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29.05.2024
cellvie’s co-founder interviewed by and featured in European Biotechnology
EuroBiotech_Mitochondria are not part of the standard repertoire of research, let alone clinical practice. Are the systems for dealing with these cell organelles sufficiently developed?
Alexander Schueller_Mitochondria remain somewhat elusive, given that most laboratory technologies available today were designed for research on cells – which are often more than 1000-fold larger than your average mitochondrion. This presents a challenge to the field as it limits our ability to characterise and trace mitochondria for example.
EuroBiotech_Would you say that regulation is more refined at this point, where does mitochondrial transplantation stand?
Schueller_The regulation for mitochondria transplantation is still evolving, but we expect that the therapy will be regulated as a biologic in the USA. Now, while there is little explicit precedent to go on, we can take cues from the regulation on cell and gene therapies or exosomes. So, I would say we roughly know what to expect, but the details remain to be determined. On the upside, as the ones pioneering the field, we will have the chance to work closely with the FDA or EMA to help shape the regulation.
EuroBiotech_What exactly is cellvie’s therapy and how to use it?
Schueller_We take mitochondria from cells and purify them. Most importantly, we developed processes and excipients to be able to freeze these mitochondria without compromising their therapeutic potential. This is essential to enable centralised manufacturing, allowing for the mandated process controls and documentation, as well as the production at scale and thus reasonable costs. So, the product are frozen mitochondria in a vial, provided with a delivery buffer, ready to use within minutes, allowing seamless integration into the clinical workflow. In terms of applications, we view mitochondria as a platform technology. We are pursuing kidney transplantation first, as a steppingstone to the large cardiac markets of ischemia-reperfusion injury. By rescuing cells that are damaged in conjunction with organ extraction, transport and transplantation, we expect to improve organ viability, longevity as well as availability. Importantly, this is not a day dream. The efficacy of our stored human mitochondria has been shown in corresponding large animal experiments. In addition to our lead-asset for ischemia-reperfusion injury, we have been developing a promising pipeline in cell and gene therapy, for example the use of mitochondria as non-viral vectors for gene therapy delivery to solid organs other than the liver.
EuroBiotech_What is known and understood to date about the therapeutic potential of mitochondria to ameliorate the ischemia-reperfusion injury, for example during an organ transplantation?
Schueller_There are still unknowns, given the relatively early stage of the field. But researchers in academia and industry have been converging on a key mechanism by which mitochondria transplantation likely rescues cells or improves their performance. Specifically, we and others have observed mitochondria transplantation to trigger mitophagy and mitogenesis and thereby reinvigorate the cell energy metabolism, which has been disturbed due to ischemia – i.e., the lack of blood flow. A finding, which was confirmed very recently in a Nature publication, one of the most rigorous and hence impactful scientific journals. Whilst a consensus seems to be building in that mitophagy and mitogenesis are key mechanisms of action, they may not be the only ones. The exact function and effect of the transplanted mitochondria are hence still being debated, particularly across different applications. But their complex nature and multi-dimensional effects are precisely why, in my opinion, they may offer a completely new starting point for thus far intractable human conditions such as ischemia-reperfusion injury.
EuroBiotech_What therapeutic applications do you foresee for mitochondria transplantation?
Schueller_We believe in mitochondria as a platform technology. However, one has to be careful to not overstate the expected use-cases. Mitochondria are not pixie dust. But there are already a range of medical conditions wherein mitochondria transplantation has shown promise. Most notably and repeatedly, in ischemia-reperfusion injury, which was the application wherein my co-founder, Dr. McCully, pioneered the field. Ischemia-reperfusion injury arises whenever the flow of blood is interrupted and subsequently re-introduced. Medical conditions include heart attacks, organ transplantations, strokes, or long surgical procedures. There are hence millions of patients that stand to benefit each year. Recently, a group in the US, in collaboration with Dr. McCully, also showed that the performance of the aging muscle may be improved by mitochondria transplantation. Another interesting area, which we are also working in, is the amplification of cell therapies by ex-vivo transplantation of mitochondria. There may be more, and, with the zeroing in on mitophagy and mitogenesis as a key mechanism of action, I believe a roadmap may be emerging to find them.
EuroBiotech_But do investors react favourably to such early, high-risk projects in the current climate?
Schueller_I have prior experience in founding a company, but in medical devices. We developed a surgical adhesive. There the story was more simple. You could see the glue, you could put it on your skin to showcase its characteristics or perform acute animal workshops for that same purpose. There was also a clear understanding of the regulations and the path to follow for approval. Now with mitochondria it’s completely different. Something this new does not commonly trigger enthusiasm among investors, but uncertainty. I frankly underestimated the extent to which ambiguity may overshadow upside potential. So, no, I would not say that investors generally view such early stage projects favorably, and even less so in the current climate.
EuroBiotech_And your experience didn’t play so much of a role in convincing investors?
Schueller_It helped, but it was insufficient. Even with our Harvard origin, a strong founding team, and first clinical proof of concept data, mitochondria transplantation was seen as too risky, or fringy by most people we spoke to. We were fundraising for nearly two years until Michael Greve with his venture capital firm Kizoo gave us the first major capital to start addressing the uncertainties that kept more traditional VC funds at bay. We are very grateful for that. Without his impact-driven investment philosophy, we would not have been able to bring Taiho Ventures on board, who led our funding round last year. Generally speaking, the average investor, especially in Europe, does not have the fund size or mandate to fund the emergence of a new field of medicine.
EuroBiotech_Buzzwords such as longevity are not enough to open the check books?
Schueller_While the attraction of longevity is real, buzzwords won’t do with sophisticated investors. I would also say that while interest in longevity has risen exponentially in the general population and with certain groups of highly affluent individuals, it has not yet come close to hype-status amongst institutional investors. In addition to the insufficiently understood biology of many aging related degenerations, time frames to results of longevity approaches commonly do not align well with traditional funds’ investment horizons.
EuroBiotech_So the reluctance to invest in mitochondria transplantation is not due to insufficient marketing within the longevity community?
Schueller_The potential application in aging-related degeneration has gotten us off the ground. It has been the shared vision of Michael Greve and cellvie. But as we are eying a substantial Series A, we must look towards more timely and tangible areas of development. Such as in organ transplantation.
EuroBiotech_Would you characterise Europe’s VC landscape as more risk averse and hence consider the US as more likely to back a concept such as mitochondria transplantation?
Schueller_Absolutely. Particularly, as we are now aiming for a Series A financing of US$30-40m. As a lead investor, a fund would need to commit US$10-15m in such a round. For one, there are not that many funds in Europe large enough to write checks of this size. And within those funds that can, there will be only a limited number of investment allocations reserved for truly novel concepts. So, it’s not just a question of risk-philosophy, but also a numbers game. Although, I would assume that there are relatively more tickets reserved for high-risk-high-rewards investments in US funds. If we were to raise a smaller round, which we might have to, we would have the benefit of a considerably larger number of fitting European VCs.
EuroBiotech_How do you sell such a novel concept? A lot of basics to teach, I guess. Do you focus your pitch on the basics of mitochondria transplantation, or on the vision of its potential?
Schueller_It’s always a bit of both. Ideally, you capture the interest and imagination of the investor with your pitch for impact, and turn him or her into a believer and advocate by presenting a well founded rationale for why such impact is possible and likely. In particular in the early days, when we got started, there was a lot of skepticism, fueled by the lack of understanding and consensus on the mitochondria’s mechanisms of action. With the reproduction of my cofounder’s results across various labs, the field has been experiencing a discernable shift from skepticism to curiosity and hope. I believe, several investors may even be close to action. The recent Nature article will hopefully further substantiate the confidence in the technology. It also helps that we are not alone. Luca Science, in Japan, for example raised a US$30m Series B and Minovia from Israel just started a clinical trial with mitochondria-enriched stem cells. I hope we will be able to benefit from this building momentum.
EuroBiotech_What is important to you now for the next steps?
Schueller_Given the round size we are after, we need to further substantiate our products’ efficacy, safety and manufacturability. We expect to be ready to fundraise in late Q3, early Q4 this year. If we succeed, the next inflection point will be the clinical trial of our allogeneic off-theshelf mitochondria in kidney transplantation. Nothing short of a clinical proof of concept will truly elevate the field.
EuroBiotech_How do you view clinicianled initiatives to start experimenting with mitochondria transplantation?
Schueller_Very critical. The field is already suffering somewhat from the history of stem cell therapies, where some doctors took it upon themselves to determine the appropriateness of the approach along with the therapy’s manufacturing and administration. Of course, we need clinicians to become early adopters and work with us in investigational clinical trials. But we don’t need these unregulated individual clinical treatments. We need to ensure patient safety and create reliable evidence of efficacy.
EuroBiotech_In other words, you need the regulation that is commonly criticised so much?
Schueller_Of course we need it. While we may sometimes rightfully grumble about its bureaucracy and rigidity, it serves to ensure patient safety and provides a framework for companies like us to test our therapy with confidence in patients. It also serves to build trust in new therapies amongst clinicians and patients. It is hence indispensable for a healthcare system to work.
EuroBiotech_ Your enthusiasm and vision in honour but he whole thing sounds like a long and winding road ahead, right?
Schueller_If it was easy, anyone could do it. On the bright side, the road ahead may feel and actually be shorter than the one already travelled.
European Biotechnology | Summer Edition | Vol. 23 | 2024
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