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Nitric oxide - Mallinckrodt

Drug Profile

Nitric oxide - Mallinckrodt

Alternative Names: Ik 7001; IK-3001; IK-7001; INOflo; INOmax; INOmax Total Care; INOMAX® Total Care package; INOtherapy; INOVENT

Latest Information Update: 06 May 2020

At a glance

  • Originator Massachusetts General Hospital
  • Developer AGA Linde Healthcare; Ikaria Holdings; Mallinckrodt plc; Massachusetts General Hospital
  • 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; Reactive oxygen species modulators
  • Orphan Drug Status

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

    Yes - Pulmonary hypertension; Hypoxic respiratory failure
  • New Molecular Entity No

Highest Development Phases

  • Marketed Hypoxic respiratory failure; Pulmonary hypertension
  • Phase III Bronchopulmonary dysplasia; Pulmonary arterial hypertension
  • Clinical Phase Unknown Adult respiratory distress syndrome; Coronavirus infections
  • Preclinical Transplant rejection
  • Discontinued Heart failure; Reperfusion injury

Most Recent Events

  • 30 Apr 2020 Massachusetts General Hospital initiates enrolment in a clinical trial for Adult respiratory distress syndrome in USA
  • 12 Mar 2020 Clinical trials in Coronavirus infections before March 2020 (Inhalation)
  • 12 Mar 2020 Preclinical trials in Acute respiratory distress syndrome infections in United Kingdom (Inhalation)

Development Overview

Introduction

An inhaled nitric oxide therapy (INOmax®) is being developed by Mallinckrodt for the treatment of hypoxic respiratory failure in neonates. The inhaled formulation is designed for use in conjunction with mechanical ventilation devices. Inhaled nitric oxide was originally being developed by Ohmeda, a subsidiary of the BOC Group, and patents for the use of inhaled nitric oxide in the treatment of pulmonary disease were licensed from Massachusetts General Hospital. Inhaled nitric oxide acts as a selective pulmonary vasodilator by activating guanylate cyclase and thus stimulating cyclic guanosine monophosphate-induced vascular smooth muscle relaxation. The inhaled formulation causes no systemic vasodilation as it is rapidly inactivated by binding to haemoglobin in the bloodstream. The drug is launched for hypoxic respiratory failure in Australia, Canada, Czech Republic, Denmark, France, Germany, Greece, Ireland, Italy, Japan, Latin America, Malaysia, Netherlands, Poland, Portugal, Singapore, South Korea, Spain, Sweden, Switzerland and the US. It is also launched for pulmonary hypertension in Australia and Japan. Clinical development for the prevention of bronchopulmonary dysplasia in pre-term infants is underway in Europe. Clinical development for pulmonary arterial hypertension and pulmonary vasoreactivity is underway in Spain and United Kingdom. Early clinical development is underway for coronavirus (SARS-CoV-2) infections at undisclosed location and preclinical development is underway for acute respiratory distress syndrome due to COVID-2019 infections in the United Kingdom.

Novoteris is developing Thiolanox® [see Adis Insight Drug profile 800042955], using Mallinckrodt's high-concentration, 5000 PPM nitric oxide gas for inhalation canisters, for the treatment of cystic fibrosis, and mycobacterial infections.

As of June 2015, no recent reports of development have been identified for nitric oxide inhalation in bronchopulmonary dysplasia in the US and Canada and development in reperfusion injury and heart failure in the US and Germany, respectively, have also been discontinued.

Mallinckrodt also conducted clinical investigations of an inhaled nitric oxide via pulsed delivery by the INOpulse DS delivery system (as a drug-device combination product) in pulmonary arterial hypertension (PAH) and pulmonary hypertension secondary to chronic obstructive pulmonary disease (PH-COPD). The worldwide rights to INOpulse programmes in PAH, PH-COPD and pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF) were exclusively acquired by Bellerophon Therapeutics as part of Ikaria's spin-out of its some research and development assets and subsidiaries [see Adis Insight Drug profile 800040818].

In April 2014, Ikaria was acquired by Mallinckrodt [1] .

Company Agreements

Lee's Pharmaceutical entered into a strategic partnership agreement with Ikaria in November 2014 for the registration and commercialisation of the INOmax® Total Care package in China, Hong Kong, Macau and Taiwan. The financial terms of the agreement were not disclosed [2] .

Bellerophon Therapeutics acquired exclusive worldwide rights to INOpulse programmes in PAH, PH-COPD and PH-IPF from Ikaria Holdings in February 2014 following Ikaria's decision to spin-out some of its research and development assets and subsidiaries [3] .

In March 2007, Ikaria Holdings acquired INO Therapeutics from the Linde Group and the combined company was renamed Ikaria Holdings. The Linde Group retained equity in the new company and appears to be a market licensee for INOmax® [4] .

BOC Medical, a company within the Linde group, will distribute and market INOmax® in Australia through an alliance with Ikaria [5] .

Ikaria Holdings has an exclusive licence in North America to the INOvent® device.

The Japanese companies Sumitomo Seika Chemicals (Sumitomo Corporation) and Air Water Inc. are licensees for INOmax® in Japan.

In 1998, Ohmeda was sold by the BOC Group. In conjunction with the sale, the Finnish company Instrumentarium Corporation acquired the patent for the INOvent® device which is used for administration of Ohmeda's nitric oxide. INOvent® has been available in certain countries, including some EU countries, since 1998 and is currently available worldwide through the global sales network of Datex-Ohmeda (a subsidiary of Instrumentarium Corporation). INOvent® is developed and manufactured at Datex-Ohmeda's facility in Madison (Wisconsin, USA). Instrumentarium Corporation was acquired by GE Medical Systems (General Electric Company) in October 2003. In April 2004, GE Medical Systems merged with Amersham to form GE Healthcare, a subsidiary of General Electric Company.

Key Development Milestones

Ikaria launched a proprietary drug-delivery system, called INOmax DSIR, in February 2011 for the delivery of INOmax®. The device has improved connectivity, delivery and monitoring components compared with its predecessors. In November 2015, the US FDA cleared INOmax DSIR® Plus MRI device for delivery of INOmax® for inhalation during MRI procedures. The device provides uninterrupted inhaled nitric oxide treatment during diagnostic imaging [6] [7] .

Bronchopulmonary dysplasia (BPD)

as of June 2015, no recent reports of development for inhaled nitric oxide have been identified for prevention of BPD.

A phase III trial was completed in May 2014. The trial investigated prevention of BPD in preterm infants who require mechanical ventilation or positive pressure support during days 5-14 after birth (IK3001-BPD-301; NCT00931632). The primary endpoint of the randomised, double-blind, placebo-controlled trial was survival of patients without BPD at 36 weeks. The trial was initiated in November 2009 and enrolled 451 patients in the US and Canada [8] [9] .

A phase III trial of inhaled nitric oxide for the prevention of BPD in 110 ventilated preterm neonates was initiated in the US in January 2008 (NCT00569530). Patient enrolment was completed in January 2010. In December 2015, INO Therapeutics completed a phase III trial that investigated inhaled nitric oxide in premature infants requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 hours of birth (NCT00551642; INOT27). The trial, initiated in May 2005, assessed the safety and efficacy of inhaled nitric oxide in reducing the incidence of BPD in such patients. The trial enrolled 800 infants in Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden and the UK. The long term effects of therapy over seven years were also being evaluated. Ikaria reported disappointing efficacy results in October 2008 from this trial, stating that the dose of nitric oxide that was administered may not have been optimal. The company anticipate that additional studies would clarify the dosage issue [10] [11] .

Coronavirus infections

In April 2020, Mallinckrodt reported that the company and Novoteris has received approval from Health Canada to evaluate Novoteris' Thiolanox® [see Adis Insight Drug profile 800042955], for the treatment of COVID-2019 infections [12] .

In April 2020, Mallinckrodt reported that the company is supporting an investigator-initiated clinical study at Massachusetts General Hospital evaluating the potential benefits of inhaled nitric oxide as a treatment for pulmonary complications like acute respiratory distress syndrome in patients with COVID-2019 infections. The trial intends to evaluate the potential efficacy of inhaled nitric oxide to rapidly reverse hypoxemia [13] .

In March 2020, Mallinckrodt announced that the company is evaluating inhaled nitric oxide for the treatment of coronavirus (SARS-CoV-2) infections. The company has conducted a clinical trial, which evaluated inhaled nitric oxide in the treatment of six patients infected with SARS-CoV. Mallinckrodt has engaged with the US FDA, NIH and BARDA for the same. Mallinckrodt is evaluating inhaled nitric oxide for the treatment of COVID-19 infections. The company intends to file an IND application to support of the potential use of iNO in coronavirus-associated acute respiratory distress syndrome [14] .

Hypoxic respiratory failure (associated with pulmonary hypertension)

INOmax® has been launched in the EU, the US, Canada, Japan, Australia, Malaysia, Singapore, South Korea and Latin America, for the treatment of hypoxic respiratory failure in neonates.

INO Therapeutics (later Ikaria Holdings) launched INOmax® in the US in the first quarter of 2000 for the treatment of hypoxic respiratory failure in neonates. A clinical trial of INOmax® in neonates with respiratory failure and pulmonary hypertension has shown that use of INOmax® reduces the need for extracorporeal membrane oxygenation. This finding, together with the results of an earlier trial, provided the basis for the FDA's approval of INOmax®. INOmax® is the first and only FDA-approved pulmonary vasodilator. The US FDA cleared the INOvent® delivery system for commercial distribution in the US on 21 January 2000. Datex-Ohmeda has stated that INOvent® is the first delivery system to gain FDA clearance for use in nitric oxide inhalation therapy.

In December 1999, INOmax® received approval from the US FDA for the treatment of full-term and near-term (born at >34 weeks' gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension [15] . INOmax® is to be used in conjunction with ventilatory support and other appropriate therapeutic agents.

In the third quarter of 2001, INOmax® received approval to be used in the EU, in conjunction with ventilatory support, for the treatment of full-term and near-term (> 34 weeks' gestation) neonates with hypoxic respiratory failure associated with pulmonary hypertension. The product has since been launched in Europe.

In July 2008, Japan's Ministry of Health, Labour and Welfare (MHLW) approved inhaled nitric oxide (INOflo®) for the treatment of hypoxic respiratory failure with concurrent pulmonary hypertension in neonates [16] . In June 2008, the MHLW's Council on Drugs and Food Sanitation recommended the approval of INOflo® [17] . The product was granted orphan drug status in Japan, in July 2008 [16] . The product has also been approved in Singapore [17] .

INOmax® received approval in Australia in November 2007 for the treatment of hypoxic respiratory failure in newborns. The product was launched by BOC Medical in 2008. The product has been granted orphan drug status by the Therapeutic Goods Administration in Australia [16] [5] .

A phase III clinical trial has been completed in the US in which INOmax® has been used to treat hypoxic respiratory failure in children and adolescents ≤ 16 years old. The trial, which enrolled 350 patients, began in January 2002.

Pulmonary arterial hypertension

In July 2004, INO Therapeutics initiated a phase III trial to compare the number of patients with reversible pulmonary hypertension (vasoreactivity) after treatment with mixture of nitric oxide at 800ppm and 100% oxygen for inhalation as compared to 100% oxygen (INOT22; EudraCT2004-000625-30). The trial is designed to assess pulmonary vaso reactivity during Pulmonary Vasodilator Testing in infants, children and adolescents with idiopathic pulmonary arterial hypertension or chronic heart disease with pulmonary hypertension or cardiomyopathy. The randomised, open-label trial intend to recruit 150 patients in Spain and United Kingdom [18] .

Pulmonary hypertension (PH)

In April 2019, inhaled nitric oxide was approved in Australia by the Australian Therapeutic Goods Administration (TGA) for perioperative pulmonary hypertension in adults in conjunction with cardiovascular surgery [19] .

In October 2015, inhaled nitric oxide was approved in Japan by the Ministry of Health, Labour and Welfare (MHLW) for the treatment of peri- and post-operative pulmonary hypertension in conjunction with heart surgery in neonates through adults. It was also approved in Australia by the Australian Therapeutic Goods Administration (TGA) for peri- and post-operative pulmonary hypertension in conjunction with cardiovascular surgery in neonates through adolescents up to age 17 [20] .

In November 2014, nitric oxide was granted orphan drug designation for the treatment of pre-,peri- and postoperative pulmonary hypertension in adults and children (including newborns) in heart surgery in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation, by the Pharmaceuticals and Medical Devices Agency (PMDA), Japan (PMDA website, November 2014).

INOmax® therapy was being evaluated by AGA Linde Healthcare for a variety of severe pulmonary hypertension conditions of varied aetiology. While Linde does not appear to be pursuing development, the NIH (NIH Clinical Center and NHLBI) have completed phase I trials with inhaled nitric oxide in this area (NCT00098072, NCT00352430, NCT00023296).

A phase III trial investigating the efficacy of inhaled nitric oxide in patients with pulmonary hypertension associated with cardiac surgery was completed in July 2014. In the open-label trial, 18 patients of different age groups (from neonates to elderly) were enrolled in Japan (NCT01959828) [21] .

Ischaemia-reperfusion injury

a phase II/III trial of inhaled nitric oxide to prevent ischaemia-reperfusion injury associated with restoration of blood flow after liver transplantation began in the US in April 2008 in approximately 40 subjects (NCT00582010). The trial was completed in October 2012; however the indication is not listed on company pipeline since January 2012 and it appears that the development in this indication has been discontinued [22] .

A phase III trial in the US was to evaluating the effects of inhaled nitric oxide on short term physiology and the development of ischaemia-reperfusion lung injury post lung transplant (NCT00060450). However, it was terminated because of slow enrolment.

Other indications

INO Therapeutics (later Ikaria Holdings) completed phase III controlled clinical trials of INOmax® in the treatment of adult respiratory distress syndrome (ARDS). It is unclear whether development is continuing in this indication.

INO Therapeutics completed a phase II trial of inhaled nitric oxide for congestive heart failure in July 2009 (NCT00060840). The trial, conducted in the US and Germany, investigated the agent during left ventricular assist device implantation following cardiopulmonary bypass. It appears that Mallinckrodt is no longer developing inhaled nitric oxide in this indication.

Mallinckrodt terminated a pilot phase I/II trial, due to slow patient enrolment (n = 7), which was designed to evaluate the physiologic efficacy (rather than effect on clinical outcomes) of nitric oxide administered by hood in improving oxygenation of neonates (aged up to 120 hours) with elevated A-a DO2 (CARLW1; NCT00041548). The randomised, double-blind, parallel, US-based trial was initiated in May 2002 [23] .

INOPulse programmes

In February 2014, Bellerophon Therapeutics acquired exclusive worldwide rights to Ikaria Holdings' INOpulse (drug-device) programmes to Bellerophon Therapeutics [3] . [See RDI profile 800040818].

Ikaria Holdings conducted clinical investigation for use of nitric oxide inhalation delivered via pulsed delivery with the INOpulse DS for the treatment of PH and pulmonary arterial hypertension (PAH).

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 [24] [3] .

In January 2012, Ikaria announced that 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 pulmonary hypertension. Ikaria submitted an IND to the FDA in November 2011. Ikaria's PAH development programme is known as IK-7001 [25] .

Chronic obstructive pulmonary disease (COPD)

a phase II trial was planned to investigate inhaled nitric oxide, delivered using the INOpulse device, for the treatment of COPD [26] .

Patent Information

Mallinckrodt holds total 17 patents listed in the US FDA Orange Book covering gas delivery systems as well as methods of using such systems related to INOMAX® (nitric oxide) gas, for inhalation.

Patent disputes

In September 2016, the U.S. Patent and Trademark Office (USPTO) has confirmed the validity of five of those 17 patents, that expire in 2031; reinforcing Mallinckrodt's intellectual property rights. The USPTO decision was the result of Inter Partes Review (IPR) proceedings, instituted by the Patent Trial and Appeal Board (PTAB) following petitions filed by Praxair Distribution [27] .

In September 2016, a second set of petitions filed by Praxair Distribution for IPR proceedings concerning four of five patents that expire in 2029 and cover use of a drug like INOMAX®, was dismissed by the PTAB. Praxair's first request made in July 2015, to institute IPR proceedings on these four patents was also dismissed by the PTAB [27] .

The PTAB instituted an IPR proceeding for the fifth patent expiring in 2029, U.S. patent no. 8,846,112 (the '112 patent) that relates to distribution of a drug like INOMAX in conjunction with its approved labelling. The validity of the patent was confirmed by the PTAB in July 2016. Further, in August 2016, the PTAB had reached a final decision regarding the validity of the claims of that patent. But, Praxair has filed an appeal of this PTAB decision to the U.S. Court of Appeals for the Federal Circuit, and Mallinckrodt subsequently filed a cross-appeal [27] .

In February and March 2016, the USPTO granted two new US patents protecting delivery of nitric oxide utilizing devices like Mallinckrodt'sINOmax DSIR® delivery system, expiring in 2031, and the third new US patent relating to the use of nitric oxide gas sensors, expiring in 2034. These three INOMAX new patents were listed in the FDA Orange Book for INOMAX and added to the company's pending patent litigation against Praxair in the U.S. District Court for the District of Delaware [27] .

Drug Properties & Chemical Synopsis

  • Route of administration Inhalation, Parenteral
  • Formulation Inhalant, Liquid, 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; 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

    C01 (Cardiac Therapy)

    C04A (Peripheral Vasodilators)

    J05 (Antivirals for Systemic Use)

    R07A-X01 (Nitric oxide)

  • EPhMRA code

    C1 (Cardiac Therapy)

    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 - Mallinckrodt 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
Adult respiratory distress syndrome in patients with COVID-2019 infections - Clinical Phase Unknown USA Inhalation / Inhalant Mallinckrodt plc, Massachusetts General Hospital 30 Apr 2020
Adult respiratory distress syndrome in COVID-2019 patients - Preclinical United Kingdom Inhalation / Inhalant Mallinckrodt plc 12 Mar 2020
Bronchopulmonary dysplasia - In neonates, Prevention Phase III Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom Inhalation / Inhalant Mallinckrodt plc 01 May 2005
Bronchopulmonary dysplasia - In neonates, Prevention No development reported (III) Canada, USA Inhalation / Inhalant Mallinckrodt plc 10 Jun 2015
Coronavirus infections - - Clinical Phase Unknown Unknown Inhalation / unspecified Mallinckrodt plc 12 Mar 2020
Heart failure - - Discontinued (II) Germany, USA Inhalation / Inhalant Ikaria Holdings 29 Dec 2011
Hypoxic respiratory failure - In neonates Marketed Australia, Czech Republic, Japan, Malaysia, Singapore, South Korea, USA Inhalation / Inhalant Mallinckrodt plc 19 Nov 2014
Hypoxic respiratory failure - In neonates Marketed Denmark, France, Germany, Greece, Ireland, Italy, Netherlands, Poland, Portugal, Spain, Sweden, Switzerland Inhalation / Inhalant AGA Linde Healthcare 31 Dec 2001
Hypoxic respiratory failure - In neonates Marketed Canada, Latin America Inhalation / Inhalant 30 Nov 2007
Pulmonary arterial hypertension Reactivity of the pulmonary vasculature Combination therapy, In adolescents, In children, In infants Phase III Spain, United Kingdom Inhalation / Inhalant Mallinckrodt plc 21 Jul 2004
Pulmonary hypertension associated with cardiac surgery in neonates through adults In adolescents, In children, In neonates Marketed Australia Inhalation / Inhalant Mallinckrodt plc 02 Nov 2015
Pulmonary hypertension for perioperative pulmonary hypertension in adults in conjunction with cardiovascular surgery In adults Marketed Australia Inhalation / Inhalant Mallinckrodt plc 12 Apr 2019
Pulmonary hypertension associated with cardiac surgery in neonates through adults - Marketed Japan Inhalation / Inhalant Mallinckrodt plc 02 Nov 2015
Reperfusion injury during liver transplantation Prevention Discontinued (II/III) USA Inhalation / Inhalant Ikaria Holdings 12 Jun 2014
Transplant rejection - - Preclinical USA Parenteral / Liquid Mallinckrodt plc 01 Apr 2019

Orphan Status

Indication Patient Segment Country Organisation Event Date
Hypoxic respiratory failure In neonates Australia Mallinckrodt plc 27 Nov 2007
Hypoxic respiratory failure In neonates Japan Mallinckrodt plc 21 Jul 2008
Pulmonary hypertension In adolescents, In adults, In children, In infants, In neonates Japan INO Therapeutics 20 Nov 2014
Pulmonary hypertension - USA Mallinckrodt plc 23 Jan 2012

Commercial Information

Involved Organisations

Organisation Involvement Countries
Massachusetts General Hospital Originator USA
Massachusetts General Hospital Owner USA
AGA Linde Healthcare Market Licensee Australia, European Union
Sumitomo Seika Chemicals Market Licensee Japan
Air Water Inc Market Licensee Japan
Lee's Pharmaceutical Market Licensee China, Hong Kong, Macau, Taiwan
Mallinckrodt plc Licensee World
Novoteris Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
INOVENT Mallinckrodt plc Pulmonary hypertension Japan
INOflo Mallinckrodt plc Hypoxic respiratory failure, Pulmonary hypertension Japan
INOmax AGA Linde Healthcare, Mallinckrodt plc Hypoxic respiratory failure, Pulmonary hypertension Australia, European Union, Latin America, USA
INOmax Total Care Lee's Pharmaceutical Hypoxic respiratory failure Asia
INOtherapy Mallinckrodt plc Adult respiratory distress syndrome Canada

Scientific Summary

Adverse Events

In neonates with hypoxic respiratory failure, inhaled nitric oxide therapy has been well tolerated. No systemic hypotension has been observed but therapy has been associated with an increase in methaemoglobin levels. In one study, the dosage of nitric oxide was reduced in 11/141 patients because of increases in methaemoglobin levels of 5-10% [32] [31] .

Therapeutic Trials

Bronchopulmonary dysplasia

there was no significant difference in efficacy between the treatment and control groups in a phase III trial (INOT27) of inhaled nitric oxide for the treatment of bronchopulmonary dysplasia in preterm infants. 800 such infants (gestational age range 24 to 28 weeks) who were administered surfactant within 24h of birth or received continuous positive airway pressure (CPAP) to maintain oxygen saturation of ≥85%, were assigned to treatment with inhaled nitric oxide or nitrogen gas. Both inhaled therapies were administered as 5 ppm for 7-21 days. The primary endpoint, survival without bronchopulmonary dysplasia, was fulfilled in 65.3% of nitric oxide recipients and 65.5% of nitrogen recipients; the difference was not statistically significant [10] .

Hypoxic respiratory failure

a multicentre US trial showed that inhaled nitric oxide reduced the need for extracorporeal membrane oxygenation among neonates with hypoxic respiratory failure, but did not reduce the mortality rate. In the study, 235 neonates born at ≥ 34 weeks gestation who had hypoxic respiratory failure were randomised to inhaled nitric oxide (800 ppm in nitrogen) in the inspiratory circuit of the ventilator or 100% oxygen. The incidence of the combined outcome of death by 120 days of age or the need for extracorporeal membrane oxygenation was significantly lower among nitric oxide recipients (46% vs 64%). However, the mortality rate was similar in the 2 groups (14% vs 17%). Improvement in arterial oxygen tension and oxygenation index was greater in the active treatment group [32] .

A second US multicentre trial, this time in the subgroup of neonates with hypoxic respiratory failure due to persistent pulmonary hypertension, showed that inhaled nitric oxide improved systemic oxygenation. Neonates who required mechanical ventilation were randomised to nitric oxide (800-1000 ppm in nitrogen) or nitrogen, with the concentration adjusted according to arterial oxygen tension. The trial was stopped early after enrolment of 58 patients when it was found that nitric oxide produced a significant improvement in oxygenation (53% improved vs 7% of controls). Long term nitric oxide therapy sustained systemic oxygenation in 75% of patients who had initial improvement. Significantly fewer nitric oxide recipients than nitrogen-only recipients required extracorporeal membrane oxygenation (40% vs 71%). Mortality was similar in the two groups [31] .

In a study which was supported in part by INO Therapeutics, 248 neonates aged ≤4 days who had persistent pulmonary hypertension of the newborn and severe respiratory failure requiring mechanical ventilation and who were born at a gestational age of >34 weeks, were randomised to receive reducing doses of inhaled nitric oxide (NO; n = 126) or nitrogen (controls) starting at 20 parts per million (ppm). The NO or nitrogen dose was reduced to 5ppm after 4h if the neonate was stable, had an arterial oxygen tension value of ≥60mm Hg and the pH was ≤7.55. Otherwise, study drug was maintained at 20ppm until the criteria were met or 24h had elapsed, then reduced to 5ppm until the inspired oxygen fraction was <0.7, treatment had been administered for 96h, or the neonate was 7 days old. Overall, significantly fewer NO recipients, compared with controls, used extracorporeal membrane oxygenation (38% vs 64% of patients, respectively). Following stratification by diagnosis, only NO recipients with congenital diaphragmatic herniation did not show a reduction in the use of extracorporeal membrane oxygenation. Chronic lung disease developed in significantly fewer NO recipients, compared with controls (7% vs 20% of patients, respectively). 30-day mortality was similar for NO recipients and controls (7% vs 8%, respectively); the between-group difference was not significant [30] .

Neonatal respiratory distress syndrome

in a study funded by INO Therapeutics, low-dose inhaled nitric oxide (NO) therapy was investigated in 207 premature neonates with respiratory distress syndrome aged <72h who were born at <34 weeks' gestation at a bodyweight of <2000g. The neonates were randomised to receive inhaled NO [INOmax®] or oxygen placebo for 7 days, plus either intermittent mandatory ventilation or high-frequency oscillatory ventilation. NO was administered at a dosage of 10 ppm for 12−24h followed by 5 ppm for the remaining 6 days. Compared with oxygen placebo, NO significantly reduced the combined incidence of death or chronic lung disease (63.7% vs 48.6% of neonates). There was no apparent interaction between treatment and birthweight. However, there was a significant interaction between treatment and disease severity. Specifically, compared with oxygen placebo, NO significantly reduced the incidence of death or chronic lung disease in neonates with an initial oxygenation index below the median (67.3% vs 36% of neonates), but not in those with an initial oxygenation index at or above the median (58.3% vs 58.8%, respectively). In addition, NO significantly reduced the incidence of severe intraventricular haemorrhage and periventricular leukomalacia, relative to oxygen placebo [28] .

Pharmacoeconomic studies

a cost-effectiveness analysis was conducted of the Canadian Inhaled Nitric Oxide Study (CINOS), in which 96 neonates of ≥34 weeks gestation requiring ventilation were randomly assigned to receive inhaled nitric oxide (n = 49) or oxygen. Costs and outcomes were assessed from baseline to 18−24 months' follow-up. Twenty neonates died, of which 13 were in the oxygen arm; the between-group difference was not significant. Per-patient costs were greater in the nitric oxide, than the oxygen, arm over the study period ($Can23 907 vs $Can19 105), with the majority of costs in both groups occurring during the initial hospitalisation; again, the between-group difference was nonsignificant. Costs (Canadian dollars; $Can1 = $US0.67) were those related to hospitalisation, medications, neonatal intensive care, extracorporeal membrane oxygenation, physician services, surfactant, air transport and all government and family private costs beyond normal care in the first 18−24 months of life. Costs were calculated using a modified societal perspective and second-year costs were discounted at a rate of 5% per annum. Costs incurred between discharge and follow-up were approximately $Can300 higher among oxygen, than among nitric oxide, recipients. The majority of this cost difference, although not significant, was represented by higher medication costs and costs associated with medical services. The researchers noted that although the overall difference in costs between the two groups was not statistically significant, there was a "general trend toward better outcomes for nitric oxide", with a significant reduction in seizure disorders of around 20%, compared with oxygen therapy [29] .

Development History

Event Date Update Type Comment
30 Apr 2020 Trial Update Massachusetts General Hospital initiates enrolment in a clinical trial for Adult respiratory distress syndrome in USA [13] Updated 06 May 2020
12 Mar 2020 Phase Change - Clinical Clinical trials in Coronavirus infections before March 2020 (Inhalation) [14] Updated 18 Mar 2020
12 Mar 2020 Phase Change - Preclinical Preclinical trials in Acute respiratory distress syndrome infections in United Kingdom (Inhalation) [14] Updated 18 Mar 2020
12 Mar 2020 Regulatory Status Mallinckrodt intends to submit an IND application to the US FDA for Acute respiratory distress syndrome associated with coronavirus infections [14] Updated 18 Mar 2020
16 Apr 2019 Phase Change - Registered Registered for Pulmonary hypertension (In adults) in Australia (Inhalation) [19] Updated 16 Apr 2019
12 Apr 2019 Phase Change - Marketed Launched for Pulmonary hypertension (In adults) in Australia (Inhalation) [19] Updated 03 May 2019
01 Apr 2019 Phase Change - Preclinical Preclinical trials in Transplant rejection in USA (Parenteral) before April 2019 (Mallinckrodt pipeline, April 2019) Updated 16 Apr 2019
14 Feb 2019 Other Chemical structure information added Updated 14 Feb 2019
23 Sep 2016 Patent Information Mallinckrodt has patent protection for nitric oxide inhalation and gas delivery systems in USA [27] Updated 25 Oct 2016
23 Sep 2016 Patent Information Praxair files an appeal against the Patent Trial and Appeal Board decision related to the US patent no. 8 846 112 in U.S. Court of Appeals for the Federal Circuit and Mallinckrodt also files a cross-appeal [27] Updated 25 Oct 2016
23 Sep 2016 Patent Information The US Patent and Trademark Office confirms the validity of five 2031 patents protecting nitric oxide inhalation [27] Updated 25 Oct 2016
22 Sep 2016 Patent Information The Patent Trial and Appeal Board dismisses a set of petitions filed by Praxair Distribution concerning four nitric oxide inhalation patents that expire in 2029 [27] Updated 25 Oct 2016
25 Aug 2016 Patent Information The Patent Trial and Appeal Board dismisses a petition filed by Praxair Distribution concerning the US patent no. 8 846 112 [27] Updated 25 Oct 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
15 Mar 2016 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
01 Dec 2015 Trial Update Mallinckrodt completes a phase-III trial in Bronchopulmonary dysplasia (In neonates, Prevention) in Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom (Inhalation) (NCT00551642) Updated 26 Dec 2016
02 Nov 2015 Phase Change - Marketed Launched for Pulmonary hypertension (In adolescents, In children, In neonates) in Australia (Inhalation) [20] Updated 03 May 2019
02 Nov 2015 Phase Change - Marketed Launched for Pulmonary hypertension in Japan (Inhalation) [20] Updated 03 May 2019
30 Oct 2015 Phase Change - Registered Registered for Pulmonary hypertension (In neonates, In children, In adolescents) in Australia (Inhalation) Updated 03 Nov 2015
30 Oct 2015 Phase Change - Registered Registered for Pulmonary hypertension in Japan (Inhalation) Updated 03 Nov 2015
29 Oct 2015 Phase Change - Preregistration Preregistration for Pulmonary hypertension in Australia (Inhalation) Updated 03 Nov 2015
29 Oct 2015 Phase Change - Preregistration Preregistration for Pulmonary hypertension in Japan (Inhalation) Updated 03 Nov 2015
10 Jun 2015 Phase Change - No development reported(III) No recent reports on development identified - Phase-III for Bronchopulmonary dysplasia (In neonates, Prevention) in Canada and USA (Inhalation) Updated 10 Jun 2015
16 Apr 2015 Company Involvement Ikaria Holdings has been acquired by Mallinckrodt plc Updated 20 Apr 2015
20 Nov 2014 Regulatory Status Nitric oxide - Mallinckrodt receives Orphan Drug status for Pulmonary hypertension (In adults, In children, In infants, In neonates, In adolescents) in Japan (PMDA website, November 2014) Updated 17 Mar 2020
19 Nov 2014 Licensing Status Nitric oxide inhalation licensed to Lee's Pharmaceutical in China, Hong Kong, Macau & Taiwan [2] Updated 21 Nov 2014
19 Nov 2014 Phase Change - Marketed Launched prior to this date for Hypoxic respiratory failure (In neonates) in South Korea (Inhalation) Updated 21 Nov 2014
01 Jul 2014 Trial Update INO Therapeutics completes a phase III trial in Pulmonary hypertension in Japan (NCT01959828) Updated 28 May 2015
12 Jun 2014 Phase Change - Discontinued(II/III) Discontinued - Phase-II/III for Reperfusion injury (prevention) in USA (Inhalation) Updated 12 Jun 2014
23 May 2014 Trial Update Ikaria Holdings completes enrolment in its phase II trial for Pulmonary hypertension (INOpulse) in USA and Canada (NCT01457781) Updated 09 Jun 2014
01 May 2014 Trial Update Ikaria Holdings completes a pivotal phase III trial in Bronchopulmonary dysplasia prevention in USA and Canada (NCT00931632) Updated 01 Sep 2015
28 Feb 2014 Licensing Status Bellerophon Therapeutics acquires exclusive worldwide rights from Ikaria to INOpulse programmes in pulmonary arterial hypertension and pulmonary hypertension associated with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis [3] Updated 20 Jun 2014
01 Sep 2013 Phase Change - III Phase-III clinical trials in Pulmonary hypertension (associated with cardiac surgery) in Japan (Inhalation) Updated 29 Nov 2013
31 Oct 2012 Trial Update Mallinckrodt completes a phase II/III trial for Reperfusion injury prevention (in patients undergoing liver transplantation) in USA (NCT00582010) Updated 05 May 2016
19 Apr 2012 Phase Change - II Phase-II clinical trials in Pulmonary hypertension in Canada (Inhalation, INOpulse) Updated 29 Nov 2013
19 Apr 2012 Phase Change - II Phase-II clinical trials in Pulmonary hypertension in USA (Inhalation; INOpulse) Updated 29 Nov 2013
28 Feb 2012 Trial Update Ikaria Holdings completes patient enrolment in a pivotal phase III trial for Bronchopulmonary dysplasia prevention in USA and Canada (NCT00931632) Updated 28 Feb 2012
25 Jan 2012 Phase Change - No development reported(II/III) No development reported - Phase-II/III for Reperfusion injury (prevention) in USA (Inhalation) Updated 12 Jun 2014
23 Jan 2012 Regulatory Status Nitric oxide inhalation in combination with the INOpulse DS system receives Orphan Drug status for Pulmonary hypertension in USA Updated 25 Jan 2012
29 Dec 2011 Phase Change - Discontinued(II) Discontinued - Phase-II for Congestive heart failure in Germany (Inhalation) Updated 29 Dec 2011
29 Dec 2011 Phase Change - Discontinued(II) Discontinued - Phase-II for Congestive heart failure in USA (Inhalation) Updated 29 Dec 2011
30 Nov 2011 Regulatory Status Ikaria Holdings files an IND application with the FDA in USA for Pulmonary arterial hypertension [25] Updated 25 Jan 2012
19 Aug 2010 Active Status Review A phase II/III trial (NCT00582010) in Reperfusion injury prevention (in patients undergoing liver transplantation) is ongoing in USA Updated 19 Aug 2010
18 Aug 2010 Active Status Review Phase-III development is ongoing for Adult respiratory distress syndrome in USA Updated 19 Aug 2010
18 Aug 2010 Active Status Review Phase-III development is ongoing for Bronchopulmonary dysplasia (Prevention, In neonates) in USA and European Union Updated 18 Aug 2010
09 Jun 2010 Trial Update Mallinckrodt terminates a pilot phase I/II trial for Respiratory disorders (In neonates) in USA due to slow enrolment (Inhalation) before June 2010 (NCT00041548) Updated 02 May 2016
09 Jun 2010 Trial Update INO Therapeutics completes a phase II trial (NCT00060840) in Congestive heart failure in USA and Germany Updated 19 Aug 2010
11 Jan 2010 Trial Update Ikaria Holdings completes enrolment in a phase III (TOLSURF Pilot) study in Bronchopulmonary dysplasia in USA Updated 03 Mar 2010
30 Nov 2009 Phase Change - III Phase-III clinical trials for prevention of Bronchopulmonary dysplasia (in preterm infants) in Canada (Inhalation) Updated 29 Dec 2011
31 Oct 2009 Phase Change - Marketed Launched for Hypoxic respiratory failure in Japan (Inhalation) Updated 19 Aug 2010
31 Oct 2009 Phase Change - Marketed Launched for Hypoxic respiratory failure in Malaysia (Inhalation) Updated 19 Aug 2010
31 Oct 2009 Phase Change - Marketed Launched for Hypoxic respiratory failure in Singapore (Inhalation) Updated 19 Aug 2010
25 Oct 2008 Scientific Update Efficacy data from a Phase-III trial in Bronchopulmonary dysplasia released by Ikaria Holdings [10] Updated 01 Nov 2008
21 Jul 2008 Phase Change - Marketed Launched for Hypoxic respiratory failure in Australia (Inhalation) Updated 10 Feb 2009
21 Jul 2008 Phase Change - Registered Registered for Hypoxic respiratory failure in Japan (Inhalation) Updated 10 Feb 2009
21 Jul 2008 Regulatory Status Nitric oxide inhalation - Ikaria Holdings received Orphan Drug status for Hypoxic respiratory failure in Japan Updated 10 Feb 2009
23 Jun 2008 Regulatory Status Japan's Council on Drugs and Food Sanitation recommends approval of nitric oxide inhalation for newborn children with hypoxic respiratory failure in Japan Updated 23 Jun 2008
18 Jun 2008 Phase Change - Registered Registered for Hypoxic respiratory failure in Singapore (Inhalation) Updated 10 Feb 2009
30 Apr 2008 Phase Change - II/III Phase-II/III clinical trials in Reperfusion injury in USA (Inhalation) Updated 01 Nov 2008
31 Jan 2008 Phase Change - III Phase-III clinical trials in Bronchopulmonary dysplasia in USA (Inhalation) Updated 01 Nov 2008
30 Nov 2007 Phase Change - Marketed Launched for Hypoxic respiratory failure in Latin America (Inhalation) Updated 30 Nov 2007
28 Nov 2007 Phase Change - Registered Registered for Hypoxic respiratory failure in Australia (Inhalation) Updated 30 Nov 2007
27 Nov 2007 Regulatory Status Nitric oxide inhalation - Ikaria Holdings received Orphan Drug status for Hypoxic respiratory failure in Australia Updated 10 Feb 2009
01 Oct 2007 Company Involvement INO Therapeutics has merged with Ikaria to form Ikaria Holdings Updated 01 Oct 2007
30 Sep 2005 Phase Change - Marketed Launched for Hypoxic respiratory failure in Canada (Inhalation) Updated 30 Nov 2007
01 May 2005 Phase Change - III Phase-III clinical trials in Bronchopulmonary dysplasia (In neonates, Prevention) in Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom (Inhalation) (NCT00551642) Updated 26 Dec 2016
21 Jul 2004 Phase Change - III Phase-III clinical trials in Pulmonary arterial hypertension (Combination therapy, In infants, In children, In adolescents) in Spain and United Kingdom (Inhalation) (EudraCT2004-000625-30) Updated 06 Sep 2019
17 Apr 2004 Company Involvement GE Medical Systems has merged with Amersham to form GE Healthcare Updated 17 Apr 2004
30 Dec 2003 Scientific Update A study has been added to the Respiratory Tract Disorders therapeutic trials section [28] Updated 30 Dec 2003
30 Jun 2003 Phase Change - II Phase-II clinical trials in Congestive heart failure in Germany (Inhalation) Updated 29 Dec 2011
30 Jun 2003 Phase Change - II Phase-II clinical trials in Congestive heart failure in USA (Inhalation) Updated 30 Nov 2007
31 May 2003 Phase Change - III Phase-III clinical trials in Reperfusion injury in USA (Inhalation) Updated 30 Nov 2007
31 Dec 2002 Phase Change - Preregistration Preregistration for Hypoxic respiratory failure in Japan (Inhalation) Updated 30 Dec 2003
04 Dec 2002 Scientific Update A cost-effectiveness study has been added to the Respiratory Tract Disorders therapeutic trials section [29] Updated 04 Dec 2002
01 May 2002 Trial Update Mallinckrodt initiates a pilot phase I/II trial for Respiratory disorders (In neonates) in USA (Inhalation) (NCT00041548) Updated 02 May 2016
31 Dec 2001 Phase Change - Marketed Launched for Hypoxic respiratory failure (In neonates) in Czech Republic, Netherlands, Ireland, Spain, Portugal, Poland, Italy, Germany, Switzerland, Sweden, Greece, France and Denmark (Inhalation) Updated 10 Jun 2015
31 Dec 2001 Phase Change - Marketed Launched for Hypoxic respiratory failure in European Union (Inhalation) Updated 30 Dec 2003
31 Aug 2001 Phase Change - Registered Registered for Hypoxic respiratory failure in European Union (Inhalation) Updated 31 Aug 2001
23 Nov 2000 Other Sumitomo Seika Chemicals and Air Water Inc. are licensees in Japan for INOmax® Updated 23 Nov 2000
15 Mar 2000 Scientific Update A study in neonates with severe respiratory failure has been added to the Respiratory Tract Disorders therapeutic trials section [30] Updated 15 Mar 2000
01 Feb 2000 Phase Change - Marketed Launched for Hypoxic respiratory failure in USA (Inhalation) Updated 01 Feb 2000
31 Dec 1999 Phase Change Investigation in Adult respiratory distress syndrome in USA (Inhalation) Updated 31 Dec 1999
31 Dec 1999 Phase Change Investigation in Pulmonary hypertension in USA (Inhalation) Updated 31 Dec 1999
31 Dec 1999 Phase Change - Registered Registered for Hypoxic respiratory failure in USA (Inhalation) Updated 31 Dec 1999
18 Aug 1998 Other Nitric oxide inhaled - Ohmeda is now called Nitric oxide inhalation - Datex-Ohmeda/INO Therapeutics Updated 18 Aug 1998
06 Nov 1997 Phase Change - Preregistration Preregistration for Respiratory tract disorders in USA (Inhalation) Updated 06 Nov 1997

References

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