LOGOLOGO
COVID-19 treatment candidate

Severity, morbidity and mortality of COVID-19 are linked to endothelial dysfunction

N2-01 has proven to reduce the level of endothelial dysfunction both in laboratory settings and clinical usage

MHRA confirmed the plausibility of these scientific arguments and reduced the requirements for initial testing

N2-01 is already proven to be safe and effective in veterinary applications related to endothelial dysfunction

Available not-for-profit to patients with COVID-19, if proven effective

More about the
role of the endothelium
COVID-19 treatment candidate

Severity, morbidity and mortality of COVID-19 are linked to endothelial dysfunction

N2-01 has proven to reduce the level of endothelial dysfunction both in laboratory settings and clinical usage

MHRA confirmed the plausibility of these scientific arguments and reduced the requirements for initial testing

N2-01 is already proven to be safe and effective in veterinary applications related to endothelial dysfunction

Available not-for-profit to patients with COVID-19, if proven effective

More about the
role of the endothelium
COVID-19 treatment candidate

Severity, morbidity and mortality of COVID-19 are linked to endothelial dysfunction

N2-01 has proven to reduce the level of endothelial dysfunction both in laboratory settings and clinical usage

MHRA confirmed the plausibility of these scientific arguments and reduced the requirements for initial testing

N2-01 is already proven to be safe and effective in veterinary applications related to endothelial dysfunction

Available not-for-profit to patients with COVID-19, if proven effective

More about the
role of the endothelium

The Role of Endothelium in COVID-19

The Endothelium is a single layer of endothelial cells lines the entire vascular and lymphatic system, from the heart to the smallest capillaries. In adults, approximately ten trillion cells form an almost 1 kg organ and covers a total surface area of 4000 to 7000 square meters - the size of a football field.

In the past, the endothelium was considered inert, described as a `layer of nucleated cellophane', with only non-reactive barrier properties, such as presentation of a non-thrombogenic surface for blood flow and guarding against pro-inflammatory insults. However, it is now becoming clear that endothelial cells actively and reactively participate in haemostasis and immune and inflammatory reactions.

As a barrier, the endothelium is semipermeable and regulates the transfer of small and large molecules into and out of the blood. Endothelial cells are dynamic and have metabolic and synthetic functions. They regulate vascular tone via production of nitric oxide, endothelin and prostaglandins and are involved in the manifestations of atherogenesis, autoimmune diseases and infectious processes. They produce and react to various cytokines and adhesion molecules and it is now clear that they can mount anti- and pro-inflammatory and protective responses depending on environmental conditions and are key immunoreactive cells. Endothelial cells exert significant autocrine, paracrine and endocrine actions and influence smooth muscle cells, platelets and peripheral leucocytes.

Endothelial dysfunction or activation also contributes to a variety of disease states.7

The endothelium is directly involved in peripheral vascular disease, stroke, heart disease, diabetes, insulin resistance, chronic kidney failure, tumor growth, metastasis, venous thrombosis, and severe viral infectious diseases. Dysfunction of the vascular endothelium is thus a hallmark of human diseases.

After conducting a recent study connecting COVID-19 and the function of the endothelium, Prof. Dr. Frank Ruschitzka, Department of Cardiology, University Hospital Zurich, stated:

"Patients suffering from hypertension, diabetes, heart failure or coronary heart diseases have one thing in common – their endothelial function is markedly impaired. If patients such as these become infected with SARS-COV-2, they will be particularly at risk, as their already weakened endothelial function will diminish even further."15
"Through our study, we are now able to provide evidence to back up our hypothesis that COVID-19 is not only able to affect the lungs, but also the blood vessels in different organs. COVID is a systemic inflammation of the blood vessels and we may now also refer to the disease as COVID-Endotheliitis."15

Technology: About N2-01

N2 Pharmaceuticals is a SMART Scotland award winner. The company is based in Roslin Innovation Centre and is developing N2-01, an injectable drug from the meat of Blue mussels. N2 Pharmaceuticals was established in the UK in 2013 with the goal of bringing the drug to the UK and worldwide markets.

N2-01 was invented by the company's founder and developed in collaboration with scientists from the Institute of Experimental Medicine and the State Academy of Veterinary Medicine in St.Petersburg, Russia.

N2-01 is a mixture of amino acids and short peptides. It is a natural composition, without artificial components, derived from the meat of blue mussels through a process of enzyme acid hydrolysis.

Market usage

Marketing Authorisation Certificate

N2-01 was already registered for veterinary use in Russia as an injectable medicine in 2010.

Efficacy

N2-01 has proven, both in laboratory settings and clinical usage, to reduce the level of endothelial dysfunction:

Most importantly, N2-01 proved to be effective in numerous conditions related to endothelial dysfunction when used on more than 25,000 animals:



Manufacturing

N2 Pharmaceuticals is ready to start GMP manufacturing with an experienced CMO in the UK.

COVID-19 THERAPY COVID-19 THERAPY

Numerous recent publications link the severity, morbidity and mortality of COVID-19 to the level of endothelial dysfunction1-6. Researchers suggest that strategies to stabilise the endothelium while tackling viral replication could be particularly relevant for patients in the risk group14.

More about
N2-01 and COVID-19

COVID-19 Application

COVID-19 is an infectious disease caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality.

Numerous recent publications link the severity and mortality of COVID-19 to the level of endothelial dysfunction (ED). 1-6

Whilst development of vaccines targeting the virus is a long-term preventative measure, treating endothelial dysfunction is a quick and direct response for disease management that could reduce mortality rate and prevent severe onset of the disease.

N2-01 was already registered in Russia as an injectable veterinary medicine. It has proven, both in laboratory settings and in clinic, to reduce the level of endothelial dysfunction.

When studied on human endothelial cells N2-01 influences the factors responsible for onset and severity of ARDS such as VCAM-1, iCAM-1 and NO (Nitric Oxide).

N2-01 proved to reduce vascular permeability (vascular leakage) in mice that is also linked to ARDS.

ARDS Pathogenesis Aggregating, thrombosis, ROS
In vitro/in vivo trials and relevant field usage of N2-01 MODEL Nitric oxide (NO) production by eNOS
SPECIES Human cells (HUVEC)
OUTCOME Severalfold increase in NO production
ARDS Pathogenesis Vascular hyperpermeability
In vitro/in vivo trials and relevant field usage of N2-01 MODEL Vascular permeability
SPECIES Mice
OUTCOME Reduction of hyperpermeability
ARDS Pathogenesis Increase in sVCAM-1 indicating endothelial dysfunction
In vitro/in vivo trials and relevant field usage of N2-01 MODEL VCAM-1 expression
SPECIES Human cells (HUVEC)
OUTCOME Severalfold reduction of VCAM-1
ARDS Pathogenesis Mortality rate 40%-50%
In vitro/in vivo trials and relevant field usage of N2-01 MODEL Porcine Circovirus (in farm)
SPECIES Pigs
OUTCOME Reduced mortality >50% to 6%
ARDS Pathogenesis Mortality rate 40%-50%
In vitro/in vivo trials and relevant field usage of N2-01 MODEL LPS-induced sepsis
SPECIES Mice
OUTCOME Reduced mortality 58% to 28%
ARDS Pathogenesis In vitro/in vivo trials and relevant field usage of N2-01
MODEL SPECIES OUTCOME
Aggregating, thrombosis, ROS Nitric oxide (NO) production by eNOS Human cells (HUVEC) Severalfold increase in NO production
Vascular hyperpermeability Vascular permeability Mice Reduction of hyperpermeability
Increase in sVCAM-1 indicating endothelial dysfunction VCAM-1 expression Human cells (HUVEC) Severalfold reduction of VCAM-1
Mortality rate 40%-50% Porcine Circovirus (in farm) Pigs Reduced mortality >50% to 6%
LPS-induced sepsis Mice Reduced mortality 58% to 28%

In addition, N2-01 proved to be effective against Porcine Circovirus Type 2 (PCV-2), when it was used on more than 1,000 piglets on the RusBelgo farm in Russia. No vaccine existed at the time. As a monotherapy the usage of N2-01 reduced mortality from more than 50% to 6%. The pathogenesis and symptoms of PCV-2 are similar to COVID-19: endothelial and epithelial barrier disruption, hyperpermeability, cough, lung oedema, severe respiratory distress.

The medicine has already been registered for veterinary use in Russia in 2010 under the leadership of the current CEO. N2-01 proved to be effective in numerous conditions related to endothelial dysfunction, when used on more than 25,000 companion and food producing animals by practicing veterinarians:

All of this makes us believe that N2-01 could be beneficial in treating patients with COVID-19 through stabilizing the endothelium.

Non-COVID-19 Applications Non-COVID-19 Applications

A wide range of diseases is directly connected with endothelial dysfunction.

ARDS, Sepsis, Septic shock, Preeclampsia are amongst them and will be targeted first.

Palliative care for patients with late stages of cancer and multimorbidity is also a possible application.

A wide range of diseases is directly connected with endothelial dysfunction.

ARDS, Sepsis, Septic shock, Preeclampsia are amongst them and will be targeted first.

Palliative care for patients with late stages of cancer and multimorbidity is also a possible application.

More about
N2-01 and other diseases

Non-COVID-19 Applications

It is proven that a number of other life-threatening conditions such as sepsis, cancer, kidney failure and even aging per se are directly related to the function of endothelium 12,13.

N2-01 has proven, both in laboratory settings and during its usage on animals, to reduce the level of endothelial dysfunction.

N2 Pharmaceuticals believe that there is a high chance that N2-01 could be effective in treating people with conditions related to endothelial dysfunction, because:

About N2 Pharmaceuticals About N2 Pharmaceuticals

SMART Scotland Grant winners

Animal Health Investment Europe showcase finalists - London 2018

Informa Disruptors & Innovators report 2018 Top 20 Animal Health start-ups

SMART Scotland Grant winners

Animal Health Investment Europe showcase finalists - London 2018

Informa Disruptors & Innovators report 2018 Top 20 Animal Health start-ups

Meet the team...

About N2 Pharmaceuticals

N2 Pharmaceuticals Limited, a Scotland based company, have developed N2-01, a unique injectable medicine derived from extracts of Mytilus edulis (Blue mussels), which was approved for veterinary use in Russia in 2010 under the leadership of the current CEO.

N2-01 was used for years by Russian veterinarians in numerous seemingly unrelated conditions such as:

Only recently, after receiving a grant from the Scottish government to continue its research in the UK, N2 Pharmaceuticals discovered that N2-01 reduces the level of endothelial dysfunction and vascular permeability, which connects together all these pathologies.

N2 Pharmaceuticals was founded in 2013 by the current CEO Nikolay Solovyev, in order to realize N2-01's enormous potential in veterinary as well as human medicine around the world.

In 2018 N2 Pharmaceuticals won a SMART Scotland grant and relocated to Roslin Innovation Centre in Edinburgh.

The invention has numerous patents in the UK, EU, USA and Russia.

Team

After successfully discovering, developing and bringing N2-01 onto the Russian market, N2 Pharma team made it their personal goal to realise N2-01's enormous potential in veterinary as well as human medicine around the world.

Nikolay

Nikolay Solovyev

Founder, CEO, process inventor

Nikolay works in the veterinary field for over 15 years. After developing and bringing to market a line of veterinary feed supplements based on marine products (Marimix). Nikolay, in collaboration with the St.Petersburg State Veterinary Academy, developed an injectable drug based on an existing mussel hydrolysate - N2-01 (Russian name - Marimix 5:0). Under his management the medicine was granted marketing authorisation in Russia in 2010. In 2013 Nikolay co-founded N2 Pharmaceuticals in order to realize N2-01’s vast potential.

Natalia

Natalia Romanova-Mossig

Business development director and co-founder

Being closely involved in the project from the very beginning, Natalia co-founded N2 Pharmaceuticals with Nikolay in 2013 with the idea to bring N2-01 to international markets. Natalia has a background in business and finance and is an experienced business development specialist with a strong portfolio of international projects under her management in the UK, Russia and Europe.

Jimi

Jimi Wills

Technical adviser

Having graduated from the University of Glasgow, and received the Struthers Prize and Medal for his PhD thesis studying Parkinsons Disease, Jimi then worked at the University of Edinburgh. Specialising in mass-spectrometry and many associated technologies, he is now an author on 20 peer reviewed academic publications. In addition to sitting on committees such as Equality, Diversity and Inclusion at the Western General hospital campus and Developing Midlothian's Young Workforce, Jimi has experience applying expertise in education, industry consultation and public engagement. Jimi joined the N2 Pharmaceuticals team in early 2019.

Nikolay Solovyev

Founder, CEO, process inventor

Nikolay works in the veterinary field for over 15 years. After developing and bringing to market a line of veterinary feed supplements based on marine products (Marimix). Nikolay, in collaboration with the St.Petersburg State Veterinary Academy, developed an injectable drug based on an existing mussel hydrolysate - N2-01 (Russian name - Marimix 5:0). Under his management the medicine was granted marketing authorisation in Russia in 2010. In 2013 Nikolay co-founded N2 Pharmaceuticals in order to realize N2-01’s vast potential.

Nikolay

Natalia Romanova-Mossig

Business development director and co-founder

Being closely involved in the project from the very beginning, Natalia co-founded N2 Pharmaceuticals with Nikolay in 2013 with the idea to bring N2-01 to international markets. Natalia has a background in business and finance and is an experienced business development specialist with a strong portfolio of international projects under her management in the UK, Russia and Europe.

Natalia

Jimi Wills

Technical adviser

Having graduated from the University of Glasgow, and received the Struthers Prize and Medal for his PhD thesis studying Parkinsons Disease, Jimi then worked at the University of Edinburgh. Specialising in mass-spectrometry and many associated technologies, he is now an author on 20 peer reviewed academic publications. In addition to sitting on committees such as Equality, Diversity and Inclusion at the Western General hospital campus and Developing Midlothian's Young Workforce, Jimi has experience applying expertise in education, industry consultation and public engagement. Jimi joined the N2 Pharmaceuticals team in early 2019.

Jimi
Nikolay

Nikolay Solovyev

Founder, CEO, process inventor

Nikolay works in the veterinary field for over 15 years. After developing and bringing to market a line of veterinary feed supplements based on marine products (Marimix). Nikolay, in collaboration with the St.Petersburg State Veterinary Academy, developed an injectable drug based on an existing mussel hydrolysate - N2-01 (Russian name - Marimix 5:0). Under his management the medicine was granted marketing authorisation in Russia in 2010. In 2013 Nikolay co-founded N2 Pharmaceuticals in order to realize N2-01’s vast potential.

Contact
Natalia

Natalia Romanova-Mossig

Business development director and co-founder

Being closely involved in the project from the very beginning, Natalia co-founded N2 Pharmaceuticals with Nikolay in 2013 with the idea to bring N2-01 to international markets. Natalia has a background in business and finance and is an experienced business development specialist with a strong portfolio of international projects under her management in the UK, Russia and Europe.

Contact
Jimi

Jimi Wills

Technical adviser

Jimi joined N2 Pharmaceuticals team in early 2019.

Contact

Scientific Board

Irina Solomonovna Freidlin

Russian Academy of Medical Sciences | RAMS · Institute of Experimental Medicine, St.Petersburg

PhD Medical Sciences, professor, Honored scientist of the Russian Federation.

From 1991 - chairman of the Department of immunology of the Institute of Experimental Medicine RAMS, and professor at the Department of Microbiology, Virology and Immunology of St. Petersburg State Pavlov Medical University.

I.S.Freidlin is the author of 210 published scientific works including 2 textbooks (both in co-authorship). She holds two patents.

Elleonora Starikova

Russian Academy of Medical Sciences | RAMS · Institute of Experimental Medicine, St.Petersburg

PhD Biological Sciences, research officer in the immunology department at Institute of Experimental Medicine in St. Petersburg since 2000. Author of over 90 publications and participant in 8 government grants.

Alexej Sokolov

Russian Academy of Medical Sciences | RAMS · Institute of Experimental Medicine, St.Petersburg

PhD in Biology 2007, specialising in Biochemistry, Professor at the Department of Fundamental Problems of Medicine and Medical Technologies, St.Petersburg State University, Head of the Laboratory of Biochemical Genetics, Department of Molecular Genetics, Institute of Experimental Medicine in St. Petersburg. Author of 133 publications. Alexey is the holder of 4 patents, took part in 30 government grant projects, leading 6 of them.

Irina Solomonovna Freidlin

Russian Academy of Medical Sciences | RAMS · Institute of Experimental Medicine, St.Petersburg

PhD Medical Sciences, professor, Honored scientist of the Russian Federation.

From 1991 - chairman of the Department of immunology of the Institute of Experimental Medicine RAMS, and professor at the Department of Microbiology, Virology and Immunology of St. Petersburg State Pavlov Medical University.

I.S.Freidlin is the author of 210 published scientific works including 2 textbooks (both in co-authorship). She holds two patents.

Elleonora Starikova

Russian Academy of Medical Sciences | RAMS · Institute of Experimental Medicine, St.Petersburg

PhD Biological Sciences, research officer in the immunology department at Institute of Experimental Medicine in St. Petersburg since 2000. Author of over 90 publications and participant in 8 government grants.

Alexey Sokolov

Russian Academy of Medical Sciences | RAMS · Institute of Experimental Medicine, St.Petersburg

PhD in Biology 2007, specialising in Biochemistry, Professor at the Department of Fundamental Problems of Medicine and Medical Technologies, St.Petersburg State University, Head of the Laboratory of Biochemical Genetics, Department of Molecular Genetics, Institute of Experimental Medicine in St. Petersburg. Author of 133 publications. Alexey is the holder of 4 patents, took part in 30 government grant projects, leading 6 of them.

References

  1. Attia EF, Jolley SE, Crothers K, Schnapp LM, Liles WC (2016) Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) Is Elevated in Bronchoalveolar Lavage Fluid of Patients with Acute Respiratory Distress Syndrome. PLoS ONE 11(2): e0149687. doi:10.1371/journal.pone.0149687
  2. Jesús F Bermejo-Martin, Raquel Almansa, Rosario Menéndez, Raúl Mendez, David J Kelvin, Antoni Torres Lymphopenic community acquired pneumonia as signature of severe COVID-19 infection. Journal of Infection. 2020 March journalofinfection.com
  3. Fang, Karakiulakis and Roth. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet 8:4 (2020) thelancet.com
  4. Vanessa Zambelli, Giacomo Bellani. Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome. Intensive Care Med Exp. 2015 Dec; 3: 8. PMC4512981/
  5. Brandon Michael Henry, Jens Vikse, Giuseppe Lippi. COVID-19 induced Renin-Angiotensin System (RAS) imbalance may drive acute lung injury: the evidence and therapeutic options. BMJ 2020 Jan. bmj.com
  6. Junyi Guo, Zheng Huang, Li Lin , and Jiagao Lv. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Journal of the American Heart Association. 2020 Apr. doi:10.1161/JAHA.120.016219
  7. H.F. Galley, N.R. Webster. Physiology of the endothelium. British Journal of Anaesthesia 93 (1) July 2004 bjanaesthesia.org
  8. Tomoya Yamashita, Seinosuke Kawashima. Resistance to Endotoxin Shock in Transgenic Mice Overexpressing Endothelial Nitric Oxide Synthase Originally published 29 Feb 2000 Circulation. 2000;101:931-937 doi:10.1161/01.CIR.101.8.931
  9. Mark T. Gladwin and Gregory Kato (2007) Hemolysis-Associated Endothelial Dysfunction and Pulmonary Hypertension, an Emerging Cause of Death in the Hemoglobinopathies. Advances in Pulmonary Hypertension: 2007, Vol. 6, No. 1, pp. 23-30. doi:10.21693/1933-088X-6.1.23
  10. Ekeloef S1, Godthaab C, Schou-Pedersen AMV, Lykkesfeldt J, Gögenur I. Peri-operative endothelial dysfunction in patients undergoing minor abdominal surgery: An observational study. Eur J Anaesthesiol. 2019 Feb;36(2):130-134. doi: 10.1097/EJA.0000000000000935. pubmed:30543557
  11. Ekeloef S1, Larsen MH2, Schou-Pedersen AM3, Lykkesfeldt J3, Rosenberg J4, Gögenür I2. Endothelial dysfunction in the early postoperative period after major colon cancer surgery. Br J Anaesth. 2017 Feb;118(2):200-206. doi: 10.1093/bja/aew410. pubmed:28100523
  12. Peramaiyan Rajendran, Thamaraiselvan Rengarajan, Jayakumar Thangavel, Yutaka Nishigaki, Dhanapal Sakthisekaran, Gautam Sethi, Ikuo Nishigaki Vascular Endothelium and Human DiseasesInt J Biol Sci 2013 ijbs.com
  13. Annibale Alessandro Puca, Albino Carrizzo, Anna Ferrario, Francesco Villa & Carmine Vecchione. Endothelial nitric oxide synthase, vascular integrity and human exceptional longevity. Immunity & Ageing November 2012 10.1186/1742-4933-9-26
  14. Zsuzsanna Varga, Andreas J Flammer, Peter Steiger, Martina Haberecker, Rea Andermatt, Annelies S Zinkernagel, Mandeep R Mehra, Reto A Schuepbach, Frank Ruschitzka, Holger Moch, 2020. Endothelial cell infection and endotheliitis in COVID-19 The Lancet doi:10.1016/S0140-6736(20)30937-5
  15. Prof. Dr. Frank Ruschitzka quoted by Prof. Dr. Holger Moch. COVID-19: also a systemic endotheliitis. April 2020 University Hospital Zurich Press release