When Your Immune System Attacks You... Prof. Dr. Niels Riedemann, Co-Founder & CEO, Inflarx
What if you contracted a serious virus or bacteria? You want your immune system to respond. But what if your immune system overreacts? Or what if the foreign invader isn't an invader at all, but your own healthy tissue? This may sound somewhat familiar to some of you, but what Inphlorex is doing about it is definitely original.
Dr. Moira Gunn:Professor Niels Reidemann is the cofounder and CEO of InflaRx. Professor Reidemann, welcome to the program.
Prof. Dr. Niels Riedemann:Thank you so much, Moira, for having me.
Dr. Moira Gunn:Now what is C5a and why does it need to be inhibited?
Prof. Dr. Niels Riedemann:Thanks for this question. Love to answer it. So C5a is a small protein in your blood that gets activated and this protein can really boost inflammation to a point where inflammation can cause harm to your own organs and tissue. Now I should mention that C5a is part of our immune response.
Dr. Moira Gunn:Now, I had say rheumatoid arthritis, how does C5a work into that? How exactly does it work? And why is it really a challenge for rheumatoid arthritis?
Prof. Dr. Niels Riedemann:So I think rheumatoid arthritis is an interesting example and you probably heard the term autoimmune disease before, right? So this term implies that kind of your immune system reacts against yourself, right? And we talked about the immune system and C. VaVe being part of our immune system. And I want to introduce you to the fact that I mentioned it's a small protein that's activated.
Prof. Dr. Niels Riedemann:It's part of several proteins floating in your blood, that can get activated and these several proteins altogether are called the complement system. Now what is the complement system? It's actually a very central part of that immune response we're talking about. That gets activated in autoimmune diseases and there is also evidence that C5a is elevated in patients with rheumatoid arthritis especially when they have a flare. So I want to explain that a bit more in detail.
Prof. Dr. Niels Riedemann:So what do these proteins floating in our blood do? Why the heck are they there? Right? What do they do there? Well, of that as a broad sensor that is in your blood and in your tissues to sense anything that shouldn't be there and give that signal to your cells, to your immune cells to tell them, hey, there's something in our system that shouldn't be there.
Prof. Dr. Niels Riedemann:Get active, get rid of it. Now these immune cells, you can think of them a little bit like they're having weapons to get rid of anything that's in our system. And these weapons are a bit like dirty bombs. They can get rid of that. But if they get activated dramatically, they can unfortunately, these dirty bombs can also start damage our own tissue.
Prof. Dr. Niels Riedemann:And what does it mean when tissue is damaged? It means, for example, organs stop functioning as well. So it gets very dangerous. And, you know, if you think of that example that you gave for rheumatoid arthritis, we all know the problem happens in our joints when you have that disease. So something activates the immune system and maybe also the complement system pretty surely in that joint.
Prof. Dr. Niels Riedemann:So cells get active, they move into that joint and they start inflammation, they release these dirty weapons. Well, guess what they do? They damage our own tissue, in this case, the cartilage and the cells that should function in your joints. So there you have it, you have an autoimmune disease and the complement system is almost always involved. And that's why I think it's important to keep that term in mind.
Dr. Moira Gunn:So the C5a is great if it's going after a true foreign invader, real intruder, you know, doing bad things to you. Really go after it. But if it happens to identify your own system, then you want to inhibit it.
Prof. Dr. Niels Riedemann:That is true. But also when it gets over activated, our body has the ability to produce a ton of this little activation product C5a and when it's over produced, that happens in life threatening inflammatory settings, then that becomes a double edged sword. The original positive meaning of starting an immune response turns into something very dangerous and in fact even deadly. And so if it's too strongly activated, you want to block it. If it is activated when it helps the system to act against your own tissue, like in an autoimmune disease, want to block it.
Dr. Moira Gunn:Now, Inflorex already has a C5a inhibitor that's been authorized by the FDA under emergency use authorization, and it's for critical COVID-nineteen. What is critical COVID-nineteen and what is your drug doing?
Prof. Dr. Niels Riedemann:Yeah, I really appreciate that question too, happy to give you a bit more color. And it's interesting now we're five years past the pandemic start and we all want to not ever hear or talk about it again, but yet we know it's kind of the pandemic is done, but that viruses may not be done with us. And that's the trouble we're in. So, we all know that we take vaccines to hopefully not get as sick. That's what we do before we get sick.
Prof. Dr. Niels Riedemann:When we get sick and the virus is in our system, when we have these flu symptoms that many, if not most of us experience, there are antivirals, they stop the virus from replicating and hopefully that helps you. However, unfortunately, with or without these medicines, some patients develop that what we talked about that strong immune response that is overboarding. And then they get severely sick, they have trouble breathing, they need oxygen support, they need a breathing mask and eventually they need invasive mechanical ventilation when the lungs are no longer able to sustain their function to give oxygen in your blood. And exactly for those patients that get so severely sick that they need invasive mechanical ventilation or even lung support therapy. For these patients, we tested this anti C5a antibody that you mentioned that blocks C5a, and we got this emergency use authorization from the US FDA.
Dr. Moira Gunn:So if we need your drug, we're in trouble.
Prof. Dr. Niels Riedemann:You could say that.
Dr. Moira Gunn:But thank goodness it's there. Okay. So now this same c five a inhibitor is in other trials. And one is very interesting to me, and this is broader than the critical COVID, response. But in 2023, BARDA, which is the biomedical advanced research arm of the office of strategic preparedness and response, which is part of the US government, hosted a pitch event just like they're in Silicon Valley or something.
Dr. Moira Gunn:They they had the judges. The judges included the CDC, the FDA, NIH, and other federal government agencies. And biotech and pharma companies came with 18 drug candidates, that were in what we call the end of phase two. They were still not approved yet, but they were, you know, they had demonstrated, some level of efficacy. These were very creative and promising drugs.
Dr. Moira Gunn:And so of the eighteen, three drugs were selected to be studied. One was from a company we would all recognize, Genentech, and one was yours, Inflorex. Now what was the medical condition that you were all talking about? Why was is this condition so critical? All of these agencies are interested in it.
Dr. Moira Gunn:And while the trials are still underway for these three drugs, how might your C5a inhibitor drug work to treat it?
Prof. Dr. Niels Riedemann:So the condition that is tested there is really a very critical condition and there are no treatments yet authorized for this broader condition. And that condition has to do with lung failure and it's referred to as ARDS or ARDS. That stands for acute respiratory distress syndrome. And that means when both of your lungs, the left and the right lung are so severely compromised, that you're in trouble, you need oxygen support, you have trouble breathing, etc. Similar to what we just discussed in COVID.
Prof. Dr. Niels Riedemann:Now, it is recognized that this condition is caused by the immune response we talked about. And it's also recognized that it can result from different, I would call it, insults. It could come from viruses like COVID or like influenza, like avian flu, but it could also come from bacterial infections in the lung. It can even come from chemical, injuries when you inhale smoke or when you ingest some chemicals. So this immune reaction to this type of invasion either by microorganisms or by other causing damages, that immune response causes this lung failure.
Prof. Dr. Niels Riedemann:And since there are no treatments, and the government recognizes the importance. Also, when you think about pandemic preparedness, just think about it. There was a drug that you could pull off the shelf available if a new virus hits and you could at least hopefully give it to the most severely sick to bring down mortality, ideally, and win time until appropriate vaccines or appropriate antivirals. You know, I'm just giving these examples from COVID because we all still remember them or until appropriate, you know, antibiotics would be developed for, you know, let's say a bacterium for which antibiotics don't work anymore. So such an approach would to society.
Prof. Dr. Niels Riedemann:So that's why the US government researches these approaches. Now, how does C5a fit in or may fit in? Well, first of all, I should say we still need to test it. We cannot just automatically assume that it will work. But we talked about earlier here today about the important function of that little protein and the complement system.
Prof. Dr. Niels Riedemann:Remember, that sensor in our system that can get over activated. So I think through COVID, we were able to show that when it was given to these very severely sick patients that it did lower the all cause mortality in these patients. So there is a hope that this function is similarly important in the broader ARDS setting. Now, as just as a side note, we are not approved in The US with the drug. We have, as you said, an emergency use authorization.
Prof. Dr. Niels Riedemann:We just recently, two months ago, got an exceptional circumstance approval in Europe. And that approval was for that COVID part that can cause moderate to severe ARDS. So it's different label than the use of the emergency use authorization in The US, but there is this recognition of the causing ARDS, in this case from COVID. Now
Dr. Moira Gunn:one more quick question about this same drug, different trial, and at least on the surface, a very different condition. It's called pyoderma gangrenosum, and I'm sure I mispronounced it, it sounds terrible. What is this disease and how might this same drug, Inflorexis drug, apply?
Prof. Dr. Niels Riedemann:Yes, so indeed it's a disease that's not just difficult to speak, pyoderma gangrenosum, it's also really a horrible skin disease. These patients suffer from large ulcers that don't heal despite of all sorts of treatment including wound care and you know off label trying and error of different therapies. Well in fact there's no drugs available or approved in The US or in Europe for this condition. It's a rare but really horrible skin disease. In some cases it can even lead to amputation of legs and arms when these ulcers don't heal and get larger and larger.
Prof. Dr. Niels Riedemann:And I should mention these patients suffer a lot. The patient advocacy group leader once told me that this is not just like a wound. Just, she said, imagine you feel skinned alive all day long. This is what this disease is. So horrible condition.
Prof. Dr. Niels Riedemann:And your second part of the question was how may that mechanism that we talked about fit in? And so this is also a condition where we believe that it's kind of in the broader autoimmune, auto inflammatory condition. So again, the immune response is recognized to play a role. Even though this condition is not fully understood, this disease, these immune cells, which I mentioned that can get activated by the complement system are abundantly present and seem to cause these ulcers or at least disturb them from healing. So we did initial studies that showed some promising results and we are currently running a larger, more international, different countries, but with focus on The US phase three study.
Prof. Dr. Niels Riedemann:So ultimately, our idea is that one day we hopefully get an approval and show that the drug is truly efficacious, but, it still needs to be tested. But again, remember the immune response we talked about, so that may be applicable in different diseases. I should probably also go one step further and say these cells, these immune cells that get activated by C5a, they are covered with the signal sensor called C5a receptor. This is what gets them activated when C5a binds to them. They have that on their cell surface.
Prof. Dr. Niels Riedemann:And particularly those that are found in this disease are part of the white blood cells, they can cause damage. So there is a link to damage in this case in the skin, in this case very locally, but you know with a very bad outcome for the patient. So we have the hope to show through this study that there is an effect also benefit for patients to heal these ulcers.
Dr. Moira Gunn:Now, you have other formulations, other trials, but I wanna talk about this. You and your cofounder, doctor Renfeng Guo, were postdocs, both MD postdocs working in the same lab at the University of Michigan. You came from this tiny town in Germany. He came from a tiny town in China. And yet, in addition to playing table tennis and all the kinds of things that that graduate students do, you discovered that you were a terrific lab team, and you also made a scientific discovery.
Dr. Moira Gunn:What were you working on? What did you discover, and how did it lead to today?
Prof. Dr. Niels Riedemann:Yeah. Absolutely. Renfeng and I met as postdocs in that discovered that we were working well and we were part of a broader discovery team in that lab of Doctor. Peter Ward, a famous complement scientist, and we were part of the team that researched exactly the role of this protein C5a and especially the receptor I mentioned on these immune cells. Ren Feng and I discovered the role of this receptor particularly in different conditions in preclinical science where it leads to damage in the lung, in the organs, in the different tissues.
Prof. Dr. Niels Riedemann:And we get so intrigued about the broad potential applicability of the mechanism for so many different disease settings that I think it was one night past midnight, and I guess I can say it today, I think we had a beer in the lab today that wouldn't be appropriate anymore, but back in the day you could do that. We had a beer and we were oftentimes working late and we started talking about, wow, this is so important. You know, we should really think about making the drug addressing this. Now you mentioned by now we have two drug candidates. The one drug is the antibody that blocks C5a and the other one is the new formulation that will be an oral tablet, a chemical inhibitor that blocks the receptor we talked about.
Prof. Dr. Niels Riedemann:So the same pathway with different mechanisms addressed. And so we were part of that discovery and yeah, here we are many, many years later, a bit more gray hair, at least on my side, Renfeng looks really stellar with no gray hair. But but, yeah, we we we founded the company. Renfeng is in The US. He's the chief scientific officer of the company, and I'm in Germany, but, you know, we have this company together.
Prof. Dr. Niels Riedemann:We oftentimes meet in The US, sometimes even in Germany. So it goes a long way. And, yeah, it was really nice times, by the way. We we both are big fans of Ann Arbor, and I'm so happy that he's still there. He moved back from Germany to Ann Arbor, so that gives me a perfect reason to go back.
Prof. Dr. Niels Riedemann:By the way, go blue. I should not say that, but
Dr. Moira Gunn:I do. K. Go Boilermakers. I have to put that in. I'm so sorry.
Dr. Moira Gunn:So who was the better table tennis player then, and who's the better table tennis player now?
Prof. Dr. Niels Riedemann:I think, Ren Feng wins that game. I have to say, yeah, he's probably the better table tennis player. So
Dr. Moira Gunn:but,
Prof. Dr. Niels Riedemann:but that's not to say we had a lot of fun, and I I think yeah. We we also do cook together. That's sometimes very interesting. You know? Me, German background, him, Chinese background.
Prof. Dr. Niels Riedemann:You can imagine we're doing fusion fusion kitchen cooking. But we have that theory that if you're a good scientist, you must be also a good chef. I we can't prove that, though.
Dr. Moira Gunn:There you go. Well, I could just just see you going back and forth. Pong. Pong. Pong.
Dr. Moira Gunn:Pong. And by the way and you're talking science. And, hey. You know, we could use it for this. So you must have a a lot of conversations about besides what you're doing now, where this both now the inhibitor as well as something that blocks the receptor that which receives it on those immune cells of the C5a.
Dr. Moira Gunn:You must have some idea where else it can be used.
Prof. Dr. Niels Riedemann:Yeah, actually I mentioned in the lab we got very intrigued about the broad applicability in these different disease settings. Should caveat that any of that still needs to be tested and proven in adequate clinical studies. But we made public that we are very interested in other diseases. We have a key focus right now as I mentioned in the immunodermatological, so skin diseases, bad skin diseases, inflammatory skin diseases. We talked about PAUDAMA.
Prof. Dr. Niels Riedemann:We have two others where we're starting with a small inhibitor, the receptor inhibitor right now trials, phase two trials. We have that focus, of the company, but we, have clear interest to take this mechanism to broader disease settings and including chronic renal diseases, kidney diseases, including some peripheral neurological diseases and others. So if you think about the broader autoimmune kind of disease space Now, now you may say, you know, well, these guys are dreaming too much, right? But there's evidence that this exists. They call this pipeline in a drug that means you have one drug that may be applicable for various different immune diseases.
Prof. Dr. Niels Riedemann:And, if you're unfortunate to have an immune disease that needs treatment with biological treatments like antibodies, there are some that are approved up to 10 different indications and more. So this happens because we talked about that certain pathways and we believe the complement C5a, C5a receptor pathways, one of those may be important for various different disease settings. And there's evidence for some of that. There's also, you know, lots of clinical studies, but we are here to prove it and we still need to.
Dr. Moira Gunn:Well, Professor Riedemann, thank you so much for joining me. I hope you come back, see us again.
Prof. Dr. Niels Riedemann:Thank you so much for having us. Really a big pleasure, Moira, and yeah, always happy to talk to you. Thank you.
Dr. Moira Gunn:Professor Niels Riedemann is the cofounder and CEO of InflaRx. More information is available on the web at inflarx.com. That's inflarx.com. Inflarx Com.
