Careers in Biotech _ Pharma_ Exploring Approaches to Developing Pharmaceuticals

And I'm a business development director with Charles River. I've been with the company. I think I'm going on 18 years this month. And my primary job responsibilities are working with clients in the New England area, biotech and pharmaceutical clients, helping them to get the answers to questions they have and help them through the drug discovery and development process from a business side of things. So I work a lot with contract negotiation, proposal development, any sort of legal type of paperwork that needs to be put in place. And I work in very close collaboration with a numerous amount of scientists, one of which is joining me here today, Sam Schwang. And he'll introduce himself a little bit more after a few slides. But I just wanted to first give you a super brief overview of Charles River and what it is we're all about. Next slide, please. Next slide. So for those of you that are not familiar with Charles River, we are a global contract research organization. And we are here to support our clients through essentially every step of the drug discovery and development process. From obtaining your early research models, the actual animal models that you're going to be using for experiments in-house, through to discovery capabilities such as medicinal chemistry, candidate selection, efficacy of your compounds, through GLP, safety assessment, all your toxicology work that you need to run, and then even helping in terms of clinical and manufacturing support. So Charles River really spans the gamut of essentially everything that you're going to need to take your compounds from the bench into treatment. Next slide. And this gives you an overview. We call this our subway map. It gives you an overview of the real end-to-end drug discovery and development continuum that we offer at Charles River. So we're able to help you along every stop along this map. So it's a wide variety of services that we offer, meaning that we're able to help clients regardless of where they are in their discovery and development pipeline. We work on all types of therapeutic areas of molecules, all types of new molecules, small, large, cell gene therapy, anything new that's coming out. We're able to support our clients' effort in bringing therapies to the world. And this gives you an overview of the types of compounds that we worked on. Charles River has worked on 85% of the drugs approved by the FDA in 2019. So it's a really big number. And then on top of that, we've worked on so much more that doesn't get approved by the FDA. So we have a really deep well of experience at Charles River. And with that being said, I think, Steve, do you want to go next talking about experience? Sure. I mean, this is a great roadmap showing the major areas of drug development research and where client companies have been focused on in developing drugs. And this is just a nice synopsis of how much we've been involved in with 100% of coverage of approved drugs in neurology and musculoskeletal diseases, a huge percentage on oncology. And so it's really for us, for Jessica and I, to really share the capabilities that we have as well as our expertise to help drug companies really leverage what they're trying to do and get those promising drugs as quickly to market as possible. And this is a nice pictorial that I like to use in defining the general overview of drug development, starting from target identification and basic research, and then looking for compounds that interact with that target to modulate its function such that it has the ability to have that beneficial effect. And then going through the regulated safety testing and development stage and clinical trials and hopefully getting it to market. I'll pause here before I start talking about drug discovery. A little bit about myself, I've been in drug development for about 20 years now, working on small and large molecule programs, as well as cell gene therapies, vaccines, oligonucleotides, across a wide variety of different therapeutic indications. And I helped work on developing these strategies from as early as target validation and drug discovery, all the way through to pre-market from a regulatory and scientific approach. And so today's presentation is really going to be focused on a very high level overview of drug discovery and strategies leading into a IND-enabled program to get your drug into the clinic. On each slide, I could probably talk for about a week about all the different nuances. And today I'm not going to take all that much time. And what I hope to achieve is just give you a flavoring of some of the things to consider when you are considering going into drug development. And there are some really great strategies and some words of wisdom that I would like to share when you're entering in that, that can help you save time, money, and effort. And so this pictorial is, again, the same as the first pictorial about the drug development topic, but showing a little bit different. This is kind of an example of a small molecule program where in basic research, many companies start with a library of thousands, hundreds of thousands. And I've known companies that have started in the millions, screening for those ideal candidates that interact with that target. And as you go through the drug discovery phase, you're rapidly welding down the number of viable candidates to a handful. And hopefully that you identify a few candidates that will go into the preclinical stage and then to the expense of clinical testing in human patients. And this can be a long iterative process taking on average eight years and can cost as much as $2.6 billion from start to the end, taking into account failures. So you can imagine it's a very arduous journey to get to one FDA approved medicine. And the key thing about it is that there's no guarantee of success. You can fail at any stage. So then you think, why do we go through all this? Well, we go through it because we want to get great medicines into the market, but there are ways to try to increase your chances of success. And that's what I hope to share today. Jessica presented the subway map of our service office and things that may be involved in your drug development journey. And the more things that you use gives you more information that can help educate whether you go forward or go backwards. And one of the key things that I like to share is that in this subway map, every program will have unique steps. You will use some of these, some of these will be common, some will be unique to your program. But in selecting, well, which steps do I need to use? Which activities do I need to use? I like to keep three major principles in mind when you're developing that strategy. And they are to help you avoid the major causes of failure of drugs in the drug development process. These are the lack of exposure in the clinic, not getting enough drug to the target tissues that have a beneficial effect. You may have the lack of efficacy. So you think you've hit the mechanism or a pathway, but it actually doesn't translate to clinical benefit. And then of course, there may be due to overt toxicity. The toxicity profile of your drug given at an efficacious level may be too dangerous to be able to give to patients safely. And so we try to use various different tests and then activities and studies to help minimize the reasons why a drug may fail and heighten your chances of success in getting it into the market. This is kind of a flow map that our discovery colleagues use to highlight some of the key activities that you may employ in the drug discovery process. You may use a lot of cell lines and discovery and research and structural biology and protein production to be able to identify a suitable target. And then you will use tests of assays to see if you can actually manipulate a particular pathway to the benefit of the drug or target therapeutic indication you may be using. Then you may use advanced technologies like CRISPR to identify or create a pharmacology model and have target expression so that you can screen for the drugs that will work, as well as using bioinformatics in multiple different ways. I think that when you think about AI and how it's really revolutionizing virtually every major part of our global economy, whereas how we pay for things with credit cards, market analysis, well, drug discovery is no different. We're leveraging AI and using bioinformatics and screening for potential ideal new targets, screening for ideal structures, as well as looking for biomarkers that can be indicators of clinical success. Then we start moving towards more translational approach, where we actually have identified a target. Now we want to make sure that it is a viable way to create a drug that will be effective in treating a patient for a particular mechanism of action. And that's through the identification, screening of compounds or proteins, and then narrowing it down through looking at different parts of characteristics, which I will go into in a moment, to be able to have a drug candidate that has the ideal properties. And then utilizing cell-based assays, biomarkers, and in vivo pharmacology models to really give you that confidence that, yes, not only am I finding a good drug that interacts with my target protein, but I'm going to actually have a predictor by which we think that it's going to have clinical benefit. So now I'm going to talk about small molecule development. And in this part, I'm just going to have a high overview of some of the major things that I would consider in a successful small molecule program. One of the key things is the screening criteria about building an ideal profile of your small molecule candidate. And you will be taking into account pharmacological properties. Does it have high affinity? Does it bind tightly to your protein or your target? Does it have that beneficial functional effect on the protein or pathway? Sometimes you want to have high affinity. Sometimes you want to have mild affinity. It depends on the indication and the properties of that particular function, which you want to modulate. Sometimes you want to inhibit. Sometimes you want to stimulate. And so these things are very important factors when you talk about how you want the drug to interact with your target. Then, of course, there's biochemical properties. You want to have a stable molecule that's not fragile, that can last a while. You want to be able to synthesize it in a repetitive way that's reproducible with high quality and purity, and also not to have a problematic synthesis. Many compounds can be created, but when you actually start trying to create and manufacture it in larger scales, this could be a rate-limiting step. It makes a big difference if your chemical synthesis process goes from using intermediates to have a three-step process versus a 15-step process. Your costs become exponential such that that drug, while it may be beneficial and economically, it may not be feasible to develop. Then, of course, we look at its pharmacokinetics. We want to have an ideal profile of how long it lasts in the body so that it can have a therapeutic effect. And then we counterbalance with its binding properties with its safety and toxicity because compounds will have a side toxicity that we want to characterize to safeguard human patients and avoid some of the major hurdles that have stopped previous drug programs from advancing further. One of the things that I mentioned was AI and how it's been driving drug discovery. A lot of companies now are focusing on utilizing and using computation analysis, as you can see from this nice little video, where they can theoretically look at different compounds of different structures and look from a physiochemical point of view, how does it fit in a potential binding partner? And being able to do the modeling, it narrows down the number of compounds that you'd want to advance to physically test and characterize. So it helps speed up the process of identifying potentially good structures by which you can build upon. This is an example of a list of really ideal chemical properties of a small molecule that you would want to have and to create kind of a decision tree and rate compounds with each other. If you're looking for the best in class of every single one, you will never find that molecule. You would want to look for ones that have the overall best profile and then set criteria limits on each one of these where you say it must have a minimum X factor or property for it to go further. And then it could be a little bit lower, but it has ideal problems on the other factors. And that's how you are able to kind of bring up a decision tree and be able to rank your compounds and decide which ones are the strongest candidates to invest time and effort into. ADME is a very important aspect of drug development. ADME stands for absorption, distribution, metabolism, and excretion. And essentially what it means is you're really studying the way a drug is absorbed into a body, where it goes in the body, and then how is it disposed of by the body. And understanding these elements can help you also in the decision tree. Some drugs may be highly soluble and may be an IV oral drug, and some are very hard, and you may have to create suspension. Or some have properties where it is actively transported out of the body, so oral absorption is not possible, so then you have to deliver that drug IV. Other things that we have to look into are things like drug-drug interactions. And they can play an important role, especially when patients have a...that you're enrolling into clinical trials may already be on such a standard of care medicine. And so what we do is we look at the major cytochrome P450 enzymes that break down enzymes as well as chemicals in the body, and we look for your drug candidate's ability to inhibit that property, to increase the activity of that property, or be a substrate of it. In these situations, you're able then to contrast to the profile of what are known drugs that are already on the market, and look at patients, whether they're taking those medications, and avoid any strong contraindications, that is, drugs that don't work well together. You might inadvertently increase the toxicity of one. You might inadvertently decrease the activity of another. And so understanding that ahead of time will also help you in the end of the selection process. Now I'd like to share a case study where this company approached me about wanting to perform GOP studies. In our call, they told us they've done a lot of great work, which they did. They did in vitro efficacy studies showing great beneficial properties. They did in vivo pharmacology studies to show in vivo modeling that it would have a clinical benefit. They did PK studies in rats and dogs. They did already the acute single-dose toxicity studies, so they already understood some of the highest levels that they could test in rats and dogs. They even performed two-week repeat dose studies. Now they're already going to the GOP studies because they felt they had a complete body of work. But in our discussions, we talked about the in vitro admin work, looking at identification of in vitro metabolites. And what that means is that we would compare human breakdown products of the drug and ensure that the tox species that we're using have generation of the same human metabolites because these metabolites have their own intrinsic properties as well as toxicities. And in the vivo setting, we want to take into account all the potential effects that could happen to a human patient. So we performed that work for them before starting the GOP studies, and lo and behold, the dog lacked the metabolism of one major metabolite that is producing in humans, which meant that all the dog work they had done was for nothing. We could not use the dog in the We had to select a different non-rodent species to support their entry into the trials. So not only did they lose all this data, they also lost time and money. So this was an exercise by which doing careful planning, doing some of the more basic work and characterization could help them have avoided this dilemma. When we're looking at the maximizing the potential efficacy, we really look at the in vivo efficacy in pharmacology models, and then looking, contrasting back to toxicity, making sure that we are able to properly characterize it. And there are a lot of factors other than just running these studies that need into account. Formulation development is really important. I'll give you two examples on that. For oral formulation, if you take it as low bioavailability, that means you have to give a lot more of the drug in order to get exposure, and that's a waste of drug. When you could have formulated something that helps increase the bioavailability of the drug, i.e. it allows it to go in systemically from the gut to the blood systems to get to the target tissues. Also, in IV, you may have used something that could be in the vehicle components that either has the wrong pH level or could contain an excipient that is irritating, and that could actually cause complications such that you're not looking at toxicities of the drug, but you're having complications from the vehicle itself. So formulation development can play a very important role and should be done ahead of the vehicle studies. Selection of the dose rate is really important to make sure that, again, the drug reaches the target tissue. And so what we try to do is try to mimic as close as possible what we do use in the human setting and how that drug reaches there, again, with formulation development, looking at absorption through the gut. You may or may not be able to use oral tablets or capsules. You may have to do an IV. Then, of course, the characterization of pharmacokinetics is really important because this is where we want to see how long the drug lasts in the body. Maybe if it's short-acting, you may want short-acting, but if you want to have only daily dosing versus three times dosing for constant exposure, choosing the right drug may help you select one candidate over another. When we think about oral formulation development, there are a lot of different factors come in, and this slide is just to highlight that. I'm not going to go through it, but as you can see, there's a number of different avenues by which you can take for formulation development, and depending on the class of classification, you will be able to designate where to go in your formulation pathways. Other dosage routes can play an important role, and there are different factors that come into it. For a topical application, formulation, you may have to do UV absorption, phototoxicity assays. You also use different components in the vehicle that you would use. Inhalation has a completely different route where you'd have to do a lot of calculations on dispersal. The method of the actual delivery of it, are you going to crush a tablet, or is it going to be a spray format? A lot of things come into effect that you'd have to do additional work in order to be able to get into the clinical trials. As I mentioned before, pharmacokinetics and pharmacodynamics are important aspects, and these two are not the same thing. Pharmacokinetics is really the measure of how much drug is in the body, and pharmacodynamics is how long does the drug have that beneficial effect that you're looking for. For drugs that inhibit, the PK and the PD curves will look very similar, but for something, let's say, a stimulatory, the PD effects may last much longer than when the presence of your drug. And so careful understanding characterization of these two important characteristics of your drug is really in determining whether you have a viable program or not. So one of the things about doing these studies for a drug is really it helps predict dosing. How are you going to dose? How often you're going to dose? How much of your drug is going to be exposed to help guide the clinical trial design? Then you'll also be able to understand some of the variability between individuals. For example, if your oral formulation gives variable results in the rodent species where you're seeing some animals have high absorption, some have low absorption, they might help interpret what's going on in the clinic. Then it also can be used to help establish a therapeutic window. Oftentimes, you need a minimum concentration to have the beneficial effect, and systemically, you can monitor how long does a drug stay systemically above that threshold to have its beneficial effect, and that can help also with how often you have to dose the patient. Now, after doing all that, why do drugs still fail in the clinic? We do all this type of work, and there are other factors that come into play. We do specialized studies to help, again, try to minimize that. As you can see from the graphs to the right, you have a lot of candidates that are entering and have been successful in being nominated as a candidate, but then as you go through phase 1, phase 2, phase 3 clinical trials, more and more drugs are being terminated because they fail for one reason or another. What we need to do is continually refine those methods and data gathering in the early stages to help prevent this and minimize failure as much as possible. In the screenings, you have early lead optimization and late lead optimization, and as you are narrowing your candidate pool, you'll invest more time and effort in characterizing and hopefully build the ability to avoid some major liabilities like cardiovascular effects causing arrhythmias or QT prolongation, which can be an important…it's a critical toxicity that's sometimes not seen until you go into the clinic. Well, there are now tests that we can do to help you mitigate that potential liability. In the early lead optimization, we'll focus on screening a lot of compounds, and so you want to go through this very quickly and minimally. Then as you narrow down to a small handful or one candidate, you go into more in-depth evaluation and characterization. Now I'm going to switch our attention to small molecule for the last half of this presentation, and what do I mean by biologic? Well, it's typically a protein or a peptide that's used or intended as a therapeutic to have claimed medical benefits to the patients taking it, and these can also include blood substitutes and vaccines. In the old days, it also included cell and gene therapies, but through the evolution of drug development, biologics in this terminology are now reviewed by the Center of Drug and Evaluation Research, so CDER, and CBER, with B being biologics, are focused on cell and gene therapies, more of the cutting edge where there's no real standardized roadmap to get into the claim. In today's talk, I'll be mainly focusing on antibodies primarily, as well as protein constructs that have antibody components, and then at the very, very end, I'll talk a little bit on cell and gene therapies and how they are unique compared to small molecule and large molecule development. So you saw this same table before for small molecules, and I'm highlighting the two differences. You can see that the properties are basically the same, but the key differences between a large and small molecule is that in the physical properties of a small molecule, you're looking at solubility, stability. Here, for proteins, we're looking for a stable protein that stays in the state of confirmation, and also the generation of a high production cell line, so cell lines that produce high amounts of your desired therapeutic. And then in safety and toxicity, so we're looking for a high safety margin, and we have to take into account the potential for immunotoxicity, that is a patient's immune system rejecting the protein or biologic drug, so they can create an immune response such that it negates it, clears it, or it can cause a serious adverse effect that they may have heard in the news, like cytokine storms, high interactions, hypersensitivity, so we try to safeguard and characterize that with protein biologics. The challenges in antibody development are a little bit unique from small molecules, but one of the key things that we try to safeguard is making sure that there's not off-target binding of antigens on healthy cells. That's particularly true with oncology drugs. We're also looking for safeguarding for toxicities that may be caused by binding onto the surface antigens that cause them to shed into the circulation and have secondary effects. There are other limitations because sometimes certain biologics can't cross the blood-brain barrier, or it cannot reach a particular target in the tissue. Then, of course, we have to look out for unwanted stimulation of the immune responses I mentioned before. The other aspect of antibody development is that it is more expensive than small molecules. You may need to use less number of studies, but these studies are more intricate in their design and also become more expensive in the methodologies that are needed to support those studies. When we think about lead identification, things to look at and to consider are the form. So, sometimes we are looking at traditional monoclonal antibodies, but now with the advancements of protein engineering, we can use the key elements that are desirable, remove the other parts, and then create novel protein structures by which we can have single domains, chain of different domains, linking of bispecific to trispecifics, recognizing three different antigens to create a unique biological effect by which the patients can have that clinical benefit. So, the creativity here is amazing and almost unlimited in the number of protein constructs that you can create. You just have to imagine it and put it together and then test it to see if it is going to be efficacious and safe. Hey, Sam. Yes. I got a question from a participant. Should I ask you now? Sure, yeah. I don't care if I wait to that. Okay. No, no. Someone was wondering if peptide drugs are considered safer than antibodies, aka large proteins. It's a great question. In some ways, yes. So, peptides may not trigger the immune system. Antibodies have FC receptors that can interact with the FC receptors or T-cell receptors, and alcohol also can interact with complement. Peptides are smaller. They can be…sometimes they can be…don't last in the body as long. So, as you know, monoclonal antibodies can stay in the body for months, and that is sometimes a desirable thing. Sometimes it's not, depending on your target and what you want to use it in the clinic. So, if you need something that's fast-acting but then only use as needed, then a peptide could be really useful for that. And plus, because of its size, it's also easier to manufacture. So, there's a lot of great advantages from that perspective. Great question. Thank you. Coming on to the ideal candidate, we want high affinity to the target, low nonspecific binding, as I mentioned before, and a couple of other things, and I also mentioned low immunogenicity, low reactions to the immune system. But some other things that are interesting for proteins are thermal stability. Does it stay in its native conformation by which it's active? As you know, sometimes they can fall out of conformation and then be inactive or denatured and not work at all. Cross-species targeting can be a benefit because then you can actually have relevant tox species to characterize it, which helps you have safety information for when you go into clinical trials. pH sensitization is really important because there can be fluctuations in different environments, and the protein may be activated in certain environments, like an acidic environment, or it may not be. So, understanding the pH sensitivity is important. Of course, we want to have aggregation resistance, and what that means, we don't want proteins to clump together. If they're clumped together, then they, one, can become physical blockages, but they also can attract unwanted clotting, as well as become ineffective because they can no longer engage the targets. So, other considerations are biomarkers, and I think especially in the last 5-10 years, this has become a more and more important role. I think you'll be in clinical trials in the early days. They look for the standard clinical endpoints, and those are very, sometimes very hard to achieve, especially for chronic diseases. The use of identifying biomarkers and disease markers are really helpful because it can help safeguard patient safety by having early signs of toxicity. You can have disease biomarkers that can help you have early signs of efficacy, and a lot of more intricate clinical trials now are seen leveraging these biomarkers by which they can go further into the clinic, gain further chances of calling a trial successful by having these biomarkers in, sometimes in replacement of the traditional endpoints that could be very difficult to achieve. Now, I'm going to go into preclinical strategies. So, this is irrespective of small molecule, large molecule, what is the overall strategies when you go into drug development? This is a very simplistic graph that I put together, having costs over time, and the three major activities, preclinical studies or non-clinical studies, clinical trials, as well as manufacturing of the drug. And as you're moving from one stage to the next stage, drug discovery, preclinical, clinical trials, you see that different activities have different pricing requirements, cost requirements, and they change as the program evolves or progresses, and also becomes far more expensive as you move down the chain closer to getting into the clinic. One of the key things about it is, of course, as I mentioned before, you'll see that now I give you a different rate of 7, average of 2.6. The broad range is around $700 million to as high as $5.3 billion that needs to be spent to get a drug into market, and no guaranteed success. That's the risk that people take. So, really careful consideration in trying to optimize is really important. And one of the key things that contributes to this is that bottom line, time. We want to save as much time, get into the clinic as fast as possible, and so careful planning is really needed. This is a sample markup of how much drug you need to get from one point to another. And this is from a generic small molecule drug you may need to get into phase one clinical trials and support for phase one clinical trials, about 6.7 kilograms of material or very, very potent material. You may need far less. For things that are quote, oh, I have a great drug and it's super safe. You may need 20, 30 kilograms of material to get to the same stage. So, it's a double-edged sword when you say I have a very safe drug. If you need a lot of it, then you're going to have to produce a lot in order to support all the work that's needed. Another factor that comes in, of course, is money. The amount for just the preclinical package, not including how much it costs to manufacture, is between one or $2 million. If you're doing a biologic, it gives you $2 to $4 million. So, there's a lot of different variables that come into play. And so, really, it depends on the complexity of the program. And what we try to do is give you everything that you need, just enough to satisfy the regulatory agencies. Anything else that's good to have, you're kind of wasting money unless it's purposeful for something else. And that sometimes can be a strategy. But for the most part, you really want to try to be mindful of how much things cost and how much material you need. This is a Gantt chart of a typical small molecule. I'm not going to go through all the lines. I just want you to have an appreciation that each of these blocks represent months. And, of course, up to 27 months, that's basically two years. You can have a lot of work that's being done, a week, sorry. And you can have a lot of work done in parallel. So, careful planning of what can be in parallel and what has to be sequential, like the dose range finding studies at the top part will lead to having that data going to contribute to the design of the 28-day studies. Staggering them this way, you can save time. When we look at a submission to the FDA to go into human clinical trials, there's three main components. Clinical trial protocol, CMC or chemistry manufacturing controls, and the pharmacology toxicology package. Many people will work on these and tackle them independently because they're very different from each other. My message to you is that they're all interrelated and you have to think about them all at the same time because they all have implications for each other. For the CMC portion, it's really meant to highlight exactly what is the drug, how do you manufacture it, can you manufacture reproducibility reliably, as well as identifying the proper strength, quality, and this feeds into how quickly you can manufacture enough in order to support the studies that need to conceal the product, as well as clinical trials. Here's a case study that I like to share about committing before planning. This is a small little company that came out of a university. The CEO is a former professor that discovered and developed this antibody. They brought in, as part of the lead management team, a CFO. He only had a finance background. The professor, she had the science, but it was all academic science. He created a board. They went, they said, here's the plan, here we're going to their timeline, 15 months timeline. Now comes the wrinkle. They come to us and they say, okay, where are you at? Well, the current status is that the protein expression is only at the transient cell line stage, so they have not created a permanent cell line which they can reliably produce protein from. They were doing this with transient transfection, but there's a little bit of it. They have to repeat it, so there's no reliable manufacturing. When they actually were told what the cell line development means and why it's needed, then they look into that, into what time would it be taken to be able to accomplish that. For cell line development, just to schedule the project into a CMO's timeline was three to five months. The cell line development was three to five months. The protein production after establishing the cell line was another four to six months, and that's if nothing went wrong, which we know there's always something that happens. Then on top of that, now you finally have enough material for your toxicology program, which takes 12 months to do. So, they promised and got approved 15-month timeline, and it is impossible to squeeze 22 to 28 months worth of work that is linear into that timeline. So, they promised something before actually doing the due diligence, and they had thought, oh, I just go into time, so I'm not thinking about the CMC. Clinical trials, they are meant to be highly designed so that FDA can actually review what's going to be done, what the patient enrollment, how are they going to be dosed, how are they going to be monitored. One of the key things about the clinical trial design is that it is critical to know this before building your toxicology program. It has to come first. The toxicology program, if properly put together, is to complement and provide the necessary information to the clinical trial. And this is highlighted in the ICHM3 guidelines that dictates what's needed for that trial. And here's the table. You basically have to match your clinical duration with your toxicology studies. Now I'm going to give a quick case study on this. Apples versus oranges. So, I had this client come to me, and I developed a program. And in the program, the IND Neighborhood Study was four doses given weekly followed by a four-week recovery period. The four dose groups was one control with three test article dose groups. And so, this is what their clinical trial design was, and this is what we put together. And everything ran smoothly, got beautiful data out of it, no issues with study conduct, and ready to file for the IND. However, during the time that we were running the studies, the clinician changed phase 1B. Phase 1A stayed the same, single sending dose. But phase 1B, instead of giving the patients a dose once weekly, now I'm going to give the same four doses, but I'm going to give it once monthly. So, when they went to the FDA, what happened? They got approved for phase 1A, but clinical hold on phase 1B, because the patient exposure is now four months, not four weeks. And so, they would now have to go back and rerun a toxicology program to be able to support this. So, they basically caused themselves greater than one year delay. It was very costly. For the toxicology programs, we developed these IND-enabled studies to achieve the following goals. The data is going to be used for estimating a safe starting dose in clinical trials, maybe identify potential biomarkers, and we discussed the importance of that. Identify potential target organs for toxicity. And then the recovery period is to assess when we do see it, we expect to see it, so we characterize it. How reversible are they? And then leveraging all this data, what is the margin of safety? And then prior to registration, so after getting the person through the clinical trials, we have additional studies to do, which are toxicology studies, repro studies, if applicable, if you're going to be dosing women of childbearing age, and of course, carcinogenic potential. We don't want to give drugs that could cause cancer. One of the key things about these studies is they have to be performed under GLP, good laboratory practices, and these are to safeguard the reliability of the data. And so, this is sometimes, some people say, well, this is a study I could do in my own lab, but with all the safeguards you need, with all the documentation, with all the rigors that you have to do, that's the reason why it needs to be done in a GLP compliant manner. Otherwise, the FDA will refuse to acknowledge the data. So, because there's an added expense to it, there are some studies that need to be GLP and some that don't. We definitely want to differentiate the two to save money as much as possible and save that for more purposeful activities like support of GLP tox studies. And this is a listing of this. I'm not going to go through this. After this, Jessica will be able to share a copy of this presentation. You'll have the recordings so that you'll have access to this data. Another new, fairly recent requirement that the FDA has posed is SEND requirements. And what is SEND? SEND is the electronic data packaging of numerical data as well as pathology data so that they receive it and they can make independent reviews of the data rather than simply relying on the interpretation that's presented in the IMD application. The other aspect of it is that they also create larger databases by which they can infer across different classes of compounds or similar drugs in the same therapeutic application to look for key findings that they need to look at. And for the benefits of industry, we can also leverage the same kind of data analysis and harmonized approach. Lastly, I really want to go into the growing number of different drugs. We have now, research has really exploded to have new advanced therapies, modifying cells that have activated T cells or insertions of genes that can then express missing proteins, gene therapies to permanently edit patients' DNA, oncolytic viruses for cancer. And then, as I mentioned before, different constructs using different parts of antibodies are becoming in a more important role. With oligonucleotides, this is amino acids, sorry, this is DNA or RNA being spliced together. There are a number of different formats by which we can use it either to express a protein like some of the vaccines that are out there like Moderna and Pfizer, or they can be used for diseases. And so, these take a different approach in regulatory guidelines. And here, I've listed the different common things to think about, how they're looked at. For small oligonucleotides, they're often viewed as small molecules. And so, CDER will be the one center of drug evaluation and research. They're the ones that will be evaluating those programs. But for longer ones, like messenger RNAs, like the products that Moderna produces, that's done by CBER in the Office of Tissues and Advanced Therapies. Stem cell and cellular therapy products are unique in the sense that we take patients' cells or other cells from humans and then be able to manipulate them to have new features to replace defective cells in a patient. And so, there are a number of different ways that this is being leveraged. The mechanisms can be incorporation into a tissue or to help start the regeneration process in an organ or tissue. And so, this is a highlight of stem cell therapies, where it illustrates taking a patient's own blood cells, activate them in vitro, or include them in gene transfer by CRISPR technology, and then reintroduce them back into the patient, or being able to culture them, select them for the desired CAR T cells or engineered cells, and reintroduce them into the patient for therapy. Because these are so unique compared to large and small molecules, they have different questions that are, though the same principles, they have different ways of being characterized for drug development. And this includes the activities, what models to use, biodistribution is critically important, how long it lasts in the body is very important. And then, because they're so unique, new guidelines have been developed and released at the beginning of last year to specifically address the developments to give companies the reliability of understanding what is needed in order to develop these and to go into the clinic. And one of the key things, one of the main messages of what makes it different is that for cell gene therapies, it's not the product itself that you're really trying to safeguard, it's actually the process. The process of changing cells, the process of manipulating genes is the product. You're not, you're actually changing the effects in the body, but it's not what you're actually delivering that makes those changes. And so, that's a really important distinction. Overall, always refer to the guidelines that are relevant to your program, whether it be small molecule, large molecule, there could be therapeutic indications. I highly recommend doing extensive research in this area. And I know I use that most of the time, but I like to conclude by saying that Charles River has extensive capabilities in supporting from all, virtually all different aspects of drug development and that it takes careful planning for us to be able to help deliver drugs as quick as possible into the clinic and hopefully into the market. And the last thing I like to share when you receive the PDF is that these are two stories on rare and orphan disease. This is something that's really a remarkable breakthrough in drug development. We're now designing real-life therapies for one. And these are the two avant-garde programs that have helped the FDA and biotech revolutionize how we evaluate the safety of potential therapies and getting them into the clinic, rather than taking years, taking months. And so I like to leave it at that. And with whatever minutes that you can spare, I'd like to take any questions.