DUBLIN—Can high-dose inhaled nitric oxide (NO) make a meaningful contribution to patients with COVID-19 infection? The FDA was sufficiently persuaded by the data presented by Bellerophon Therapeutics Inc. to grant it expanded access approval for its iNOpulse system for pulmonary delivery of NO. This means that the Warren, N.J.-based firm can start shipping its at-home system immediately. If it works – and there is, as yet, no clinical evidence to suggest that it does – it could help take at least some of the burden off the hospital system as the case load starts to climb.
“We’re in a dual track with the FDA,” Bellerophon CEO Fabian Tenenbaum told BioWorld. The company has also developed a clinical trial protocol, which is currently under review. The intention is to kickstart a trial to capture the safety and efficacy data that the rollout will generate.
Patients use the system for three one-hour sessions per day, which potentially opens up the possibility of sharing devices. The drug is shipped in a cartridge and patients – who undergo training – basically insert a nasal cannula and switch the device on. The system is intended for COVID-19 patients who do not yet require ventilator or extracorporeal membrane oxygenation support. Its use is at the discretion of the treating physician.
Bellerophon had been developing its pulsatile NO delivery system for pulmonary hypertension associated with chronic inflammatory and fibrotic lung diseases, such as interstitial lung disease, chronic obstructive pulmonary disease and sarcoidosis. In those settings, the clinical intent was to harness the vasodilatory properties of NO to reduce blood pressure in the affected arteries and to boost blood oxygenation. The company has been gearing up for a phase III trial of the drug-device combo in patients with PH associated with pulmonary fibrosis. “We have built a very significant inventory to support that trial,” Tenenbaum said.
The company started investigating the potential role of NO in treating COVID-19 in recent weeks. NO, which is a highly reactive endogenous signal molecule with a short half-life, also plays a role in the innate immune response against certain viral, bacterial and parasitic pathogens. Nitric oxide synthase, which is one of three enzymes responsible for its production, is induced by interferon-gamma, which is itself released following viral infection.
The company has drawn on external data to build its case, as well as its own data to demonstrate the safety and feasibility of using its system. “We developed this data over the last few weeks,” said Tenenbaum. “This has been healthy volunteer work to establish safe dosing.” The dose levels are multiples of those used in its chronic disease studies, but, he noted that “there is no systemic exposure.”
A group in Sweden reported more than a decade ago that NO interrupted the replication cycle of SARS-CoV, the virus responsible for the more limited 2002–2003 outbreak. They reported that a NO donor, S-nitroso-N-acetylpenicillamine, had a dose-dependent effect on SARS-CoV replication in vitro. The agent achieved a four-log reduction in viral replication at the highest dose. The data appeared in the February 2005 issue of the Journal of Virology, in a paper, titled “Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus.”
There is also some tentative clinical data to hand. Inhaled NO was studied in a small rescue trial in Beijing, during the last SARS outbreak. Patients who received NO in the unblinded but controlled study exhibited improved arterial oxygenation, which allowed for the reduction of oxygen therapy and airway pressure support, the trial investigators reported. The data appeared in the Nov. 15, 2004, issue of Clinical Infectious Diseases, in a study, titled “Inhalation of Nitric Oxide in the Treatment of Severe Acute Respiratory Syndrome: A Rescue Trial in Beijing.” Chest radiography also indicated a reduction in lung infiltrates – such as blood, protein or other biological material. The effects seen were maintained after cessation of NO therapy, which, the study authors suggest, is due to an antiviral as well as a vasodilatory effect.
Bellerophon is itself a small outfit but it has outsourced production of its iNOpulse systems to large contract manufacturers. “They are actively building our systems and are open for business,” Tenenbaum said. “We have hundreds in inventory and can build many more.”
Shares in the company (NASDAQ:BLPH) surged more 500% on opening March 20, ending the day at $18, up $14.61, or 431%, on the news. The stock had been in a slump due to the COVID-19 crisis, which makes clinical testing in patients with chronic pulmonary conditions challenging. In addition, the company, which has about $12 million in cash, needed to raise more to undertake the planned phase III trial. It still needs to raise financing, but it may not need to do so through an equity raise. “There are different avenues we can explore here,” Tenenbaum said.