Hi everyone, and welcome. My name is Jacqueline Ruff and I will serve as your moderator here today. Thank you for joining us for today's webinar building, better degraders, targeted protein degradation partnership from lead discovery to production. As your moderator, it is my role to ensure that we make the most of your time with us. I'm here today with our speakers Aditya Vaida, Hugo Vienna and Jason Modest. The DT is a Senior Scientist in the Chemical Biology Innovation team, focusing on creating innovative solutions for the chemical biology and drug discovery community, including novel tools for targeted protein degradation. Hugo is a Global Product Manager for the chemical biology team as well, where he is responsible for overseeing the strategy of the global chemical biology portfolio and Jason is a Director of Manufacturing Science and Technology at our Madison Verona, CDMO site. Where he leads the technical transfer and validation teams and provides life cycle management for commercial programs. Before I think turn things over to our first presenter, I'd like to cover a few housekeeping items. At the bottom of your screen are multiple application widgets you can use. There you can also find our reaction button indicated by the thumbs up emoji that allows you to give immediate feedback on the presentations, topics or anything that stands out. All the widgets are resizable and movable, so feel free to move them around to get the most of your desktop space. You can expand your slide area or maximize it to full screen by clicking on the arrows in the top right corner. If you have any questions during the webinar, you can submit them through the Q&A widget. We will try to answer these during the webinar, but if a more detailed answer is needed or if we run out of time, it will be answered later via e-mail. Please know we do capture all of your questions. You will also have the opportunity to participate in a couple of quick poll questions throughout the session. I encourage you to take part in these surveys. If you are watching the webinar on demand, you can still submit poll responses and questions via the Q&A widget. The webinar is being streamed to your computer, so there is no dial in number for the best audio quality. Please make sure your computer speakers or headset are turned on and the volume is up so you can hear the presenters. An on demand version as well as a copy of the slides of the webinar will be available after and can be accessed during the same link that was sent to you earlier. So that's it from my side. It's my pleasure to turn things over to Aditya. Aditya, I'm sorry we you must be muted, we can't hear you. Can you hear me? No, I can. Yes. Should we just start over? Yeah. Should we? Patricia, what do you think? Was I the only one, any ideal to hear him or because I thought I was on unmute? OK, well, OK, Patricia, are we able to just take it from the top and then start the recording over again? We can just start again and I will cut it afterwards. Perfect. I'm sorry, I thought I was on mute. Can everybody hear me now? Yes. OK. Yes, Yes, Yes, we can. OK. OK. All right. Sorry, guys. You got to listen to my spiel one more time. Sorry about that. No, no, no, you're good. Wait, can you? Hugo, can you come back on camera, too? Perfect. Okay. Yeah. So I did you. You were muted. I then unmuted you. Can you unmute me? Can you take over the control of my muteness or unmuteness? Yes. Thank you so much. So that I don't accidentally press something. Okay. Yeah. All right. Yes, you can go. Go ahead. Perfect. All right. Hi, everyone, and welcome. My name is Jacqueline Ruff and I will serve as your moderator today. Thank you for joining us for today's webinar building, better degraders, targeted protein degradation partnership from lead discovery to production. As your moderator, it is my role to ensure that we make the most of your time with us. I am here today with our speakers Aditya Vaida, Hugo Vienna, and Jason Modest. Aditya is a Senior Scientist in the Chemical Biology Innovation team, focusing on creating innovative solutions for the chemical biology and drug discovery community, including novel tools for targeted protein degradation. Hugo is a Global product manager for the chemical Biology team as well. Where he is responsible for overseeing the strategy of the global chemical biology portfolio and Jason is a Director of Manufacturing Science and Technology at our Madison Verona CDMO site where he leads the technical transfer and validation teams and provides life cycle management for commercial programs. Before I think turn things over to our first presenter, I'd like to cover just a few housekeeping items. At the bottom of your screen are multiple application widgets you can use. There you can also find our reaction button, indicated by the thumbs up emoji that allows you to give immediate feedback on the presentations, topics, or anything that stands out. All the widgets are resizable and movable, so feel free to move them around to get the most out of your desktop space. You can expand your slide area or maximize it to full screen by clicking on the arrows in the top right corner. If you have any questions during the webinar, you can submit them through the Q&A widget. We will try to answer these during the webinar, but if a more detailed answer is needed or if we run out of time, it will be answered later via e-mail, Please know we do capture all of your questions. You will also have the opportunity to participate in a couple of quick poll questions throughout the session. I do encourage you to take part in these surveys. If you are watching this webinar on demand, you can still submit poll responses and questions via the Q&A widget. The webinar is being streamed through your computer, so there is no dial in number for the best audio quality. Please make sure your computer speakers or headset are turned on and the volume is up so you can hear the presenters. An on demand version as well as a copy of the slides of the webinar will be available afterwards and can be accessed using the same link that was sent to you earlier. So that's it from my side. It's my pleasure to turn things over to a detail. Thank you so much Jackie for that kind introduction. It is my pleasure to be here today discussing the journey of building better degraders from discovery to production. In this webinar we will learn about why nature has built a cellular clean up group within each of us which we refer to protein degradation, how we can chemically hijack this group which we call as targeted protein degradation. Why is start with protein degradation or TPD, the next gold rush in the land of the Uncharted? What is the mechanistic magic behind TPD that is behind the cleanup crews E3 ligases, particularly Cereblon and VHL? What are the chemical advancements that make degraded design modular and strategic? What is the chemical toolbox that we should use for building better degraders? And finally, a journey through the clinic as your partner for TPD development and manufacturing. So let's look at nature's cleanup room. Why do we need protein degradation? So when proteins are formed in cells, they are typically in unfolded form and they become folded and then functional. If the same proteins become misfolded, they become toxic and this leads to either a healthy state. Or a diseased state of our body. Now nature has have this clean up group called the E3 complex which gets rid of unwanted proteins through a cellular disposal unit. And this is an elaborate machinery composed of three critical enzymes, E1E2 and E3 as shown here. Now these enzymes play a crucial role in the process called ubiquitination. A post translational modification that regulates protein stability and function. E1 enzymes or ubiquitin activating enzymes activate ubiquitin molecules, the ones shown in purple here, and transfer them to E2 enzymes. Ubiquitin conjugating enzymes. These enzymes then transfer the activated ubiquitin to E3 ligases. Which then specifically target proteins and mark them for cellular degradation. These enzymes work in a coordinated manner to add ubiquitin molecules to target proteins, marking them for degradation by the proteoso alternately de ubiquitinases or dubs as they are called. These enzymes remove the ubiquitin from proteins, thus reversing the ubiquitination process. And regulating protein stability, signaling, and traffic. Now, targeted protein degradation comes in two major flavors. One, shown here in the top left, is a molecular glue, a small molecule which makes complementary surfaces on the E3 ligase and protein of interest, otherwise referred to as poi for now. Basically, this molecule brings these two enzymes together in a ternary complex. And marks the target protein for ubiquitination and subsequent degradation. Protax or proteolysis targeting Chimeras is another version of the same. It's just that the E3 ligase recruiting arm is joined by a linker to the protein of interest. They also form a ternary complex with the two proteins and mark the protein of interest for degradation and proteosomal degradation. Well, it all started with the seminal paper in PNAS from Professor Greg Cruz and Raymond Duche in 2001. But the field really bloomed after this paper in Science from Jay Bradner and York Winter where they used thalidomide for conjugation as a strategy for in vivo target degradation. Now, why do we need to chemically hijack the Nature Screener? Why not just inhibit it? Why do we have to degrade it? Well. It's all about biology. Traditionally medicines have targeted proteins through a type binding inhibition mechanism. But the same proteins can go under mutations and that's why we see drug resistance. So this degradation modality overcomes drugs resistance. Some target proteins have no enzyme activity at all, some have only scaffolding function. Some proteins are part of larger protein complexes. Designing small molecules to target or inhibit this function can be a bit tricky and that's why degradation or small molecule degraders as a modality is coming into the forefront. Inhibition alone also may not be sufficient. Sometimes high concentrations of the same inhibitors leads to possible toxicity and the catalytic nature of protact degradation, where one small molecule of protact recruits a protein of interest. Transfers the ubiquitin molecule, marks it for degradation and recruits another protein of interest. This mechanism leads to lower concentration and lower toxicity. Now before going into the modality of TPD, let's see why is it considered the next Gold Rush interrupt discovery now? Over the past 22 years of research, over 70 companies have jumped into this space. With more than $6.5 billion in pure plated PTP equity investments, but only that we have 20 plus clinical candidates in these various indications. It is considered the next chemical version of presper. Most importantly, 85% of proteins remain undropable or poorly dropped creating huge opportunities in this area. So let's talk about DPD in terms of what are the opportunities and challenges associated in this space. Now if you look at this figure here amongst the 22 years of research, only 3% of some 600 plus E3 ligases in the human genome have been used for targeted protein degradation. If you look at protractable proteins, only 19% of some 1300 plus proteins of interest. Have been used in target protein depredation. So there are huge opportunities not only in terms of the E 3 ligases that can be used, but also the proteins that can be degraded for various disease indications. Now this phylogenetic tree shows the 600 plus E 3 ligases in the human genome, but you can see the red ones. Here are only the ones that are used in TPD research. Now you might wonder why. And that's because expanding the E3 repertory has its own challenges. The E3 activity is tightly controlled by post translational modifications. There is lack of knowledge of the native substrates as well as news molecule binders for E3 ligases. Sometimes mutations in the same E3 ligases make them unworthy for TPD research, and sometimes ubiquitination does not lead to degradation. And that's why choice of E3 ligase is very important. While starting TPD caffeines, let's look at some of the Tpd's that have been used in E3 in targeted protein degradation. The first one starts with cereblon, now cereblon or CRBN. It goes back in the 1980s where this molecule thalidomide was used for morning sickness in pregnant women. At that time it was discovered that cereblon degraded this protein sulfor which is shown in pre here. And this degradation leads to limb abnormalities in babies and this leads to the teratogenic properties of thalidomide due to sulfor degradation come in 2000 purely due to serendipity cereblon. Degrades IKZF and this degradation of this transcription factor called IKZF leads to its anti cancer properties. Now this is a crystal structure of cereblon in complex with IKZF and iberdomide which is an analog of thalidomide and this serendipitous discovery was used for designing normal Protac degraders around Cereb. Now this is a structural information obtained of binding of thalidomide to cereblon binding site and these arrows show the solvent exposed vectors or the sites on this molecule which can be used to design protactic readers. An example is shown here in ARV 825 where you can see this part of the molecule. The five position has been used to create a linker and attach it to this BRD 4 target. And consequently you can see that most of the cereblon degraders is along this vector for TPD research. If you look at VHL or one HIPAA Linda protein, the story begins with hypoxia inducible factor 1A or HIP 1A, which is a transcription factor that plays a critical role in cellular responses to changes in oxygen level. In Normoxia or normal oxygen levels, HIF 1A is hydroxylated by these enzymes called PhDs or proryl hydroxylases which marks it for recognition for VHDL and subsequent degradation. Now the activities of PhDs is inhibited in hypoxia and this leads to translocation of the HIF 1A to the nucleus. And then pipfanolfa binds to HRE or hypoxia response elements and activates transcription of certain genes, including genes responsible for angiogenesis, glycolysis and erythropoiesis. One of the most important genes is the gene for erythropoietin, which is very crucial for treatment of anemia and chronic kidney diseases. So it all started with designing normal inhibitors that would block the interaction between F 1A and VHL and then how they were used for designing novel protag degraders around VHL. This is a complex of VH2. Rinate another small molecule inhibitor of the interaction of VHL and F1 alpha. This molecule also has solvent exposed vectors shown in purple here. These vectors were used to design novel degraders. One example is shown here as MC1, another BRD for degrader. You can see this vector has been used. It's been conjugated to an carboxyl linker to make a BRD for degrader. It is more than 50% of degraders right now around VHL use the solvent exposed vector. To design novel small molecule degraders. This is a crystal structure of the same molecule MZ one in complex with its target BRD four and PHL. Now other emerging E3 ligases are also used in TPD research and that's because as I mentioned E3 ligases themselves have mutations and which leads them to be ineffective in TPD research amongst the emerging E3 ligases we have. IAPS or inhibitor of apoptosis proteins which is a family of proteins that regulates cell death and survival. Now shown here is a peptidic molecule that targets this protein AVPF and based on the small molecule people can design degraders around this based on the solvent exposed vectors. Another E3 ligase is shown here is decaf 15. Which refers to DDB one and Cal 4 associated factor 15. Now decaf proteins are also a family of substrate recognition components that associate with DDB one and Cal 4E3 ubiquitin lycase. The function is adaptive proteins and recently this small molecule E7820 was discovered to bind to this decaf 15 molecule. And based on this nitrile solvent exposed vector, many degraders have been designed particularly centered around the cap 50. So with this, I would like to conclude my presentation and thank you so much for your time. Thank you so much Aditya. Before we move on to the next presenter, we do have a short poll question here, so we'll pose to you. As a knowledge check, which of the following is not a key component of Protax for targeted protein degradation? Is it the target protein ligand? The E3 ligase ligand? The proteasome inhibitor or ubiquitin ligase? We'll give you a few minutes to submit your pull questions, and in the meantime, if you do have any other questions for Aditya, please feel free to put them in the Q&A widget. So we'll give it another couple seconds here. All right, Let's go ahead and move on and and check our responses. So the actual correct answer for this particular poll question is C, the proteasome inhibitor. But with that, we'll go ahead and move on here to our next presenter I'd like to introduce, Hugo. Thanks, Jackie. So I really appreciate the the chance to be here and talk a little bit about our offer in the TVD space. And so I will start with why and how can we make the most out of the reagents, the tools that are available and how can we rationally design A product that is going to be able to satisfy our research needs so. If we consider the ATRO bifunctional aspect of a Protac, we can clearly see that there are three different products involved. We have the E3 ligase, we have the linker that binds these two, let's say portions of the Pro, the Protac, and we also have the target for it in IN. Regarding this, obviously there are questions that need to be addressed. When trying to build the product questions like which is the the best E3 line gaze considering our protein targets. What is the the the right length of the you know considering the protein protein interactions, what is the the right linker And also how can we toggle some of the aspects of the of the the basically the the system that we have in front of us things like rigidity or sell ability. And obviously this takes us to to an aspect of TPD or building the greater studies. This is a super challenging task to design products. And So what we want is to make sure that when we are offering and making tools available that they are going to be able to satisfy some of these conditions and so being a bit more specific. I mentioned the warheads, the the the linker and the E3 ligase and how can they actually provide the, you know the the the chance and the opportunity to build and to run TPD or targeted protein degradation assays. And that in the end I built are able to satisfy the the final or the objectives of your of your research And all the way this works is obviously I mentioned this modular approach. Taking account that we have three different entities or molecular entities in this case and for that we start our starting or breaking down this, let's say this first partial partial product which is what we see here. We see the E3 light gaze in the center and then connected or bound to a linker and if we consider what is the offer, the current offer for us. We have the the terminal chemistry in the case of the the target warheads and obviously considering and bearing in mind that we have different types of chemistries that are going to be linked to this, to this, to this part of the partial product, we have to consider different functional groups as well. We also have the different 3E3 ligands or ligases and I had the mention a few. And we are going to show some of the offer that we have available, the final one, the linker part as well, which is super crucial in this, in this, in this type of reactivity and reactions. And we can see that we have different types of linkers both providing different different types of characteristics, more or less hydrophobic or hydrophilic. We have more or less rigid or more semi flexible. And all of these accounts for accounts for obviously the best the grade. There are the best protect that we can assemble depending on our targets. More information can be found in in resources such as the Avshinica Akhta. This is our journal and there's a lot of information that can be read through this moving on into the next. Part of this also just as an example, so we have a target specific ligand that we know that is active towards our our protein. And what we want to do is we want to grab the other portion which is called the partial product that contains the linker and the E3 ligase, react these two together and then assemble the product we can see. Now this as an example, so this is on the right side we see and assemble the the Protac and what we can see if you look if you do the rest of synthesis of this was is we have this whole Moly Domite PEG, CO2, H so carboxylic acid partial Protac that basically is reactive with this target warhead to provide our desired final product Protac. This is one example. So in terms of making sure that we understand how this should be done and what kind of steps should be taken into this kind of rational approach, the 1st is always to understand what is the reactivity, what are the functional groups that are present in in in both the partial product and also the the terminal or the ligand or the warhead. And depending on these, we want to make sure that this is, this is chemistry that is going to be working and we want to make sure that all the functional groups that are on each of the sides are going to be reacting. And so that's that's a crucial step of understanding, making sure that we can select the best reagents for our chemistry. Obviously Dan is looking at. And once we understand what is the kind of chemistry, we move on and select the best group of partial products within that line of chemistry. So in this case, we have a CO2 group on one side. Obviously, we want to make sure that we have a name and containing functional group in order to make sure that we can react and assemble our final products. So this is how it works from a functional and rational. Perspective, it's looking at the the ligands that we desire and then choosing the best partial products depending on on the chemistries and functional groups present in those accountants. So moving on, we're going to talk a little bit about some of these interest, some of these partial products when we are talking about partial products or ligand linker conjugates which is the same. On the top we can see the the VHL or the one epol 1 epol leaned out to more suppressor protein and which is is one of the most utilized E3 ligases in the design of protein degraders. However, it has been recognized that the exit factor or how the degraded exits the E3 ligas can impact ternary complex formation. So structurally this is demonstrated by how the linker attaches to the ligand. To empower researchers the ACT to access the utility of VHL with different exit factors, we have begun launching a set of V L285 phenol partial products with alkyl peg and rigid linkers as shown on the right side okay. So this is the offer in terms of other E3 ligazes such as the sereblon or we also understand. The interest in exploring new types of scaffolds and chemistries with with wild Cereblon, VHL and I EP may be the most established. It has been exciting to observe the use of other E3 like these ligands and and which ones are developed for them so. For example, the Nomura group recently degraded BR T4 by developing A degrader varying the covalent ligand CCW16. As such, we have launched a set of CC double 16 conjugates with alkyl peg and mixed linkers to allow rapid assessment of R and F4 mediated degradation alongside our other Ethan ligands. So now. So Adi also mentioned some of these inhibitor of apoptosis or I AP, this is another E3 like this that has been exploited for the greater development. And this is actually a partnership that we have with Comminex to make sure that we offer novel chemistries in the protein TBD space. So with their modeling and library building capabilities, Comminex designed a 148 member Mimetics library. Based on the known I EP binding motive, a VPI virtual screening led to in silico identification of three top scoring leads, shown by three red boxes As it was accommodated in the modeling, each lead was conjugated to a linker at both the N terminals and C terminus to create the full suite of 24 lead linker conjugates featuring novel I EP chemistry. All of these all contain terminal amines. They can be used alongside amine conjugates for the other E3 ligands. In here we can see a sample of some of our, let's say offer we. I mentioned that we have different functionalities, different chemistries, also different types of linkers and for the VHL or for the one people Lindo tumor suppressor, these are some of the. Partial products that we are currently offering and and obviously this is to try to address the kind of opportunity that we have in in this space and to make sure that the customer can access the highest number of of partial products in the in the in the market. Moving on for for the cereblon protein as well. We also have a combination of different pegs. Or alkyl or N of the other let's say linker types associated with with this E3 like this that is as I said focused in the cereblon protein And and again just to show that we have a big offer, big range of products and making sure that we are addressing some of the needs or most of the needs in the market also. Obviously we want to make sure that we address you know most of the needs as I said and making sure that the space is covered well covered. So if we transition from discussing the E3 ligands and I'll focus more in the linker, let's say side we mentioned that we have many alkyl pegs and mixed linkers to provide different specifications and so. Addressing this, we can say that rigidity is is of increasing interest in optimization of degraders because it can impact both direct light properties as well as the 3D orientation of the degrader and thus ternary complex formation. Excitingly, we also saw the 1st 2 degraders in clinical trials from our Venus to possess linker rigidity. To improve access to such linkers, we've begun launching many linker conjugates with rigidity already incorporated. Some structural examples are shown here on the right side, and each has has been given a descriptive name to help group them with similar conjugates. The the interesting rigid linkers has been so high that we decided to also provide them as a actual bifunctional linkers. Meaning not as the conjugates with E3 ligands attached. We are launching over 70 of these that allow the researchers to select the target and the E3 ligands for either and using differentiated functional groups on opposing ends of the linkers, we've categorized them into sets on the upper left. Many of the linkers are 4 aerial pepridings, which we've organized into three sets based on derivatization sites. On the right side we are calling the others diversity sets that contain small groups of linkers with the same structural features as shown by the shading. The rest of the linkers vary slightly, so utilizing the sets that provide a glimpse at structure and activity relationship each are color-coded. The green linkers are launched, the yellow are launching right now. And the red will be mostly launched within the next month. So now I would just like to show in a nutshell kind of what kind of offer and do we have that covers the charts that the amines are the let's say the functional groups present in the partial products that are more popular. And this is obviously interesting to see as we see that you know more and more amine containing partial products are being released to the market every day. Regarding the E3 ligase, recruiter Pomolygonite is the biggest let's say containing E3 ligases along with BH Zero 32 and this also has a repercussion in our strategy in making sure that. Whatever the the customer is looking for we are going to address and so we tend to release some of these without obviously forgetting the rest of the E3 like this. Finally in terms of the linking the linker composition in partial products, I mentioned that we offer different types of linkers pegs that are more or less rigid Alto containing groups mixed or for to switch as well. We see that pegs and mixed are definitely some of the most popular ones in the market. And so we just want to make sure again that we go with what the market is, is looking for. And again we are constantly releasing and making these types of compounds available in our portfolio. Finally, I would just just like to show. And highlight many of the new degraded building blocks that give access to new history, like is this exit vectors, linkers or automation to make browsing of the product line easier. All relevant products have been compiled into a spreadsheet for easy sorting. This may look quite busy on the screen, but the ship will allow you to sort by conjugate, linker or ligand. In addition the linker properties each contains. Their SMILES string to make it easy to translate lists into structured analysis programs or structured data files. We are happy to share the spreadsheet with you after the presentation and I'm finished my presentation. Thank you for for listening and I will now pass on to my colleague. Thank you. Wonderful. Thank you so much Hugo. So we're shifting gears a little bit here now at this point of the presentation from essentially discovery phase targeted protein degradation to CT DMO support in in clinical or commercial phases down the road. Before I turn things over to Jason, we do have one other quick poll question for you guys really looking to understand where you are at as an audience looking ahead. So how soon would you expect to need GMP for I, MD enabling studies? Is your compound already in the clinic? Do you expect in the next next year, zero to 12 months, the next one to three years or more than three years from now? Very interested to hear from you guys. Again, any questions you have for Aditya for Hugo, please feel free to continue putting those into the Q&A widget. We will make sure to address the questions throughout the end of the webinar or via e-mail after the webinar. We'll give it one more minute for for you to submit your polling questions here. All right, so let's go ahead and take a look at these results. Very interesting here, which is, which is great. Thanks for the feedback, guys. But with that, I'll go ahead and turn it over to Jason. All right, Thank you, Jackie, and thank you DJ and Hugo. I'd like to round out today's conversation as Jackie mentioned and sharing some considerations that should be made when you're in that process of identifying A CDML partner. Many of these you'll, you'll be familiar with, but they're vitally important and so we'll go ahead and jump. Jump right into it. The first one really is around experience and capabilities. And so it's part of that vetting process. You're going to want to dive into a couple of specific areas and and we'll say the first one really is the, the project management area. And so I I think it's incredibly important to understand one, what are the offerings in in the project management realm, what are the management tools that will be utilized as far as. How things will be reported out, how data will be shared, how meetings will be captured, things that seem very tactical but are certainly vitally important to the transparency of the program. And then also, what is the makeup of that team? So who's on the team at the beginning? Does the team evolve as your program matures and evolves? And then how does that round out as far as? You know your ability to access the the different individuals on the team and then I think lastly but certainly not not not least is when resourcing additional resources are needed, What does that look like? Does does the project management team have the ability to augment the existing program as as work is needed to augment there and then moving on process and analytical development. This is always important because you want to know who's going to be the subject matter experts. You want to understand who what their experiences on the team so that you can properly leverage that experience. So you you're going to want to understand what access looks like to the subject matter experts on the team. This will translate into some daytoday activities as far as when you're problem solving, when you're working out the logistical details of the development or the tech transcriptor process. So access to subject matter experts and then who the makeup of that team is and then once again leveraging those strengths. So you may have some different intentions as far as your development plan, but there may be strengths within the subject matter expert team that can be leveraged in other areas that were unanticipated and so. Back to really knowing what they're capable of, what they can offer and bring to the table is is part of that development process and then ultimately even the transfer process. So all of that can be leveraged if properly understood to efficiencies gained throughout the throughout the life cycle of your program. So very important when when dealing with a broad range of complex technologies and modalities. And then lastly, as developments progressed and and you're ready to move into manufacturing, having a strong experienced production and quality staff is is vitally important to really navigate your way through the GNP environment and to that all important GNP batch. Let's move on here Okay, I I like to talk about safety and quality as being a competitive advantage to look for and so. One thing that you'll find in a strong, strong quality culture is is usually right the first time performance. And so when you're looking in vetting that CDMO, you want to understand what do the quality metrics look like, what is the what, what metrics are captured from a safety perspective. All of these are what I would say inside indicators to what that right the first time performance looks like and then. Then moving on to this idea of continuous improvement and across the life cycle of your program, quality, culture of quality and a culture of safety will will translate into a continuous improvement of your program as it matures from the early phase states to the later GMP and maybe even validation states as you move along. So you want to, you want to, you want to understand that. As far as how the safety and quality impact there, Additionally, these are complex modalities and so in many cases you may find yourself at multiple sites. We're fortunate enough that we do share a same as a shared quality system and so why is that important? Challenges do arise. It's important to be able to manage those challenges consistently. And with some continuity from from, from topics like deviations or corrective actions and and then certainly change controls, those are vitally important and when you have a shared quality system, you generally invite some efficiencies throughout your process. So very, very important there. And then then lastly, no one wants an unanticipated interruption into their process, so. This goes back to having a a insight into the the positive quality and safety tracker within the organization. You you just don't you don't want to have delays as a result of that. So understanding that it is vitally important to the success of your program. Now I'm I'm excited about this part as as the head of MS&T tech transfer is is a big, big function that my team plays and so. This gets exciting because you're starting to see favorable favorable signs in, in R&D and development which means it's it's time to start talking about transferring that into the manufacturing space. So understanding what does the tech transfer process look like, what does the tech transfer team look like and then what mechanisms are in place so that you have a a seamless transition from the the R&D and development phases into the GMP environment, so. Who's The Who who makes up that team and then how frequently do they they connect? Is it at members of the R&D team that connect with the tech OPS team that connect with the manufacturing team? What does that look like? What what are the escalation pathways? Not only do challenges arise, but certain sometimes there's opportunities that arise and you you want to know that there there's a pathway to to bring these topics. So that one. A challenge can be addressed or an opportunity can be can be taken in the event that these things arise. So understanding what escalation pathways look like and then certainly the tech transfer process really is a time when all things start to come together. All that work that happened, it's not only in the process but certainly an 80 to QC but ultimately prior to the start of that that GMP batch. You're going to have a culmination of activities that strip, that have to wind down and and then function as key deliverables that are needed before we start the GMP run. So understanding what that looks like, how those things are tracked, what's critical path, having visibility into all of that is vitally important supply chain planning. So if anything, if if we've learned anything from the pandemic, it's really understanding our supply chain. Understanding how robust it is and you know or what flexibilities live within there so anything can happen at a given time. You may have a raw material that you thought would be available and now you've you've needed you need to go out and identify identify one And so understanding what that CDMO's capabilities are as far as not only sourcing, procuring but also qualifying which could be which can be a process. That can take time if it's not well defined. So understanding what that looks like logistically having a a a established ERP system for for daytoday management, logistical management of your raw material and then certainly understanding how your materials are stored, shipped and then ultimately what that billing process looks like. We're we're fortunate to have a unfortunate to be part of the network that is a global network that has. A vast array of experience in the world of of procuring, securing and qualifying raw materials. In addition to that our organization has has the means to to actually synthesize a number of raw materials. So we we're we're very fortunate to have that level of robustness within our supply chain and then change management. So this seems obvious but change occurs. Throughout the entire process And so understanding how do we manage that change. And so a good example is early on you have a kickoff meeting and you've got a scope of work to find what that project will look like. Invariably, you may find that things need to change. Development has taken a different path. And So what does that look like? Is it a scope change within the project? What is the impact of that scope change? How do I ensure that that scope changes and impact them overall timeline, How do I manage scope creep? Those are those are very important things to understand as your program matures. So in the early phase it might be a scope change, but then as your program moves on, maybe you've got a GMP batch under your belt and you really are in the realm of of utilizing change controls and and having us having a change control process is vitally important within that CDMO that you selected. So the key there really is making sure that. You've got a process that ties into early phase work and and and later the the more mature work that moves along during the process. So that's that's vitally important to understand what your CD Mo utilizes and manages for change as as the program develops. And Jackie, with that I'll turn it back over to you. Thank you so much, Jason and and thank you to all the speakers for such great presentations. Now it's going to be time that we answer a few questions that have come in from the audience today. Before we jump into that, I would like to remind everyone it's certainly not too late to send us your questions using that Q&A widget. This also applies to any on demand viewers as well. We will try to get through all of them, but if we do run out of time, we will make sure to respond to you individually. As a reminder, this webinar will also be available on our website soon. All participants will receive an e-mail notification when it's available for viewing. Now we'll go ahead and jump back to answering some of the questions that have come in. The first question I have here on the list, a DT of this question is for you. How are Protax designed and optimized for specific protein targets? That's a very nice question, so. It all starts with the target or the protein of interest. So once you've identified your protein of interest, you would have a warhead or a ligand that binds to the protein of interest. And once you've identified that ligand or warhead, structural information is present to identify sites on that ligand where you can attach a linker. And that's the site where you would attach the partial product that Hugo mentioned. And this is the start for a new library of degraders centered around that warhead. So the more warheads you have, the more degraders you would get from the same warhead. And this is how you would start making degraders for a specific protein with a specific warhead for that protein. Thank you awesome. Thank you Aditya. Going through the question list here, this next question I will pose to Hugo. What kind of chemical linkages are most popular in Protac design and does your Protac offer include these? Thanks for the question. So as shown in in some of the slides, the most popular chemical linkages in Protac design are amites. And and we could easily see that from those those pie charts where we could see that the chemistry is present in the partial products, most of them they are amines or are also carboxylic acids. So carbonyl containing groups obviously reacting with amines we're talking about amides and this is the perfect example that I can I can give and yes as as I've already answered. We do push and try to target these as being as we know that they are quite popular. Thank you. Great. Thanks Hugo. We do have a couple CDMO questions that did come in. Jason, the first question I have for you is is do you have any experience with breakthrough therapy or fast track programs? Great question. Thank you, Jackie. Yes, we we do and and I would say. Part of part of that experience comes with being audit ready because these do pop up, we do get customers that they get the positive signals from, from the regulatory authorities that say yes, this is a candidate for fast track and so that allows us the ability to. Structure our team to support that fast track effort, but also it does bring in a number of external audits which which really by default puts us in a very, very favorable audit ready state having having frequent audits because of the portfolio that we have. But yes, we are, we are very accustomed to dealing with programs that that get that breakthrough therapy or fast track status and being able to move efficiently to meet those timelines. Great. Thanks, Jason. Looking at the time here, it looks like we've got time for one more question before we close for today. So Jason, I'll I'll pose this last question to you. How many steps of chemistry are in a typical project that your sites can support? And with that question, what batch sizes can you produce? OK, yeah, no great question. So with complex modalities like the one we're talking about today, those those can range. Pretty, pretty wide quite honestly And so we we can have something two to four steps or up to 36 steps that can translate into anywhere a process that can take two to three weeks or six months. And so we we have experience kind of handling those long complex by design drawn out processes but but. Yes. Ultimately it really depends on on the program itself and what the needs of the program are. As far as batch size, our our typical batch sizes can range anywhere from 100 grams to two to 400 kilograms. Now we also are able to provide a a platform for high potent synthesis processing here at the site of that I'm a part of that that scale is a little bit smaller. I would say that scale really ranges from anywhere from. 100 grams to up to 600 grams for for high potent synthesis. Awesome. Thank you so much, Jason. All right, well, thank you so much everyone for all the questions that that were submitted today. Again, if we did not get to your question, please feel free to e-mail our speakers directly or we'll be in contact with you after the webinar. To register for any future webinars or to access our archived webinar library, please visit our website. The slides will also be available to download after the webinar as well. Again, I would like to thank Aditya, Hugo and Jason for today's wonderful presentations. And thank you so much to our audience for joining us. Have a great day. Thank you. Thank you. _1731460899388

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