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Nitric oxide inhalation - INOpulse - Bellerophon Therapeutics

Drug Profile

Nitric oxide inhalation - INOpulse - Bellerophon Therapeutics

Alternative Names: Inhaled nitric oxide - Bellerophon; inhaled NO - Bellerophon; iNO- Bellerophon; Nitric oxide-INOpulse®

Latest Information Update: 13 May 2020

At a glance

  • Originator Ikaria Holdings
  • Developer Bellerophon Therapeutics
  • Class Anti-inflammatories; Antiacnes; Antiandrogens; Antibacterials; Antifibrotics; Antifungals; Antihypertensives; Antivirals; Cardiovascular therapies; Diagnostic agents; Free radicals; Nitrogen oxides; Non-opioid analgesics; Small molecules; Vasodilators
  • Mechanism of Action Androgen receptor antagonists; Angiogenesis inducing agents; Cell death stimulants; Guanylate cyclase stimulants; Nitric oxide donors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - Pulmonary arterial hypertension; Idiopathic pulmonary fibrosis
  • New Molecular Entity No

Highest Development Phases

  • Phase III Pulmonary arterial hypertension
  • Phase II/III Pulmonary hypertension
  • Clinical Phase Unknown COVID 2019 infections

Most Recent Events

  • 11 May 2020 US FDA approves IND application for nitric oxide inhalation in COVID-19 infections
  • 08 Apr 2020 Bellerophon Therapeutics files an IND application with the US FDA to commence PULSE-CVD19-001 trial for COVID-2019 infections in the USA
  • 08 Apr 2020 Bellerophon Therapeutics plans a PULSE-CVD19-001 trial for COVID-2019 infections in the USA

Development Overview

Introduction

Nitric oxide inhalation delivered using its INOpulse device 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) is being developed by Bellerophon Therapeutics. Bellerophon also plans to use its drug candidate for three additional indications; chronic thromboembolic PH, PH associated with sacoidosis and PH associated with pulmonary oedema from altitude sickness. Clinical development for PAH and pulmonary hypertension is under progress in several countries. Nitric oxide inhalation being administered in the US for treatment of COVID-19 infections under emergency expanded access.

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 [1] .

Company Agreements

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. [2] [3] [4]

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 [5] .

Key Development Milestones

COVID-2019 infections

In May 2020, US FDA approved IND application to commence phase III PULSE-CVD19-001 trial of nitric oxide inhalation for the treatment of COVID-19 infections. Earlier 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 proposed IND study [6] [7] [8] .

In April 2020, Bellerophon Therapeutics treated three patient with nitric oxide inhalation under emergency expanded access programme. The US FDA granted nitric oxide inhalation an emergency expanded access allowing it to immediately be used for the treatment of COVID-19 patients. Three patients who completed the treatment with nitric oxide inhalation demonstrated improved oxygenation and allowed them to avoid the need for mechanical ventilation and two of them were discharged [7] [9] [10] [11] .

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 [12] .

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 subjects 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 [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [22] [23] [24] [25] [26] [27] [28] [29] .

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 [30] [12] [31] .

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 [32] [33] .

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 [22] [2] [34] . Final results from the study were released in February 2016 [35] .

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 [36] .

Ikaria submitted an IND application to the FDA in November 2011 [36] .

Pulmonary hypertension associated with sarcoidosis

In January 2019, Bellerophon initiated a dose escalation study a phase II dose escalation study to asses the safety and efficacy of pulsed, inhaled nitric oxide in patients with pulmonary fibrosis or sarcoidosis (PULSE-PHPF-002, NCT03727451). The intends to enrol 16 patients in the US. In August 2019, the company initiated a phase II dose escalation study to assess the hemodynamic benefit of INOpulse via right heart catheterization in pulmonary hypertension associated with sarcoidosis [37] [38] .

Pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD)

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 [39] .

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 subjects. The primary endpoint is change in 6MWD, with several additional secondary endpoints including improvement in right ventricular function [3] [40] .

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) [41] [18] [42] [43] [44] [20] [27] [45] [46] .

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 [44] [24] [36] [47] .

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 [48] .

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 [49] .

Pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF)

In March 2020, Bellerophon Therapeutics successfully completed End-of-Phase 2 Meetings with the US FDA regarding design of a planned phase III 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 [50] .

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) [51] .

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 [19] [20] . Bellerophone released topline data for the study in May 2017 [52] [53] . The study supported iNO 30 as a potentially safe and effective dose [54] [55] .

In January 2018, Bellerophon Therapeutics announced that the first patient was randomised in the phase II/III iNO-PF 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), including patients with idiopathic pulmonary fibrosis (PH-IPF) (PULSE-PHPF-001; NCT03267108) [56] [57] . The primary endpoint of the study is the change in 6 Minute Walk Distance from baseline to week 8. The trial will also evaluate change in exercise capacity, oxygen saturation, right ventricular function, activity monitoring, patient reported outcomes, as well as several composite endpoints. The randomised, double-blind, placebo-controlled trial is enrolling 100 patients in the US. 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 subjects 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 [14] [15] [58] [18] [54] . 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. Cohort 3 initiation is expected in the first quarter of 2020 with approximately 300 patients [59] [60] [61] . 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) [62] . 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 [63] [64] [37] [65] . In December 2019, Bellerophon Therapeutics released the safety and efficacy data of the cohort B of the trial [66] [57] .

Financing Information

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 $US40 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 [67] .

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 [68] .

Patent Information

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) [69] .

Drug Properties & Chemical Synopsis

  • Route of administration Inhalation
  • Formulation Controlled release, unspecified
  • Class Anti-inflammatories, Antiacnes, Antiandrogens, Antibacterials, Antifibrotics, Antifungals, Antihypertensives, Antivirals, Cardiovascular therapies, Diagnostic agents, Free radicals, Nitrogen oxides, Non-opioid analgesics, Small molecules, Vasodilators
  • Target Androgen receptor; Cell death; Guanylate cyclase
  • Mechanism of Action Androgen receptor antagonists; Angiogenesis inducing agents; Cell death stimulants; Guanylate cyclase stimulants; Nitric oxide donors
  • WHO ATC code

    C04A (Peripheral Vasodilators)

    J05 (Antivirals for Systemic Use)

    R07A-X01 (Nitric oxide)

  • EPhMRA code

    C4A (Cerebral and Peripheral Vasotherapeutics)

    J5 (Antivirals for Systemic Use)

    R7X (All Other Respiratory System Products)

  • Chemical name Nitric oxide
  • Molecular formula N O
  • Chemical Structure
  • CAS Registry Number 10102-43-9

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

bacterial infections

Outcome Measure

Nitric Oxide

1

chronic obstructive pulmonary disease

Outcome Measure

Inosine

1

cystic fibrosis-associated respiratory tract infections

Outcome Measure

Nitric Oxide

1

hypoxic respiratory failure

Exclusion

tumor protein, translationally-controlled 1

1

hypoxic respiratory failure

Inclusion

tumor protein, translationally-controlled 1

1

hypoxic respiratory failure

Outcome Measure

VEGF-C

VEGF-A

tumor protein, translationally-controlled 1

PGE2

Inosine

Endothelin 1

8-oxo-7-hydrodeoxyguanosine

1

1

1

1

1

1

1

idiopathic pulmonary fibrosis

Outcome Measure

Nitric Oxide

hemoglobin subunit gamma 2

1

1

lung disorders

not specified

MPO

IL8

IL6

IL10

hemoglobin subunit gamma 2

Endothelin 1

1

1

1

1

1

1

myocardial infarction

Outcome Measure

Troponin T, cardiac

Nitric Oxide

CKB

BNP

1

1

1

1

platelet dysfunction

not specified

Thrombin

1

platelet dysfunction

Outcome Measure

hemoglobin subunit gamma 2

1

Pulmonary arterial hypertension

Exclusion

phosphodiesterase 5A

1

Pulmonary arterial hypertension

Inclusion

phosphodiesterase 5A

1

Pulmonary arterial hypertension

Outcome Measure

phosphodiesterase 5A

opsin 1 (cone pigments), long-wave-sensitive

Nitric Oxide

Inosine

immunoglobulin kappa variable 1D-39

hemoglobin subunit gamma 2

1

1

1

1

1

2

pulmonary hypertension

not specified

trafficking protein particle complex 9

1

pulmonary hypertension

Exclusion

Prostacyclin

1

pulmonary hypertension

Outcome Measure

Prostacyclin

Nitric Oxide

Inosine

hemoglobin subunit gamma 2

GLI family zinc finger 3

DSP

1

2

2

1

1

1

respiratory insufficiency

not specified

MPO

IL8

IL6

IL10

hemoglobin subunit gamma 2

Endothelin 1

1

1

1

1

1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Nitric oxide inhalation - INOpulse - Bellerophon Therapeutics 8-oxo-7-hydrodeoxyguanosine Outcome Measure
BNP Outcome Measure
choroideremia (Rab escort protein 1) Outcome Measure
chromodomain helicase DNA binding protein 7 Outcome Measure
CKB Outcome Measure
CKM Outcome Measure
Creatinine not specified
CRP Outcome Measure
Endothelin 1 Outcome Measure
Haptoglobin Outcome Measure
hemoglobin subunit gamma 2 Exclusion, Outcome Measure
Hemopexin Outcome Measure
IFN-gamma Outcome Measure
IL10 Outcome Measure
IL12A not specified
IL12B not specified
IL2 not specified
IL6 Outcome Measure
IL8 Outcome Measure
Inosine Outcome Measure
Insulin Outcome Measure
Nitric Oxide Outcome Measure
PGE2 Outcome Measure
Prostacyclin Exclusion, Outcome Measure
S100B Outcome Measure
T-box 1 Inclusion
Thrombin not specified
TNF-alpha Outcome Measure
troponin I, cardiac Outcome Measure
Troponin T, cardiac Outcome Measure
tumor protein, translationally-controlled 1 Exclusion, Inclusion, Outcome Measure
VEGF-A Outcome Measure
VEGF-C Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
COVID 2019 infections - - Clinical Phase Unknown USA Inhalation / unspecified Bellerophon Therapeutics 20 Mar 2020
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 with pulmonary hypertension associated with pulmonary fibrosis - Phase II/III USA Inhalation / Controlled release Bellerophon Therapeutics 21 May 2019
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
Bellerophon Therapeutics Licensee World
University of Antwerp Collaborator Belgium

Scientific Summary

Adverse Events

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. 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 [35] [34] .

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 [45] [46] .

Pulmonary hypertension:

A top-line results of interim analysis of the phase IIb iNO-PF trial in both patients at high and low risk of pulmonary hypertension associated with Interstitial Lung Disease (PH-ILD) and idiopathic pulmonary fibrosis (PH-IPF), pulsed inhaled nitric oxide (iNO) was well-tolerated without any safety concerns. The results were reported post eight week treatment with pulsed inhaled nitric oxide (iNO) in patients from Cohort A of the trial [61] [57] .

Top-line results of an interim analysis of the phase II/III trial in patients with pulmonary hypertension associated with interstitial lung disease demonstrated that INOpulse was well-tolerated with no safety concerns in patients from the cohort B of the trial [66] [57] .

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 [45] [46] .

Antimicrobial Activity

Summary

Therapeutic Trials

Pulmonary hypertension:

In additional data from cohort 1 of the phase II/IIIb iNO-PF trial in both patients at high and low risk of pulmonary hypertension associated with Interstitial Lung Disease (PH-ILD) and idiopathic pulmonary fibrosis (PH-IPF), 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 of the trial, inhaled nitric oxide improved MVPA, as well as other activity parameters, such as overall activity and caloric expenditure. 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 [63] [64] [62] [59] [61] [57] .

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). 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). The SGRQ activity score improved by 5 points. The SGRQ Impacts score improved by 6 points. University of California and the San Diego Shortness of Breath Questionnaire improved by 5 points [57] [66] .

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 [14] [15] [29] .

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 [35] [22] [34] .

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 [54] [52] [53] [55] .

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) [41] [18] [46] .

Future Events

Expected Date Event Type Description Updated
31 Dec 2020 Trial Update Bellerophon Therapeutics plans a registrational phase III trial in Pulmonary hypertension associated with pulmonary fibrosis in USA in 2020 (Inhalation,Controlled release) (700319710) [50] 09 Apr 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 [37] 26 Aug 2019
31 Dec 2019 Trial Update Bellerophon plans a phase IIa trial for Pulmonary hypertension (associated with sarcoidosis) in 2019 [14] 08 May 2019
31 Jan 2019 Trial Update Bellerophon Therapeutics plans a phase IIb trial for Pulmonary arterial hypertension (associated with COPD) in 2019 [14] 16 Nov 2018
31 Dec 2018 Trial Update Bellerophon plans phase IIb iNO-PF trial for Pulmonary hypertention in 2018 [58] 08 Jan 2018

Development History

Event Date Update Type Comment
11 May 2020 Regulatory Status US FDA approves IND application for nitric oxide inhalation in COVID-19 infections [6] 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 [7] Updated 14 Apr 2020
08 Apr 2020 Trial Update Bellerophon Therapeutics plans a PULSE-CVD19-001 trial for COVID-2019 infections in the USA [7] Updated 14 Apr 2020
20 Mar 2020 Phase Change - Clinical Clinical trials under emergency expanded access in COVID-2019 infections in USA (Inhalation) [10] Updated 24 Mar 2020
10 Mar 2020 Trial Update Bellerophon Therapeutics plans a registrational phase III trial in Pulmonary hypertension associated with pulmonary fibrosis in USA in 2020 (Inhalation,Controlled release) [50] Updated 09 Apr 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 [66] Updated 24 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 [63] 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 [64] 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 [51] 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 [37] Updated 26 Aug 2019
08 Aug 2019 Trial Update Bellerophon initiates a phase II trial for Pulmonary hypertension associated with sarcoidosis in USA [37] Updated 20 Aug 2019
21 May 2019 Phase Change - II/III Phase-II/III clinical trials in Pulmonary hypertension in USA (Inhalation) [62] 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) [62] 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 [61] Updated 14 Jan 2019
07 Nov 2018 Trial Update Bellerophon plans a phase IIa trial for Pulmonary hypertension (associated with sarcoidosis) in 2019 [14] Updated 08 May 2019
07 Nov 2018 Scientific Update Efficacy data from a phase III trial in Pulmonary arterial hypertension released by Bellerophon [14] 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 [14] 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 [15] Updated 12 Oct 2018
09 Oct 2018 Trial Update Bellerophon Therapeutics expands the phase IIb iNO-PF trial in USA [15] 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 [16] 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) [41] 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 [45] 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 [45] 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 [18] Updated 09 Aug 2017
07 Aug 2017 Scientific Update Preliminary efficacy data from a phase II trial in Pulmonary hypertension released by Bellerophon Therapeutics [18] Updated 09 Aug 2017
03 Aug 2017 Trial Update Bellerophon plans phase IIb iNO-PF trial for Pulmonary hypertention in 2018 [58] 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 [54] Updated 06 Jun 2017
15 May 2017 Scientific Update Efficacy data from a phase II trial in Pulmonary hypertension released by Bellerophon [52] Updated 29 May 2017
01 May 2017 Scientific Update Efficacy data from a phase II trial in Pulmonary hypertension released by Bellerophon [53] Updated 09 May 2017
13 Mar 2017 Trial Update Bellerophon withdraws prior to enrolemt the INOvation-2 study in Pulmonary hypertension [30] 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 [12] 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) [12] (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 [44] 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) [19] 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 [20] 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 [20] 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 [32] Updated 28 Mar 2016
15 Mar 2016 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
09 Feb 2016 Scientific Update Final efficacy and safety data from a phase II trial in Pulmonary arterial hypertension released by Bellerophon Therapeutics [35] 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 [22] Updated 20 Oct 2015
24 Sep 2015 Scientific Update Interim efficacy data from the phase II trial in Pulmonary hypertension released by Bellerophon [22] 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 [4] Updated 02 Aug 2015
15 May 2015 Trial Update Bellerophon Therapeutics plans a phase III trial for Pulmonary hypertension in USA [26] 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 [27] 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 [2] 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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  2. Bellerophon Therapeutics Completes Enrollment for its Phase 2 Trial of INOpulse(Rm) For Treatment of Pulmonary Arterial Hypertension (PAH).

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  11. Expanded Access: Pulsed, Inhaled Nitric Oxide (iNO) for the Treatment of Patients With Mild or Moderate Coronavirus Disease (COVID-19)

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  17. 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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  25. Bellerophon Therapeutics Announces Top-Line Results From PRESERVATION I Clinical Trial for Bioabsorbable Cardiac Matrix (BCM).

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  27. Bellerophon Reports 2014 Full Year Financial and Operational Results.

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  28. Bellerophon Therapeutics Strengthens Drug and Device Development Capabilities with Key Management Additions.

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  29. 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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  42. Bellerophon Reports Third Quarter 2016 Financial Results and Provides Business Update.

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  43. Bellerophon Reports Second Quarter 2016 Financial Results and Provides Business Update.

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  44. Bellerophon Receives Approval to Commence Phase 2 Trial in PH-COPD.

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  45. 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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  46. 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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  47. 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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  48. 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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  49. 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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  50. 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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  51. Bellerophon Receives Orphan Drug Designation for Nitric Oxide in the Treatment of Idiopathic Pulmonary Fibrosis.

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  52. Bellerophon Reports First Quarter 2017 Financial Results and Provides Business Update.

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  53. Bellerophon to Present Positive Clinical Data on INOpulse(Rm) at the American Thoracic Society 113th International Conference.

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  54. Positive Clinical Data on INOpulse(Rm) Presented at the American Thoracic Society 113th International Conference.

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  55. 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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  56. 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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  57. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL STUDY TO ASSESS THE SAFETY AND EFFICACY OF PULSED, INHALED NITRIC OXIDE (iNO) IN SUBJECTS WITH PULMONARY HYPERTENSION ASSOCIATED WITH PULMONARY FIBROSIS ON LONG TERM OXYGEN THERAPY (PART 1 AND PART 2)

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  58. 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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  59. 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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  60. 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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  61. 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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  62. 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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  63. 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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  64. 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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  65. 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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  66. 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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  67. Bellerophon Therapeutics Announces Pricing of Public Offering of Common Stock and Concurrent Registered Direct Offering.

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  68. Bellerophon Announces Closing of $15.3 Million Registered Direct Offering of Common Stock.

    Media Release
  69. 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
  70. Bellerophon to Host Key Opinion Leader Meeting Focused on Pulmonary Hypertension Associated with Interstitial Lung Disease.

    Media Release
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