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    .
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     .
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  .
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                   .
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    .
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   .
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    . Final results from the study were released in February 2016  .
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  .
Ikaria submitted an IND application to the FDA in November 2011  .
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   .
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  .
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   .
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)          .
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     .
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  .
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  .
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  .
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)  .
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   . Bellerophone released topline data for the study in May 2017   . The study supported iNO 30 as a potentially safe and effective dose   .
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)   . 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      . 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    . 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)  . 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     . In December 2019, Bellerophon Therapeutics released the safety and efficacy data of the cohort B of the trial   .
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  .
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  .