Mallinckrodt plc is engaging with the U.S. FDA, NIH and the Biomedical Advanced Research and Development Authority to address the potential use of its INOmax (nitric oxide) inhaled gas to treat COVID-19-associated lung complications. INOmax is marketed in the U.S. by the Staines-upon-Thames, U.K.-based company to treat full- and near-term neonates with hypoxic respiratory failure associated with pulmonary hypertension.

In a very small study, it previously was tested to treat patients with severe acute respiratory syndrome-related coronavirus (SARS-CoV). It was found to improve oxygenation and reduce the necessary supplemental oxygen and ventilator support in SARS-CoV patients. INOmax also has been studied to treat acute respiratory distress syndrome (ARDS), which can result from a coronavirus or influenza virus infection and is characterized by fluid in the lungs and difficulty breathing. Mallinckrodt is in early discussions with FDA about the submission of an IND for a study of INOmax in coronavirus-associated ARDS.

Legal problems

Mallinckrodt had guided previously to lower 2020 sales for INOmax following a 2018 FDA approval for a generic competitor from Praxair Technologies Inc., known as Noxivent. The companies then were locked in a legal battle, which Mallinckrodt lost last August in a U.S. federal appeals court.

One Wall Street analyst said in a note earlier this month: “Regarding INOmax, management is essentially guiding to a decline of 10% to 15% compared [with] 2019, with the company noting that as it renegotiates customer contracts, it will be making significant concessions on price given the entry of the Praxair product,” concluded Piper Sandler analyst David Amsellem.

INOmax had $571 million in revenues in 2019, with an anticipated $488 million projected for 2020 by Piper Sandler with further declines going forward due to the loss of exclusivity.

Shares of Mallinckrodt (NYSE:MNK) at first surged on the COVID-19 news, but then retreated again. It remains a small-cap stock with a market valuation of about $255 million.

This isn’t Mallinckrodt’s only significant legal battle; it also is involved in ongoing opioid abuse litigation in the U.S. But despite its loss of exclusivity with INOmax, one of its top products, and the ongoing opioid overhang that includes an anticipated upcoming bankruptcy for its specialty generics business, the company now is turning to COVID-19 as a potential means of reinvigoration.

"Mallinckrodt is evaluating the limited data presently available on inhaled nitric oxide [INO] as a supportive measure for treating coronavirus-associated lung complications," said Steve Romano, executive vice president and chief science officer at Mallinckrodt. "We are in ongoing discussions with scientific, regulatory and governmental organizations regarding the potential use of [INO] in assisting with this global emergency and are committed to determining whether [INO] has a benefit for those diagnosed with COVID-19. We will share updates as information becomes available."

COVID-19 trials ramp up

While INOmax and Noxivent only are approved for use in infants, there are additional suppliers of INO gases for medical use. Four potential clinical trials to examine the use of INO to treat COVID-19 patients were posted on Clinicaltrials.gov early this month in severe patients and in mild-to-moderate patients.

The trials are not yet enrolling patients, according to the records that were all updated within the last week. Each is a randomized, controlled trial against the standard of care that’s slated to enroll roughly 100 to 200 patients. Sponsors and collaborators in the trials include Xijing Hospital in Xi'an, China; Massachusetts General Hospital in Boston; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico in Milan, Italy, and Niguarda Hospital, which is also in Milan.

“The new coronavirus (2019-nCoV) infection (COVID-19) is highly contagious and responsible for thousands of casualties. Originated in Wuhan (China), the 2019-nCoV is spreading to many countries, including Italy, Korea and Japan,” summed up one trial record. “While no targeted-treatment against 2019-nCoV virus is available to-date, [INO] gas … has shown antiviral activity against Coronavirus during the 2003 SARS outbreak. The investigators designed this study to assess whether [INO] improves survival in patients affected with severe COVID-2019.”

The researchers note that in China the reported COVID-19 fatality rate has been 2.2%. Roughly one-quarter of hospitalized COVID-19 patients required admissions to the intensive care unit, and, of these, roughly 61% met the clinical criteria for ARDS.

They also observe that in 2004, research found that INO reversed pulmonary hypertension, improved severe hypoxia and shortened the length of ventilatory support for SARS-CoV patients. Another study found that INO could have an antiviral effect because it “greatly increased” the survival rate of SARS-CoV-infected eukaryotic cells.

Mallinckrodt points to similar data, specifically noting that in SARS-CoV, a six-person study with eight controls found that INO offered improvements in blood oxygenation, a reduction in supplemental oxygen and a reduction in the amount of ventilator support.

ARDS, regardless of its infectious cause, also has been studied with INO. One study in adults and pediatric patients found a partially dose-dependent improvement in blood oxygenation and decreased pulmonary artery pressure.

Any mechanisms of action in COVID-19 patients aren’t quite clear yet, but researchers offer some speculation, “Nitric oxide is a selective pulmonary vasodilator gas used in as a rescue therapy in refractory hypoxemia due to … ARDS,” summed up another trial record. “In-vitro and clinical evidence indicate that [INO] gas … also has antiviral activity against other strains of coronavirus.”

Thus far, physicians are trying a range of interventions, including various antiviral medications, in an effort to improve prospects for this rapidly transmitting and sometimes deadly virus. But treatment protocols remain far from established for the novel coronavirus.

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