two years. The company is testing the finished product to potentially establish a shelf life of up to three years. INOpulse Drug Delivery Systems In February 2015, the company entered into an agreement with Flextronics Medical Sales and Marketing Ltd., a subsidiary of Flextronics International Ltd., or Flextronics, to manufacture and service the INOpulse device. In June 2018, the company entered into a similar agreement with Benchmark Electronics, Inc. to manufacture and service additional INOpulse devices. In February 2014, the company and a subsidiary of Ikaria entered into a drug supply agreement which was subsequently amended in November 2015. Under this agreement, Ikaria has agreed to use commercially reasonable efforts to supply inhaled nitric oxide for the company in its clinical trials, and the company has agreed to purchase its clinical supply of inhaled nitric oxide from Ikaria. The company has also granted Ikaria a right of first negotiation in the event that it desires to enter into a commercial supply agreement with a third party for supply of nitric oxide for inhalation. Patents and Proprietary Rights INOpulse As of December 31, 2022, the company held exclusive licenses from Ikaria to at least 100 patents and pending patent applications in both the United States and foreign countries, including Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, the Philippines, Russia, Singapore and South Africa. Certain of these issued patents and patent applications, if issued, will expire as late as 2033. These patent rights have been exclusively licensed for the treatment of patients with Bellerophon indications and cover methods of delivery and the drug delivery device, as well as important safety features and the ornamental design of the drug delivery device. A primary basis for patent exclusivity is based on pending and issued in-licensed patents directed to proprietary methods of administering pulsed inhaled nitric oxide, as well as a device for delivering the same. At least one patent has been issued in the United States, as well as Australia, Brazil, Canada, China, Europe, Hong Kong, Japan and Mexico. Patent applications are pending in Australia, Mexico and the United States. This patent family expires as late as 2027 in the United States and in 2026 in the other countries. Another important basis for patent exclusivity is based on an in-licensed portfolio of patents, directed to novel nasal cannula features that are necessary for the accurate, safe and efficacious administration of pulsed nitric oxide. The patent family consists of seven issued U.S. patents and issued patents in Australia, Brazil, China, Eurasia, Europe, Hong Kong, Israel, Japan, Korea, Mexico and South Africa, as well as pending applications in the United States as well as Australia, Canada, Europe, Israel, India, Japan, Korea, Mexico and South Africa. Each of these patents and patent applications, if issued, will expire in 2033 in the United States and abroad. Another in-licensed patent family relates to features of the drug delivery canister necessary for providing drug product for use with the company's proprietary pulsing drug delivery device. This patent family includes at least one issued patent in each of the United States, Australia, Brazil, Canada, China, Europe, Hong Kong, Indonesia, Israel, India, Japan, Korea, Mexico, the Philippines, Russia and Singapore, as well as pending patent applications in the United States and Mexico. These pending applications, if issued, as well as the non-U.S. issued patents will expire in 2029. Two issued U.S. patents will expire in 2030. Several other patent families directed to device and safety features are issued and pending. One U.S. issued patent directed to the valve configuration of the company's proprietary drug delivery device and the shape of the nitric oxide pulses will expire in 2039. Furthermore, design patents covering the ornamental designs of the intended commercial device and clinical device have been granted. The company has also filed several Company-owned patent applications relating to the use and administration of nitric oxide and devices for administering nitric oxide. These Company-owned patent families are pending as international PCT patent applications, U.S. applications and/or applications in foreign countries, including Argentina, Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, New Zealand, the Philippines, Singapore, South Africa and/or Taiwan, and any patents that issue in these families will expire in 2039, 2040, 2041 or 2043. The patent families relate to the use of inhaled nitric oxide for the improvement of right and/or left ventricular function, the use of inhaled nitric oxide for the treatment of PH-ILD, the use of inhaled nitric oxide and oxygen for the treatment of PH, and treating PH by maintaining dosing frequency and/or minimizing skipped breaths during pulsed administration of inhaled nitric oxide. Additional patent families relate to methods of administering pulsed nitric oxide, administration of nitric oxide for improvement of severe hypoxemia, administration of nitric oxide in combination with PDE-5 inhibitors, administration of nitric oxide to improve activity levels in patients having lung-related impairment, improvement in pulmonary arterial compliance with inhaled nitric oxide treatment, use of inhaled nitric oxide treatment of infection (including infection with SARS-CoV2) and treatment of COVID-19, use of inhaled nitric oxide for decreasing pulmonary arterial pressure and pulmonary vascular resistance and methods for pulsatile delivery of a gaseous drug. In addition, the U.S. Food and Drug Administration (the FDA) has granted orphan drug designation to the company's nitric oxide program for the treatment of PAH and idiopathic pulmonary fibrosis (IPF), which could result in marketing exclusivity of seven years in the United States should this be the first NDA approved for inhaled nitric oxide in this indication. The active ingredient, nitric oxide, was previously approved by the FDA as a drug in a separate clinical application. Research and Development Expenses For the year ended December 31, 2022, the company's total research and development expenses were $16.4 million. Government Regulation The company's product candidates must be approved by the FDA before they may be legally marketed in the United States. History The company was founded in 2009. It was incorporated under the laws of the state of Delaware in 2013. The company was formerly known as Ikaria Development LLC and changed its name to Bellerophon Therapeutics LLC in 2014. In 2015, it converted from a Delaware limited liability company into a Delaware corporation and changed its name to Bellerophon Therapeutics, Inc.