Beyond Efficacy: Why DMPK and Toxicology Matter Earlier Than You Think

Hello, welcome to this episode of Crowncast. I'm your host, Michelle Dawn Mooney. When people hear Crown Bioscience, they often think of world class in vivo oncology models. For good reason, that is a core strength. But today, we are going beyond tumor growth curves and efficacy endpoints because behind every successful oncology program is something just as critical, understanding how a drug behaves in the body and whether it can do so safely. We are talking about DMPK and toxicology and why these disciplines need to be part of the conversation earlier than many teams expect. Joining us today are Rekha Paul, senior director of scientific engagement for Crown Bioscience, and Santi Soriani Chen, Director of Business Development from Crown Bioscience to help us unpack where DMPK and toxicology fit into the broader drug discovery picture and then how getting them right can save programs from costly detours. You so much for being with me today. Welcome to the show. Thank you, Michelle. Thank you, Michelle. Nice to see you. Yes. You as well. Before we get started, we have a great conversation ahead of us. But, Reka, starting with you, could you give us a brief bio if you wouldn't mind, please? Yeah. So hi, everyone. My name is Reka Pala. I'm a senior director for centric engagement at Crown Bio. I am a trained cancer biologist, a specialization in immuno oncology translation research and the tumor microenvironment. I have extensive, you know, experience across both discovery and clinical development. I was at UPMC, University of Pittsburgh Medical Center for twelve years as a cancer as well as translational scientist, and I then... I joined a clinical trial group to run their preclinical program for four years. So my expertise are both preclinical as well as translational oncology. Thank you. And Santi? Thank you, Michelle. Hi, everybody. My name is Santi. I'm the director of business development here at Crown, originally trained as an immuno oncologist from Australia in the Children's Cancer Institute. And for the last six years, I've been in the business development and strategic partnership role. And for the last three years, I have been proud to be part of the Crown team. Wonderful. So let's start off here. When people hear Crown Bioscience, as I mentioned in the intro, they usually think in vivo oncology models. So can you tell us a little bit about where DMPK and toxicology fit into the broader drug discovery picture? Crown Bio is well known for their in vivo oncology model. Like, Crown has almost 3,000 PDX model. We do routinely a lot of in vivo xenograft as well as PDX model. But DMPK and toxicology are really what determines whether that the efficacy is meaningful or just the interpretation whether the drug is working biologically does not limit the observation. So I think it's very important to do the DMPK and toxicology, which sits in between the chemistry and biology. Before going for the in vivo efficacy, we need to know what the body does to the drug, as well as what drug does to the body as a toxicology. We really need to know the full ADME, basically what the drug is absorption, what is the distribution, metabolisation, as well as excreted, and talks answer the question whether we can go above or beyond the therapeutic windows of the drug. I think it's very important to put first detailed analysis of the lead compound for the DMPK as well as toxicology to find out the real dose, as well as the safety profile of the drug, whether it's not have the severe side effects. To add on to that, at the end of the day, this is going to be pushed to the clinic. So having the perspective, the long term perspective, not just about the efficacy of a drug of that particular study, but how can this impact somebody in, you know, the patient, and how can it be improved and used in the actual patient? I think that's very critical, and hopefully, we can answer those questions today. So can you share an example without naming names where early DMPK or tox data help teams pivot faster or maybe avoid a dead end? Yeah. So I have seen many cases where PK data completely change the program, trajectory of the program, like where it's going. You know, sometimes the compound looks great in vitro and even showed the in vivo tumor regression. But, you know, early DMPK work revealed very high clearance and the and the short half life. So that exposure barely covered the IC50 window. The team, you know, realized that the tumor effect was not sustainable and the dose which we are using it for the efficacy. Or if you... Based on your DMPK analysis, you may want to hit the higher dose, which might hit the toxic... Toxicity ceiling. So I think instead of forcing it toward, it's very important to back up the molecule with slightly weaker potency because, you know, if it's even though a molecule is working great in your efficacy study, but having the toxicity profile at that dose as well as not getting the clearance very quickly or half short life, that makes the molecule much weaker, actually. So it's better to move further ahead another compound or maybe tweak the chemistry of that compound to do better in DMPK as well as toxicity and achieve maybe the, you know, lower dose of the drug, which might have the best therapeutic window. And to add on to what Rekha mentioned, it can definitely change a program. Each of the studies typically takes us some time. And if it can be designed correctly from the start to already incorporate certain DMPK and toxicology parameters, then we can avoid having to repeat the study just to get certain amount, certain data that is needed in order to push this into IND and also into the clinic. So all of this at the beginning, study design is absolutely critical to make sure that the right parameters are included rather than just a pure efficacy to start. And you mentioned to, you know, prevent having to repeat those testings, which is time and money, right, which is so crucial. So I wanna ask you, what are the most common DMPK or tox related surprises you see once a program is already in vivo? Sometimes the biggest one is when the drug looks great in the lab test, but like in in vitro, but completely behaves differently in the animal models. For example, the drug might seem stable when you test in a test tube with the liver cells, but once it's in an actual animal, the body finds other ways to break it down. So the common shock is when the drug reaches the blood fine, but barely makes it into the tumour. That we have seen some of the studies where the drug levels are fine in the blood plasma. But if you check the tumour tissue, and we are not seeing therapeutic efficacy also on the tumour because the drug is not able to reach to the tumour. And then another hiccup is the drug is perfectly safe in rat, the species specific side effects. You might see the drugs perfectly safe in the rat, but toxic in dogs, which can kill a program right before it's supposed to enter human trial. Often, I think the most painful step. So species specific toxicity is very important to lead the molecule further into the IND enabling studies. And in addition to that, it's not only species specific. Even within the species itself, the initial PK typically is done in a naive, so non tumor bearing animals. And then the PK can change quite drastically once it is in the presence of tumor. So all of this aspect, I think it will be important to have a discussion and also to start designing it. And again, at the end of the day, this is to save time and to save money and push the program forward and getting it closer to the clinic. There are cases where we have done the PK, DM PK before, as well as toxicity. We have finalized the drug final dose for the efficacy study. But still, it would be great to add that therapeutic dose, what's been finalised from the DMPK, as well as toxicity, to look at the tumour, also drug concentration. That kind of allowed the investigators to correlate tumour efficacy, like tumour growth inhibition versus the drug concentration, as well as PD biomarker works great. Sometimes if you add it, it kind of build up the hypothesis of building the biomarker prediction with the drug treatment response. So I think it's very important to do that, Santi was referring, the naive animal. That's what routinely we do for DMPK, but it would be great to add the drug concentration level, at least the first therapeutic efficacy study where you... Where the, you know, investigators can... Should correlate the tumour growth inhibition versus a drug concentration in the tumour itself. And again, time is crucial with the work being done here. So how do you recommend teams prioritize DMPK studies when timelines and or budgets are tight? Yeah. It's always... You know, these days, we know it's it's it's... Budgets are really tight, and timelines are very important. So I usually recommend prioritizing the studies that answer the most fundamental questions as well as the basic question and align the drug properly to take it further for the IND enabling study. I think we need to first answer the question whether we are achieving meaningful exposure of the drug at particular dose. Most of the time, single dose PK study and the basic in vitro metabolism work can provide tremendous feedback as well as answers of all the basic questions. And there are a few parameters or readout which helps to establish the drug to prioritise it as using the DMPK data, like microsomal stability, plasma protein binding, preliminary safety screen, which really gives you feedback and guide to decision. And without exposure study, results are really very hard to interpret properly. So even naive mice as well as the tumor bearing mice, the TMPK study would allow to look at the drug exposure as well as the drug concentration in the tissue specific, you know, sample. And to add on to that also, I think understanding what Rekha mentioned, the fundamental question, what is the questions that we're really trying to answer from a study? We will try to obviously optimize it, but sometimes if there are too many questions, it becomes suboptimal. So sometimes you do have to prioritize certain things in order to really maximize a study. There is always more studies that can come. There is more studies that can be done. But really, if you wanna answer everything in only one study, sometimes it it it does, become a hindrance rather than, propelling it forward. From your conversations with clients, how do they usually think about DMPK when they're planning an efficacy study? If listeners take one thing away about DMPK and tox, what should it be? So it really varies. But, you know, most of the time, the the experienced team or the group very well established, They... As investigator or scientist, you really want to know that the compound is exposed enough, as I mentioned before, before starting the tumor study itself and has the safety profile lined up very nicely. This will allow users to shape the entire efficacy study. You know, the most experienced group use PK data to drive dose selection. It allow you to look for the duration of the study, even route of administration. Some drugs are quite, you know, very efficacious to reach into the system by using the oral dosing or, you know, IP dosing required or the IV dosing required. They will ask, does the explore... Exposure actually actually cover your in vitro IC50 or IC90 window? And is the half life of the drug compatible with the once daily oral dosing? And are we using the model for the efficacy study? Is receiving the exposure enough? But sometimes, because of the budget or limitation, people really want to see the drug effect directly on the tumour's model or not first itself. But that's kind of create a loop where you really need to know first your drug has no side effects, no toxicity profile, and whether it reaches to the specific tissue efficiently and then use inhibiting the tumor growth or any other disease models. I think it's critical. My advice to potential clients would be expect the unexpected. You're always ready to pivot, to optimize as the data is coming through to your study. And you can pivot immediately and to optimize it, to gain momentum. And also, a lot of the time, it actually becomes a much better study. And obviously, for Rekha and I, we work together very closely with our clients to make sure that for each of the studies, how can we obtain the best data to answer the the the fundamental questions that you're trying to answer. Are there any early DMPK signals that tend to predict downstream efficacy or safety challenges? Yeah. Miss, I would really like to highlight few other very important things which are which are really, you know, signals for the DMPK, whether the drug is going to work it or not. These are the very careful steps. The first is a solubility. We have seen multiple times that the drug not been solubilized. That kind of create a confusion loop, whether the drug is reaching to the... If it's in precipitation form, you don't know. Not gonna be dissolved completely. It may not be reached to the specific target or specific tissue. So it's add a lot of variability. So it's very important that the drug is having poor... Nice solubility, whatever the formulation you are proposing. And then the second one is the high clearance. Means that the body breaks the drug down very quickly. If the body doing it very quickly and the drug half life is very short, it's it's kind of give you a clue that either you need to do the dosing frequent... More frequently, and then you also may need to increase the dose of the drug, but depend on the toxicity profiling of the drug too. The third one is also very important that what we have seen very routinely in Crown that sometime we are seeing the DMPK works really nice. The drug is having great toxicity in safety profile, as well as we are seeing drug concentration in the blood plasma. But when you move on to the tumor model, the drug is not... Means that we are not seeing tumor growth inhibition. And that that brings the third question, whether the drug is reaching to the tumor tissue or not. If the client already set up any specific PD profiling, that would be great to add in the DMPK or PK study using the tumor bearing mice. But it's very important to check the tumor tissue sample from the efficacy group to see how much the drug concentration in those tumor tissue and whether it correlates the drug concentration in the tumor tissue. I think these are the very basic, you know, fundamental questions, which if we can have some information from this, it allow us to design very nice efficacy study and, you know, do more modeling based, you know, experimental plan to look at the drug therapeutic windows. It is advisable to design a study where you do an efficacy and maybe just add a satellite arm for PKPD so that you can answer all of those questions all in one go rather than having to repeat a study because you just discovered something that's new. So I think that, again, it's answering to what we originally talked about is saving time, saving money. Because in this day and age, everything is quite costly and budget is always tight. So how can we optimize it? So having this discussion and, again, designing it correctly at the very beginning, at the end of the day, it will save time and money. And knowledge is power, which is all the more reason we're having a conversation like this to to put out not just the issues, the challenges, but some solutions as well. So, as we're wrapping up here, any final thoughts? And with that, if there are people out there listening and saying, I have more questions. I want to learn more. Where can you send them? What can you tell them? Yeah. Thank you, Michelle. So either we're very excited to support your development program. We have a lot of expertise here at Crown. It will be fantastic for you to reach out to us either through our LinkedIn profile, message us, or you can also email us directly. But most importantly is visit CrownBio website. So it's www.crownbio.com. Our team is ready. We are located globally. There are always people online, in the different region of the world. So we're very excited, here at Crown to support your drug development. Sante Suriani Chan, director of business development for Crown Bioscience, and Rekha Pal, senior director of scientific engagement for Crown Bioscience, thank you both for being here today and sharing your knowledge. And, it's exciting to see the things that are happening, especially as we get closer and closer to having some great breakthroughs. But, again, knowledge is power, we need to have these conversations so we can keep things moving swiftly from a time standpoint and from a cost standpoint. So I appreciate you being here today. Thank you. Thank you, Michelle. And I wanna thank all of you for listening and tuning in to this episode of the Crowncast podcast. If you'd like to hear more engaging conversations like the one you heard today, we invite you to subscribe to the podcast. And of course, you can visit crownbio.com for more information there. I'm your host, Michelle Dawn Moody. Thanks again for joining us. We hope to connect with you on another podcast soon.