Nitric oxide inhalation - INOpulse - Mallinckrodt
Alternative Names: Inhaled nitric oxide - Bellerophon; inhaled NO - Bellerophon; iNO- Bellerophon; Nitric oxide-INOpulse®Latest Information Update: 07 Aug 2023
At a glance
- Originator Ikaria Holdings
- Developer Bellerophon Therapeutics
- Class Anti-infectives; Anti-inflammatories; Antiacnes; Antiandrogens; Antibacterials; Antibronchitics; Antifibrotics; Antifungals; Antihypertensives; Antineoplastics; Antituberculars; Antivirals; Cardiovascular therapies; Diagnostic agents; Foot disorder therapies; Free radicals; Nitrogen oxides; Non-opioid analgesics; Skin disorder therapies; Small molecules; Vascular disorder therapies; Vasodilators
- Mechanism of Action Androgen receptor antagonists; Angiogenesis inducing agents; Cell death stimulants; Guanylate cyclase stimulants; Nitric oxide donors; Reactive oxygen species modulators
-
Orphan Drug Status
Yes - Pulmonary arterial hypertension; Idiopathic pulmonary fibrosis
Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.
- New Molecular Entity No
Highest Development Phases
- Phase III Pulmonary arterial hypertension; Pulmonary hypertension
- Phase II Chronic obstructive pulmonary disease; Idiopathic pulmonary fibrosis
- Discontinued COVID 2019 infections
Most Recent Events
- 30 Jun 2023 Bellerophon Therapeutics terminates a phase III REBUILD trial in Pulmonary hypertension in Canada, USA (Inhalation) as the trial did not meet its primary endpoint (NCT03267108)
- 05 Jun 2023 Efficacy and adverse events data from phase-III REBUILD trial in Pulmonary hypertension released by Bellerophon Therapeutics
- 09 Feb 2023 National Medical Products Administration approves IND application for nitric oxide inhalation for a phase III trial in fibrotic Interstitial lung disease
Development Overview
Introduction
Nitric oxide inhalation, delivered using its INOpulse device, is being developed by Mallinckrodt, 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). Clinical development for PAH, COPD, IPF, and pulmonary hypertension, is under progress in several countries.
Clinical development for the treatment of COVID-19 infections was ongoing in the US; however the company discontinued the development due to lack of efficacy and availability of multiple vaccines.
In March 2024, Bellerophon Therapeutics has winded down its business and is no longer active [1] [2] .
Bellerophon Therapeutics acquired exclusive worldwide licensing rights to develop and commercialise INOpulse programmes from Ikaria Holdings (now Mallinckrodt) in February 2014 as part of Ikaria's spin-out of some of its research and development programmes and subsidiaries. Prior to a spin-out, Ikaria conducted clinical investigation for use of nitric oxide inhalation delivered via pulsed delivery with the INOpulse delivery system (INOpulse DS) for the treatment of PH and PAH [see Adis Insight Drug profile 800009315].
In April 2014, Ikaria was acquired by Mallinckrodt [3] .
Company Agreements
In January 2023, Bellerophon Therapeutics entered into a license agreement for the development and commercializstion of INOpulse® with Baylor BioSciences in Greater China. Under the terms of the license agreement, Bellerophon will receive a license payment of $US6 million, payable within 90 days subject to certain closing conditions set forth in the agreement. Additionally, Bellerophon is entitled to royalties of 5% on net sales resulting from all of the licensed INOpulse indications within Greater China. Baylor BioSciences will receive exclusive rights to develop and commercialise INOpulse within Greater China for diseases associated with pulmonary hypertension, including the lead indication of fibrotic interstitial lung disease (fILD), as well as PH-Sarcoidosis and PH-COPD. [4]
In May 2018, Bellerophon announced the amendment of its license agreement with Ikaria to expand the scope from idiopathic pulmonary fibrosis (IPF) to a broader category of interstitial lung diseases, which includes IPF as well as other fibrotic lung diseases. In July 2015, Bellerophon Therapeutics expanded its existing license agreement with INO Therapeutics (a division of Mallinckrodt plc) to develop INOpulse® for the treatment of three additional cardiopulmonary diseases, including chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension associated with sarcoidosis and pulmonary hypertension associated with pulmonary oedema from high altitude sickness. As per the terms of the expanded license agreement, a 5% royalty on net sales for the three additional indications is included. Bellerophon Therapeutics acquired exclusive worldwide royalty-free rights to INOpulse programmes in PAH, PH-COPD and pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF) from Ikaria Holdings in February 2014 following Ikaria's decision to spin-out some of its research and development assets and subsidiaries. Additional details were not disclosed. [5] [6] [7]
In April 2015, Mallinckrodt plc completed acquisition of Ikaria Inc.
In March 2015, Mallinckrodt plc and Ikaria Inc entered into a definitive agreement under which a subsidiary of Mallinckrodt will acquire Ikaria Inc from a Madison Dearborn led investor group in a transaction valued at approximately $US2.3 billion. [8] [3]
In March 2015, Bellerophon Therapeutics entered into an agreement with Flextronics. Under the terms of which Flextronics will manufacture, repair and service the Mark2 devices to be used in Bellerophon's INOpulse clinical development programs [9] .
Key Development Milestones
In March 2024, Bellerophon Therapeutics has winded down its business and is no longer active [1] [2] .
COVID-2019 infections: In March
2021, Bellerophon Therapeutics discontinued the development of inhaled nitric oxide therapy, for the treatment of COVID-19 infections, due to lack of efficacy and availability of multiple vaccines [10] (Bellerophon Therapeutics' pipeline, March 2021).
In March 2021, Bellerophon Therapeutics discontinued the phase III COViNOX trial which was evaluating the safety and efficacy of pulsed, inhaled nitric oxide in hospitalised patients with COVID-2019 infections who require supplemental oxygen without assisted ventilation (PULSE-CVD19-001, NCT04421508). The company decided not to continue the trial die to lack of efficacy of pulsed, inhaled nitric oxide, as well as availability of multiple vaccines. earlier in November 2020, based on recommendation of the Data Monitoring Committee following completion of a pre-specified interim analysis from the first 100 randomised patients, the phase III COViNOX trial was put on clinical hold. A total of 10 respiratory failure of death events were observed in the interim analysis. The company intended to complete trial procedures for remaining patients(n=100), and evaluate the full data set including endpoints such as change in clinical status and duration of hospitalisation, to decide on the potential next steps for this programme. In July 2020, Bellerophon initiated and dosed the first patient in the trial. The patients received nitric oxide, 125 mcg/kg/hour 24 hours daily up to 14 days or until resolution or discharge. The randomised, double-blind, placebo-controlled trial was enrolling approximately 500 patients in the US. Earlier in May 2020, US FDA approved IND application to commence the phase III trial. In April 2020, Bellerophon Therapeutics submitted an IND application to the US FDA for the same. The company also reported that it has applied for federal funding, through BARDA (Biomedical Advanced Research and Development Authority) and NIH (National Institutes of Health), to support the trial. Data from the study are expected to support potential approval in this indication. Upon completion of the protocol defined monitoring period, the pre-specified efficacy and safety analysis of the 191 patients was reviewed by the DMC and was concluded that there were no safety concerns [11] [12] [13] [14] [15] [16] [17] [18] .
In March 2020, the US FDA granted emergency expanded access to allow the INOpulse system to immediately be used as supportive treatment for patient with COVID-19 infections under the care and supervision of the patient’s physician [11] . In June 2020, Bellerophon Therapeutics completed the emergency expanded access programme which was initiated in April 2020, and treated 180 patient with nitric oxide inhalation under emergency expanded access programme (NCT04358588; PULSE-EAP001). The US FDA granted nitric oxide inhalation an emergency expanded access allowing it to immediately be used for the treatment of COVID-19 patients. The patients who completed the treatment with demonstrated improved oxygenation and allowed them to avoid the need for mechanical ventilation. The recovery rate at day 14 was 73% and mortality rate was 6.3% among the patients. The inhaled nitric oxide therapy was safe and well tolerated [14] [15] [17] [19] [20] [21] .
In August 2020, Bellerophon Therapeutics withdrew its planned phase II NO-COVER trial prior to enrollment initiation due to IRB and FDA reviews deferred (20200449; NCT04398290). The randomised trial was designed to evaluate the efficacy and safety of nitric oxide inhalation in hospitalised patients with COVID-19 infection and require supplemental oxygen [22] .
Fibrotic interstitial lung disease
In February 2023, Bellerophon Therapeutics announced clearance of its Investigational New Drug (IND) application from the Center for Drug Evaluation of China’s National Medical Products Administration (NMPA) to conduct a phase III trial to support the registration of INOpulse® for the treatment of fibrotic interstitial lung disease (fILD) in China. The study will utilize Moderate to Vigorous Physical Activity (MVPA) as the primary endpoint [23] .
In September 2022, Bellerophon Therapeutics announced that the US FDA accepted the Company’s proposal to reduce the study size for its ongoing registrational REBUILD phase III trial [See below] of INOpulse® for the treatment of fibrotic Interstitial Lung Disease (fILD). The new study size of 140 patients does not impact the trial’s principal objective or endpoints and maintains power of >90% (p-value < 0.01) for the primary endpoint of Moderate to Vigorous Physical Activity (MVPA) based on the effect size observed in phase II. Enrollment is now expected to conclude in Q1 2023. As of November 2022, the independent Data Monitoring Committee (DMC) also supported reducing the target study size from 300 to 140 patients [24] [25] .
Pulmonary arterial hypertension (PAH)
In January 2017, the US FDA approved all the proposed modifications in the phase III clinical programme for nitric oxide inhalation. As per the newly modified programme, two phase III trials, ongoing one-year INOvation-1 study, and a second confirmatory randomised withdrawal study with approximately 40 patients who will be crossing over from the INOvation-1 study, will be sufficient to support a New Drug Application filing for nitric oxide inhalation. With the previous clinical trial programme, regulatory approval for nitric oxide inhalation was expected in 2022. But, the approved modifications to the programme will reduce the time to get regulatory approval, and with this the anticipated approval date is preponed to 2020 [26] .
In June 2016, Bellerophon Therapeutics announced enrolment of the first patient in the phase III confirmatory trial, INOvation-1 trial. The phase III program will include two confirmatory trials [INOvation-1 trial and a withdrawal study (see below)] with approximately 450 patients. The INOvation-1 trial is designed to evaluate the safety, tolerability, and efficacy of pulsed, inhaled nitric oxide versus placebo in symptomatic patients with pulmonary arterial hypertension, and uses an adaptive design (NCT02725372; PULSE-PAH-004). The company received a special protocol assessment from the FDA in September 2015. Acceptance for the protocol was granted by the EMA through their Scientific Advice Working Party (SAWP) in January 2015. In August 2018, Bellerophon reported that a pre-specified interim analysis conducted by a Data Monitoring Committee (DMC) prompted the DMC to recommend stoppage of the trial for futility, despite accrual of positive safety and efficacy results. There were no safety concerns and an improvement in pulmonary vascular resistance was also observed. However, the DMC deemed that the overall change in six minute walk distance, the primary endpoint of the trial, was insufficient to merit trial continuation. The interim analysis included 75 patients who completed the 16-week blinded treatment phase in the trial. The trial enrolled approximately 200 patients in the US. Efficacy data from the trial were released by the company in October 2018. The trial did not achieve the primary endpoint of six-minute walk distance. As of March 2019, more than 50% patients were enrolled [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [36] [37] [38] [39] [40] [41] [42] [43] .
In August 2018, Bellerephon Therapeutics, withdrew the phase III INOvation-RW trial prior to enrolment, in the US and Canada (PULSE-PAH007; NCT03602781). The withdrawal study was designed to enrol patients who have completed INOvation-1 trial and comprised of a four-month enrichment period and two-month randomised withdrawal, with the treatment of 75 mcg/kg IBW/hr inhaled nitric oxide. Patients showing 30 meter improvement in six minute walk distance in this enrichment period were to be enrolled in the withdrawal part of the trial and randomised to receive either placebo or nitric oxide inhalation [44] [26] [45] .
Bellerophon Therapeutics initiated a phase III long-term safety study of inhaled nitric oxide in patients with pulmonary arterial hypertension (PULSE-PAH-006; NCT02652429). The open-labelled study intends to enrol approximately 28 patients by invitation only, in the US and Canada. In March 2016, the company received a special protocol assessment from the FDA [46] [47] .
In July 2016, Bellerophon Therapeutics completed a two-part, randomised, placebo-controlled phase II trial of nitric oxide inhalation using INOpulse DS for the treatment of PAH. The trial was initiated in April 2012 to evaluate the safety and efficacy of inhaled nitric oxide as an add-on therapy in patients with PAH whose disease is progressing on other PAH medications (IK-7001-PAH-201; NCT01457781). The nitric oxide was administered via the company's INOpulse DS, which delivers the compound in a pulsatile manner. This double-blind trial completed enrolment of 80 patients in June 2014 in the US and Canada. The primary endpoint was the change in pulmonary vascular resistance at 16 weeks compared with baseline. Secondary endpoints include the change in mean pulmonary arterial pressure and cardiac index along with the change in six-minute walk distance. In September 2015, the company released the interim results from the part 2 of the phase II trials [36] [5] [48] . Final results from the study were released in February 2016 [49] .
In January 2012, the US FDA granted orphan drug designation for the use of inhaled nitric oxide with the INOpulse DS delivery system as a combination therapy for the treatment of PAH [50] .
Ikaria submitted an IND application to the FDA in November 2011 [50] .
Pulmonary hypertension associated with sarcoidosis
As of August 2022, Bellerophon Therapeutics received US FDA clearance to conduct the exploratory phase II trial. Prior to August 2022, Bellerophon designed and submitted to the US FDA a proposed exploratory phase II double-blinded placebo-controlled trial to investigate the safety and efficacy of nitric oxide inhalation dosed chronically for six months in patients with pulmonary fibrosis or sarcoidosis [51] .
Prior to May 2022, Bellerophon completed the phase II PULSE-PHPF-002 study that assessed the safety and efficacy of pulsed, inhaled nitric oxide in patients with pulmonary fibrosis or sarcoidosis (PULSE-PHPF-002, NCT03727451). Earlier, in January 2019 Bellerophon initiated the trial. In November 2021, Bellerophon Therapeutics concluded the enrolment of 16 patients in the US. In August 2019, the company initiated the dose escalation phase to assess the hemodynamic benefit of INOpulse via right heart catheterization in pulmonary hypertension associated with sarcoidosis. Topline results from the trial were released by the company in December 2020. In December 2021, updated data were released by the company [52] [53] [54] [55] [56] [57] .
Pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD) and idiopathic pulmonary fibrosis (PH-IPF)
In March 2019, Bellerophon in collaboration with Rabin medical center initiated a phase II study to evaluate the influence of inhaled NO on the saturation and exercise capacity of patients with COPD and idiopathic pulmonary fibrosis (0135-18-rmc; NCT03873298). The randomised study intends to enrol approximately 100 patients in Israel. The primary outcome of placebo-controlled study is saturation level during the test at 26 minutes [58] . In July 2020, interim efficacy results from the trial was released at the 116th International Conference of the American Thoracic Society (ATS-2020) [59] .
In May 2018, Bellorophon announced that following positive results from the phase II study in PH-COPD, the company, with its steering committee, finalized the design of a Phase IIb study in PH-COPD. An agreement with the US FDA was reached on the trial design, which will be a double-blind, placebo-controlled study, which will enrol approximately 90 patients. The primary endpoint is change in 6MWD, with several additional secondary endpoints including improvement in right ventricular function [6] [60] .
In August 2017, Bellerophon Pulse Technologies completed a phase II trial (n = 10), which evaluated the effect of pulsed, inhaled nitric oxide inhalation delivered using INOpulse device safely reduces PH in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (FLUI-2016-163; PULSE-COPD007; EudraCT2016-002389-29; NCT03135860). Inhaled nitric oxide was given at a dose of 30 µg/kg IBW (Ideal Body Weight)/hour for four weeks with a follow up visit two weeks after discontinuation of iNO. The primary endpoint were patients’ vasodilation in pulmonary arteries measured by high resolution CT scanning (HRCT), after four weeks of treatment, with a key secondary endpoint of 6MWD at four weeks. The open label trial enrolled ten patients in Belgium, and was initiated in July 2016. Results were released by the company in August and September 2017. In May 2018, updated efficacy results were presented at the 114th International Conference of the American Thoracic Society (ATS-2018) [61] [32] [62] [63] [64] [34] [41] [65] [66] .
In July 2014, Bellerophon Therapeutics completed the phase IIa INHALE 1 study that evaluated the pharmacodynamic effect of pulsed iNO in patients with World Health Organisation (WHO) group 3 PH-COPD on LTOT (IK-7002-COPD-201; NCT01728220). The randomised, double-blind trial was initiated in December 2012 and enrolled 159 patients in the US. Based on the results from this trial, Bellerophon started working with FLUIDDA and the work has further validated the mechanism of action of INOpulse. In July 2016, Bellerophon reported that INOpulse device safely reduced PH for COPD patients and increased blood volume in the vessels within the lung [64] [38] [50] [67] .
In June 2017, Bellerophon Therapeutics completed a phase I trial that assessed the effect of pulsed, inhaled nitric oxide (iNO) on functional pulmonary imaging parameters, using the investigational medical device INOpulse® DS-C, in patients with World Health Organization (WHO) group 3 pulmonary hypertension (PH) associated with COPD on Long Term Oxygen Therapy (LTOT) and patients with PH associated with idiopathic pumonary fibrosis on LTOT (IK-7002-COPD-006; NCT02267655; EudraCT2014-003423-21). Change from baseline in lobar blood volume at total lung capacity (TLC) was the defined primary endpoint of the trial. The randomised, open-label trial was initiated in November 2015 and enrolled eight patients in Belgium [68] .
In September 2015, Bellerophon Therapeutics presented clinical data from patients with pulmonary hypertension associated with COPD (NCT02267655), at the European Respiratory Society International Congress (ERS-2015). The data showed that patients who were administered with inhaled nitric oxide, showed an improved vasodilation, and resulted in increased blood volume in the blood vessels in the lungs, while also preserving oxygen saturation following treatment. An acute dose of INOpulse inhaled nitric oxide was given to the six patients, aged 65-79 years, with PH-COPD, on long term oxygen therapy, enrolled in the trial [69] .
Pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF)
In June 2023, Bellerophon Therapeutics terminated a phase III REBUILD trial due to futility as it did not meet its primary endpoint related to the change in moderate to vigorous physical activity (PULSE-PHPF-001; NCT03267108). The trial was initiated in December 2020 to evaluate the safety and efficacy of pulsed inhaled nitric oxide (iNO) in patients at risk for pulmonary hypertension associated with pulmonary fibrosis on long term oxygen therapy (part 1 and part 2) The randomised, placebo-controlled trial, enrolled 145 patients in the US and Canada [13] [70] .. In May 2023, Bellerophon Therapeutics announced that last patient completed blinded treatment in phase III REBUILD trial [71] In January 2023, Bellerophon Therapeutics completed the enrolment of patients in the trial [13] . In December 2020, first patient was enrolled in the trial [54] . In January 2018, Bellerophon Therapeutics announced that the first patient was randomised in the phase II/III iNO-PF/REBUILD trial which will evaluate the efficacy and safety of pulsed, inhaled nitric oxide in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) and idiopathic pulmonary fibrosis (PH-IPF) on long term oxygen therapy [72] . The primary endpoint of the study is the change in 6 Minute Walk Distance from baseline to week 8. The company also announced expansion of the iNO-PF study to assess higher doses of iNO and duration of treatment through the addition of two further cohorts. Cohort 1 contained 41 patients. Cohort 2 included approximately 20 patients randomised (2:1) to receive either iNO 45 or placebo. Cohort 3 will include approximately 20 patients randomised (2:1) to receive either iNO 75 or placebo. In addition to evaluating higher doses, cohorts 2 and 3 will increase the blinded treatment period from 8 weeks to 16 weeks. In addition to the further cohorts, the study is also being modified to allow dose escalation during the open-label period. In August 2017, Bellerophon Therapeutics announced that the US FDA had accepted the design of the phase IIb iNO-PF trial in pulmonary hypertension associated with Interstitial Lung Disease (ILD). The FDA also accepted an IND application to assess the effect of INOpulse on patients at both low and high risk for pulmonary hypertension associated with pulmonary fibrosis [28] [29] [73] [32] [74] . In January 2019, top-line data from the Cohort 1 of the trial was released by Bellerophon Therapeutics. Based on the top-line results from Cohort 1 in which inhaled nitric oxide showed statistically significant and clinically meaningful effect, Bellerophon Therapeutics conducted discussions with the US FDA to formalise a streamlined and efficient regulatory approval path for inhaled nitric oxide in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). In April 2019, the US FDA agreed to primary endpoint of change in moderate to vigorous physical activity from baseline to week 16, as measured by actigraphy. FDA has also agreed to modify the ongoing phase IIb trial into a phase II/III trial, with cohort 3 serving as the pivotal phase III trial (REBUILD). Cohort 3 initiation is expected in the first quarter of 2020 with approximately 300 patients [75] [76] [77] . As of May 2019, 40 patients were enrolled in Cohort 2. In May 2019, positive efficacy data from the phase II/III trial were presented at the 115th International Conference of the American Thoracic Society (ATS-2019) [78] . In August 2019, Bellerophon Therapeutics completed enrollment from the cohort 2 of its ongoing phase II/III iNO-PF trial. This cohort 2 included 44 patients randomised 2:1 to either iNO 45 (45 mcg/kg IBW/hr) or placebo. In October 2019, Bellerophon Therapeutics released additional data from the cohort 1 of the study. Additional data from a subgroup analysis of cohort 1 patients were released in November 2019 [79] [80] [56] [81] . In December 2019, Bellerophon Therapeutics released the safety and efficacy data of the cohort B of the trial In May 2020, updated efficacy and safety data from the trial were presented at the 1156h International Conference of the American Thoracic Society (ATS-2020) [82] [83] . In June 2023, company released efficacy and safety data from the trial [84] .
In March 2020, Bellerophon Therapeutics successfully completed End-of-Phase 2 Meetings with the US FDA regarding design of the phase III REBUILD trial of nitric oxide inhalation delivered using INOpulse® for the treatment of pulmonary hypertension associated with pulmonary fibrosis. In the meeting, the company agreed with the agency regarding use of moderate to vigorous physical activity (MVPA) as the primary endpoint of the phase III trial for approval. The company also finalised that the trial will be conducted at 45 mcg/kg IBW/hr nitric oxide inhalation in pulmonary fibrosis patients who are at risk of pulmonary hypertension as the patient population [85] .
In September 2019, the Us FDA granted Orphan Drug Designation to pulsed nitric oxide, delivered via Bellerophon’s patented INOpulse® device for the treatment of Idiopathic Pulmonary Fibrosis (IPF) [86] .
In May 2017, Bellerophon Therapeutics completed a phase II trial that met its primary endpoint of a statistically significant increase (15.3%) in average blood vessel volume correlated with the best ventilated areas of the lung. The trial evaluated the safety and efficacy of nitric oxide inhalation delivered using INOpulse, in four patients with PH-IPF. In June 2016, the company had reported enrolment of the first patient in the trial. The trial consisted of an exploratory acute haemodynamic phase followed by a four week chronic use phase to evaluate exercise capacity. The study was conducted in collaboration with University Hospital and University of Antwerp [33] [34] . Bellerophone released topline data for the study in May 2017 [87] [88] . The study supported iNO 30 as a potentially safe and effective dose [74] [89] .
Financing Information
In March 2023, Bellerophon Therapeutics announced that it has entered into a subscription agreement with a life sciences-focused institutional investor to sell, in a registered direct offering, 718,474 shares of common stock at a price of $US2.00 per share and 1,781,526 prefunded warrants at a price of $US1.99 per pre-funded warrant for total gross proceeds of approximately $US5 million, before deducting estimated offering expenses. The offering is expected to close on March 7, 2023, subject to the satisfaction of customary closing conditions. The company intends to use the proceeds of this $US5 million offering to complete its phase III REBUILD study and for working capital and general corporate purposes [90] .
In May 2020, Bellerophon Therapeutics announced an underwritten public offering and a registered direct offering of its common stocks, for total gross proceeds of approximately $US43.7 million, before deducting underwriting discounts, fees and offering expenses. The company intends to use the net proceeds from this offering for funding its ongoing clinical trials, working capital needs and other general corporate purposes [14] [91] .
In April 2020, Bellerophon Therapeutics closed its previously announced registered direct offering of 1,275,000 shares of its common stock at a purchase price of $US12.00 per share for total gross proceeds of $US15.3 million, before deducting placement agent fees and offering expenses. The company intends to use the net proceeds from this offering for working capital, general corporate purposes, and other research and development efforts [92] .
Patent Information
As of December 2022, Bellerophon Therapeutics has patents pending and issued 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 US, Australia, Brazil, Canada, China, Europe, Hong Kong, Japan and Mexico. Patent applications are pending in Australia, Mexico and the US. This patent family expires as late as 2027 in the US 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 we believe are necessary for the accurate, safe and efficacious administration of pulsed nitric oxide. The patent family consists of seven issued US 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 US 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 US and abroad. Another in-licensed patent family relates to features of the drug delivery canister necessary for providing drug product for use with our proprietary pulsing drug delivery device. This patent family includes at least one issued patent in each of the US, 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 US and Mexico. These pending applications, if issued, as well as the non-US 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 US issued patent directed to the valve configuration of our proprietary drug delivery device and the shape of the nitric oxide pulses will expire in 2039. Design patents covering the ornamental designs of the intended commercial device and clinical device have been granted [93]
As of April 2022, Bellerophon Therapeutics have 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 currently pending as international PCT patent applications, US 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 pulmonary hypertension-ILD, the use of inhaled nitric oxide and oxygen for the treatment of pulmonary hypertension, and treating pulmonary hypertension 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, and methods for pulsatile delivery of a gaseous drug [94] .
Bellerophon Therapeutics holds exclusive licenses from Ikaria to at least 100 patents and pending patent applications in the US, 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 patents cover methods of delivery and the drug delivery device, and the rights have been exclusively licensed for the treatment of patients with pulmonary arterial hypertension (PAH), pulmonary hypertention associated with chronic obstructive pulmonary disease, and pulmonary hypertension associated with idiopathic pulmonary fibrosis. 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 US, Australia, China, Europe, Hong Kong, Japan, and Mexico. Patent applications are pending in Australia, Brazil, China, Europe, Hong Kong, Mexico and the US. This patent family expires as late as 2027 in the US, and as late as 2026 in the other countries. Another basis for patent exclusivity is based on an in-licensed portfolio of patents, directed to novel nasal cannula features. The patent family consists of three issued US patents and pending applications in the US, Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, Israel, India, Japan, Korea, Mexico and South Africa. A patent application has been allowed in Europe where the PTO has issued a Notice of Intention to Grant. Each of these patents and patent applications, if issued, will expire in 2033 in the US and abroad. Another in-licensed patent family relates to features of the drug delivery canister necessary for providing drug product for use with our proprietary pulsing drug delivery device. This patent family includes one issued patent in the US, Japan, Mexico, Singapore, Israel, China, Indonesia, Korea, Russia, the Philippines, and three issued patents in Australia, as well as pending patent applications in the US, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Mexico, Russia and Singapore. The patent application in Europe has been allowed, following issuance of a Notice of Intention to Grant by the PTO. These pending applications, if issued, as well as the non-US issued patents will expire in 2029. The issued US patent will expire in 2030 (Bellerophon Therapeutics Form 10-K, March 2017) [95] .
Drug Properties & Chemical Synopsis
- Route of administration Inhalation
- Formulation Controlled release, unspecified
- Class Anti-infectives, Anti-inflammatories, Antiacnes, Antiandrogens, Antibacterials, Antibronchitics, Antifibrotics, Antifungals, Antihypertensives, Antineoplastics, Antituberculars, Antivirals, Cardiovascular therapies, Diagnostic agents, Foot disorder therapies, Free radicals, Nitrogen oxides, Non-opioid analgesics, Skin disorder therapies, Small molecules, Vascular disorder therapies, Vasodilators
- Target Androgen receptor; Cell death; Guanylate cyclase; Reactive oxygen species
- Mechanism of Action Androgen receptor antagonists; Angiogenesis inducing agents; Cell death stimulants; Guanylate cyclase stimulants; Nitric oxide donors; Reactive oxygen species modulators
-
WHO ATC code
C04A (Peripheral Vasodilators)
J05 (Antivirals for Systemic Use)
R03B (Other Drugs for Obstructive Airway Diseases, Inhalants)
R07A-X (Other respiratory system products)
R07A-X01 (Nitric oxide)
-
EPhMRA code
C4A (Cerebral and Peripheral Vasotherapeutics)
J5 (Antivirals for Systemic Use)
R3B (Xanthines)
R7X (All Other Respiratory System Products)
- Chemical name Nitric oxide
- Molecular formula N O
- SMILES [N]=O
-
Chemical Structure
- CAS Registry Number 10102-43-9
Biomarkers Sourced From Trials
| Indication | Biomarker Function | Biomarker Name | Number of Trials |
|---|---|---|---|
|
acidosis |
Outcome Measure |
hemoglobin subunit gamma 2 |
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aspergillosis |
Eligibility Criteria |
neurotrimin |
|
|
bacterial infections |
Arm Group Label |
Nitric Oxide (NO) |
|
|
bacterial infections |
Brief Title |
Nitric Oxide (NO) |
|
|
bacterial infections |
Arm Group Description |
Nitric Oxide (NO) |
|
|
bacterial infections |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
bacterial infections |
Official Title |
Nitric Oxide (NO) |
|
|
bronchiectasis |
Official Title |
Nitric Oxide (NO) |
|
|
bronchiolitis |
Arm Group Label |
Nitric Oxide (NO) |
|
|
bronchiolitis |
Brief Title |
Nitric Oxide (NO) |
|
|
bronchiolitis |
Eligibility Criteria |
phosphogluconate dehydrogenase 6-Phosphogluconic acid |
|
|
bronchiolitis |
Official Title |
Nitric Oxide (NO) |
|
|
bronchopulmonary dysplasia |
Arm Group Label |
Nitric Oxide (NO) |
|
|
bronchopulmonary dysplasia |
Brief Title |
Nitric Oxide (NO) |
|
|
bronchopulmonary dysplasia |
Eligibility Criteria |
Fibrinogen |
|
|
bronchopulmonary dysplasia |
Official Title |
Nitric Oxide (NO) |
|
|
Burkholderia infections |
Eligibility Criteria |
neurotrimin |
|
|
calcinosis |
Official Title |
Nitric Oxide (NO) |
|
|
chronic obstructive pulmonary disease |
Arm Group Description |
Nitric Oxide (NO) |
|
|
chronic obstructive pulmonary disease |
Arm Group Label |
Nitric Oxide (NO) COPD |
|
|
chronic obstructive pulmonary disease |
Brief Title |
Nitric Oxide (NO) COPD |
|
|
chronic obstructive pulmonary disease |
Official Title |
Nitric Oxide (NO) COPD |
|
|
COVID 2019 infections |
Brief Title |
Nitric Oxide (NO) |
|
|
COVID 2019 infections |
Eligibility Criteria |
neurotrimin |
|
|
COVID 2019 infections |
Official Title |
Nitric Oxide (NO) |
|
|
COVID-19 respiratory infection |
Arm Group Label |
Nitric Oxide (NO) |
|
|
COVID-19 respiratory infection |
Brief Title |
Nitric Oxide (NO) |
|
|
COVID-19 respiratory infection |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
COVID-19 respiratory infection |
Official Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Arm Group Label |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Brief Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Arm Group Description |
Nitric Oxide (NO) |
|
|
cystic fibrosis |
Eligibility Criteria |
hemoglobin subunit gamma 2 ATPase H+ transporting accessory protein 1 |
|
|
cystic fibrosis |
Official Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Arm Group Label |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Brief Title |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Arm Group Description |
Nitric Oxide (NO) |
|
|
cystic fibrosis-associated respiratory tract infections |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
cystic fibrosis-associated respiratory tract infections |
Official Title |
Nitric Oxide (NO) |
|
|
hypoxaemia |
Outcome Measure |
hemoglobin subunit gamma 2 |
|
|
hypoxic respiratory failure |
Arm Group Description |
serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen binding protein 1) |
|
|
hypoxic respiratory failure |
Outcome Measure |
Vascular endothelial growth factor A (VEGF) tumor protein, translationally-controlled 1 Malondialdehyde Endothelin 1 8-oxo-7-hydrodeoxyguanosine |
|
|
idiopathic pulmonary fibrosis |
Arm Group Label |
Nitric Oxide (NO) COPD |
|
|
idiopathic pulmonary fibrosis |
Brief Title |
Nitric Oxide (NO) COPD |
|
|
idiopathic pulmonary fibrosis |
Eligibility Criteria |
phenylalanine hydroxylase |
|
|
idiopathic pulmonary fibrosis |
Official Title |
Nitric Oxide (NO) COPD |
|
|
interstitial lung diseases |
Arm Group Label |
Nitric Oxide (NO) |
|
|
interstitial lung diseases |
Brief Title |
Nitric Oxide (NO) |
|
|
interstitial lung diseases |
Official Title |
Nitric Oxide (NO) |
|
|
leg ulcer |
Arm Group Label |
Nitric Oxide (NO) |
|
|
leg ulcer |
Brief Title |
Nitric Oxide (NO) |
|
|
leg ulcer |
Arm Group Description |
Nitric Oxide (NO) |
|
|
leg ulcer |
Official Title |
Nitric Oxide (NO) |
|
|
leg ulcer |
Brief Summary |
Nitric Oxide (NO) |
|
|
liver injury |
Brief Title |
Nitric Oxide (NO) |
|
|
liver injury |
Official Title |
Nitric Oxide (NO) |
|
|
liver injury |
Outcome Measure |
Alkaline phosphatase (ALPL) |
|
|
lung disorders |
Detailed Description |
MPO Interleukin-8 (IL-8) Interleukin-6 (IL-6) Interleukin-10 (IL-10) Endothelin 1 |
|
|
lung disorders |
Outcome Measure |
hemoglobin subunit gamma 2 |
|
|
methicillin-resistant Staphylococcus aureus infections |
Arm Group Description |
Nitric Oxide (NO) |
|
|
methicillin-resistant Staphylococcus aureus infections |
Arm Group Label |
Nitric Oxide (NO) |
|
|
methicillin-resistant Staphylococcus aureus infections |
Brief Summary |
Nitric Oxide (NO) |
|
|
Mycobacterium avium complex infections |
Eligibility Criteria |
neurotrimin |
|
|
myocardial infarction |
Outcome Measure |
phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha Cardiac Troponin T BNP |
|
|
nontuberculous mycobacterium infections |
Brief Title |
Nitric Oxide (NO) |
|
|
nontuberculous mycobacterium infections |
Eligibility Criteria |
neurotrimin |
|
|
nontuberculous mycobacterium infections |
Official Title |
Nitric Oxide (NO) |
|
|
oesophageal motility disorders |
Official Title |
Nitric Oxide (NO) |
|
|
pain |
Official Title |
Nitric Oxide (NO) |
|
|
platelet dysfunction |
Outcome Measure |
Prothrombin (PT) P-selectin hemoglobin subunit gamma 2 C-reactive protein (CRP) |
|
|
pneumonia |
Brief Title |
Nitric Oxide (NO) |
|
|
pneumonia |
Official Title |
Nitric Oxide (NO) |
|
|
postoperative complications |
Arm Group Description |
Nitric Oxide (NO) |
|
|
postoperative complications |
Brief Summary |
NGAL GFAP |
|
|
postoperative complications |
Outcome Measure |
NGAL GFAP |
|
|
pressure ulcer |
Arm Group Description |
Nitric Oxide (NO) |
|
|
pressure ulcer |
Arm Group Label |
Nitric Oxide (NO) |
|
|
pressure ulcer |
Brief Summary |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Arm Group Label |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Outcome Measure |
pyroglutamyl-peptidase I GPI BNP biglycan |
|
|
Pulmonary arterial hypertension |
Brief Title |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Arm Group Description |
Nitric Oxide (NO) |
|
|
Pulmonary arterial hypertension |
Eligibility Criteria |
phenylalanine hydroxylase Cardiac Troponin I |
|
|
Pulmonary arterial hypertension |
Official Title |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Arm Group Label |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Brief Title |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Arm Group Description |
Nitric Oxide (NO) |
|
|
pulmonary hypertension |
Detailed Description |
tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) |
|
|
pulmonary hypertension |
Eligibility Criteria |
tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) phenylalanine hydroxylase |
|
|
pulmonary hypertension |
Official Title |
Nitric Oxide (NO) |
|
|
Raynaud's disease |
Official Title |
Nitric Oxide (NO) |
|
|
reperfusion injury |
Brief Title |
Nitric Oxide (NO) |
|
|
reperfusion injury |
Official Title |
Nitric Oxide (NO) |
|
|
reperfusion injury |
Outcome Measure |
Alkaline phosphatase (ALPL) |
|
|
respiratory insufficiency |
Arm Group Label |
Nitric Oxide (NO) |
|
|
respiratory insufficiency |
Brief Title |
Nitric Oxide (NO) |
|
|
respiratory insufficiency |
Detailed Description |
MPO Interleukin-8 (IL-8) Interleukin-6 (IL-6) Interleukin-10 (IL-10) Endothelin 1 |
|
|
respiratory insufficiency |
Eligibility Criteria |
hemoglobin subunit gamma 2 |
|
|
respiratory insufficiency |
Official Title |
Nitric Oxide (NO) |
|
|
sclerodactyly |
Official Title |
Nitric Oxide (NO) |
|
|
severe acute respiratory syndrome |
Brief Title |
Nitric Oxide (NO) |
|
|
severe acute respiratory syndrome |
Official Title |
Nitric Oxide (NO) |
|
|
telangiectasis |
Official Title |
Nitric Oxide (NO) |
|
|
tinea pedis |
Arm Group Description |
Nitric Oxide (NO) |
|
|
tinea pedis |
Brief Title |
Nitric Oxide (NO) |
|
|
tinea pedis |
Eligibility Criteria |
T-cell surface antigen CD4 |
|
|
tinea pedis |
Official Title |
Nitric Oxide (NO) |
|
|
varicose ulcer |
Arm Group Description |
Nitric Oxide (NO) |
|
|
varicose ulcer |
Brief Title |
Nitric Oxide (NO) |
|
|
varicose ulcer |
Official Title |
Nitric Oxide (NO) |
Biomarker
| Drug Name | Biomarker Name | Biomarker Function |
|---|---|---|
| Nitric oxide inhalation - INOpulse - Mallinckrodt | (R)-lipoic acid | Arm Group Description, Arm Group Label, Brief Title, Official Title |
| 16S rRNA | Outcome Measure | |
| 2,3-Diphosphoglyceric acid | Detailed Description, Outcome Measure | |
| 3-Nitrotyrosine | Detailed Description | |
| 8-Isoprostaglandin F2a | Outcome Measure | |
| 8-isoprostane | Outcome Measure | |
| ABL2 | Outcome Measure | |
| Acetylcholine | Arm Group Description | |
| Acetylcysteine | Brief Title, Official Title | |
| Adenosine monophosphate | Official Title | |
| Adiponectin (ADIPOQ) | Outcome Measure | |
| ADMA | Eligibility Criteria, Outcome Measure | |
| aldehyde dehydrogenase 7 family, member A1 | Eligibility Criteria | |
| Aldosterone | Outcome Measure | |
| Alkaline phosphatase (ALPL) | Outcome Measure | |
| Allantoin | Detailed Description, Outcome Measure | |
| Allergic rhinitis | Arm Group Label, Brief Title, Official Title, Outcome Measure | |
| alpha-1 antitrypsin (SERPINA1) | Eligibility Criteria | |
| Alpha-Tocopherol | Arm Group Description | |
| AMH | Eligibility Criteria | |
| Amphiregulin | Detailed Description, Outcome Measure | |
| Angiotensin II | Outcome Measure | |
| Angiotensinogen (AGT | Outcome Measure | |
| Apelin | Arm Group Description, Arm Group Label, Brief Title, Official Title | |
| Apolipoprotein A1 (APOA1) | Outcome Measure | |
| Apolipoprotein B (AOPB) | Outcome Measure | |
| Arachidonic acid | Detailed Description, Outcome Measure | |
| arginine-glutamic acid dipeptide repeats | Outcome Measure | |
| Argininosuccinic acid | Outcome Measure | |
| Ascorbic acid | Arm Group Description, Official Title | |
| ASS1 | Brief Summary | |
| BDNF | Outcome Measure | |
| Beta-Alanine | Arm Group Description, Arm Group Label, Detailed Description, Outcome Measure | |
| biglycan | Detailed Description | |
| BNP | Detailed Description, Eligibility Criteria, Outcome Measure | |
| bone morphogenetic protein 15 | Detailed Description, Outcome Measure | |
| Bradykinin | Brief Summary | |
| C-peptide | Outcome Measure | |
| C-reactive protein (CRP) | Arm Group Description, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure | |
| CA 15-3 | Detailed Description | |
| CALCA | Detailed Description | |
| carboxypeptidase B1 | Detailed Description | |
| Cardiac Troponin I | Detailed Description, Eligibility Criteria, Outcome Measure | |
| Cardiac Troponin T | Outcome Measure | |
| CFTR | Brief Summary, Detailed Description | |
| CGA | Outcome Measure | |
| cholecystokinin | Outcome Measure | |
| chorionic gonadotropin beta subunit 5 | Outcome Measure | |
| Citric acid | Arm Group Description | |
| Citrulline | Arm Group Description, Arm Group Label, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure | |
| CKB | Outcome Measure | |
| CKM | Outcome Measure | |
| Cobalamin | Eligibility Criteria | |
| Coenzyme Q10 | Detailed Description, Outcome Measure | |
| COPD | Arm Group Description, Arm Group Label, Brief Title, Eligibility Criteria, Official Title | |
| COX1 | Detailed Description, Outcome Measure | |
| COX2 | Arm Group Description, Brief Summary, Detailed Description, Official Title, Outcome Measure | |
| Creatine | Detailed Description, Outcome Measure | |
| Creatinine | Detailed Description | |
| Cyanocobalamin | Eligibility Criteria | |
| Cyclic GMP | Outcome Measure | |
| Cystatin C | Outcome Measure | |
| D-dimer | Outcome Measure | |
| D-Ornithine | Outcome Measure | |
| Deacetyldiltiazem | Arm Group Description, Arm Group Label | |
| decorin | Detailed Description | |
| Dihydrobiopterin | Outcome Measure | |
| dynein, axonemal, assembly factor 3 | Brief Summary, Detailed Description, Eligibility Criteria | |
| dynein, axonemal, heavy chain 5 | Brief Summary, Detailed Description, Eligibility Criteria | |
| dynein, axonemal, intermediate chain 1 | Brief Summary, Detailed Description, Eligibility Criteria | |
| ECP | Outcome Measure | |
| Elastase auto-antibodies | Detailed Description | |
| Elastase, neutrophil | Detailed Description | |
| Endothelin 1 | Arm Group Description, Brief Title, Detailed Description, Official Title, Outcome Measure | |
| eNOS | Brief Summary, Brief Title, Detailed Description, Official Title, Outcome Measure | |
| EOS | Outcome Measure | |
| Eotaxin (CCL11) | Outcome Measure | |
| Estradiol-17beta 3-sulfate | Eligibility Criteria | |
| Estrogen receptor alpha (ER alpha) | Eligibility Criteria | |
| eukaryotic translation initiation factor 2 alpha kinase 4 | Arm Group Description, Brief Summary, Brief Title, Eligibility Criteria, Official Title, Outcome Measure | |
| FANCC | Outcome Measure | |
| Ferritin | Outcome Measure | |
| FEV | Eligibility Criteria | |
| Fibrinogen | Brief Summary, Eligibility Criteria, Outcome Measure | |
| Fluticasone | Arm Group Description | |
| Folic acid | Arm Group Description, Arm Group Label, Brief Title, Official Title | |
| FSH | Eligibility Criteria, Outcome Measure | |
| Gastrin (GAS) | Detailed Description | |
| GCG | Detailed Description, Outcome Measure | |
| GFAP | Brief Summary, Outcome Measure | |
| Ghrelin | Outcome Measure | |
| Glutathione | Detailed Description, Outcome Measure | |
| GPI | Detailed Description | |
| growth differentiation factor 9 | Outcome Measure | |
| Guanosine monophosphate | Outcome Measure | |
| Gut Microbiome | Brief Title | |
| Haptoglobin | Outcome Measure | |
| HCY | Brief Summary, Detailed Description | |
| hemoglobin subunit gamma 2 | Arm Group Description, Detailed Description, Eligibility Criteria, Outcome Measure | |
| Hemopexin | Outcome Measure | |
| HER2/ERBB2 | Eligibility Criteria | |
| histone deacetylase 9 | Brief Summary, Brief Title, Official Title, Outcome Measure | |
| Human Microbiome | Official Title | |
| Hydrocortisone | Outcome Measure | |
| hypertrichosis 2 (generalized, congenital) | Outcome Measure | |
| IGF1 | Outcome Measure | |
| IKAROS family zinc finger 4 | Outcome Measure | |
| immunoglobulin heavy constant epsilon | Brief Summary, Detailed Description, Eligibility Criteria, Outcome Measure | |
| iNOS | Arm Group Description, Brief Summary, Brief Title, Detailed Description, Official Title, Outcome Measure | |
| Insulin | Detailed Description, Outcome Measure | |
| Interferon Gamma (IFNg) | Outcome Measure | |
| Interleukin 1 alpha (IL-1α) | Detailed Description | |
| Interleukin 1 Beta (IL-1β) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-10 (IL-10) | Arm Group Description, Detailed Description, Outcome Measure | |
| Interleukin-12A (IL-12p35) | Outcome Measure | |
| Interleukin-12B (IL-12p40) | Outcome Measure | |
| Interleukin-13 (IL-13) | Arm Group Description, Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-17 (IL-17) | Arm Group Description, Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-18 (IL-18) | Outcome Measure | |
| Interleukin-2 (IL-2) | Detailed Description, Outcome Measure | |
| Interleukin-22 (IL-22) | Detailed Description | |
| Interleukin-4 (IL-4) | Arm Group Description, Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-5 (IL-5) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-6 (IL-6) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-8 (IL-8) | Brief Summary, Detailed Description, Outcome Measure | |
| Interleukin-9 (IL-9) | Detailed Description | |
| KIM-1 | Outcome Measure | |
| kininogen 1 | Brief Summary | |
| L-Aspartic acid | Eligibility Criteria | |
| L-Cysteine | Detailed Description, Outcome Measure | |
| L-FABP | Outcome Measure | |
| L-Tryptophan | Brief Title, Official Title | |
| Lactate dehydrogenase (LDH) | Outcome Measure | |
| Leptin | Outcome Measure | |
| Lipoxin A4 | Detailed Description | |
| Lp-PLA2 | Outcome Measure | |
| LPA | Outcome Measure | |
| Luteinizing hormone (LH) | Detailed Description, Eligibility Criteria | |
| lymphatic vessel endothelial hyaluronan receptor 1 | Detailed Description | |
| MAFD2 | Arm Group Description, Brief Title, Official Title | |
| Malondialdehyde | Brief Summary, Outcome Measure | |
| Mannitol | Arm Group Description, Arm Group Label | |
| mannose-binding lectin (protein C) 2, soluble | Outcome Measure | |
| Methylcobalamin | Arm Group Description | |
| Methyldopa | Arm Group Label | |
| mitochondrially encoded tRNA leucine 1 (UUA/G) | Eligibility Criteria | |
| MMP9 | Outcome Measure | |
| Monocyte chemoattractant protein-1 (MCP-1/CCL2) | Detailed Description | |
| MPO | Detailed Description, Outcome Measure | |
| mucin 2, oligomeric mucus/gel-forming | Detailed Description | |
| mucin 5AC, oligomeric mucus/gel-forming | Detailed Description | |
| mucin 5B, oligomeric mucus/gel-forming | Detailed Description | |
| myelin basic protein | Outcome Measure | |
| myoglobin | Outcome Measure | |
| Neuron-specific enolase (NSE) | Brief Summary, Detailed Description | |
| neurotrimin | Eligibility Criteria | |
| NFkB | Detailed Description, Outcome Measure | |
| NGAL | Brief Summary, Outcome Measure | |
| Nitric Oxide (NO) | Arm Group Description, Arm Group Label, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure | |
| Norepinephrine | Detailed Description | |
| Ornithine | Outcome Measure | |
| Osteocalcin (OC) | Outcome Measure | |
| Oxidized glutathione | Brief Summary | |
| PAI-1 | Brief Summary | |
| PGE2 | Detailed Description, Outcome Measure | |
| PGR | Eligibility Criteria | |
| phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha | Outcome Measure | |
| pregnancy specific beta-1-glycoprotein 5 | Brief Summary, Detailed Description, Eligibility Criteria | |
| progastricsin | Detailed Description | |
| Progesterone | Eligibility Criteria | |
| proprotein convertase subtilisin/kexin type 9 | Official Title | |
| Prostacyclin | Arm Group Description, Arm Group Label, Brief Title, Detailed Description, Official Title | |
| prostaglandin E receptor 1 | Brief Summary, Detailed Description | |
| prostaglandin-endoperoxide synthase 1 | Detailed Description, Outcome Measure | |
| protease, serine 33 | Outcome Measure | |
| proteoglycan 2, pro eosinophil major basic protein | Outcome Measure | |
| Prothrombin (PT) | Outcome Measure | |
| pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 alpha | Brief Summary, Detailed Description, Eligibility Criteria | |
| pyroglutamyl-peptidase I | Detailed Description | |
| S100B | Detailed Description, Outcome Measure | |
| SOD1 | Detailed Description, Outcome Measure | |
| SOD2-OT1 | Detailed Description, Outcome Measure | |
| solute carrier family 26 (anion exchanger), member 3 | Brief Summary | |
| Stearic acid | Arm Group Description | |
| Substance P | Outcome Measure | |
| sulfotransferase family 1E member 1 | Brief Summary | |
| superoxide dismutase 2, mitochondrial | Detailed Description, Outcome Measure | |
| surfactant protein B | Outcome Measure | |
| Symmetric dimethylarginine | Outcome Measure | |
| syndecan 4 | Outcome Measure | |
| tachykinin, precursor 1 | Arm Group Description, Outcome Measure | |
| Tetrahydrobiopterin | Outcome Measure | |
| Thromboxane A2 | Detailed Description | |
| Thromboxane B2 | Detailed Description | |
| thymic stromal lymphopoietin | Detailed Description | |
| Thyroid stimulating hormone beta (TSH) | Eligibility Criteria | |
| TIMP-2 | Detailed Description | |
| tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) | Detailed Description, Eligibility Criteria | |
| TLR2 | Detailed Description | |
| Toll-Like Receptor 4 (TLR4) | Detailed Description | |
| Transforming growth factor-beta (TGF-beta) | Detailed Description, Outcome Measure | |
| Trypsin | Detailed Description | |
| Tubulin beta class IVb | Arm Group Description, Official Title | |
| Tumor necrosis factor alpha (TNF-alpha) | Brief Summary, Brief Title, Detailed Description, Outcome Measure | |
| urocortin | Brief Summary | |
| urocortin 2 | Arm Group Description | |
| urocortin 3 | Arm Group Description | |
| Vascular endothelial growth factor A (VEGF) | Detailed Description, Official Title | |
| Vasopressin | Official Title, Outcome Measure | |
| VCAM-1 | Detailed Description, Outcome Measure |
Development Status
Summary Table
| Indication | Qualifier | Patient Segment | Phase | Countries | Route / Formulation | Developers | Event Date |
|---|---|---|---|---|---|---|---|
| COVID 2019 infections | under emergency expanded access | - | Discontinued (III) | USA | Inhalation / unspecified | Bellerophon Therapeutics | 11 Mar 2021 |
| Chronic obstructive pulmonary disease | - | In adults | Phase II | Israel | Inhalation / unspecified | Bellerophon Therapeutics | 04 Mar 2019 |
| Idiopathic pulmonary fibrosis | - | In adults | Phase II | Israel | Inhalation / unspecified | Bellerophon Therapeutics | 04 Mar 2019 |
| Pulmonary arterial hypertension | - | In adults, In children, In the elderly | Phase III | Canada, USA | Inhalation / Controlled release | Bellerophon Therapeutics | 01 Feb 2016 |
| Pulmonary arterial hypertension | - | In adults, In the elderly | Phase III | Australia, Austria, Belgium, Czech Republic, France, Germany, Israel, Italy, Netherlands, Portugal, Serbia, Spain, Ukraine, United Kingdom | Inhalation / Controlled release | Bellerophon Therapeutics | 01 Apr 2016 |
| Pulmonary hypertension | associated with pulmonary fibrosis | - | Phase III | Canada, USA | Inhalation / Controlled release | Bellerophon Therapeutics | 08 Nov 2021 |
| Pulmonary hypertension | in COPD and IPF patients | - | Phase II | Belgium | Inhalation / Controlled release | Bellerophon Therapeutics | 25 Jul 2016 |
Orphan Status
| Indication | Patient Segment | Country | Organisation | Event Date |
|---|---|---|---|---|
| Idiopathic pulmonary fibrosis | - | USA | Bellerophon Therapeutics | 16 Sep 2019 |
| Pulmonary arterial hypertension | - | USA | Bellerophon Therapeutics | 23 Jan 2012 |
Commercial Information
Involved Organisations
| Organisation | Involvement | Countries |
|---|---|---|
| Ikaria Holdings | Originator | USA |
| Mallinckrodt plc | Owner | Ireland |
| Baylor BioSciences | Sub-licensee | China, Hong Kong, Macau, Taiwan |
| University of Antwerp | Collaborator | Belgium |
Scientific Summary
Adverse Events
Pulmonary hypertension:
Phase-III:
In phase-III REBUILD trial, INOpulse was safe and well-tolerated, consistent with the overall safety profile demonstrated in phase-II and other INOpulse programs in PH-COPD and PH-Sarcoidosis. Treatment emergent adverse events were noticed in 84.0% patients with INOpulse compared to the placebo (74.3%). Similarly, serious treatment emergent adverse events was 20% vs 21.4% in INOpulse treatment group and placebo respectively.
Deaths were balanced in both group (INOpulse -4.0% and placebo- 4.3%) [84] . [70]
Updated results from cohort 2 of phase II/IIIb trial in patients at risk of pulmonary hypertension associated with interstitial lung disease (PH-ILD) and idiopathic pulmonary fibrosis (PH-IPF), showed that inhaled nitroc oxide (iNO45 mcg/kg ) with the lower number of serious adverse events in the iNO group versus placebo (10% vs 21%). No deaths were reported. Previous data from Cohort A showed no safety concerns. The results were reported post eight week treatment with pulsed inhaled nitric oxide (iNO) [77] [82] [83] [70] .
Phase II
Inhaled nitric oxide was reported to be well tolerated in long term analysis of patients with pulmonary arterial hypertension. None of the patients showed elevated methaemoglobin levels or pulmonary rebound. In the 75 mcg high-dose active treatment arm, nine patients had SAEs. The most common SAEs reported were syncope and bronchitis/tracheobronchitis, one of which was assessed as possibly related to trial therapy. Discontinuation of trial therapy due to adverse events occurred for two patients in the 75 mcg arm and one subject in the 25 mcg arm. Serious adverse events in two patients were possibly related to the study medication, but did not result in treatment discontinuation in the two-part phase II study, after 16 weeks of blinded therapy in part 1, 65 patients were randomised for the part 2 of the trial, to receive 25 or 75 mcg/kg per hour doses of INOpulse [11] [49] [48] .
Inhaled nitric oxide was well tolerated in a phase II study carried out in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. No safety related concerns were observed. The open-label study had enrolled ten participants [65] [66] .
According to data from three patients with pulmonary hypertension associated with pulmonary fibrosis in the phase II PULSE-PHPF-002 study, treatment with inhaled nitric oxide at all doses was well tolerated, with no changes in oxygen saturation. No treatment-emergent adverse events (TEAEs) or serious adverse events (TESAEs) occurred during the acute hemodynamic dose escalation phase of the study. There were no clinically relevant deterioration in pulmonary capillary wedge pressure or other hemodynamic parameters, even at the higher iNO doses [53] [96] [57] .
In an expanded assess programme, inhaled nitric oxide therapy was safe and well tolerated in patients with COVID-2019 infections. The data were reported from 180 patients [15] [21] .
Pharmacodynamics
INOpulse administration significantly improved six-minute walking distance (6MWD), haemodynamics and blood vessel volume in a phase II study. The results from the study demonstrated statistically significant increase (average 4.2%) in blood vessel volume on inhaled nitric oxide (iNO) compared to baseline (P=0.03) along with a statistically significant correlation in ventilation-vasodilation (P=0.01), indicating targeted delivery to the well-ventilated alveoli. The chronic results were noted to be statistically significant and clinically meaningful increase in 6MWD at both two weeks and four weeks (+50.7m; p=0.04), as compared to baseline. A statistically significant and clinically meaningful decrease of 19.9% in systolic pulmonary arterial pressure at four weeks (P=0.02), as compared to baseline was also observed. The open-label study had enrolled ten participants [65] [66] .
Antimicrobial Activity
Summary
Therapeutic Trials
Pulmonary hypertension:
Phase-III:
In phase-III REBUILD trial, INOpulse did not meet its primary endpoint related to the change in moderate to vigorous physical activity. iNO45 performed worse than placebo by 5.49 minutes per day (p=0.2646). The secondary endpoints demonstrated minimal difference between the two groups with none approaching statistical significance. Overall activity showed 3.51 count/min benefit in favor of iNO45 (p=0.8572). Six minute walk distance showed 0.19 meter benefit in favour of iNO45 (p=0.9866) [84] . [70]
The topline results from the phase II/III trial in cohort 2 demonstrated a statistically significant improvement in moderate to vigorous physical activity (MVPA) in patients with pulmonary hypertension associated with interstitial lung disease. The patients in cohort 2 treated with iNO45 (45 mcg/kg IBW/hr) showed a statistically significant improvement in walking, climbing stairs, yard work, and similar activities as compared to patients who received placebo. The improvement in the moderate to vigorous physical activity was also noted by actigraphy parameters. The moderate to vigorous physical activity improved by 14 minutes per day, representing a 20% improvement (p=0.02), following treatment over four months. There was a 7% improvement in the overall activity improved by 100 counts/min. The total score improved by 3 points on St. George Respiratory Questionnaire (SGRQ), whereas the SGRQ activity and impacts scores improved by 5 points and 6 points, respectively. University of California and the San Diego Shortness of Breath Questionnaire improved by 5 points. The MVPA and the SGRQ Activity domain analysis demonstrated a difference for MVPA of 4.8 minutes per day. Additional data from cohort 1 inhaled nitric oxide improved MVPA, overall activity and non-sedantarty activity of 46%, 62% and 39% of patients, respectively when compared with 15% of patients who received placebo in each category. Updated results of from cohort 1 (n=41), showed that following eight weeks of therapy, patients treated with nitric oxide inhalation at 30 mg demonstrated clinically and statistically significant benefits in MVPA (p=0.04) as well as other activity parameters, such as overall (p=0.05) activity and caloric expenditure.(p=0.05). Following treatment with inhaled nitric oxide (iNO) a clinically significant improvement in MVPA (15% increase in MVPA from baseline) was experienced by 23% of patients on iNO compared with none in placebo group (placebo corrected difference of 23%). A clinically significant decline (>15% decrease in MVPA from baseline) in MVPA was observed in 39% of patients on iNO compared with 71% of subjects on placebo (placebo corrected difference of 32%). Proportion of awake time spent in MVPA improved by 38% with a 16% increase in iNO patients vs. 22% decrease on placebo patients; p = 0.04). A 12% improvement in calorie expenditure was reported with 6% decrease on iNO vs. 18% decrease on placebo; p = 0.05). A continuous benefit post treatment was observed in patients inn open-label extension compared with patients who transitioned from placebo to active treatment experiencing a change from deterioration to improvement in both MVPA and overall activity. Among patients in placebo group, an average weekly decrease of 3 minutes per day of MVPA during blinded treatment, was reversed to an average weekly increase of 1 minute per day during open-label. Also, an average weekly decrease of 22 counts per minute in overall activity during blinded treatment, which reversed to an average weekly increase of 15 counts per minute during open-label. Patients in the iNO arm remained stable for during blinded treatment for both MVPA and overall activity both of which improved during open-label, with an average weekly increase of 1 minute per week in MVPA and 15 counts per minute in overall activity. Earlier in patients from Cohort A of the trial statistically significant and clinically meaningful improvements in overall activity with NT-ProBNP levels and oxygen saturation. There was significant improvement (34%, p = 0.04) in moderate to vigorous physical activity (MVPA) (Minutes of MVPA, such as walking, stairs, yardwork, etc.) with 8% increase on iNO versus 26% decrease on placebo. There was 12% improvement in overall activity (0% change on iNO vs. 12% decrease on placebo; p = 0.05), as measured by a wearable medical-grade activity monitor (actigraphy). NT-ProBNP (a peptide marker of right ventricular failure) improved by 27% (15% increase on iNO versus 42% increase on placebo). Oxygen saturation improved by 20% (9% improvement on iNO versus 11% deterioration on placebo). Data from a subgroup analysis of the trial revealed a placebo corrected benefits of 33% and 28% in MVPA respectively, for intermediate/high and low probability of pulmonary hypertension. A placebo corrected benefit of 40% in MVPA for subjects with baseline 6MWD =300 meters and 33 meters in 6MWD and 39 meter% in distance saturation product (6MWD × SpO2 Nadir) was observed. The trial is enrolling 80 patients [82] [79] [80] [78] [75] [77] [70] .
Updated results from the phase II PULSE-PHPF-002 trial showed that inhalation formulation of nitric oxide provided clinically meaningful and statistically significant improvements in pre-specified hemodynamic parameters, including a 21% reduction in pulmonary vascular resistance, with increased benefit (p<0.01) on dose escalation from iNO30 to iNO45, and a 12% reduction in mean pulmonary arterial pressure. All 8 patients demonstrated decreases in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) across the doses of INOpulse utilized in the study. The dose of iNO45 (45 mcg/kg IBW/hr) resulted in a median drop of 20% (-54% to +22%) in PVR, compared with a median baseline PVR of 329 dyne/cm.sec-5; a reduction of 20% or more in PVR is generally considered to be clinically meaningful. Increasing to the highest dose, iNO125 (125 mcg/kg IBW/hr), demonstrated further improvement in PVR, with a median drop of 29% (-43% to -5%), achieving statistical significance from baseline (p=0.02) and from the preceding lower dose of iNO75 (75 mcg/kg IBW/hr) (p=0.02). During the study, 7 out of 8 patients escalated to the highest dose, iNO125. Along with the improvements in PVR, mPAP decreased by a median of 6-10% across the doses of iNO30 to iNO125, compared with a median baseline mPAP of 37.2 mmHg. According to data from three patients with pulmonary hypertension associated with pulmonary fibrosis in a phase II study, treatment with inhaled nitric oxide reduced mean pulmonary artery pressure and pulmonary vascular resistance. In addition, improvement in cardiac index suggestive of a dose response was also reported [53] [54] [96] [57] .
Phase II:
In the phase II trial, inhaled nitric oxide (iNO) indicated distance walked during the test (6MWD) was 338.0 and 323.6 after iNO and placebo treatment, respectively (mean change 14.47, confidence interval (CI): 2.0 - 26.8, P= 0.02). The distance saturation product (DSP) was 278.4 and 263.2 after iNO and placebo treatment respectively (mean change 15.1, CI: -0.9 - 31.2, P = 0.06). There w as no difference in the desaturation (SpO2 < 90%) time (mean difference 7 seconds, P=0.5), oxygen saturation AUC (mean change -2.3, P=0.7) and Borg dyspnea score (mean change 0, P=0.49). The interim data from the randomised, placebo-controlled trial was reported from 13 patients [59] [58] .
Pulmonary arterial hypertension
Phase III: In the phase III INOvation-1 trial in patients with pulmonary arterial hypertension, decline in 6 minute walk distance (6MWD) (>15%) was twice as high in the placebo arm as compared to INOpulse, while the 6MWD improved 41 meters (mono PAH therapy) and 25 meters (excluding prostanoids) for inhaled nitric oxide. Pulmonary vascular resistance (PVR) improved by 186 dyne/sec/cm-5 in INO arm. Cardiac output (CO) improved by 0.7 L/min with INO. NT-ProBNP, a peptide biomarker for right ventricular failure, improved by 68 pmol/L with INO. The trial demonstrated a clinical benefit in haemodynamic and right ventricular function consistent with currently marketed PAH therapies. Patients not on prostanoids or multiple background therapies experienced an improvement in 6MWD. 6MWD increased by 23 meters for patients on mono-PAH background therapy and increased by 17 meters for patients without prostanoid background therapy. Clinically meaningful decline in 6MWD (>15%) was twice as high in the placebo arm as compared to INOpulse [28] [29] [43] .
Final results from the two-part phase II study demonstrated that treatment with iNOPulse 75 mcg/kg (iNO 75) with Long-Term Oxygen Therapy (LTOT) for at least 12 hours a day demonstrated an increase of 55.2 meters in 6 minute walk distance (6MWD) from baseline (n=7), compared with a decrease of 18 meters in patients receiving treatment for less than 12 hours per day (n=6), in patients with pulmonary arterial hypertension. Patients receiving iNO 25 mcg/kg with LTOT demonstrated a mean decrease of 43.7 meters in 6MWD (n=12). A mean improvement in the pulmonary vascular resistance (PVR) was seen in the 14 LTOT patients in the iNO 75 treatment group, who underwent right heart catheterisation. An overall improvement in WHO Functional Classification was seen in LTOT patients in the iNO 75 treatment group. An improvement in 6MWD and PVR was seen in the LTOT patients in the 25 iNO treatment group, who received therapy for 8-12 months. In the two-part phase II study, after 16 weeks of blinded therapy in part 1, 65 patients were randomised for the part 2 of the trial, to receive 25 or 75 mcg/kg per hour doses of INOpulse [49] [36] [48] .
A phase IIa study evaluating INOpulse nitric oxide inhalation (iNO) met its primary endpoint, showing an average of 15.3% increase in blood vessel volume (p < 0.001) during acute inhalation of iNO in four idiopathic pulmonary fibrosis patients with pulmonary hypertension (PH-IPF). Clinically important improvements were seen acutely and at 4 weeks in both haemodynamics and exercise capacity in all patients. An improvement in haemodynamics was observed in all patients with an average reduction of 14% in systolic pulmonary arterial pressure (sPAP), as compared with baseline. Dose titration indicated that iNO 30 dose can safely provide clinically significant reduction in sPAP. After 4 weeks of chronic use of nitric oxide inhalation, the six-minute walk distance (6MWD) led to an increase of an average of 75 metres from baseline was observed. The study demonstrated an improvement of approximately 80% in the composite endpoints of 6MWD and oxygen saturation with four weeks of treatment [74] [87] [88] [89] .
Preliminary results from a phase II trial in the treatment of pulmonary hypertension associated with chronic obstructive pulmonary disease displayed a significant association between ventilation and vasodilation on acute treatment and a clinically meaningful reduction of 17.4% on sPAP on chronic treatment over four weeks. Statistically significant and clinically meaningful improvements, in 6MWD, as compared to baseline was observed, as well as systolic pulmonary arterial pressure with 4 weeks of chronic use. Acute increases in blood vessel volumes following iNO treatment (+4.2%, p = 0.03) was seen in all ten patients. There was a significant association (p < 0.01) between ventilation and vasodilation during iNO therapy. The patients who completed 4 weeks of iNO therapy experienced reductions in pulmonary arterial pressure (-19.9%, p = 0.02) and had on average a 50.4 ± 54.4 meter of increase in 6MWD (p = 0.04) [61] [32] [66] .
COVID-2019 infections:
In an expanded assess programme, inhaled nitric oxide therapy demonstrated improved oxygenation in patients (n=180) with COVID-2019 infections. In the study recovery rate at day 14 was 73% and mortality rate was 7.3% among the patients [15] [21] .
Future Events
| Expected Date | Event Type | Description | Updated |
|---|---|---|---|
| 31 Dec 2020 | Trial Update | Bellerophon Therapeutics plans the registrational phase III REBUILD trial in Pulmonary hypertension associated with pulmonary fibrosis in USA, in the second half of 2020 (9299740) [85] | 10 Nov 2020 |
| 31 Mar 2020 | Trial Update | Bellerophon Therapeutics plans a pivotal phase III trial in Pulmonary hypertension associated with interstitial lung disease in H2 2019 [56] | 26 Aug 2019 |
| 31 Dec 2019 | Trial Update | Bellerophon plans a phase IIa trial for Pulmonary hypertension (associated with sarcoidosis) in 2019 [28] | 08 May 2019 |
| 31 Jan 2019 | Trial Update | Bellerophon Therapeutics plans a phase IIb trial for Pulmonary arterial hypertension (associated with COPD) in 2019 [28] | 16 Nov 2018 |
| 31 Dec 2018 | Trial Update | Bellerophon plans phase IIb iNO-PF trial for Pulmonary hypertention in 2018 [73] | 08 Jan 2018 |
Development History
| Event Date | Update Type | Comment |
|---|---|---|
| 30 Jun 2023 | Trial Update | Bellerophon Therapeutics terminates a phase III REBUILD trial in Pulmonary hypertension in Canada, USA (Inhalation) as the trial did not meet its primary endpoint (NCT03267108) Updated 07 Aug 2023 |
| 05 Jun 2023 | Scientific Update | Efficacy and adverse events data from phase-III REBUILD trial in Pulmonary hypertension released by Bellerophon Therapeutics [84] Updated 09 Jun 2023 |
| 09 Feb 2023 | Regulatory Status | National Medical Products Administration approves IND application for nitric oxide inhalation for a phase III trial in fibrotic Interstitial lung disease [23] Updated 15 Feb 2023 |
| 09 Feb 2023 | Trial Update | Bellerophon Therapeutics and Baylor BioSciences plan a phase III trial in fibrotic Interstitial lung disease in China (Inhalation) [23] Updated 15 Feb 2023 |
| 18 Jan 2023 | Trial Update | Bellerophon Therapeutics completes enrolment of patients in phase III REBUILD trial in Pulmonary hypertension in Canada and USA (Inhalation) (NCT03267108) Updated 21 Jan 2023 |
| 05 Jan 2023 | Licensing Status | Nitric oxide inhalation - INOpulse licensed to Baylor BioSciences in Greater China [4] Updated 09 Jan 2023 |
| 31 Dec 2022 | Patent Information | Bellerophon Therapeutics has patent protection for nitric oxide inhalation-INO pulse in USA, Australia, Brazil, Canada, China, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, the Philippines, Russia and Singapore [93] Updated 25 Apr 2023 |
| 31 Dec 2022 | Patent Information | Bellerophon Therapeutics has patents pending for nitric oxide inhalation in USA, Argentina, Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, New Zealand, the Philippines, Singapore, South Africa and Taiwan [93] Updated 25 Apr 2023 |
| 14 Nov 2022 | Trial Update | Bellerophon Therapeutics plans a exploratory phase II trial in Pulmonary arterial hypertension [24] Updated 18 Nov 2022 |
| 27 Sep 2022 | Regulatory Status | US FDA accepts proposal of Bellerophon Therapeutics to reduce the study size for its registrational REBUILD phase III trial [25] Updated 03 Oct 2022 |
| 15 Aug 2022 | Regulatory Status | Bellerophon Therapeutics submits an IND to US FDA for an exploratory phase II trial in Pulmonary hypertension before August 2022 [51] Updated 19 Aug 2022 |
| 15 Aug 2022 | Regulatory Status | Bellerophon Therapeutics receives clearance from the US FDA for Nitric oxide inhalation-INOpulse in Pulmonary hypertension [51] Updated 19 Aug 2022 |
| 11 May 2022 | Trial Update | Bellerophon completes a phase II trial in Pulmonary hypertension in the US, prior to May 2022 [52] Updated 03 Jun 2022 |
| 06 Apr 2022 | Patent Information | Bellerophon Therapeutics has patents pending for nitric oxide inhalation in USA, Argentina, Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, New Zealand, the Philippines, Singapore, South Africa and Taiwan [94] Updated 08 Apr 2022 |
| 17 Dec 2021 | Scientific Update | Updated safety and efficacy data from the phase II PULSE-PHPF-002 trial for Pulmonary hypertension released by Bellerophon Therapeutics [53] Updated 24 Dec 2021 |
| 15 Nov 2021 | Trial Update | Bellerophon Pharmaceuticals concludes the enrolment in a phase II trial for Pulmonary hypertension associated with sarcoidosis in USA [55] Updated 25 Nov 2021 |
| 08 Nov 2021 | Phase Change - III | Phase-III clinical trials in Pulmonary hypertension in Canada (Inhalation) before November 2021 (NCT03267108) Updated 25 Nov 2021 |
| 01 Nov 2021 | Biomarker Update | Biomarkers information updated Updated 03 Nov 2021 |
| 11 Mar 2021 | Phase Change - Discontinued(III) | Discontinued - Phase-III for COVID-2019 infections in USA (Inhalation) [10] (Bellerophon Therapeutics' pipeline, March 2021 ) Updated 23 Mar 2021 |
| 11 Mar 2021 | Trial Update | Bellerophon Therapeutics discontinues the phase III COViNOX clinical trial in COVID-2019 infections in USA due to lack of efficacy and availability of multiple vaccines (Inhalation) [10] Updated 23 Mar 2021 |
| 31 Dec 2020 | Scientific Update | Additional safety data from a phase II trial for Pulmonary hypertension released by Bellerophon Therapeutics [11] Updated 22 Mar 2021 |
| 01 Dec 2020 | Scientific Update | Additional efficacy data from a phase II trial for Pulmonary hypertension released by Bellerophon Therapeutics [54] Updated 04 Dec 2020 |
| 01 Dec 2020 | Trial Update | Bellerophon Therapeutics initiates enrolment in the phase III REBUILD trial for Pulmonary hypertension in USA (Inhalation) [54] Updated 04 Dec 2020 |
| 23 Nov 2020 | Trial Update | Bellerophon Therapeutics places the phase III COViNOX trial in COVID-2019 infections on clinical hold [12] Updated 26 Nov 2020 |
| 30 Sep 2020 | Phase Change - III | Phase-III clinical trials in Pulmonary hypertension in USA (Inhalation) before September 2020 [13] (NCT03267108) Updated 10 Nov 2020 |
| 21 Aug 2020 | Trial Update | Bellerophon Therapeutics withdraws its planned phase II NO-COVER trial in COVID-2019 infection, due to IRB and FDA reviews deferred, in USA (NCT04398290) Updated 27 Aug 2020 |
| 13 Jul 2020 | Scientific Update | Efficacy and adverse events data from a clinical study in COVID-2019 infections released by Bellerophon Therapeutics [15] Updated 16 Jul 2020 |
| 11 Jul 2020 | Phase Change - III | Phase-III clinical trials in COVID-2019 infections in USA (Inhalation) (NCT04421508) [15] Updated 16 Jul 2020 |
| 02 Jul 2020 | Scientific Update | Interim efficacy data from a phase II trial in Pulmonary arterial hypertension associated idiopathic pulmonary fibrosis presented at the 116th International Conference of the American Thoracic Society (ATS-2020) [59] Updated 17 Jul 2020 |
| 10 Jun 2020 | Trial Update | Bellerophon completes clinical trial under emergency expanded access programme for COVID-2019 infections in USA (Inhalation) (NCT04358588) Updated 23 Jun 2020 |
| 15 May 2020 | Scientific Update | Efficacy and adverse events data from a phase II trial in Pulmonary hypertension associated with pulmonary fibrosis presented at the 116th International Conference of the American Thoracic Society (ATS-2020) [96] Updated 15 Jul 2020 |
| 15 May 2020 | Scientific Update | Updated efficacy and adverse events data from a phase II/III in Pulmonary arterial hypertension presented at the 116th International Conference of the American Thoracic Society (ATS-2020) [82] Updated 14 Jul 2020 |
| 11 May 2020 | Regulatory Status | US FDA approves IND application for nitric oxide inhalation in COVID-19 infections [16] Updated 13 May 2020 |
| 08 Apr 2020 | Regulatory Status | Bellerophon Therapeutics files an IND application with the US FDA to commence PULSE-CVD19-001 trial for COVID-2019 infections in the USA [17] Updated 14 Apr 2020 |
| 08 Apr 2020 | Trial Update | Bellerophon Therapeutics plans a PULSE-CVD19-001 trial for COVID-2019 infections in the USA [17] Updated 14 Apr 2020 |
| 20 Mar 2020 | Phase Change - Clinical | Clinical trials under emergency expanded access in COVID-2019 infections in USA (Inhalation) [20] Updated 24 Mar 2020 |
| 19 Mar 2020 | Regulatory Status | US FDA grants emergency expanded access in COVID-2019 infections for Nitric oxide inhalation - INOpulse [11] Updated 22 Mar 2021 |
| 10 Mar 2020 | Trial Update | Bellerophon Therapeutics plans the registrational phase III REBUILD trial in Pulmonary hypertension associated with pulmonary fibrosis in USA, in the second half of 2020 [14] [85] Updated 10 Nov 2020 |
| 18 Dec 2019 | Scientific Update | Interim safety and efficacy data from a phase II/III trial in Pulmonary arterial hypertension released by Bellerophon Therapeutics [83] Updated 19 Dec 2019 |
| 07 Nov 2019 | Scientific Update | Additional efficacy data from a subgroup analysis of the phase II/IIIb iNO-PF trial in Pulmonary arterial hypertension released by Bellerophon Therapeutics [79] Updated 20 Nov 2019 |
| 23 Oct 2019 | Scientific Update | Additional efficacy data from a phase II/III trial in Pulmonary arterial hypertension released by Bellerophon Therapeutics [80] Updated 30 Oct 2019 |
| 16 Sep 2019 | Regulatory Status | Nitric oxide inhalation - INOpulse - Bellerophon Therapeutics receives Orphan Drug status for Idiopathic pulmonary fibrosis in USA [86] Updated 18 Sep 2019 |
| 08 Aug 2019 | Trial Update | Bellerophon Therapeutics plans a pivotal phase III trial in Pulmonary hypertension associated with interstitial lung disease in H2 2019 [56] Updated 26 Aug 2019 |
| 08 Aug 2019 | Trial Update | Bellerophon initiates a phase II trial for Pulmonary hypertension associated with sarcoidosis in USA [56] Updated 20 Aug 2019 |
| 21 May 2019 | Phase Change - II/III | Phase-II/III clinical trials in Pulmonary hypertension in USA (Inhalation) [78] Updated 24 May 2019 |
| 21 May 2019 | Scientific Update | Updated efficacy data from a phase II/III trial in Pulmonary arterial hypertension presented at the 115th International Conference of the American Thoracic Society (ATS-2019) [78] Updated 24 May 2019 |
| 04 Mar 2019 | Trial Update | Bellerophon initiates enrolment in a phase II trial for Pulmonary hypertension associated with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis in Israel (NCT03873298) Updated 22 Mar 2019 |
| 01 Feb 2019 | Other | Chemical structure information added Updated 01 Feb 2019 |
| 07 Jan 2019 | Scientific Update | Top-line efficacy and adverse events data from the phase IIb iNO-PF trial in Pulmonary hypertension released by Bellerophon Therapeutics [77] Updated 14 Jan 2019 |
| 07 Nov 2018 | Trial Update | Bellerophon plans a phase IIa trial for Pulmonary hypertension (associated with sarcoidosis) in 2019 [28] Updated 08 May 2019 |
| 07 Nov 2018 | Scientific Update | Efficacy data from a phase III trial in Pulmonary arterial hypertension released by Bellerophon [28] Updated 16 Nov 2018 |
| 07 Nov 2018 | Trial Update | Bellerophon Therapeutics plans a phase IIb trial for Pulmonary arterial hypertension (associated with COPD) in 2019 [28] Updated 16 Nov 2018 |
| 09 Oct 2018 | Scientific Update | Efficacy data from the phase III INOvation-1 trial in Pulmonary arterial hypertension released by Bellerophon Therapeutics [29] Updated 12 Oct 2018 |
| 09 Oct 2018 | Trial Update | Bellerophon Therapeutics expands the phase IIb iNO-PF trial in USA [29] Updated 12 Oct 2018 |
| 10 Aug 2018 | Trial Update | Bellerophon Therapeutics withdraws the phase III INOvation-RW study in Pulmonary arterial hypertension in Canada and USA, prior to enrolment (Inhalation) (NCT03602781) Updated 31 Aug 2018 |
| 07 Aug 2018 | Regulatory Status | Data Monitoring Committee (DMC) recommends concluding the phase III INOvation-1 trial in Pulmonary arterial hypertension due to insufficiency of primary endpoint [30] Updated 14 Aug 2018 |
| 18 May 2018 | Scientific Update | Updated efficacy data from a phase II trial in Pulmonary hypertension presented at the 114th International Conference of the American Thoracic Society (ATS-2018) [61] Updated 04 Jul 2018 |
| 10 May 2018 | Licensing Status | Ikaria Hldings and Bellerophon expand licensing agreement for Nitric oxide inhalation to include Interstitial lung diseases Updated 17 May 2018 |
| 29 Dec 2017 | Trial Update | Bellerophon initiates enrolment in a phase II trial for Pulmonary hypertension in USA (NCT03267108) Updated 08 Jan 2018 |
| 05 Sep 2017 | Trial Update | Bellerophon completes a phase II trial in Pulmonary hypertension in Belgium [65] Updated 13 Sep 2017 |
| 05 Sep 2017 | Scientific Update | Adverse events and pharmacodynamics data from a phase II trial in Pulmonary hypertension released by Bellerophon [65] Updated 07 Sep 2017 |
| 31 Aug 2017 | Trial Update | Bellerophon Pulse Technologies completes a phase II trial in Pulmonary hypertension in Belgium (EudraCT2016-002389-29) Updated 07 Sep 2017 |
| 07 Aug 2017 | Regulatory Status | US FDA accepts IND application for a phase IIb trial of nitric oxide inhalation in Pulmonary hypertension [32] Updated 09 Aug 2017 |
| 07 Aug 2017 | Scientific Update | Preliminary efficacy data from a phase II trial in Pulmonary hypertension released by Bellerophon Therapeutics [32] Updated 09 Aug 2017 |
| 03 Aug 2017 | Trial Update | Bellerophon plans phase IIb iNO-PF trial for Pulmonary hypertention in 2018 [73] Updated 08 Jan 2018 |
| 28 Jun 2017 | Trial Update | Bellerophon completes a phase I trial in Pulmonary hypertension associated with chronic obstructive pulmonary disease in Belgium (Inhalation) (NCT02267655) Updated 16 Aug 2017 |
| 22 May 2017 | Scientific Update | Efficacy data from a phase II trial in Pulmonary hypertension presented at the 113th International Conference of the American Thoracic Society [74] Updated 06 Jun 2017 |
| 15 May 2017 | Scientific Update | Efficacy data from a phase II trial in Pulmonary hypertension released by Bellerophon [87] Updated 29 May 2017 |
| 01 May 2017 | Scientific Update | Efficacy data from a phase II trial in Pulmonary hypertension released by Bellerophon [88] Updated 09 May 2017 |
| 13 Mar 2017 | Trial Update | Bellerophon withdraws prior to enrolemt the INOvation-2 study in Pulmonary hypertension [44] Updated 23 Mar 2017 |
| 04 Jan 2017 | Regulatory Status | The US FDA approves all the proposed modification to the phase III clinical programme for nitric oxide inhalation [26] Updated 06 Jan 2017 |
| 04 Jan 2017 | Trial Update | Bellerophon Therapeutics plans a phase III withdrawal study in Pulmonary arterial hypertension in Canada and USA (Inhalation) [26] (NCT03602781) Updated 06 Jan 2017 |
| 25 Jul 2016 | Phase Change - II | Phase-II clinical trials in Pulmonary hypertension in Belgium (Inhalation) (EudraCT2016-002389-29) Updated 14 Nov 2016 |
| 25 Jul 2016 | Regulatory Status | Belgium health authority approves phase II trials for nitric oxide inhalation in Pulmonary hypertension associated with chronic obstructive pulmonary disease [64] Updated 28 Jul 2016 |
| 01 Jul 2016 | Trial Update | Bellerophon Therapeutics completes a phase II trial in Pulmonary arterial hypertension in USA and Canada (NCT01457781) Updated 19 Aug 2016 |
| 16 Jun 2016 | Trial Update | Bellerophon Therapeutics initiates enrolment in a phase II trial for Pulmonary hypertension (associated with Pulmonary fibrosis) [33] Updated 17 Jun 2016 |
| 16 Jun 2016 | Trial Update | Bellerophon Therapeutics initiates enrolment in the phase III INOvation-1 trial for Pulmonary arterial hypertension (In adults, In the elderly) in USA (NCT02725372) Updated 25 May 2016 |
| 10 May 2016 | Trial Update | Bellerophon Therapeutics plans a phase III trial for Pulmonary arterial hypertension in USA [34] Updated 12 May 2016 |
| 10 May 2016 | Trial Update | Bellerophon Therapeutics plans a phase II trial for Pulmonary hypertension (associated with Pulmonary fibrosis) in USA [34] Updated 12 May 2016 |
| 01 Apr 2016 | Phase Change - III | Phase-III clinical trials in Pulmonary arterial hypertension (In adults, In the elderly) in Australia, Austria, Czech Republic, France, Germany, Israel, Italy, the Netherlands, Portugal, Serbia, Spain, Ukraine and United Kingdom (Inhalation) (NCT02725372) Updated 09 Aug 2017 |
| 21 Mar 2016 | Patent Information | Bellerophon THerapeutics has patent protection for nitric oxide inhalation-INO pulse in USA, Australia, Brazil, Canada, China, Europe, Hong Kong, India, Indonesia, Israel, Japan, Korea, Mexico, the Philippines, Russia and Singapore (Bellerophon Therapeutics, form 10-K, March 2016) Updated 20 Jun 2016 |
| 21 Mar 2016 | Regulatory Status | Bellerophon Therapeutics receives a special protocol assessment for the phase III registration trial from the US FDA [46] Updated 28 Mar 2016 |
| 09 Feb 2016 | Scientific Update | Final efficacy and safety data from a phase II trial in Pulmonary arterial hypertension released by Bellerophon Therapeutics [49] Updated 11 Feb 2016 |
| 01 Feb 2016 | Phase Change - III | Phase-III clinical trials in Pulmonary arterial hypertension (In children, In adults, In the elderly) in Canada (Inhalation) (NCT02652429) Updated 01 Feb 2016 |
| 01 Feb 2016 | Phase Change - III | Phase-III clinical trials in Pulmonary arterial hypertension (In children, In adults, In the elderly) in USA (Inhalation) (NCT02652429) Updated 01 Feb 2016 |
| 01 Nov 2015 | Phase Change - I | Phase-I clinical trials in Pulmonary hypertension associated with chronic obstructive pulmonary disease in Belgium (Inhalation) (NCT02267655) Updated 13 Jan 2015 |
| 24 Sep 2015 | Regulatory Status | Bellerophon Therapeutics receives a special protocol assessment for the phase III registration trial from the US FDA [36] Updated 20 Oct 2015 |
| 24 Sep 2015 | Scientific Update | Interim efficacy data from the phase II trial in Pulmonary hypertension released by Bellerophon [36] Updated 16 Oct 2015 |
| 29 Jul 2015 | Licensing Status | Bellerophon Therapeutics expands its licensing agreement to develop nitric oxide inhalation for the treatment of three additional cardiopulmonary diseases, Chronic thromboembolic pulmonary hypertension, Pulmonary hypertension associated with sarcoidosis and Pulmonary hypertension associated with pulmonary oedema [7] Updated 02 Aug 2015 |
| 15 May 2015 | Trial Update | Bellerophon Therapeutics plans a phase III trial for Pulmonary hypertension in USA [40] Updated 26 Jun 2015 |
| 16 Apr 2015 | Company Involvement | Mallinckrodt acquires Ikaria Updated 20 Apr 2015 |
| 31 Mar 2015 | Trial Update | Bellerophon Therapeutics plans a phase IIb trial for Pulmonary hypertension associated with chronic obstructive pulmonary disease [41] Updated 08 Apr 2015 |
| 07 Oct 2014 | Trial Update | Bellerophon Therapeutics plans a phase I trial in Pulmonary hypertension associated with chronic obstructive pulmonary disease in Belgium (NCT02267655) Updated 17 Nov 2014 |
| 01 Jul 2014 | Trial Update | Bellerophon Therapeutics completes enrolment in its phase II trial for Pulmonary hypertension associated with chronic obstructive pulmonary disease in USA (NCT01728220) Updated 30 Jun 2014 |
| 17 Jun 2014 | Phase Change - II | Phase-II clinical trials in Pulmonary hypertension in USA (Inhalation) Updated 20 Jun 2014 |
| 17 Jun 2014 | Trial Update | Bellerophon Therapeutics completes enrolment in a phase II trial in Pulmonary arterial hypertension in USA and Canada (NCT01457781) Updated 20 Jun 2014 |
| 01 Jan 2014 | Licensing Status | Bellerophon Therapeutics acquires exclusive worldwide licensing rights to INOpulse® programmes in Pulmonary arterial hypertension, Pulmonary hypertension associated with chronic obstructive pulmonary disease and Pulmonary hypertension associated with idiopathic pulmonary fibrosis [5] Updated 02 Aug 2015 |
| 19 Apr 2012 | Phase Change - II | Phase-II clinical trials in Pulmonary arterial hypertension in Canada (Inhalation) Updated 20 Jun 2014 |
| 19 Apr 2012 | Phase Change - II | Phase-II clinical trials in Pulmonary arterial hypertension in USA (Inhalation) Updated 20 Jun 2014 |
References
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SEC filing, March 2024 - Bellerophon Therapeutics. Internet-Doc 2024;.
Available from: URL: https://www.sec.gov/Archives/edgar/data/1600132/000110465924031183/tm248062d1_1512g.htm -
SEC filing, March 2024 - Bellerophon Therapeutics. Internet-Doc 2024;.
Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1600132/000110465924030552/tm247932d1_8k.htm -
Mallinckrodt Completes Acquisition Of Ikaria.
Media Release -
Bellerophon Therapeutics Announces License Agreement for the Commercialization of INOpulse(Rm) in Greater China with Baylor BioSciences.
Media Release -
Bellerophon Therapeutics Completes Enrollment for its Phase 2 Trial of INOpulse(Rm) For Treatment of Pulmonary Arterial Hypertension (PAH).
Media Release -
Bellerophon Provides Business Update and Reports First Quarter 2018 Financial Results.
Media Release -
Bellerophon Therapeutics Expands License Agreement With INO Therapeutics to Develop INOpulse(R) for Three Additional Cardiopulmonary Diseases.
Media Release -
Mallinckrodt Pharmaceuticals To Expand Hospital Growth Platform With Ikaria, Inc. Acquisition.
Media Release -
Bellerophon Therapeutics Selects Flextronics to Manufacture the Mark2, Next-Generation INOpulse(Rm) Device.
Media Release -
Bellerophon Provides Clinical Program Update and Reports Fourth Quarter and Full-Year 2020 Financial Results.
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Bellerophon Therapeutics, SEC fillings, 31 Dec 2020. Internet-Doc 2021;.
Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1600132/000155837021002768/blph-20201231x10k.htm -
Bellerophon Therapeutics Announces Results of Interim Analysis of Phase 3 COViNOX Study of INOpulse(Rm) for the Treatment of COVID-19.
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Bellerophon Provides Clinical Program Update and Reports Third Quarter 2020 Financial Results.
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Bellerophon Provides Clinical Program Update and Reports Second Quarter 2020 Financial Results.
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Bellerophon Therapeutics Announces First Patient Treated in Phase 3 Clinical Study of INOpulse(Rm) Inhaled Nitric Oxide Therapy for COVID-19.
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Bellerophon Therapeutics Announces FDA Clears Initiation of Phase 3 Study for INOpulse(Rm) Inhaled Nitric Oxide Therapy to Treat COVID-19.
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Bellerophon Therapeutics Submits Investigational New Drug Application to Study INOpulse(Rm) Inhaled Nitric Oxide Therapy for the Treatment of COVID-19.
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A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Pulsed, Inhaled Nitric Oxide (iNO) Versus Placebo in Subjects With Mild or Moderate Coronavirus (COVID-19)
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Bellerophon Therapeutics Announces First Patient Treated with INOpulse(Rm) Inhaled Nitric Oxide Therapy for COVID-19.
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FDA Grants Bellerophon Emergency Expanded Access for INOpulse(R) for the Treatment of COVID-19 Virus.
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Expanded Access: Pulsed, Inhaled Nitric Oxide (iNO) for the Treatment of Patients With Mild or Moderate Coronavirus Disease (COVID-19)
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Randomized Controlled Trial Of A Delivered Continuously By Nasal Cannula For The Treatment Of Patients With COVID-19 And Mild To Moderate Hypoxemia Requiring Supplemental Oxygen
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Bellerophon Therapeutics Receives IND Clearance from China NMPA to Conduct Phase 3 Clinical Trial in China for INOpulse(Rm) in Fibrotic Interstitial Lung Disease.
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Bellerophon Provides Clinical Program Update and Reports Third Quarter 2022 Financial Results.
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Bellerophon Announces FDA Acceptance of Change to Ongoing Phase 3 REBUILD Study of INOpulse(Rm) for Treatment of Fibrotic Interstitial Lung Disease.
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Bellerophon Therapeutics Announces FDA Acceptance of Modifications to INOpulse Pulmonary Arterial Hypertension Phase 3 Program.
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Bellerophon Provides Business Update and Reports Fourth Quarter and Full-Year 2018 Financial Results.
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Bellerophon Provides Business Update and Reports Third Quarter 2018 Financial Results.
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Bellerophon Provides Update on INOpulse(R) Phase 2b Clinical Program for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.
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Bellerophon Announces Results of Interim Analysis of Phase 3 INOvation-1 Study Evaluating INOpulse(R) for Treatment of Pulmonary Arterial Hypertension.
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Bellerophon Therapeutics Announces Enrollment Exceeds 100 Patients in Phase 3 INOvation-1 Study Evaluating INOpulse(R)for Treatment of Pulmonary Arterial Hypertension.
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Bellerophon Reports Second Quarter 2017 Financial Results and Provides Business Update.
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Bellerophon Therapeutics Announces Enrollment of the First Patient in the INOvation-1 Phase 3 Clinical Trial for Pulmonary Arterial Hypertension (PAH).
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Bellerophon Reports First Quarter 2016 Financial Results and Provides Business Update.
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Bellerophon Reports 2015 Third Quarter Operational and Financial Results.
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Bellerophon Therapeutics Announces Positive Data From Interim Analysis of Phase 2 Long-Term Extension Study of INOpulse(Rm) for Treatment of Pulmonary Arterial Hypertension.
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Bellerophon Therapeutics Announces Leadership Team Changes.
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Bellerophon Reports 2015 Second Quarter Operational and Financial Results.
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Bellerophon Therapeutics Announces Top-Line Results From PRESERVATION I Clinical Trial for Bioabsorbable Cardiac Matrix (BCM).
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Bellerophon Reports 2015 First Quarter Financial and Operational Results.
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Bellerophon Reports 2014 Full Year Financial and Operational Results.
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Bellerophon Therapeutics Strengthens Drug and Device Development Capabilities with Key Management Additions.
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A PHASE 3, PLACEBO CONTROLLED, DOUBLE-BLIND, RANDOMIZED, CLINICAL STUDY TO DETERMINE EFFICACY, SAFETY AND TOLERABILITY OF PULSED, INHALED NITRIC OXIDE (iNO) VERSUS PLACEBO IN SYMPTOMATIC SUBJECTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH): INOvation-1 (Part 1 and Part 2)
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Bellerophon Reports Fourth Quarter 2016 Financial Results and Provides Business Update.
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Phase 3, Multicenter, Randomized, Double-blind, Placebo Controlled Withdrawal Study of Pulmonary Arterial Hypertension(PAH) Subjects With LTOT Use That Have Demonstrated Improved Exercise Tolerance With the Use of Inhaled Nitric Oxide (INO)
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Bellerophon Reports 2015 Financial Results and Provides Business Update.
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An Open-Label Long-Term Safety Study of Inhaled Nitric Oxide (iNO) for PAH for Subjects in the PULSE-PAH-006 and PULSE-PAH-004 Studies Who Continue to Need iNO Therapy
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A Phase 2, Placebo Controlled, Double-Blind, Randomized, Clinical Study to Determine Safety, Tolerability and Efficacy of Pulsed, Inhaled Nitric Oxide (iNO) Versus Placebo as Add-On Therapy in Symptomatic Subjects With Pulmonary Arterial Hypertension (PAH)
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Bellerophon Therapeutics Announces Positive Data From the Final Analysis of the Phase 2 Long-Term Extension Study of INOpulse for Treatment of Pulmonary Arterial Hypertension.
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FDA Grants Orphan Drug Designation to Ikaria For Use of Inhaled Nitric Oxide in Pulmonary Arterial Hypertension.
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Bellerophon Provides Clinical Program Update and Reports Second Quarter 2022 Financial Results.
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Bellerophon Provides Clinical Program Update and Reports First Quarter 2022 Financial Results.
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Bellerophon Reports Positive Top-Line Data from Phase 2 Acute Dose Escalation Study of INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Sarcoidosis.
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Bellerophon Therapeutics Announces First Patient Enrolled in Phase 3 REBUILD Study Evaluating INOpulse(Rm) for the Treatment of Fibrotic Interstitial Lung Disease.
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Bellerophon Provides Clinical Program Update and Reports Third Quarter 2021 Financial Results.
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Bellerophon Provides Business Update and Reports Second Quarter 2019 Financial Results.
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A Dose Escalation Study to Assess the Safety and Efficacy of Pulsed, Inhaled Nitric Oxide in Subjects With Pulmonary Hypertension Associated With Pulmonary Fibrosis or Sarcoidosis on Long Term Oxygen Therapy Followed by an Optional Open-Label Long Term Extension Safety Study
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The Influence of Inhaled Nitric Oxide on Oxygen Saturation of Patients With COPD and IPF During Six Minute Walk Test.
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Pertzov B, Freidkin L, Kramer MR. The Acute Effect of Pulsed Inhaled Nitric Oxide on Exercise Capacity in Patients with Idiopathic Pulmonary Fibrosis: A Randomized Placebo Controlled, Cross-Over Trial. ATS-2020 2020; abstr. P595.
Available from: URL: http://link.adisinsight.com/Fk6q8 -
Phase 2b randomized, double-blind, placebo-controlled study of Nitric-oxide in Pulmonary-hypertension patients associated with Chronic Obstructive Pulmonary Disease
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Hajian B, Shivalkar B, Leemans J, Van Holsbeke C, Vos W, De Backer J, et al. Pulsed Inhaled Nitric Oxide (NO) Improves Exercise Tolerance in Severe Chronic Obstructive Pulmonary Disease (COPD) Patients with Pulmonary Hypertension (PH). ATS-2018 2018; abstr. A4229.
Available from: URL: http://link.adisinsight.com/c4N2L -
Bellerophon Reports Third Quarter 2016 Financial Results and Provides Business Update.
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Bellerophon Reports Second Quarter 2016 Financial Results and Provides Business Update.
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Bellerophon Receives Approval to Commence Phase 2 Trial in PH-COPD.
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Bellerophon Announces Positive Top Line Phase 2 Data of INOpulse(R) for Treatment of Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease.
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Exploratory Study to Assess the Effect of Pulsed Inhaled Nitric Oxide on Functional Respiratory Imaging Parameters in Subjects With WHO Group 3 Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (COPD) on Long Term Oxygen Therapy (LTOT)
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A Placebo-Controlled, Double-Blind, Parallel, Randomized, Two-Part, Clinical Dose-Confirming Study Of Pulsed, Inhaled Nitric Oxide (iNO) In Subjects With World Health Organization (WHO) Group 3 Pulmonary Hypertension (PH) Associated With Chronic Obstructive Pulmonary Disease (COPD) On Long Term Oxygen Therapy (LTOT) INHALE 1
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An Exploratory, 3-Part, Clinical Study to Assess the Effect of Pulsed, Inhaled Nitric Oxide (iNO) on Functional Pulmonary Imaging Parameters in Subjects With World Health Organization (WHO) Group 3 Pulmonary Hypertension (PH) Associated With Chronic Obstructive Pulmonary Disease (COPD) on Long-Term Oxygen Therapy (LTOT) (Part 1) and in Subjects With WHO Group 3 PH Associated With Idiopathic Pulmonary Fibrosis (IPF) on LTOT (Part 2 and Part 3)
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Bellerophon Announces Functional Respiratory Imaging Data From Company Sponsored Clinical Trial of INOpulse(R) in COPD Patients With Pulmonary Hypertension Presented Today at the European Respiratory Society (ERS) International Congress.
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A Randomized, Double-Blind, Placebo-Controlled Dose Escalation and Verification Clinical Study to Assess the Safety and Efficacy of Pulsed Inhaled Nitric Oxide (iNO) in Subjects at Risk of Pulmonary Hypertension Associated With Pulmonary Fibrosis on Long Term Oxygen Therapy (Part 1 and Part 2) - REBUILD
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Bellerophon Therapeutics Announces Last Patient Has Completed Blinded Treatment in Phase 3 REBUILD Study for INOpulse(Rm) in Fibrotic Interstitial Lung Disease.
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Bellerophon Announces First Patient Enrolled in Phase 2b Study Evaluating INOpulse(R) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.
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Bellerophon Announces FDA Agreement on Phase 2b Study Design for INOpulse(R) in Pulmonary Hypertension Associated with Interstitial Lung Disease (PH-ILD).
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Positive Clinical Data on INOpulse(Rm) Presented at the American Thoracic Society 113th International Conference.
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Bellerophon to Present Additional Data from Cohort 1 of Ongoing Phase 2/3 Study of INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease at American Thoracic Society 115th International Conference.
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Bellerophon Announces Agreement with FDA on Regulatory Approval Pathway for INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.
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Bellerophon Announces Top-line Results from Cohort 1 of the INOpulse(Rm) Phase 2b Clinical Trial for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.
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Bellerophon Presents Additional Positive Data from Cohort 1 of Ongoing Phase 2/3 Study of INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease at American Thoracic Society 115th International Conference.
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Bellerophon Presents New Data from Cohort 1 of Ongoing Phase 2/3 Study of INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease at Pulmonary Fibrosis Foundation Summit 2019.
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Bellerophon Presents New Positive Data from Cohort 1 of Ongoing Phase 2/3 Study of INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease at CHEST 2019 Annual Meeting.
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Bellerophon Completes Enrollment in Cohort 2 of Ongoing Phase 2/3 Study of INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.
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Nathan SD, Flaherty KR, Glassberg M, Raghu G, Swigris JJ, Alvarez RA, et al. A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Pulsed, Inhaled Nitric Oxide (iNO) in Subjects at Risk of Pulmonary Hypertension (PH) Associated with Fibrotic Interstitial Lung Disease (fILD) on Long Term Oxygen Therapy. ATS-2020 2020; abstr. N/A.
Available from: URL: http://link.adisinsight.com/r7M3T -
Bellerophon Announces Positive Top-line Results from Cohort 2 of Phase 2/3 Study of INOpulse(Rm) for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.
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Bellerophon Announces Top-Line Data from Phase 3 REBUILD Clinical Trial of INOpulse(Rm) for Treatment of Fibrotic Interstitial Lung Disease.
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Bellerophon Announces Agreement with the FDA on its Planned Pivotal Phase 3 Study for the Treatment of Pulmonary Hypertension Associated with Pulmonary Fibrosis.
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Bellerophon Receives Orphan Drug Designation for Nitric Oxide in the Treatment of Idiopathic Pulmonary Fibrosis.
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Bellerophon Reports First Quarter 2017 Financial Results and Provides Business Update.
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Bellerophon to Present Positive Clinical Data on INOpulse(Rm) at the American Thoracic Society 113th International Conference.
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A phase 2a Proof-Of-Concept Trial Investigating Pulsed Inhaled Nitric Oxide (iNO) To Treat Pulmonary Hypertension Associated With Idiopathic-Pulmonary-Fibrosis (PH-IPF)
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Bellerophon Therapeutics Announces $5 Million Registered Direct Offering.
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Bellerophon Therapeutics Announces Pricing of Public Offering of Common Stock and Concurrent Registered Direct Offering.
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Bellerophon Announces Closing of $15.3 Million Registered Direct Offering of Common Stock.
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Bellorophon Pharma SEC. Internet-Doc 2023;.
Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1600132/000155837023005200/blph-20221231x10k.htm -
Bellerophon Therapeutics 10K- 2022. Internet-Doc 2022;.
Available from: URL: https://www.sec.gov/ix?doc=/Archives/edgar/data/1600132/000155837022004898/blph-20211231x10k.htm -
Bellerophon Therapeutics Form 10-K, March 2017. Internet-Doc 2017;.
Available from: URL: https://www.sec.gov/Archives/edgar/data/1600132/000160013217000006/blph12312016-10k.htm -
Alvarez RA, Dudenhofer R, Ahmad K, Glassberg Csete MK, Lancaster L, Raghu G, et al. An Acute Dose Escalation Study to Assess the Safety and Hemodynamic Efficacy of Pulsed Inhaled Nitric Oxide (iNO) in Subjects with Pulmonary Hypertension Associated with Pulmonary Fibrosis (PF) or Sarcoidosis. ATS-2020 2020; abstr. P591.
Available from: URL: https://www.abstractsonline.com/pp8/8998/presentation/12495 -
Bellerophon to Host Key Opinion Leader Meeting Focused on Pulmonary Hypertension Associated with Interstitial Lung Disease.
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