Patrick Short 0:03 Hi, everyone. Welcome to the genetics Podcast. I'm really excited to be here today with Ronald Vander geese, the co founder and chief development officer of tree way, which is a company based in the Netherlands that focuses on ALS and other neurodegenerative diseases like Alzheimer's. And in particular, we're going to talk about their unique approach, which starts really with the CO founding story of the company, where they co founded the company with patients who were affected by ALS. And we're going to cover a number of things today. But they've made significant progress on an oral treatment, potential oral treatment for ALS, in an area where other started, an oral administration actually wouldn't be possible. So, Ronald, thank you for taking the time and excited to have you today. Ronald Van Der Geest 0:45 Thanks to be here Patrick, and thanks for inviting me. Patrick Short 0:48 My pleasure. I'd love to start with the founding story, because I think you're one of the very few companies that really has patience at your DNA at the very core. So I'd love to hear about how it came about and a little bit about where you are today. Ronald Van Der Geest 1:00 Yeah, glad to tell. Ya, actually, the story is even more drastic than you just explained. Because when we stepped into the company, the company was actually already founded by the patients. So they basically had taken their own initiative to start a company, because they were diagnosed in 2010, and 2011. And they simply so they met each other. They both from Rotterdam here in the Netherlands. And they both concluded at their first meeting, the first chap basically, that they were not going to sit down, and they were not going to accept that they were going to die basically, and founded this company together, these were two intrapreneurial guys, one coming from the venture capital industry. And the other one from the from a company growing company, significantly growing company in the Rotterdam harbour, where he was one of the management team members. So these were people that knew how to set up companies, how to fund them, etc. So special individual special characters, because of course, this was a unique event that that nobody, not everybody knows how to handle that. But then, after they did that, they basically travelled around the world, especially Burnett, Bennett, Miller was one of the founders to see whether there were any companies that were having promising drugs, he read everything there was to read in scientific articles, made himself very quickly familiar with that. And then through one of the biotech companies that were based here in the Netherlands, he was tipped off to talk to us, which is in SDI for myself, and we have a company called 3d pharma exchange. That is basically, you know, the way you could describe this is that we have brought together a group of development experts that cover the key areas of drug development. And there are a couple of those. And we thought it was good to bring those people together and make them available to small biotechs. And startups because often what you see in this biotech and startup arena, is that there are insufficient experts, there is an incomplete team. And then if inefficiencies start in the development of the drug, now, we sometimes have difficulty to explain that to biotech companies, you know, because this is a new model. And when we talk to Bennett of origin, they, they understood it right away. So we got together, there was a good click between myself and Inez and them. And so they said, Okay, you'll be the CEO and the CTO of this team. And we support you with whatever we can support you with, to get this off the off the ground as quickly as possible. And there we went. Patrick Short 3:48 And I were gonna think spend most of the time diving into the the ALS story. But I I was intrigued by what you mentioned there about many companies getting things wrong at the beginning or not quite right. Maybe you could talk a little bit about those major development areas. And what are some of the common things that go wrong? Ronald Van Der Geest 4:05 Yeah. Well, it's actually you know, what, what we thought of, and that's now 12 years ago, when we started the companies that, you know, I come from the big pharma companies, I started my career at j&j. And you learn a lot when you are in these big pharma companies. And they do a lot of things, right. And I think they, you know, if you think about development of products, they do things a little bit more efficient, that startup companies because they have everything in place, they have a team in place, they have money, and you know, if the vibe is good, and if the setup is good, then you can make tremendous space. And that is sometimes although the biotech company companies have a lot of bright ideas and a lot of creativity to add to that they sometimes have difficulties making it happen. And that has to do with the fact that if you're in a startup company, you have a high risk profile, you have little money If you're not so attractive to, you know, the best people in the biotech kid in the pharmaceutical world. So what we did we first of all looked at, you know, how are the the teams organised? What kind of expertise is are always in a project team from a big pharma company. And we made sure that we basically brought those people on board and made them available to the smaller companies. So yes, if you talk about how you develop a drug, there are basically four disciplines, four major disciplines. And that is the development of your formulation. So everything around the bill, the injection or the nasal spray, there is preclinical toxicology, to test in preclinical setups, whether your drug is safe enough to introduce it to humans, then you get to your clinical phase. And your fourth expertise is the whole regulatory environment around it to make sure that everything complies with these highly regulated environments that we work in on a day to day basis. So those kinds of people are in our group. And, you know, that's what was picked up by our ALS patients. And they said, Okay, you know, you guys have sort of a running engine of developers that can we can plug in a drug, and they had some ideas about about drugs, we'll plug it in, and we get going from day one, and not after we've hired people and whether we raise money. It was all there, and we got going from day one onwards. That's how we might speed Patrick Short 6:30 Yeah, it's it's really helpful in a great framework. So maybe you could talk me through from day one, when you first started speaking to the co founders and the team, what was in place, then? And then where are you now? And what was the journey like along the way? Ronald Van Der Geest 6:44 Yeah, that was interesting. When we started, they had already done some research work, and had worked with some consultants to scope out what works, we're basically there. And what they picked up on was one, basically one proof of concept study that was executed in Japan, where the drug, a DERA phone was used in a small set of patients. And what was shown in that article that was an article from 2006 2007. What was shown in that article is that not only did they saw indications of a clinical effect of this drug in patients, but they also saw some biomarkers, and those were biomarkers in the blood that were predictive of oxidative stress, they saw those biomarkers go down. So we re evaluated those data. And we also concluded that this was highly interested. So if you see multiple things moving in the right direction, that usually tells you that you're on the right track. But these were small data. They were there were some pluses and minuses on the way that set it up. But we have we saw sufficient promises there, that that this could work. The one drawback though of the molecule that was introduced into these patients was that that it was dosed via an IV dosing. So patient, this was a fast drug that was eliminated in the body quickly. So they had to put these patients on an infusion of an hour or half an hour to make sure that sufficient amount of drug came into the body. And then so the rest of the day you were done. But you had to repeat that every day. Because the drug needs to be there on a continuous basis. Now, you can imagine that if you're an ALS patient, you have a chronic chronic disease, and you need to go on an infusion every day, you have to go to the hospital, you need to bring somebody in to make that happen. That is not an easy task and is high is a high burden. So usually, IV dosing is not suitable for chronic diseases. That's what all the experts say. And it's true because of the burden. And so we immediately knew that we needed to develop an alternative to that. And of course, the most preferred route of administering a drug is through oral delivery, because you can swallow tablet or something else. And that's the easiest way to do daily dosing. So we talked to a couple of experts, we talked to companies that have tried this before. And everybody basically discouraged us and said, Well, we've tried this, but it cannot be done. So don't bother. And the mantra to ALS patients has always been if somebody tells you that it's not possible, then it becomes interesting. Yeah. So we were inspired, of course by them. And we are basically inspired by that same mantra ourselves. So we said we're going to try anyways and so we we have a couple of very smart formulation experts here in the group. And I worked on it myself as well because I have a little bit of background in formulation work as well. So we still are trying with all kinds of approaches trying to be first time, right? Because you can do things in a lot of different ways. So we tried to be smart about the way that we developed our oral formulation. And to make a long, short story short, we made it happen. We had a pilot formulation that we thought was already good enough, and took it to the outside world. And there were some drawbacks on that formulation that we knew. But we, we thought about the high patient needs, and try to introduce that, you know, faster than anybody else had already done it. But basically, we got whistled back by investors and by, by, by, by by the market. And so we went in, we did not get discouraged. Well, we got discouraged a little bit, that's we went in again, and came up with a significant improvement or the formulation that we have. So you know, it's it's going back and forth. You know, you have upsides and downsides, but you keep going. And we finally found a formulation that really complied with all the needs of, of a marketing formulation up to the highest standards that we that we wanted to apply, just wanted to emphasise that that was done with a small group of people that we have here. And that was, of course, a real excitement. We're really proud of that. And it just tells you that, you know, it's not sometimes sheer quantity of people or sheer budget that make good things happen, that it's you know, it's about smart design, continuous efforts and keep on going until you get a good result. So, you know, we've been pushing hard with, yeah, it's been a long journey. But but we finally got there. Patrick Short 11:41 And since you and I met a few months ago, there have been big changes in the industry as well, with really Rio getting approval from the FDA, maybe you could talk a little bit about the current state of the art in ALS and a little bit about the disease itself, for those who aren't familiar, and then what the opportunity looks like, where do we where do we go from here? And and what are you guys thinking about your contribution there? Ronald Van Der Geest 12:04 Yeah, it's it's extremely exciting. I think also for patient these days that these developments are going on, and that new drugs are being developed. It never goes fast enough, of course, if you consider the patients because ultimately it becomes interesting to patients when they are when the drug is available. And there is a little bit of a difference between you know, what is available in Europe and what is available in the US. And Europe, basically, nothing is there yet, because they are you know, the EMA has been very, let's say critical on the body of evidence that is being produced for for these drugs. Whereas FDA has taken a little bit of a different approach in the past, more pragmatic, basically saying what with this drug could work, we're not quite fully convinced about the full efficacy, but let's put it out there anyways, because we have such a high need from patients. So there's different approaches. And that has led to different let's say availabilities of drugs in these countries. But we are working hard. Now we have partnered I programme, our Phase Three programme with the Fair, which is a Spanish company to at least make sure that this drug also becomes available in in Europe, we're making together with them fast progress on the recruitment. And then of course, we have done this study in such a way that we after the last patient is recruited to them, we need to follow them for a year to make sure that we can fully evaluate whether there's a clinical improvement because this is this is as we know, a slow process. This is chronic disease. So you need to evaluate that for a sufficient amount of time. That was one of the critical points from EMA in the past where other companies have only assessed that for shorter periods of time. And so we need to we need to make sure that that is being done, according to the proper requirements that Eva sets for this. So that's going on at the moment. It's very exciting. The study is still continuing, obviously, everything is still under confidentiality and all the data are still blinded as they should be at this stage. But things are looking good. Then there's new developments, of course in the field, that that are really exciting as well. So I think with the approvals now that are coming through that there's more hope for patients and on different mechanisms of actions. So what Dara Vaughn is doing aidera Vaughn is a radical Scavenger. So what that basically means it is a compound that cleans up the garbage that is being caused by neuro degeneration. So the tissues of the neurons disintegrate and that causes what we call reactive oxygen, re being released by these deteriorating tissues and if that is left out there, then you basically x tolerate the breakdown of your neurons. So you need to clean that up in order for the disease to be slowed down. And that is what this molecule does. And that is what has been also shown in study so that it does not improve the disease, but it allows the disease to slow down in its progress. And that's how it usually goes. But it tells you that it is, you know, it's the it's not a symptom. There are a couple of symptomatic treatments also out there that are being moved forward. But different from that. Either one is really disease modifying in the way that it tries to present prevent the disease really at its core to proceed faster, to proceed fast as it as it does by itself. So we're trying to slow that down. So so that's that's really exciting. I think. Patrick Short 15:49 Now, that mechanism that you described, to me suggests that the earlier you could treat, potentially, the better, right, if you could start really early and symptom onset or even prior to symptom onset, but I know it's a challenge that you all have is early identification, there aren't great biomarkers, and it's a rare disease. How do you think about that, and the the opportunity there versus the challenges it presents? Ronald Van Der Geest 16:13 Yeah, that there are two elements to death. First of all, there has been also in recent years may be made really progress on identifying potential genetic markers that caused the disease. So if you have patients that carry that genetic marker, then you could say to that specific group of people, well, we're going to start treating you prophylactically, before the disease starts, because you're at higher risk. But the unfortunate fact is, well, yeah, it's an unfortunate fact in ALS is that that's only a small portion of patients that has those genetic factors. For the majority of patients, we basically don't know what is causing the disease. And there's little to go on, if little other things to go on, if anything to determine that you are at risk as a patient. So in that group, you have a more difficult task. Now what we do in our late stage als trial is that we indeed specify that patients should be thoroughly diagnosed, so that they're not that the disease is not deteriorating, or preventing the product to act, and to make sure in that trial, that we have the highest chance of success in that patient population. So if you theorise about it, you would indeed, say that it is likely that patients that are more progressed, are you know, would benefit less from the drug. But that remains to be proven, it may well be that we're surprised by the potency of the compounds, and tested also in those later stage patients and see that the drug works. But of course, that needs to be determined, you know, we first need to make sure that there is least a significant portion of patients that that benefit from that. And then of course, if we approve that, then we are at least sure that all the patients that are early diagnosed, that they can go immediately on the drug to to make sure that they are on treatment. What has happened in the US is that FDA has said well, you know, guys, this is this is so great that you've done this for ALS patients, despite the fact that you have only included early diagnosed patients in your trial, we are going to give you the disease indication for the entire population. Because, you know, we we do not want to withhold this from patients that may benefit also from it. And I think it's also it was a let's say a also an encouragement of the company that was you know, brave enough to do this in this in this patient group. Patrick Short 18:52 How do you think about the trial design, your your framework, or the four piece of this extra is really helpful for me at the beginning. So you've got the the formulation, you've got the preclinical toxicology, and then in the third bucket that development, we know that in any disease but especially in rapidly progressing diseases, no one has any interest in putting patients on a placebo. And you know this, there are all kinds of interesting trial designs that mean you don't necessarily have to I'm curious about the designs that you've looked at or taken and how do you balance the statistical rigour that you need to establish what works versus the real ethical realities of of not wanting to deny anybody up potentially transformative treatment? Ronald Van Der Geest 19:36 Yeah, yeah, we've I mean, in terms of clinical trial designs, we are living in an exciting time because there is a lot going on. People are trying a lot of new type of setups in all kinds of trials. You have these days you have umbrella trials, you have platform trials, where they even merge multiple diseases into one trial or multiple drugs for one disease into one trial, and then all kinds of adaptive designs where as you go along, you are able to adapt the trial to basically be interim outcomes that you that you get. So we are following that closely, that type of thinking had not progressed that far at the time that we started to study to really incorporate that. So in that sense, I think the trial is ongoing now in ALS is or a classical design where you have a placebo group versus an active group, we have randomised that two to one so that there's a higher chance that you get on the active group than on the placebo group. And you have to realise at the same time, that with all these tricks that you put in place, in a trial, you usually pay a price in terms of statistics. So you either have to include more patients, or you have to prolong the duration of your trial, to maintain the amount of power that we call that you get out of a trial. So the power sort of determines how much chances of success that you have in a trial. And if you start to change those parameters, the power changes, and you need to correct for that to bring it back to your proper power that is required also from a regulatory point of view. So in that sense, I think it was not so bad that we had the trial, obviously, in a way that we designed it obviously because you know, you retain a lot of rigour in your trial, you know, if the outcome of the trial is right, then then you're done, especially for an orphan indication, or a normal indication, you need to have two pivotal trials before an orphan indication you are done with one trial now. So with that, you better make sure that you do that one trial properly, because you get only one chance. And if you fail, even if you feel because you find out that he had that you have some design errors, you usually do not get a second chance to make it happen again, because, you know, trials are very expensive, as we all know. So So you need to be right the first time. And I think we we made sure that that we did that, of course, there's always a chance that you have what we call a type one or type two error so that the drug actually works. But the trial gives something else because it's always a matter of chance and distribution of chances. But I think with the trial design that we have, we tried everything we can to make it as rigorous as possible. Patrick Short 22:27 Yeah. And maybe you can talk a little bit about how you measure because another factor in this is, is the endpoint and every disease has, you know, you work across a number of different diseases and the neurodegeneration in particular, there's a lack of good indicative biomarkers and the things that you're measuring take a very long time in both Alzheimer's and ALS and ALS is is it progressive disease that can be very fast in some cases, but not in, in others. So maybe you can you talk a little bit about what you're measuring. And if you if you had a wish list of of what you could be measuring and for some of the biomarker people to be thinking about where what would the better ideal be? Ronald Van Der Geest 23:05 Yeah, yeah. So in ALS, the one of the classical responses that you look at is the so called ALS FRS score, which is a clinical score that totals up to 50 points. And those 50 points are based on clinical questions to the patient's or to the to the caregiver, and you rate them with, with numbers. And if you see a faster decline in that, or if you see a less faster decline, so a slower decline in those scores, then you quantify that. And there's various ways to quantify that, in terms of biomarkers, you still see that that is fully in development, of course, biomarkers, you know, you have to realise that if drug effects have different mechanism of actions, they start to hit other buttons in the body that react. So if you have a radical Scavenger, like we have, you need to look at other parameters when you then when you have a drug that works on an outer mechanism of action. So since this was such a unique drug, those biomarkers needed to be developed. So we have included a couple of them in the trial. Our main endpoint will be on those clinical scores, but we take the biomarkers along to see if they follow the same path as the major clinical scores so to speak. So we are investigating that as we go along in this phase three trial and those the biomarkers that we elected are all looking primarily at the oxidative stress pathway, but we take along even a couple of other ones to see whether we can hit more buttons than than the most likely ones. Patrick Short 24:52 I know we're running up against time here I gotta get a couple more questions just because the I think this we can go so deep on this topic. The role of genetics nail as you touched on earlier, about 10 to 15% of patients have a known genetic factor sodwana, FOS C nine or seven, two, there's a growing list of more common and rarer ones. But as you mentioned before, the vast majority of patients appear to be sporadic and with no clear genetic cause. But the genetic drivers can vary pretty dramatically in progression, right? From very fast to very slow Progressors. And I've got to imagine that this is something you think about as well and trial design, both prospectively you don't want to just by chance, end up with a fast progressor in your treatment arm and slow Progressors in your placebo arm, which would throw off the results. And equally, I think after you run the trial, you may think about retrospectively going in and getting an understanding of are there certain patient groups, whether by genetics or otherwise, that respond differently? How do you think about that? And also, what are the regulator's asking you for their? Are they are they making any requirements or just recommendations at this point of how to think about genetic? Ronald Van Der Geest 26:08 Yeah, yeah, we,this goes into the technicalities of how you design a smart trial. And we've worked long and hard about thought about this, and also interacted with regulators, of course, a lot, after we have sort of completed our thought process. And one of the things that you need to realise that if you have ALS is a very heterogeneous disease. And even within the group that is known, genetics are the sporadic group, if you take that group by itself, you see a huge difference in deterioration rate of the disease. And if you look at this from just from a statistical manner, and we've done that in the past with various working groups, then you can even differentiate different groups that decline in a different with a different speed, so to speak. And the reasons why those groups are declining at a different rate is not yet clear. But you can define them from a statistical analysis point of view. Now, the fastest progresses in the disease are the ones that have a genetic mutation. That's pretty clear. And especially the patients that are unfortunate to have a sub one mutation, it is known that they progress very fast. But there has been some recent very promising developments for this specific group of patients where they are treated with a genetic approach, where the specific mutation is being targeted with a drug. And in the genetic area, there's lots going on with oligonucleotide antisense technologies, etc. So they're specifically targeting that. And apparently, some really good results have been obtained here. So that's how we That's how for only 2% of the total puppy population, because those are the ones that have the sub one mutation, but but there's really good hopes for that group currently. And there are some companies brave enough that they even take such a small patient group and help them so commercially dense is of course, for companies not the most attractive one. And the pharma companies get criticised, often, that they only go for the commercially interesting indications, because here you have an example of a company. And there are many companies that are brave enough to do these things. But they are not. So try, this is not an attractive thing to target. But you know, these positive things are also there, these positive companies that go for the indication, even though it is small, if they're able to make this difference, they go for it, right. So that that's a really good, that's a really good thing that is happening. And I see that happen all over the place in the field. So it's it's a good news for a lot of rare diseases, as you'd say that their company is going off to them. In terms of smart trial design. There's another aspect that we considered when we designed this trial is that if you have patients in your trial, even if they're diagnosed relatively early, you have these patients that are fast progresses and are slow progresses in that highly heterogeneous population. Now, if you take patients that progress relatively slowly, you'd say, Oh, that's good news for the patient. But that's actually bad news for the trial. Because if they progress only slowly, and they would have a change of that progression by half by a drug that would counter that. There's only a very small difference there that you're able to measure. Yeah. So you can if the line is if the line goes like this, it has a little room to go up. But if the line is already almost flat, then there is no room room on the top side to improve and that is difficult to measure. So that's an important aspect. The other aspect is that if you have a patient that goes like this, he will he or she will probably have a very severe disease and a drug will have a hard time to counter that because the disease He's mechanism is so deteriorating. And so you need to be in that middle group for your drug to give it a chance to work. And then once you've proven that, then you can, of course, expand to all the layers of the of the disease, and provide it to all the patients and see how it works there. But for your initial trial, it is important, you know, to give your drug to optimal chance of success and make it happen. And that is what we did by thinking through all these, these, these mechanisms and all these aspects of a clinical trial that can make or break it, basically, Patrick Short 30:35 yes, just in the last couple of minutes here, maybe a broad one. But we've got a couple 100 diseases really that have good treatments, and then we've got 6000 Plus that don't. So as an industry, we face, call it a challenge or an opportunity. But we know only a handful of new drugs get approved every year.tr And I want to get your thoughts on were across those four buckets that you described at the beginning? Where are the greatest opportunities to increase the throughput? If we wanted to live in a world where we were approving 100 new drugs 1000 new drugs, because we sort of do need to get to the point where we're in the three digits, if we're going to make progress on every disease in our lifetimes. So where are the where are the biggest opportunities that you see, for us to not necessarily increase the speed we've spoken about this before? It's not speed is part of it, right? If you can get a drug through in five years instead of 10. That's great. But it's also just about volume, right? If it takes 10 years, but we can be pushing more things through successfully that that gets us there as well. Ronald Van Der Geest 31:39 Yeah, so So there's still plenty of job opportunities for life science professionals, I would say for for many years to come. And also for us, because we want to tackle all these diseases, and also the smaller diseases, as as I mentioned. What is interesting, though, is what you what you mentioned about the success of drug development, and there are some studies that have been done throughout the years where they've looked at what successes of drugs are really based on. And there have been a couple of good analysis. And what what what always strikes me in this in these types of analysis is that there is a sort of consistent ratio of where effects are where where success of drug development is based on. And if you divide it out in the main parameters, two of the main parameters are the drug itself, how good is that. And another parameter is, is the people and the group and the way that you structure the organisation to make that happen. And the striking thing and the consistent thing about these analysis is that the ratio is is 3070. So 30% is the drug. And 70% is the people that end a team that does it and the way that is organised. And what you see is that so that's a striking number, right? Because we're all focused on getting new drugs and right drugs, but But equally, so and maybe even more, so you have to make sure that you put all the proper measures and the organisation in the right way in place to make it a success. And it just tells you that a lot of wrong decisions can be made. Because success or failure determine that 70%. Right. And so that's the challenge, I think, to me, that's the main challenge. That's the way also how we try to organise our teams, we give a lot of ownership to the teams that develop these drugs, you know, they really need to feel that what they are developing is their baby. And they are determining, you know, they are in a in a very important position for patients basically, basically an ALS especially, which is such a severe disease, that we put them in their strength, but also the responsibility, make it happen and make it happen in a creative way. And if we provide ownership and of course sufficient funding to these teams, that is a key driver for success. So I think that is not something that everybody wears off. But that is what we try to do with our team. And that is also what we preach to the world to say okay, guys, make sure that you have the best pulpit possible people doing that. The entrepreneurial guys and girls, because this is a creative process, you can take many wrong turns, basically. And then you destroy a potentially very good drug. So make sure that you have that right. Patrick Short 34:34 Yeah, absolutely. It's such important work. Well, thank you. I appreciate you taking the time to talk through the important work you're doing. And thanks, everyone for taking the time to listen if people want to follow your progress. It's tree way.nl. Is that right? Anywhere else that you want people to visit? Yep, that's right. Great. Well, thank you and thanks, everybody for tuning in. If you'd liked the episode, we'd appreciate if you shared it one to one with a friend or colleague or Go on and leave us a review thanks again and we'll see you next time Transcribed by https://otter.ai