On April 29, the INOwill N200 nitric oxide inhalation therapy instrument of Nuoling Biogen was approved by the State Food and Drug Administration for the registration of class III medical devices, and officially entered the clinical commercial application. This is the first approved medical grade nitric oxide gas treatment equipment in China, which combines the functions of instant occurrence, real-time monitoring and intelligent integration of high-end medical devices on demand, and is also the first approved instant nitric oxide treatment equipment based on electrochemical catalysis in the world. The approval of this product has achieved a breakthrough of domestic original zero, opening a new era in the global nitric oxide gas treatment blue ocean market.
Nitric oxide (NO) is the first endogenous gas molecule to be found to be involved in cell signaling, which is widely present in the human body and is involved in a variety of physiological processes. The mechanism of no gas molecules to dilate blood vessels made a major breakthrough at the end of the last century and won the Nobel Prize in 1998; in the years since, clinical studies have successively revealed the relevant mechanism of NO as an endogenous gas signaling molecule, confirming the important physiological role of NO in promoting vasodilation, anti-infection, stimulating soft tissue regeneration, and preventing platelet adhesion.
Nitric oxide (NO) inhalation therapy is an emerging gas therapy that began to develop in the 1990s. In 1999, the world's first cylinder NO transmitter INOmax obtained THE FDA certification in the United States, opening a chapter in the commercialization of NO medical treatment. Since then, NO inhalation therapy has been widely used in clinical practice at home and abroad, which can effectively reduce the fatality rate of related diseases and become one of the important first aid methods in the ICU. Indications are also defined by treatment of neonatal persistent pulmonary hypertension, acute respiratory distress syndrome (ARDS), acute pneumonia, bronchial asthma, inhalation lung injury, and tumor expansion into COVID-19.
During the epidemic period, NO inhalation therapy has attracted much attention in the international market, and NO inhalation therapy from international companies such as Bellerophon and VERO Biotech has been approved by the FDA for the treatment of COVID-19. Especially in the acute and severe treatment of pulmonary hypertension and respiratory failure, the effectiveness and safety of NO inhalation therapy have been highly unanimously recognized by clinical experts at home and abroad, and have formed departmental guidelines and recommendations.
Up to now, NO inhalation therapy and other topical therapies still need to use NO gas cylinders with complex drug delivery systems to regulate and monitor the concentration of NO, and defects in convenience, safety and economic accessibility restrict the application and development of NO gas therapy.
As the first medical-grade electrochemical catalytic nitric oxide gas treatment equipment in China and internationally, INOwill N200 can not only achieve instant nitric oxide gas, but also accurately regulate NO concentration, meet major clinical needs, fill domestic gaps, and provide revolutionary options for the NO gas inhalation treatment market at home and abroad.
There is a strong demand for gas inhalation therapy,
Nitric Oxide Therapy Instrument rises in the wind
InOwill N200 Nitric Oxide Gas Therapy is the main indications for acute illness associated with pulmonary hypertension, including arterial hypertension (idiopathic/hereditary PAH, congenital heart disease, neonatal persistent pulmonary hypertension, etc.), pulmonary hypertension due to pulmonary disease and/or hypoxia (COPD, sleep apnea, ARDS, interstitial lung disease, altitude pulmonary edema, etc.), and pulmonary hypertension due to obstructive pulmonary artery lesions. The number of patients with such diseases is large, and there are problems such as dangerous diseases and high mortality rates, and the clinical needs need to be met urgently.
Take, for example, neonatal persistent pulmonary hypertension (PPHN). The latest research shows that there will be about 10 million newborns in the country in 2021, of which 20,000 children with PPHN are expected to be directly added [1]. In addition, about 927,000 new children with respiratory failure are added each year in China[2], of which 10% [3] are accompanied by pulmonary hypertension, that is, 93,000. According to the WHO Global Report on Premature Babies, up to 19.3% of approximately 2 million premature babies per year[4] develop bronchial dysplasia (BPD), while the average proportion of neonatal pulmonary hypertension is as high as 26%[5], or 100,000. In total, the number of newborn PPHN patients in the mainland is about 213,000 new every year.
In clinical medicine, the underlying logic of treating neonatal pulmonary hypertension is to rely on NO to dilate the pulmonary arterioles and alleviate pulmonary hypertension. In 2019, the Neonatologist Branch of the Chinese Medical Doctor Association launched the "Application Guidelines for Nitric Oxide Inhalation Therapy in Neonatal Intensive Care Units (2019 Edition)", in which the indications and indications for NO inhalation therapy are mostly strong recommendations or high-quality levels. In addition to the above guidelines, many experts in the field of neonatology in China have also published a number of high-quality studies in recent years, elaborating on the important role of NO in neonatology, especially in the treatment of neonatal pulmonary hypertension.
However, what is not commensurate with clinical treatment guidelines is the very limited access to NO treatments available on the market. Currently the traditional treatment in China is the use of industrial NO cylinders or sildenafil (Viagra). However, the former is subject to the problems of large cylinder equipment, insufficient precision monitoring, limited gas sources, etc., can not make the NO to the fullest use, and there are certain safety risks; the latter stimulates endogenous NO molecule generation through pharmacological action, which has a certain role in expanding blood vessels in the lungs, but will bring headaches, vomiting, vision abnormalities and other side effects, and is not suitable for newborns. Because of this, there has long been a situation in China where there are NO treatment plans to follow and no NO treatment methods available, and the demand for cheap and portable pure NO treatment gas sources in the market is very urgent.
Previously, due to the global patent protection of no gas cylinders and flow control instrument products iNOmax, NO gas instant generation treatment products remained in the technical storage stage for a long time. After the iNOmax patent expired in 2017, the U.S. FDA finally approved Vero Genosyl for the first time in 2019, a no-gas instant generation treatment product. The domestic NO gas treatment track is still a blue ocean: before the approval of the Noring BioINOwill N200, there were no domestic or imported products involved in the field of NO immediate occurrence treatment, and the competition in the field of traditional NO gas cylinder treatment was relatively limited.
The technical difficulties that need to be overcome in the medical grade immediate inhalation NO include safe and easy access to raw materials, controllable reaction conditions, efficient separation of gas and liquid, and high-purity transport of NO [can not form a considerable amount of toxic nitrogen dioxide (NO2) gas], etc., involving chemistry, biology, materials science, engineering and other fields of research and development.
Looking at the world, the new generation of inhaled NO treatment equipment currently approved for marketing is only one of the Vero Biotech in the United States, which uses the technical path of cleavage reduction to catalyze the conversion of nitrogen tetroxide (N2O4) into NO2 and further generate NO gas. However, its defects are also very obvious: the raw material N2O4 is a highly toxic substance, and the NO obtained by cracking and reducing method contains a considerable amount of toxic NO2 gas, which has a large safety risk. In China, at present, only the traditional cylinder NO flow control instrument is used with gas cylinders, and there are obvious shortcomings in accessibility, safety, portability and other aspects.
No need for cylinder air supply, portable and easy to bring,
Preparation is fast and precise
There are currently only three technology schools in the world that can continuously and uninterruptedly provide medical-grade inhaled nitric oxide (NO), namely electrochemical catalytic system, crack reduction system, and plasma discharge system.
The Norling Biological Nitric Oxide Therapy Instrument INOwill N200 combines the subversive electrochemical catalysis core patented technology with a number of engineering patents: the use of safe inorganic salts as raw materials to mix the electrolyte, under the action of the catalyst, by electrolytic reduction of nitrite ions, the production of high-purity nitric oxide on the electrode; the use of specially designed gas-liquid separation technology, further extraction of the generated nitric oxide from the electrolyte and into the gas delivery unit; according to the concentration requirements of the treatment, Relying on a well-designed pneumatic system and high-precision flow control components, the gas delivery unit delivers nitric oxide precisely to the patient end.
Based on the internationally pioneered electrochemical catalytic NO instant generation method, INOwill N200 stably provides a gas capacity of five times the volume of a conventional cylinder with a volume of one-twentieth of the cylinder, which can achieve long-term, fast, accurate and stable high-purity nitric oxide gas output and realize barrier-free and easy and safe movement, which is applied to the treatment of pulmonary hypertension in a variety of scenarios. As a result, it bids farewell to the cumbersome steps and high operating costs of NO cylinder transportation, storage and recycling, and opens a new pattern of clinical application of domestic medical grade NO gas.
In addition, the INOwill N200 incorporates several engineering patents:
Sophisticated and compact replaceable micro-release reactors that combine sustained-release and dynamic control technologies. When no gas is used, only the "micro-release reactor" needs to be replaced regularly to ensure a sustainable supply of NO.
High-precision flow sensors are superimposed with intelligent compensation technology to ensure fast, precise and long-term constant output of NO gas. Even under high-frequency oscillatory ventilation, the NO concentration can be precisely controlled, and different doses and modes of NO release can be achieved according to the application scenario.
Phase change sensor sampling technology can monitor NO, NO2 and O2 concentrations in real time with high accuracy to ensure safe and reliable clinical treatment.
Norling Bio Nitric Oxide Therapeutic Instrument INOwill N200
INOwill N200 nitric oxide has stable growth, concentration error does not exceed ±1PPM, and the safety is better. At the same time, based on the antibacterial and anticoagulant biological mechanism of no molecules, the use of INOwill N200 can reduce the risk of inflammation and concurrent reactions caused by the use of the extracorporeal circulatory system in surgery.
Received investment from Eli Lilly Asia, Northern Lights Venture Capital, etc.
Accelerate the global footprint of nitric oxide therapy
As the first technology platform medical enterprise focusing on NO gas treatment in China, Nuling Bio can take the lead in laying out the field of pulmonary hypertension and launching the first domestic NO treatment instrument, which is inseparable from its product development logic starting from clinical needs, and also inseparable from the strong scientific research, clinical expert team support and strong commercialization capabilities behind it.
In terms of talent reserve, the core management team of Nuling Biology is composed of experts with rich practical experience in clinical and medical management, professors in the field of NO sustained release hair growth technology, senior experts in the field of biological sciences and high-end life support medical equipment, and many of them have overseas study and senior management experience of Fortune Global 500 companies.
In terms of patents, Nuling Bio has laid out nearly 50 patents at home and abroad around NO real-time generation technology, gas sensing and gas sustained release control technology, which fully establishes the commercial barriers of various core modules in product design, such as electrochemical chelation catalysis method, gas-liquid separation device, circulatory filtration system, and flow sensing precision algorithm.
In terms of commercialization, from 2020 to 2021, Nuoling Bio overcame the impact of the epidemic to develop rapidly against the trend, and added nearly 4,000 m2 of R&D laboratories and production offices to the R&D and production headquarters located in Jiangbei New Area, Nanjing. The main functional areas include the new laboratory center, automated production line, cleaner production workshop, quality inspection area and other ancillary office areas. International advanced R & D and industrialization instruments and equipment have been configured, and the factory has passed the European system assessment, is expected to form an annual output of nearly 1,000 sets of equipment and nearly 10,000 reflector consumables target product industrialization capabilities.
R&D and production headquarters of Nuling Bio Nanjing
In terms of financing, the company has developed rapidly since its inception, and has completed the B round of financing in 2021, and has received more than 100 million yuan of investment from well-known institutions such as Eli Lilly Asia Fund, Northern Lights Venture Capital, Materia Medica Capital, Eagle Alliance Capital, and Nanjing Jiangbei Science and Technology Investment. At present, the preparation of the B+ round of financing is about to be completed in preparation for continuous efforts in the direction of product research and development, clinical trials, market access, academic cooperation, market promotion, and capacity expansion.
pipeline expansion,
“in China for global”
Since its inception, Nuling Bio has been firmly committed to the "in China for global" strategy, on the one hand, the requirements for technology research and development are comparable to the international frontier level, on the other hand, actively planning overseas market layout, and truly leading the global progress of NO treatment.
The company has set up an overseas operation headquarters in California, USA, responsible for R&D scientific discussion, overseas business development and registration compliance matters, full-time employees are doctoral background, with more than ten years of global registration and operation experience in the fields of medicine, medical devices, functional food and other fields. In addition, Nuling Bio has established R&D and production headquarters in Nanjing, a medical market center in Beijing, and a medical consumer goods operation base in Changsha.
As of April 2022, Norling Bio has launched the EU CE certification process for two products, the first of which is expected to be obtained in the second half of 2022.
According to Dr. Mao Wen, founder of Nuling Biologics, the company has a clear phased strategy for the domestic promotion and sales of INOwill products. Based on the core technology platform of NO and gas instant occurrence, Nuling Bio has opened the exclusive whole industry chain layout for the clinical application of domestic medical grade NO gas.
At present, the company has five molded NO product pipelines, including portable NO inhalation therapy instrument, NO gas therapy instrument, outdoor portable NO generator, portable NO minicomputer, exhalation NO detector, to COPD, pulmonary fibrosis and other more unmet clinical needs to expand, is expected to obtain at least 3 Class III medical device registration certificates within five years. Many areas related to gas detection and treatment outside of NO are also steadily exploring.
At present, the company has carried out medium- and long-term development planning for R&D direction, market strategy, business expansion, financing nodes, etc. In 2022, it will focus on promoting the listing of INOwill N200, while maintaining the progress of R&D registration of each production line, and expanding the R&D and listing of platform-based products and consumer goods.
Bibliography:
[1] Neonatology Group of the Science Branch of Chinese Medical Association, Expert Consensus on the Diagnosis and Treatment of Neonatal Pulmonary Hypertension, Chinese Journal of Pediatrics, 2017
[2] Clinical data analysis of 409 cases of neonatal respiratory failure, Hu Shuying et al., 2011 Zhejiang Medical Association Science Branch Academic Annual Meeting and New Progress in the Diagnosis and Treatment of Pediatric Diseases National Study Class Papers Compilation, 2015
【3】Steinhorn RH．Neonatal pulmonary hypertension[J]．Pediatr Cric Care Med，2010
[4] Evolution and Therapeutic Progress of Definition and Nomenclature of Bronchopulmonary Dysplasia, Liwen Chang, Chinese Pediatric Emergency Medicine, 2016
[5] Problems related to the diagnosis and treatment of pulmonary hypertension in bronchopulmonary dysplasia and pulmonary vascular development, Liping Shi, Chinese Pediatric Emergency Medicine, 2016
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