A Conversation With Professor Josef Penninger on the Journey to a COVID-19 Therapeutic
A Conversation With Professor Josef Penninger on the Journey to a COVID-19 Therapeutic
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Angiotensin-converting enzyme 2 (ACE2) – the receptor used by the SARS-CoV-2 virus as a gateway to enter and infect host cells – has garnered significant attention for the wrong reasons over recent months. But could it also point towards an exit route out of this pandemic? In an interview with Technology Networks, the renowned immunologist Professor Josef Penninger – nicknamed "Mr ACE2" – explains why he thinks so, and discusses the latest clinical data obtained from testing the soluble ACE2 receptor, APN01.
The history of ACE2
Professor Josef Penninger is the director of the Life Sciences Institute at the University of British Columbia, Vancouver, and a group leader at the Institute of Molecular Biotechnology in Vienna. Across two labs in two different continents, his teams adopt a holistic approach to studying human physiology and disease, exploring cancer, immunity, neuroscience, the cardiovascular system, the circulatory system and glycoproteomics – to name just a few focus areas. Put simply, Penninger is a "jack-of-all-trades" in modern medicine and biological research.
In 2001, Esquire prophesied that Penninger would be "the greatest scientist of our time". In his early thirties at the time, he was regularly publishing papers in prestigious journals and receiving a growing number of accolades.
The following year, Penninger's research group in Toronto published an article in Nature on angiotensin-converting enzyme 2 (ACE2) that would see him nicknamed "Mr ACE2" for years to come.1 "We were not the first group to publish the sequence [of the ace2 gene] – that glory goes to two other groups," he says. "But as genetic engineers we were making knockout mice." Using these knockout mice, the scientists were able to demonstrate – for the first time – that ACE2 regulates heart function in vivo, in addition to mapping the ace2 gene to the X chromosome.
The significance of the research was somewhat disregarded at the time, an ironic tale that reoccurs regularly in science. "I remember when we cloned ACE2, I was really excited, and so I talked to a senior scientist at the university. He told me that I should stop the project because it was totally uninteresting as we already know everything about the renin-angiotensin system that is to be known," Penninger says. He laughs, before adding: "If some senior guy tells me that I should not do something, it's probably a good idea to actually do it, it adds extra motivation to go for it."
Before the Nature paper was published, the researchers discovered that ACE2 was also expressed in the lung, a curious finding which "didn't make any sense".1 They wanted to get to the bottom of it. "All of my postdocs worked on models for intensive care units for mice so that we could study acute lung injury. At that time, between 2000–2003, there were maybe two or three groups on the planet which did this. The reason being it was difficult to create stable and reproducible models. My postdocs worked for many years to get the model going and then we studied ACE2 using it. We found that when we delete ACE2 in animal models the lung injury got much worse. The renin–angiotensin unit is a critical component of lung injury."2
Through their increased understanding of ACE2's role in lung injury, Penninger and colleagues discussed the possibility of creating a soluble version of ACE2. "When you knockout ACE2 in animals, lung disease worsens. We figured maybe we should make a soluble version of ACE2, put it back into the mouse, and we'd expect the lung disease to get better," he says.2 That's exactly what they did. In 2002, recombinant human angiotensin-converting enzyme 2 (rhACE2) was patented by Penninger, and in 2003 he founded the Austrian biotech company Apeiron Biologics.
Along came SARS
Meanwhile in 2003, an infectious disease known as Severe acute respiratory syndrome (SARS) caused by a new coronavirus, now known as SARS-CoV, began to spread, triggering severe pneumonia and often fatal lung injury in patients. Cell-based models pointed towards ACE2 as being a functional receptor for the virus.4
Penninger and colleagues had the only ACE2 knockout mouse model available in the world at that time, which they sent to China, so that researchers could infect the model with SARS-CoV. The outcome was a paper published in Nature Medicine outlining the first genetic, in vivo proof that ACE2 was in fact a crucial receptor for the SARS-CoV virus, and that SARS-CoV infection reduces ACE2 expression. "We put one and one together. The virus uses ACE2 for cellular entry, and in doing so it downregulates ACE2 expression. If ACE2 is downregulated, the enzyme function of ACE2 on the surface of the cell is lost, driving injury and inflammation." This explained the respiratory symptoms observed in SARS patients.
Penninger and his team published a number of other papers in which they further described the implications of ACE2 in SARS infection, severity of the disease and a protective role for vital organs such as the heart, lungs and kidneys." He describes the work as beautiful and well received, and pays thanks to his former postdoc students Yumiko Imai and Keiji Kuba for their contributions.
However, in 2005, the World Health Organization (WHO) declared that SARS was contained. "Of course, now everyone was saying “who cares”. It's beautiful work but it has no relevance because there is no SARS," Penninger recalls. Fast-forward to 2020, the novel coronavirus SARS-CoV-2 has brought life to a screeching halt, and the irony of this research being declared "irrelevant" leaves a sour taste.
Big pharma takes on rhACE2
Undeterred by critics, Penninger pursued the development of rhACE2 and its testing in acute lung injury. His logic was that acute respiratory distress syndrome (ARDS) is not solely a symptom of viral infection, it can have many causes, and so the applications of this potential therapeutic extended way beyond infectious diseases such as SARS. rhACE2 was branded as APN01 by Apeiron and reached Phase I development for the treatment of ARDS.
Big pharma caught wind of APN01 and in 2010 Apeiron announced that it had signed a £207 million agreement with GlaxoSmithKline (GSK), giving the company exclusive rights to the soluble ACE2 receptor, which became GSK2586881.
The results of a pilot clinical trial of GSK2585881 are published in the journal Critical Care, which states: "GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes."5
Over the course of 2018–2019, GSK had a "clean-up" and made some big changes. The company terminated its progression of several products in their respiratory pipeline, including GSK2586881, and redirected its portfolio to oncology. "Our respiratory franchise… has been a driver for GSK R&D for a long time and we've been very successful with it… but it's also pretty flat. There is not much growth to be expected," Axel Hoos, GSK's head of oncology told S&P global in 2018. As such, GSK2586881 was returned to Apeiron and became APN01 again in 2019, just months before the emergence of SARS-CoV-2.
Then came SARS-CoV-2
I asked Penninger what his initial thoughts were when the news broke of the novel coronavirus outbreak. He recalls: "It immediately clicked in my brain that ACE2 must be the target receptor for SARS-CoV-2 because of the similarities between the Spike protein of SARS and SARS-CoV-2." Sure enough, he was right. As the number of COVID-19 fatalities began to rapidly climb, scientists, industry leaders and global authorities assembled to search for an effective therapeutic against the virus.
In April 2020, Apeiron announced it had received regulatory approvals in Austria, Germany and Denmark to initiate a Phase II clinical trial of APN01 in 200 severely infected COVID-19 patients. The announcement followed preclinical testing of APN01 in SARS-CoV-2 cell models and human-derived organoids. Often referred to as "mini-organs", organoids are three-dimensional cell cultures that can recapitulate, to a certain degree, the complexity of an organ.
Penninger believes that APN01 is probably "one of the most rational therapies you can think of" which goes beyond antibody therapies that work to neutralize the virus. In a press release, Professor Henning Bundgaard, principal investigator of the clinical trial and professor at the Faculty of Health and Medical Sciences at the University of Copenhagen said: “We are eager to participate in this very promising and critical study. APN01 is an advanced drug candidate with a very strong dual rationale that may provide an important therapeutic contribution to fight the COVID-19 pandemic."
First COVID-19 patient data of APN01
Today, a paper published in The Lancet Respiratory Medicine describes the first compassionate use of APNO01 in a 45-year-old female with severe COVID-19 over a nine-day period.7 The study shows that APN01 retained its enzymatic activity. "This is very important data," Penninger told Technology Networks shortly before the study was published. "It provides us with information on whether the enzyme is still functioning in a patient. We assume it is, but of course we must show that it is."
Infusion of APN01 was correlated with a gradual reduction in the levels of several diseas relevant mediators over the nine-day period, in addition to a rapid loss of viremia, and a delayed reduction in viral titers from tracheal samples and nasopharyngeal swabs.
Furthermore, infusion of APN01 did not adversely impact the patient's adaptive immune response, which was a huge factor of consideration, as Penninger told Technology Networks: "You could argue that if our molecule binds to the virus, it could divert the virus somehow so that immunity cannot kick in, making the disease even worse. Now we know the answer to this question – and it looks very good."
Of course this data is obtained from just one patient, which must be considered. However, it's a positive start, and the Phase II APN01 clinical trial is still recruiting.
Peter Llewellyn-Davies, CEO of APEIRON Biologics, said in a press release: "We are delighted our drug candidate APN01 may have helped this patient to overcome the life-threatening disease and are confident to confirm these positive results in our ongoing and progressing pivotal clinical Phase II trial. The further scientific validation by this renowned journal encourages us in our efforts to providing an efficacious therapy against COVID-19 for the benefit of patients and society."
When asked whether he feels optimistic about the future of APN01, Penninger immediately responds: "Absolutely. The science here, that me and other companies are doing, points in the same direction. It will be interesting to see how this [APN01] plays out, in terms of viral load and the protecting of organs. As we know COVID-19 has other long-term effects in tissues around the body. ACE2 explains this distribution."
Penninger sounds confident, but not arrogant. It is evident that he truly believes in the science behind APN01; after all, he has committed many years of his research career to exploring it, discounting critics along the way. But in the context of the global pandemic, the clinical data is everything.
"What we do not know is: What dose should we use? Which timing for therapy is right? Should we start earlier? The clinical trial is testing the drug in severe COVID-19 patients. Would it work better when tested in patients for which the disease is not severe? These are the questions we have, and that's why we do careful clinical testing," he says. "I am totally confident about the science, but the clinical outcome – let's see what the data tells us."
Josef Penninger was speaking to Molly Campbell, Science Writer for Technology Networks.
1. Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417(6891):822-828. doi:10.1038/nature00786.
2. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112-116. doi:10.1038/nature03712.
3. Fountain JH, Lappin SL. Physiology, Renin Angiotensin System. Treasure Island (FL): StatPearls Publishing; 2020. https://www.ncbi.nlm.nih.gov/books/NBK470410/. Accessed September 24, 2020.
4. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-454. doi:10.1038/nature02145.
5. Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Critical Care. 2017;21(1):234. doi:10.1186/s13054-017-1823-x
6. Monteil V, Kwon H, Prado P, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE1. Cell. 2020;181(4):905-913.e7. doi:10.1016/j.cell.2020.04.004.
7. Zoufaly A, Poglitsch M, Aberle JH, et al. Human recombinant soluble ACE2 in severe COVID-19. The Lancet Respiratory Medicine. doi:10.1016/S2213-2600(20)30418-5