Tag: Sepsis

sepsis sepsis sepsis sepsis

One Step Closer to an Innovative Therapy for Sepsis

Not many people know how dangerous sepsis is. Even fewer people know that there is no specific therapy available to treat sepsis. Sepsis, a disorder that is developed from infections, can lead to limb amputations and deaths in a matter of days. For decades, it has remained one of the deadliest and costliest medical conditions. Now a startup is getting one step closer to finding an innovative therapy.

Finding an innovative approach

Computer illustration of a cutaway view of the human cell membrane. The yellow channels are aquaporins.

Aquaporin is a channel protein found in plants, animals, and humans. The discovery of aquaporin won Dr. Peter Agre a Nobel Prize in 2003. However, despite having a profound physiological impact, aquaporins have so far not been transformed into practical applications. Could aquaporins offer an innovative therapy for sepsis? Supertrends has been following the development of ApoGlyx, a start-up dedicated to creating aquaporin-based therapies. This year, ApoGlyx has seen promising achievements after more than a decade of hard work. 

In April, ApoGlyx won the NLSInvest Rising Star Award on the first Nordic Life Science Investment Day. The award provided the opportunity for ApoGlyx to highlight its innovative therapy in front of investors. 

Attracting new investors

For the last few years, ApoGlyx has been busy working on two preclinical studies with Professor Giuseppe Calamita of Bari University in Italy, Professor Angela Tesse Ragot, University of Nantes, and Prof. Christoph Thiemermann at the William Harvey Research Institute in London. Both studies have delivered promising results. “The results proved that a modulated aquaporin might offer a new approach for sepsis management,” Calamita told Supertrends in an interview. Thiemermann went one step further in describing the result as “striking”.  

“We have never seen a drug that is administered after three hours after the onset of sepsis and is still effective.” – Professor Christoph Thiemermann, Director of the Centre for Translational Medicine and Therapeutics at the William Harvey Research Institute, and Supertrends expert

With sound scientific evidence to back up its claims, no wonder ApoGlyx stood out in the NLSInvest event. Following the event, Aploglyx successfully completed a US$700,000 (six million Swedish kronor) financing round. Among the new investors is the Swedish fund Almi Invest, a venture capital fund that supports early-stage start-ups with high growth potential and a scalable business plan. 

Entering “Medicon Village” 

To support its further development, ApoGlyx is entering the SmiLe incubator located in Medicon Village, in Lund, Sweden. Seated around the Öresund bridge between Sweden and Denmark in the thriving life-science region nick-named “Medicon Valley”, SmiLe is a prestigious life science incubator that has already produced 16 IPOs and demonstrated a success rate of 86 percent. 

In its new home at SmiLe, ApoGlyx will further analyze valuable biomarkers with its already completed experiment and carry out further studies to provide more evidence for its aquaporin-based therapy. 

“ApoGlyx is transforming from research into scaling and commercialization,” said Kristina Nyzell, an early investor who has witnessed the transformation of the start-up. 

Contributing to sepsis awareness education

Sepsis, one of the earliest medical syndromes to be described in the history of medicine, remains one of the most dangerous and costly medical conditions even today. Nevertheless, public awareness of sepsis is poor across the globe. Surveys showed that only 7 to 50 percent of respondents were familiar with the term, including many who had an incorrect understanding of the condition.

To help the public understand sepsis better, ApoGlyx, in collaboration with Disruptiveplay, has developed a minicourse about what sepsis is, how to identify the condition, and how to manage it. The course is part of the Educate All initiative led by the United Nations Institute for Training and Research (unitar) and micro-learning platform EdApp. The Sepsis Awareness course can be accessed for free on EdApp.

Preparing for clinical trials

Preclinical models that are often used for regulatory safety studies involve a rodent and a non-rodent species and must be relevant for the drug’s mode of action and expected off-target effects. Once sufficient safety information is obtained, dosage and treatment schedules are determined for Phase I trials in humans. I see no major obstacles for ApoGlyx’s next stage of clinical trials.” – Dr. Frank Staedtler, biologist, and Supertrends expert

Before the drug candidate is tested on humans, ApoGlyx must gain a better understanding of potential risks that their aquaporin-based therapy might have. The company will start a preclinical toxicology program in early 2022. After the toxicology data is analyzed, ApoGlyx will officially start its regulatory process for clinical trials. 

The company plans to start its discussion with the European Medicine Agency (EMA) in 2022. If all goes well in Europe, ApoGlyx will then start the process in the US with the United States Food and Drug Administration (FDA).  

It will certainly be a lengthy and uneasy journey to bring a new drug into clinical practice. The challenge will be even bigger when dealing with a condition like sepsis, which has previously defeated numerous attempts at therapeutic intervention. Today, factors such as emerging viral infections, antibiotic resistance crisis, and an aging population have caused sepsis to be an even bigger threat. More than ever, we need a successful therapy against sepsis. Aquaporin-based therapy provides an innovative approach to this challenge. Our report on Supertrends in Aquaporin and Sepsis describes how the future of aquaporin could be intertwined with the future management of sepsis. 

Sepsis patients Sepsis patients Sepsis patients Sepsis patients

Four Supertrends Experts Share Their Insights on Sepsis

On 13 September 2021, World Sepsis Day will be observed for the tenth time. Sepsis, a disorder that is caused by infections, can lead to limb amputations and deaths in a matter of days. The condition kills at least 11 million people every year globally. However, the condition is still not well known, with only from 7 to 50 percent of respondents being familiar with the term, and many having an incorrect understanding of the condition. Supertrends asked four experts to comment on current sepsis-related trends and challenges. 

COVID-19 and viral sepsis

Traditionally, bacterial infections had been regarded as a leading cause of sepsis. The COVID-19 pandemic has revealed viral sepsis to be one of the characteristics of modern-day sepsis syndrome. Studies found that sepsis was the most frequently observed complication of COVID-19. The elevation of cytokine levels, an indicator of dysregulated immune response to the virus infection, was linked to viral sepsis and critically ill COVID-19 patients. 

Dr. Masab Moumneh, who has been an ICU physician in Abu Dhabi for the past ten years, still cannot believe how many lives COVID-19 took during the peak days of the pandemic. He told Supertrends that almost all COVID-19 patients are killed by the dysregulated immune response rather than the virus itself.

“I have never seen anything as bad as this. Patients typically develop a high fever, their Interleukin 6 (a type of cytokine) is high. If we can get them to pass the two-week mark, they will survive.”

– Masab Moumneh, MD, ICU physician, and Supertrends expert

Sepsis in contemporary healthcare 

Dr. Mads Koch Hansen, an intensive care specialist and hospital administrator, believes that we are facing a greater challenge from sepsis today due to shortened post-surgery hospital stay, emerging viral infections, antibiotic resistance crisis, and an aging population.

“Today, there are more elderly patients and more patients with chronic conditions. Another factor we should pay attention to is that we do more surgeries on elderly people, with fewer post-surgery staying days in the hospital. This means we will not be able to detect these patients early if they develop sepsis.”

– Mads Koch Hansen, MD, intensive care specialist, hospital administrator, and Supertrends expert

Currently, there is still no drug specifically targeting sepsis. Hansen felt that doctor’s hands were quite tied when it came to treating sepsis patients. 

A promising new approach

Aquaporin (AQP) is a channel protein found in plants, animals, and humans. The discovery of aquaporin won Dr. Peter Agre a Nobel Prize in 2013. However, despite having a profound physiological impact, aquaporin has not been transformed into practical applications. Dr. Michael Rutzler, CEO and founder of start-up Apoglyx, told Supertrends that aquaporin could be a potential treatment for sepsis. 

“We found strong evidence that the inhibition of AQP9 demonstrated a protective effect from sepsis in rodent models, especially on heart function. We are hoping to get similar results in humans.”

– Michael Rutzler, CEO and founder of Apoglyx, Supertrends expert

Rutzler has been collaborating with Professor Giuseppe Calamita of Bari University in Italy. Calamina’s team was the first in the world to study aquaporin’s involvement in sepsis in a living animal model. 

“We got a very promising result with more than 25 percent of the mice surviving sepsis […] The results proved that modulated AQP might offer a new approach for sepsis management.”

– Giuseppe Calamina, professor in biosciences and Supertrends expert

A new era for sepsis management

Advances in the field of biology and computer science are changing the way we prevent, diagnose, and treat diseases. Innovations in medicine mean we can understand and manage many health issues better than before. 

Aquaporin-based therapy or other innovative approaches one day will help clinicians to overcome the challenge of sepsis. Our report on Supertrends in Aquaporin and Sepsis describes how the future of aquaporin could be intertwined with the future management of sepsis. 

aqua drop aqua drop aqua drop aqua drop

Finding the elusive aquaporin modulators

Aquaporins are channel proteins that facilitate the transport of water across cells. The discovery of aquaporins in 1992, for which researcher Peter Agre received the Nobel Prize in Chemistry, opened the door to a new therapeutic approach for treating many health conditions. On one particular start-up’s journey in finding applicable aquaporin modulators, the student has become the master.

Water is one of the substances that are essential for life on Earth and for the survival of all plants and animals. Although the importance of water transport has been recognized since ancient times, the precise mechanism by which water is transported in and out of cells remained elusive until aquaporins were discovered by Peter Agre in 1992. These proteins form pores in the cell membrane to allow water to be transported between cells. 

The importance of this fundamental discovery and its potential impacts was acknowledged in 2003, when Agre won the Nobel Prize in Chemistry for “discoveries concerning channels in cell membranes”. However, nearly 30 years after the discovery of aquaporins, the only practical application is in the understanding and treatment of water balance disorders. Despite their pervasive presence in human organs, aquaporins have not featured in any new medical therapies. To understand the mystery surrounding these elusive proteins, Supertrends approached Apoglyx, a Swedish start-up leading the development of aquaporin-based treatments, for a joint interview with Michael Rutzler (CEO and founder of Apoglyx), Søren Nielsen (co-founder and shareholder), and Kristina Nyzell (investor).

Tiny water channels

Søren Nielsen, a professor at the Department of Biomedicine, Aarhus University and the Department of Health Science and Technology, Aalborg University in Denmark, worked very closely with Peter Agre for many years. Both have always believed in the magic of aquaporins. “Aquaporins exist globally in animals, plants, and microbes. These channels are fundamental for life. We are one of the leading groups in identifying different aquaporins and exploring their roles in physiology and medicine. From a biotech perspective, Apoglyx’s approach is to identify inhibitors of aquaporins to exploit their medical importance. This is a new approach, and a very challenging one due to the molecular structure of aquaporins,” Nielsen told Supertrends. 

Nielsen is a firm believer in the importance and clinical potential of aquaporins: “It is fundamental. Take the kidney as an example. Aquaporins have a critical role in kidney function and a variety of kidney and cardiovascular diseases. Another example is the brain, where AQP4 has an important role in water transport and in brain edema. It has recently also been shown that aquaporins as glymphatics have additional roles in facilitating brain function. Identifying aquaporins that serve as channels for water transport and in regulation of water balance and water balance disorders was relatively straightforward conceptionally. It is much more difficult to understand the roles of aquaglyceroporins that also serve other functions in addition to water transport. That has turned our focus to AQP7 and AQP9, which play a role in metabolic diseases and sepsis.” 

The student has become the master

aquaporin-9 inhibitors

In 2007, Michael Rutzler met Nielsen at Aarhus University. By then, Rutzler had already done some well-received research on olfactory receptors in insects in identifying potential inhibitors. With the support of many leading scientists like Nielsen, Rutzler now devotes his time to finding aquaporins modulators to treat medical conditions in humans. 

“Aquaporins are channels or holes in the cell membrane. They selectively let water and some other small molecules pass. The channels have enormous capacities to let water and other molecules through. That is one reason why it is difficult to find blockers that can stop all these molecules from going through.”  

The aquaporin modulators have proven difficult to identify, but Rutzler has successfully identified aquaporin-9 inhibitors and demonstrated promising applications on metabolic diseases and later sepsis. 

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite modern medical advances, it remains a global public health emergency affecting millions of people worldwide and one of the main causes of death across the world. It is also a medical condition for which no effective treatments exist. The COVID-19 crisis has brought this ancient condition into the spotlight again. Developing new treatments for sepsis has always been a difficult task; now, it is even more urgent.

With due caution, Rutzler lays out a possible pathway to success: “In sepsis, the dysfunction of the immune system starts to damage vital organs. The global effects also have an impact on blood circulation. Vital organs, including the brain and kidneys, become impaired. This, in turn, causes further damages to other organs. Through our collaboration with other universities, we found strong evidence that the inhibition of AQP9 demonstrated a protective effect from sepsis in rodent models, especially on heart function. We are hoping to get similar results in humans.” Rutzler and Nyzell are quite excited regarding the promising results of this potential treatment. Nyzell explains in layman’s terms: “Impaired blood flow can cause long-term consequences in vital organ functions. The current COVID-19 debate has been very much focused on keeping patients alive without thinking about long-term complications. I think it is important to look into new ways of treatments from a broader view in sepsis.” And Nielsen adds: “We are working on the role of AQP9 in sepsis and other conditions. Many aisles in finding new efficient treatments have been closed. It is crucial to develop something new based on this preliminary evidence.”

The path to a promising future

In conclusion, Supertrends asked the question that is on everybody’s mind: When will an aquaporin-based treatment be available for sepsis patients?

Starting from humble beginnings in 2012, after Rutzler discovered aquaporin inhibitors, Apoglyx has managed with a small amount of financial support and a great team of scientists to become one of the leaders in developing aquaporin modulators for therapeutic applications. After many years of hard work, Apoglyx now is ready for its breakthrough.

“It also depends on funding. Sepsis is a medical condition, not a disease. Aquaporins and sepsis are under-funded. What Michael and Søren are doing is much more difficult than developing the COVID tracking app,” Nyzell adds, supplying the investor’s perspective.  

Apoglyx is planning to submit its Investigational New Drug (IND) application to the FDA and start a Phase 1 clinical trial in 2022; whether alone or potentially in partnerships with larger pharmaceutical companies, it is looking at potentially gaining approval and entering the market in less than ten years.

Apoglyx's planned milestones
Apoglyx’s planned milestones

Before the end of the decade, we may finally be able to lift the veil of mystery that still obscures the path towards aquaporins-based therapies.

This article only scratched the surface of the implications of aquaporins in healthcare. With the support of experts like Michael Rutzler and Søren Nielsen, Supertrends has created an extensive report on aquaporins (AQP) in healthcare, particularly with regard to the challenges and opportunities we face in sepsis and the potential role that AQPs could play in sepsis management. For investors, policymakers, healthcare providers, and entrepreneurs, this report offers insights into both topics and a novel approach in combining the two concepts to explore new solutions. Click here to learn more about it.
© 2020 Supertrends  

The new challenge in fighting old sepsis

While we have been battling with sepsis for centuries, now COVID19 added new challenges to this battle. Can Aquaporin-based therapy be our newest weapon against this malicious viral sepsis?

“Patients typically develop a high fever, their Interleukin 6 (IL-6) is high. If we can get them to pass the two-week mark, they will survive.” Dr. Masab Moumneh, MD, ICU physician

Sepsis – an elusive syndrome

Sepsis has been defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. First described by Hippocrates, it is one of the oldest topics in the history of medicine. Even with advances in care, it remains a global public health emergency affecting millions of people worldwide and one of the main causes of death across the world. Sepsis is also one of the costliest conditions in hospitals. Accounting for more than US$20 billion (5.2 percent) of total US hospital costs, it was the most expensive condition treated in US hospitals in 2011.

Despite the worldwide importance of sepsis, public awareness remains low. In a survey conducted in 2009 in Italy, Spain, the UK, France, and the US, 88 percent of interviewees had never heard of the term “sepsis” – and from those who did recognize the term, 58 percent were not aware that sepsis is a leading cause of death. Similar results were found in another survey in 2014 in South Korea.

The reason for the elusiveness of sepsis probably lies in the fact that sepsis is not a specific illness, but rather a syndrome encompassing a still-uncertain pathobiology. It is recognized today that a complex and multi-factorial host response is responsible for the development of sepsis. Infection triggers both pro-inflammatory and anti-inflammatory processes that ultimately contribute to both the clearance of infection and the tissue damage that lead to organ failure.

Viral sepsis and cytokine storm

Previously, bacterial infections were usually regarded as a leading cause of sepsis. The COVID-19 crisis has brought viral sepsis into the spotlight. In a study of 191 COVID-19 patients treated in December 2019 and January 2020 in Wuhan (China), sepsis was found to be the most frequently observed complication. Sepsis was diagnosed in 59 percent of all patients included in the study. Furthermore, 100 percent of the non-survivor patients were diagnosed with sepsis. Was it viral sepsis that was killing the COVID-19 patients?

To understand the immune reaction in viral infections, we have to understand the phenomena triggered by cytokine and cytokine storms. Cytokines are a group of proteins. Through a process called cell signaling (communication between cells), cytokines control inflammation in our body. When we get an infection, our immune system releases more cytokines. Unfortunately, sometimes the body goes into overdrive and releases more cytokines than it should. As the body loses control of cytokine production, a “cytokine storm” is created. Cytokine storms might explain why some people have severe reactions to the coronavirus while others only experience mild symptoms.

In another study from Wuhan, viral sepsis and cytokine storms were more directly linked to critically ill COVID-19 patients. This study found that pro-inflammatory cytokines and chemokines were significantly elevated in COVID-19 patients. It further suggested that the cytokine storm might play an important role in the immunopathology of COVID-19.

“I have never seen anything as bad as this. COVID-19 patients were killed by cytokine storms,” said Dr. Masab Moumneh, who has been an ICU physician in Abu Dhabi for the past ten years. Of the 700 hospital beds in the public hospital where Dr. Moumneh works, 110 are ICU beds. From April to June 2020, at the height of the COVID-19 crisis in the United Arab Emirates, Dr. Moumneh and his colleagues saw a 38 percent mortality rate in their ICU COVID-19 patients – a very respectable survival rate.

A search for dedicated immune suppressor

Working on the assumption that it was the cytokine storms that were causing the deaths of COVID-19 patients, Dr. Moumneh and his colleagues tried to use drugs that could reduce the overreaction of the immune system. In their ICU wards, corticosteroids – the standard anti-inflammatory medicine – were administered once COVID-19 patients were admitted. Although they were not included in the official guideline of sepsis management[1], corticosteroids were the only immunomodulator that was recommended for regulating overreacting immune systems in the guidance on “Care of Critically Ill Patients With COVID-19”, published by US National Institutes of Health [2].

Discovered in the 1940s, corticosteroids are one of the most widely used and effective treatments for inflammatory and autoimmune diseases. However, they do cause serious adverse effects, especially if used over a longer term or in high doses. Doctors have been looking at using newer immunosuppressants to develop more effective treatment options. Attempts by Dr. Moumneh and his colleagues to find other effective and safe immunosuppressants were unsuccessful. “One of the newer immunosuppressants caused bowel perforation, and the patient died,” Dr. Moumneh said regretfully. The fact is that at the moment, there is no dedicated medicine that explicitly targets immune over-reaction in sepsis or viral sepsis.

Can an Aquaporin-based drug fill the gap?

Aquaporins (AQPs) are channel proteins that form pores in cell membranes. As such, they are involved in a wide range of physiological functions. In general, aquaporins play a role in maintaining a constant water homeostasis and homeostasis of many physiological processes. There is solid evidence that AQPs facilitate both phagocytic functions of immune cells and migration of immune cells [3] [4] [5]. Furthermore, research has demonstrated that AQPs contribute to regulating fluid trafficking and inflammation process in lung infection [6]. This could be particularly helpful in seeking remedies for COVID-19 patients. Clinical data indicate that mortality attributable to COVID-19 infection is mainly due to the development of viral pneumonia-induced acute respiratory distress syndrome (ARDS) [7].

Cytokine storms and viral sepsis are serious complications of virus infections such as COVID-19, SARS, MERS, and the flu. They have caused hundreds of thousands of deaths around the world. Supertrends would like to help by supporting a community that focuses on fighting sepsis, especially viral sepsis. If you are interested in joining our community, please reach out to us to share your ideas, research, or inspirations at https://supertrends.com/call-for-experts/.
© 2020 Supertrends


[1] Rhodes, A, LE Evans et al. 2017. “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.” Intensive Care Med 43:304–377.

[2] NIH. 2020. COVID-19 Treatment Guidelines. 27 August. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/.

[3] Zhu, N., X. Feng, C. He, H. Gao, L. Yang, and Q Ma. 2011. “Defective macrophage function in aquaporin-3 deficiency.” FASEB J. 25, 4233–4239.

[4] Loitto, V. M., T. Forslund, T. Sundqvist, K. E. Magnusson, and M. Gustafsson. 2002. “Neutrophil leukocyte motility requires directed water influx.” J. Leukoc. Biol. 71, 212–222.

[5] Tyteca, D., T. Nishino, H. Debaix, P. Van Der Smissen, F. N’Kuli, and D. Hoffmann. 2015. “Regulation of macrophage motility by the water channel aquaporin-1: crucial role of M0/M2 phenotype switch.” PLoS ONE 10: e0117398.

[6] Towne, J. E., K. S. Harrod, C. M. Krane, and A. G. Menon. 2000. “Decreased expression of aquaporin (AQP1) and AQP5 in mouse lung following acute viral infection.” Am. J. Respir. Cell Mol. Biol. 22, 34–44.

[7] WHO. 2020. Coronavirus disease (COVID-19) Pandemic. https://www.who.int/emergencies/diseases/novel-coronavirus-2019.

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