I would now like to hand the conference over to your speaker today, Faheem Hasnain. Please go ahead. Thank you, operator. Well, welcome everyone to Gossamer's CNS-Penetrant BTK Investor Day. We appreciate everyone for joining us today. As a reminder, if you have to leave us early or if you'd like to revisit anything we say here today, a recording will be available on our website at gossamerbio.com, as well as a copy of the presentation we're walking through today. Before we go any further, I'd like to introduce the Gossamer team that you'll be hearing from today. I am Faheem Hasnain, Co-Founder, CEO, and Chairman of Gossamer Bio. Laura Carter is our Chief Scientific Officer. Laura has 20 years of industry experience spanning target identification and validation activities through Phase 2 clinical trials in multiple therapeutic areas, and she leads our diligent research team. Richard Aranda is our Chief Medical Officer. Happens to be his birthday today. A gastroenterologist and clinician by training. He also was a key member of the ozanimod development team program at Receptos. We also have invited the development team behind these molecules to join us and walk us through these programs and answer your questions. Brett Skolnick is the program lead for both the GB5121 and GB7208 programs. He's a neurophysiologist with over 20 years of drug discovery experience in neurological indications. He also was part of the ozanimod Phase 3 trials. Rachel Altura has joined our team last month as an oncologist with previous leadership experience at both Merck and Bristol Myers Squibb. She also had an accomplished academic career at Ohio State as the principal investigator of a federally funded laboratory, and she'll be available for Q&A. Ishrat Yusuf is the biology lead on both the GB5121 and GB7208 programs. She's an immunologist with over 12 years of drug discovery experience, with a background in autoimmunity, inflammation, and immuno-oncology. Gossamer Bio is a clinical stage biotech company focused on therapeutic areas of immunology, inflammation and oncology. We have two ongoing Phase 2 proof of concept trials in pulmonary arterial hypertension and ulcerative colitis. You may have heard me refer to 2021 as the year of execution, today we're here to discuss our first internally developed products from Gossamer's internal research development engine. The Gossamer has assembled a deep bench of scientists and clinicians who are working tirelessly to advance the therapies of tomorrow and today. We're excited to give you a peek behind this curtain during this call. Before we go further, I did also want to head off any concerns about the timing of today's announcement. We remain incredibly excited about the prospects of both seralutinib and GB004 to transform the treatment paradigms in pulmonary hypertension and inflammatory bowel disease, respectively. 2021, again, is the year of execution for the Phase 2 studies in this program. Our team has been executing extremely well. We look forward to sharing these results of these studies with you next year. The why now answer for why we're announcing these programs today is, quite frankly, quite simple. Enrollment in our Phase 1 study of GB5121 is set to begin soon. With that comes a posting on the Australian New Zealand Clinical Trials Registry. We're very excited about both GB5121 and GB7208 and wanted you to hear the highlights from us first before these programs started making their way into the public eye. You may know Gossamer for its clinical product candidates, but today we're here to show the fruits of our internal preclinical work. Since inception, Gossamer's internal research team has been diligently working to develop the next generation of therapies. Not everything that Gossamer works on preclinically has progressed into the clinic. We have a very stringent and rigorous funnel by which these programs go through and get evaluated. We're optimistic about the potential of both of our Phase 2 programs. As a rule, any additional clinical product candidate must have a strong and justifiable value proposition. The Gossamer is looking to advance molecules with strong biological rationale that fill existing treatment deficiencies. Preferably, we're looking for a clear development path to market with clear differentiation. Today we'll discuss our latest programs, which we believe fulfill all of these asks. This morning, we disclosed the products we're advancing into the clinic, GB5121 and GB7208, both of which are oral CNS-penetrant BTK inhibitors. As you know, BTK is a validated target, we believe that existing BTK therapies are ill-equipped to address diseases and disorders within the CNS, including indications in oncology and autoimmune disorders. Our newest molecules, GB5121 and GB7208, are specifically optimized and designed for this current treatment deficiency. GB5121 will be advanced into the clinic for the treatment of primary CNS lymphoma, which is an underserved rare disease. BTK, in addition, has already demonstrated efficacy in PCNSL with above-label doses, of course, tolerability quickly becomes a concern. GB5121 is a highly selective molecule and a highly CNS-penetrant. Therefore, we believe it's well-suited for PCNSL. Higher penetrance leads to lower required dosing. High selectivity mitigates off-target concerns. Given the unmet need in this rare disease population, we believe we have a quick path to a registrational study with a registrational Phase 1b/2 expected to start in the first half of next year. GB7208 is an oral CNS penetrant BTK inhibitor, which we'll be advancing into the clinic for the treatment of multiple sclerosis. With this molecule, in preclinical models, we're seeing superior CNS penetrance and efficacy as compared to tolebrutinib. Not only do we see potential for this product candidate in neuroinflammatory disease, but also potentially neurodegenerative diseases, given the molecule's CNS penetrance and its effect on microglia. The development team from Receptos that was responsible for ozanimod is excited to reenter the clinic with another product candidate in MS. With that, I'd like to hand this session over to Laura Carter, our Chief Scientific Officer. Laura? Thanks, Faheem. Go to the next slide, please. Why BTK? As scientists, we, like others, have appreciated that this kinase is critical to the function of several immune cells important in the pathogenesis of hematologic malignancies and some autoimmune disease. In B cells in particular, BTK is downstream of the B cell receptor and is critical for the maturation, activation, proliferation, trafficking of these cells, as well as for antibody production and cytokine secretion. As we will see, the BTK signaling pathway can be dysregulated in B cell malignancies, leading to uncontrolled proliferation. In addition, BTK is not only important as a B cell regulator. BTK is a key signaling node in myeloid cells, including CNS resident myeloid cells called microglia. In these cells, BTK functions downstream of antibody receptors called Fc receptors and is implicated in the production of inflammatory cytokines and other mediators. Next slide. In addition to the compelling basic science we understand for BTK, this target is validated in oncology and is increasingly being tested and considered for some autoimmune diseases where B cells and myeloid cells, as well as autoantibodies, are thought to drive disease. In particular, in hematologic malignancy, there are three BTK inhibitors that are FDA-approved for B cell lymphomas. These molecules have high response rates with long duration of response. As Faheem mentioned, these non-selective inhibitors do have off-target side effects that limits the therapeutic window and the ability to dose up higher. The development of BTK mutations, potentially as a result of incomplete inhibition of the target or incomplete target occupancy, can result in loss of response. The suboptimal CNS exposure of these first approved molecules does require increased and often intolerable doses in these CNS diseases. In inflammation, the initial development of BTK inhibitors has focused on systemic inflammatory diseases, for example, asthma, rheumatoid arthritis, and lupus. BTK pathogenesis in neurodegenerative and neuroinflammatory processes makes MS and other diseases an attractive place to try BTK inhibitors. The current compounds that are out in the public domain have limited CNS exposure, and to date have had limited potential therapeutic impact, particularly in the systemic diseases. The poor selectivity and off-target effects have limited the therapeutic window. In addition to the basic science and the clinical validation for BTK inhibition, we recognized that there was an opportunity to develop differentiated molecules within this space. We believe Gossamer's BTK inhibitors are differentiated candidates because they integrate three key features, which were the focus of our SAR discovery campaign. First, we, like others, believe that covalent, irreversible BTK inhibitors will have an advantage over more traditional reversible kinase inhibitors. This chemistry was the first underpinning of our drug discovery efforts. Secondly, our molecules were optimized for CNS penetrance, which would allow for more effective use in neuroinflammatory and neuro-oncologic indications, where there's a requirement for high target occupancy within the CNS. Finally, we focused our SAR efforts on generating highly selective molecules, which would improve the tolerability and therapeutic index associated with BTK inhibition. In the next few slides, we'll unpack these three defining features of GB5121 and GB7208. Gossamer's BTK inhibitors are designed to be covalent, irreversible binders of BTK, meaning that they form a permanent bond to a cysteine residue in the active site of the BTK molecule versus traditional non-covalent inhibitors, which are in equilibrium with their target and continually bind and unbind and rebind. Covalent inhibitors are advantageous, as you can see diagrammed in the graph on the right, because they not only have enhanced potency and selectivity, but in particular, they have a prolonged duration of action versus the detection of circulating drug levels. Both GB5121 and GB7208 have covalent binding warheads and show this prolonged duration of target occupancy and pharmacodynamic effects which outlast the systemic circulating drug levels. Next slide. The second distinguishing feature of Gossamer's compounds, and again, a key part of our discovery effort over the last couple of years, was the optimization of CNS penetrance. Based on our data, we believe that GB5121 and GB7208 demonstrate superior brain penetrance in preclinical models. This slide shows internally generated data in mice who've undergone three days of oral dosing with a 10 mg per kg dose of each of the compounds listed in the graph. Importantly, these animals have an intact blood-brain barrier, so we are looking at the intrinsic ability of these compounds to cross an intact CNS barrier. GB5121 and GB7208 can be seen here to outperform some key competitor compounds. The third key feature of Gossamer's BTK inhibitors, and again, a key focus of our discovery effort, was to improve the selectivity versus other kinases, particularly kinases which also contain a similar cysteine in their catalytic sites to which these inhibitors may become covalently bonded. As you can see in the kinome trees on the left and on the graph on the right, GB5121 and GB7208 are highly selective molecules with fewer off-target hits than some of the competitor compounds that we have profiled. Taken together, these data show that GB5121 and GB7208 are differentiated BTK inhibitors that are ready to make the transition to the clinic. Best-in-class preclinical CNS penetration, as well as the high degree of selectivity and covalent binding profile, position these molecules as differentiated BTK inhibitors for neurologic indications in both the oncology and the autoimmune space. These programs were developed in-house by the Gossamer research team and have patent protection expected to extend into the 2040s. Gossamer has significant clinical development expertise in these spaces, and I'll now turn it over to our Chief Medical Officer, Richard Aranda, to discuss the clinical plans. Thank you, Laura. We want to take the opportunity to provide an overview of our clinical plan with GB5121 in primary CNS lymphoma or PCNSL as the initial indication. As a brief background, PCNSL is a subtype of diffuse large B cell lymphoma of the central nervous system. In the U.S., approximately 1,500 new patients are diagnosed in a year. The current standard of care is initially high-dose IV methotrexate, often in combination with other chemotherapeutic agents. Despite treatment and initial responses, outcomes remain poor due to the morbidity associated with chemotherapy as well as disease recurrence. Outcomes are particularly poor for the relapsed/refractory population. Selecting PCNSL as the initial indication is well-aligned with the role of BTK in driving this malignancy, the unmet medical need, and the attributes of GB5121. These points are highlighted on this slide, just to emphasize a couple of points. BTK inhibitors such as ibrutinib have demonstrated activity against PCNSL, yet the therapeutic profile of ibrutinib and other BTKs remains suboptimal due to several factors. These include limited CNS concentrations that does not achieve full BTK target coverage, as well as safety and tolerability issues as a result of the need to push doses higher. Consequently, treatment is often discontinued and responses are not durable. We believe that GB5121, by virtue of its superior brain penetrance and selectivity, may directly address these limitations. Additionally, our clinical study plan is designed to rapidly establish proof of concept with the potential for an accelerated approval. The next slide emphasizes the mechanistic basis of targeting BTK and PCNSL, as well as two examples from the literature highlighting the lack of durable responses that are generally observed with poorly CNS penetrant BTKs. The graphic on the left illustrates that PCNSLs frequently harbor mutations which potentiate BTK activity, driving the growth and survival of these cells. GB5121 should be highly active against these tumors and, in fact, we have in vitro data that suggests that GB5121 has potent activity regardless of phenotype and mutational profile. The swim lanes on the right are from two publications and highlight the general lack of durable responses with the BTKs, ibrutinib and tirabrutinib. There are, however, insights from these reports that greater and more durable responses may be achieved with greater CNS exposure and BTK target coverage, thus supporting our thesis. With that, I would like to turn it back over to Laura, who will summarize the superior CNS penetrance profile of GB5121. Thanks, Richard. As seen on the graph on this slide as well as earlier, GB5121 achieves robust CNS drug levels and occupancy, which supports its use in the PCNS lymphoma population. Because this molecule has been optimized for the CNS penetrance, you can see here that the brain drug levels show that GB5121 has superior brain drug levels to other competitive drugs and a higher brain to plasma ratio, which suggests that we would be able to use a lower dose to achieve higher CNS target coverage than some of the competitor molecules, which will hopefully open up a bigger therapeutic index. GB5121 has shown potent activity in vitro against a panel of DLBCL cell lines, regardless of the phenotype and mutational profile. We are collaborating closely with several top academic investigators in the PCNSL lymphoma space in order to test these molecules in animals in vivo. The excellent brain penetrance and the selectivity of GB5121, combined with this activity against the DLBCL cell line, position GB5121 for differentiated efficacy and improved safety in mutations with unmet medical needs in PCNS lymphomas. Thank you, Laura. Turning to our clinical program. It consists of 2 studies. We plan a Phase 1 SAD and MAD study in normal healthy volunteers, where we will evaluate the safety, tolerability, and PK of escalating single and multiple doses of GB5121. A key component of this study includes the evaluation of cerebrospinal fluid to determine drug levels. This study will initiate the fourth quarter of this year. Our other study is the Phase 1b/2 study in PCNSL. The Phase 1b will consist of a dose escalation portion where we will select the recommended Phase 2 dose in an expansion phase. The Phase 2 portion will be our registrational Phase 2 study with the recommended Phase 2 dose in relapsing and refractory PCNSL. Our primary endpoint in the Phase 2 will be overall response rate. A key secondary endpoint will be the duration of response, where we believe that the superior CNS penetrance of GB5121, and hence greater exposure and target coverage, may lead to improved durability. We plan to initiate this study in the first half of 2022. This slide highlights for us that with favorable results, we will have the opportunity to expand beyond the initial indication in PCNSL to explore maintenance therapy, secondary CNS lymphoma, and potentially even frontline treatment. In summary, we believe that GB5121 is a differentiated BTK inhibitor that can offer a best-in-class profile to address the limitations of current BTKs in PCNSL. The reasons for this are highlighted on this slide. We are extremely excited to introduce GB5121 into the clinic this year. Next, I would like to turn it over to Dr. Brett Skolnick, who will take us through the plan for GB7208. Thank you, Richard. As an introduction to our next product candidate, which you've already heard about, GB7208, with its potential indications in both neuroinflammatory as well as neurodegenerative diseases, I'd like to provide a brief background on our lead indication, which is MS, multiple sclerosis. Despite having several approved therapies, there remains an unmet medical need across the spectrum of MS that includes both RRMS as well as secondary progressive MS and primary progressive MS. There also remains a great degree of therapy switching in the MS domain as disease progresses, while currently there are limited options that exist for secondary progressive MS as well as primary progressive MS. Greater clinical efficacy, particularly for SPMS and PPMS, is therefore needed. The implications being that a drug that potentially targets mechanisms responsible for disease pathology would be a relevant addition to the current therapeutic armamentarium. There remains an opportunity to develop new therapies that would enhance the benefit risk across the spectrum of MS disease. This slide illustrates the mechanistic basis for targeting BTK in the neuroinflammatory neurodegenerative diseases such as multiple sclerosis. The BTK pathway intersects with several cell types involved in inflammatory components such as B cells, Fc receptor-mediated signaling of myeloid cells that also includes, importantly, the CNS-resident microglia cells. Research has demonstrated that in secondary progressive MS, B cell follicles in the CNS correlates with poorer prognosis, and in PPMS, the pathogenesis appears to be more compartmentalized into the brain or the CNS. Aberrant microglia activation is emerging as an important cell type in driving neurodegenerative diseases. BTK inhibitors with limited CNS penetrance would be suboptimal in addressing both the CNS and the peripheral drivers of disease. The potential advantage of a superior CNS-penetrant BTK, such as GB7208, is its ability to target the CNS compartment more directly while also having an effect in peripheral components of the disease. I will now turn over to Ish to describe the preclinical data which supports GB7208's profound impact on modulating multiple functions, both in the periphery and in the CNS, resulting from its superior CNS penetrance. Thank you, Brett. As Brett just mentioned, a CNS-penetrant BTK inhibitor would target multiple pathogenic mechanisms in MS, not only in the periphery but also within the CNS. To measure CNS penetrance, we used naive mice again that have an intact blood-brain barrier to track the exposure of GB7208 within the CNS and periphery, and compared it to two other BTK inhibitors under clinical development for multiple sclerosis, tolebrutinib and evobrutinib. Here, the graph on the left shows compound concentrations in the brain, while the graph on the right shows the brain to plasma ratio of these compounds following once-daily oral dosing for three days. Both of these two parameters together demonstrate that GB7208 can achieve higher levels of compound in the brain and higher brain to plasma ratio compared to the other two BTK inhibitors. Having demonstrated superior CNS penetrance, we next wanted to test the efficacy of GB7208 in vivo. Next slide. To do this, we first turned to a model that is routinely used in the BTK field and is considered a gold standard for testing efficacy of BTK inhibitors. Here we used the collagen antibody-induced arthritis disease model, which, as you can see from the cartoon on the left, results from the Fc receptor-mediated inflammation driven by antigen-antibody immune complexes. As we heard earlier, BTK plays a critical role downstream of Fc receptor signaling. Therefore, inhibition of BTK has been shown to ameliorate the joint inflammation that's seen in this model. Also, as we heard earlier, Fc receptor signaling is thought to play an important role in microglia within the CNS, and it contributes to neurological diseases such as MS. In this slide here, the graph on the right shows that in a BTK-dependent model, GB7208 demonstrates a dose-dependent reduction of disease severity. In a head-to-head comparison, efficacy of GB7208 is significantly superior to tolebrutinib at multiple doses tested. Next, as we are interested in developing GB7208 in neurological diseases such as multiple sclerosis, we tested the activity of our compound in a mouse model of MS called EAE. Although EAE is routinely used as a preclinical model of MS, it poorly recapitulates the role of B cells as well as myeloid cells in this disease, and the pathogenesis here is mainly driven by T cells. Despite these limitations, however, what we see is that GB7208 demonstrates a dose-dependent efficacy in the EAE model when dosed prophylactically. Having now demonstrated efficacy with GB7208 in two preclinical models, including a model of MS, we next wanted to further investigate the ability of our compound to modulate the function of CNS-resident microglia cells. As we discussed earlier, there is growing evidence in MS that Fc receptor signaling in microglia drives inflammatory responses such as increased production of TNF alpha and contributes to disease pathogenesis. As we also heard, BTK is thought to play a critical role in these responses. To test the ability of GB7208 to inhibit the microglia function, we first used an in vitro system using human iPSC-derived microglia cells. Here we stimulated the microglia cells with immune complexes and measured TNF alpha production. Our results demonstrate that GB7208 is a potent inhibitor of TNF alpha production by microglia. Having demonstrated this in vitro, we next wanted to further explore the ability of GB7208 to inhibit microglia activation in vivo. To do this, we used a mouse model of microglia activation where high levels of anti-MOG antibodies are injected intraperitoneally. A fraction of these antibodies, as you can see from the cartoon on the left, crosses the intact blood-brain barrier to then form immune complexes with MOG protein within the CNS. This then results in Fc-mediated proliferation of microglia cells, as here we're measuring by Ki67 staining. The graph on the right shows, consistent with our in vitro data, that GB7208 significantly reduces proliferation of microglia in vivo in both the brain and the spinal cord. Altogether, these preclinical data that we've generated thus far demonstrate that GB7208 is a potent and potentially best-in-class CNS-penetrant BTK inhibitor, making it an attractive candidate for neuroinflammatory and neurodegenerative diseases such as MS. With that, I'd like to hand it back to Brett to give us an overview of our clinical plans. As you can see on this slide, our expected timeline to clinic is that we are currently progressing GB7208 with IND-enabling studies. Our plan is to initiate our first-in-human study in normal healthy volunteers in the second half of 2022, with an intention of beginning our MS studies in 2023. This slide is intended to highlight that given the intersection of inflammation and neurodegenerative diseases, which has been highlighted over the past multiple years in the MS community, that we intended to target BTK, which may be applicable across a diverse range of CNS disorders. This includes the spectrum of MS that we've talked about, as well as potentially Parkinson's disease, ALS, and Alzheimer's disease. In summary, we have discussed the profile of BTK with a superior CNS penetrance, which should have advantages in disorders with both inflammatory and neurodegenerative components to disease pathogenesis. Our pre-clinical data that Ishrat just reported has demonstrated that GB7208 has the following critical features. It has potential for best-in-class CNS penetrance. It has a favorable impact on activated microglia in the brain, and we've shown the relevance of impacting on the pre-clinical disease models that were just presented. As noted earlier, we anticipate entering the clinic in 2022 with the potential to evaluate GB7208 in a variety of neuro indications. As the next slide will depict, the aspiration and realization of our efforts, as reflected both with GB5121 and GB7208, is emblematic of the stable of compounds that Gossamer Bio has developed with a focus on addressing the relevant underlying biology, targeting the specific cell populations that are impactful for the disease process, ensuring that the therapeutics are delivered to the target organ, in this case, the central nervous system, while ensuring selectivity of that impact, which is anticipated to improve both tolerability and ultimately alter disease progression. Now I'll turn to Faheem. Thanks, Brett. In closing, I just want to remind you of Gossamer's diversified pipeline. Of course, we have our two programs in Phase 2 currently, seralutinib or GB002, which is focusing in on patients with pulmonary arterial hypertension. This compound has been specifically and quite deliberately engineered to target what we think are the underlying causes of PAH and put it into an inhaled format. We're in Phase 2 currently enrolling patients. We also have GB004, a gut-targeted HIF-1 alpha stabilizer oral program that we're vectoring towards ulcerative colitis and potentially eventually, diseases like Crohn's. This is also in Phase 2, enrolling as we speak. We've further diversified our pipeline by the programs that we've just talked about today, GB5121 and GB7208, our 2 CNS-penetrant BTK inhibitors. We're extremely excited about bringing these programs towards the clinic and vectoring them towards indications like primary CNS lymphoma and of course, multiple sclerosis for GB7208. Beyond these two programs, we have multiple pre-clinical programs that we will continue to explore and continue to evaluate for their delivery into the clinic. As a reminder, our programs, the CNS-penetrant BTK programs that we've just talked to you about, the healthy volunteer study for GB5121 in oncology, CNS lymphoma specifically, will initiate Phase 1 fourth quarter of this year. You'll be hearing more about the start of that program shortly. Secondly, GB7208 will be initiating in healthy volunteers second half 2022. I also forgot to mention GB5121 actual patients, CNS lymphoma patients, that study will be kicked off with a Phase 1b and then the two registrational component will be first half of 2022. 2022 is shaping up to be an exciting year for us. I reiterate, 2021 has been a year of execution, including bringing these programs towards the clinic, and 2022 is a critical year of data for Gossamer. We look forward to talking with you more about these programs as this data starts to mature. In the meantime, we'll turn it over to any questions that you might have. Thanks for spending time with us today. Your first question comes from the line of Yasmeen Rahimi. Your line is open. Hi, team. Congratulations on the fantastic update, and sharing all the information with us. A few questions for you. Maybe the first one is, I guess it wasn't really clear to me the differences between the two compounds. If you could just highlight that to me, what are the similarities and differences? Second question for you is, when we think about BTK inhibition, what type of PD biomarkers should we be looking at, especially in the CNS, to reflect activity? Then I have a follow-up question. Ish? Sure. As you saw today in both GB5121 and GB7208 are highly selective and highly CNS penetrant. GB7208 has some additional features that we think will be beneficial in the autoimmune and then multiple sclerosis space. More to come on that later. Hi, this is Richard. Yeah, I could address the PD biomarker. We have a strong translational medicine program and the relevant point here is that usually in diseases that we can assess cells, they're more abnormal in the CSF. Typically in a peripheral, we could use target engagement, BTK receptor occupancy. It's probably less done in the CNS, but we're exploring that, as well as looking at transcriptomics, particularly when there's a lot of cells available in either oncology or in autoimmune diseases. Those are the type of biomarkers that we will be evaluating. Thank you, Richard. A third question was to you in regards to the differentiation. I understand the enhanced potency and selectivity, the comment was made that there is prolonged duration of action. Is that because these are covalent inhibitors, is there differences in the chemistry that leads to maybe different half-life? Is it just the nature of being covalent? Yes, that's correct. As the nature of being a covalent inhibitor, that's when we expect a prolonged PD effect. Consistent with the properties of a covalent inhibitor. Okay. Thank you so much. I'll jump back into the queue. Your next question is from the line of Carter Gould. Your line is open. Great. Good afternoon. Thanks for hosting this. I guess the first question is when we think about PCNSL, obviously ibrutinib's been used off label and in some studies here, to what extent that I know you guys referenced it in the slides a little bit kind of qualitatively, but to the extent that sort of sets the target in terms of what you think you can hit efficacy-wise and, if some of those sort of, open label studies are sort of what's how you think about the sort of target product profile here, at least from an efficacy perspective. Then second question, maybe a little bit of a bigger picture for Faheem's team, just in terms of, as you think about delineating differentiation in MS, some time has passed since sort of the ozanimod versus fingolimod days. If you have any other kind of broader lessons or takeaways as you've kind of had some time to reflect on that over the past two years and some of the challenges there. I have a quick follow-up. Yeah. I could address the target product profile question a bit. If you look across the studies and you look at ORR as your endpoint, it's between 31%-55% across the studies. We would obviously like to be on the upper bound of that, if not greater. Perhaps another way to look at it is that, the current BTKs, they have very limited CNS exposure and hence limited BTK coverage. If you could prolong your BTK coverage over time or over a dosing cycle, if you will, we hope to achieve greater durability. Currently, the PF, progression-free survival in many cases are only two to four months. Hopefully we could extend that and that's what we want to achieve. You want me to do the second part? Yeah. As it relates to the market, I think a number of things have changed, but a number of things have remained consistent. I think what's consistent is that patients continue to look for oral solutions in the marketplace and more options, more choices for triggers in patients in the context of oral agents continues to be welcomed. Having said that, a number of things have adjusted as well, and that is that we're starting to see a trend towards earlier use of agents that are higher efficacy. That trend, I think, plays very nicely to the entrance of a BTK like ours, that potentially could have a higher efficacy profile. We're starting to see ocrelizumab, anti-CD20, starting to get used earlier in the course of treatment. Again, those are injectable agents. Those are agents that clearly biologics. If we could actually supplant some of that early utilization with an easier to use, more patient-friendly oral format, I think that represents a real opportunity. Lastly, none of these patients are cures, unfortunately for these patients. These patients will continue to cycle through pretty much everything that's available, and that's the unfortunate truth associated with this disease. That's where I think, again, more choices, more options. Brett? Just to add to that, I think the other point here is that the CNS penetrance of these molecules, and particularly GB7208 in the MS domain, will stand hopefully above some of the limited penetration of the antibodies that you just spoke to. Exactly, Brett. Recall as well our interest to actually move towards both SPMS and PPMS, where the unmet need is still quite sizable. Perfect. I appreciate the perspective. Apologies in advance for asking one somewhat off topic today, but we noticed that the GB004 UC study, it appears, is no longer actively recruiting. Could you just clarify if that study is now fully enrolled? Thank you. Carter, it's Bryan. We'll be giving an update on our quarterly call the beginning of November. As Faheem has said, this is the year of execution. Thanks. I'll just say we're very excited about the profile of this agent. Obviously, this is a profile that has the potential, we've stated this before, to be used pre-biologic, pre-immunosuppressant therapy. That really represents a really important position in the context of treatment of ulcerative colitis patients. Thank you. Your next question is from Olivia Brayer. Your line is open. Hey, guys. Thanks for the question and congrats again on the pipeline update. Faheem, I know it's still early days, but when you think about the value proposition in CNS, is there a strategic interest in partnering either of these programs to maybe help expedite the development path forward? Or is there more incentive to keep them wholly owned at this point? On GB5121, have the starting dose levels been decided yet moving into the Phase 1a? Can you give us any more color around the dose titration schedule for the MAD portion? I've got one follow-up on GB7208. I'll ask Richard to handle the second part of that. First up, I'll just mention that we have over $406 million in cash, so our runway is strong. Our intention, of course, is to execute not only on seralutinib, on the IBD program, GB004, and now these two BTK programs, all within the context of the runway and capital that we have access to. That puts us in a really strong position to offer additional value inflection points for investors. Our view is that we are choosing indications that we have the ability to put our arms around. These are indications that are specialty driven and therefore indications that we have the ability to execute on. Once we get through our Phase 2 inflection points, of course, we'll reevaluate whether or not partnership could accelerate our development into Phase 3 and accelerate our path to registration. That's always a consideration for us to be thinking about how we can most rapidly get these drugs to patients. Richard, you want to comment on the second? Olivia, you broke up during your question, I believe one component of it was you asked regarding our dose titration for our normal healthy volunteer study. Let me just say that, obviously our clinical pharmacologists and preclinical colleagues have nicely modeled out what we think we need to start off with. The nice thing about BTK is there's a lot known about target engagement and receptor occupancy. We will use that to help guide us. I believe the other part that was emphasized earlier, because we have a good brain to plasma penetration ratio, if you will, the likelihood is that we'll be able to start off at low doses and remain at lower doses to minimize some of the systemic issues that one can see when you dose escalate. I'm sorry I missed your second question. Yeah, it was just around whether the starting dose levels have been decided yet. I think you answered the question already. Richard, just one follow-up. I know you talked about this already for PCNSL, but have you been able to identify any biomarkers or other characteristics for GB7208 that could make sense to enrich for? I'm just trying to get a better sense for how you're thinking about trial designs and the ultimate success of that asset. This is for GB7208 in the MS program? Yep. Is that correct? I'll let Brett, do you have any comments? We're keeping our eyes on the literature. Obviously, the normal players that have been out there, such as NfL and a variety of other markers that we can get from the CSF, will be evaluated. How predictive they'll be in terms of a potential enrichment of a population remains to be seen. We're actively pursuing, as Richard mentioned earlier, a translational medicine program that will include as much as we can discern from these data sets, both the healthy volunteers and the early phase trials. Great. Thanks, guys, and congrats again. Your next question is from Joseph Schwartz. Your line is open. Hi. Thanks very much, and thank you fo r the update. I was wondering if you can give us a sense for how much higher you can dose your BTK inhibitors in animals before you see the dose-limiting toxicities that the other BTK inhibitors show as a result of less selectivity? This is Laura, by the way. One of the big toxicities has been associated with EGFR inhibition, and we don't see the same sorts of toxicities in rodents. That we would see in people with that particular profile. However, what I can say is our compounds have been very well tolerated and have not shown any of the types of liver signals that plagued some of the earlier BTK compounds at any of the dose we tested in our toxicology studies, which have, I would say, very robust therapeutic margins associated with them relative to. Interesting. Thank you. Sorry, Richard. Your last question is from Patrick Trucchio. Your line is open. Can you hear me? Yes, can, Patrick. Hi. Yeah. Just a couple of follow-ups on GB7208. On slides 28, 29, and 30, I was hoping you could provide some additional context on these preclinical models, how well they translate in the clinic, and what we should be looking for in the clinical data that's to be generated that would give us a hint that this compound is performing as your therapeutic hypothesis would suggest. Also, with regard to the neurodegeneration indications, is there ongoing preclinical work being conducted, or would you be looking for some additional data in the MS program before expanding the indications for the compound? Maybe I can start and go through the models on the slides that you indicated. This is Ishrat. On slide 28, we're measuring, as Laura mentioned earlier, measuring CNS penetration in mice. We do this because we wanted to be able to measure CNS penetration in an environment where the blood-brain barrier was intact. A lot of times people measure in disease models such as EAE where there is a breakdown of the blood-brain barrier. The use of mice really gives us a nice accurate window of CNS penetration. The lab also measures CNS penetration with higher species, and we continue to see superior penetration as we move up species. That's slide 28, the data there. Slide 29 is a model that I mentioned very routinely used in the BTK space. We think captures one of the key features of the BTK-driven pathogenesis, which is downstream of the Fc receptor signaling. In that sense, we think we're capturing a very important function of BTK, especially in the context of MS, because, as we mentioned, even though this model is looking at peripheral myeloid cells, microglia cells use the same mechanism to drive inflammation within the CNS. We think in that sense, this is a very relevant model and very dependent on BTK. I think the last slide is on slide 30 is the EAE model, and we talked about this briefly. We ran the EAE model because we are interested in MS. As people in the field would know that this is not an ideal model to really investigate the role of B cells or maybe even myeloid cells. It's really driven mainly by T cells. Despite these limitations, we see some very impressive efficacy with our compound, and you can see that we can go down to very low doses. We do plan to continue profiling our compound in additional preclinical models as well as models that are more focused on neurodegeneration. The data that you saw today is from the microglia models, and the other two slides are just the beginning, and we are continuing to profile them further. I would just add to this by saying that these are very broad models that demonstrate the efficacy of BTK in these model systems. You'll keep in mind that there have been many already reports as well as publications demonstrating that mechanism of action of BTK works nicely in the setting of MS. What remains to be seen is whether that works equally effectively in a primary progressive MS patient population, but there are a number of developmental studies ongoing now that will support that role of BTK in those disease processes. Your next question would be from Joseph Schwartz. Your line is open. Oh, great. Thanks for coming back to me. I was just curious, kind of a big picture, basic science question about the microglial aspect of MS that BTK inhibition could be valuable for targeting. It seems like the scientific understanding has been evolving really rapidly, and a lot still is not known. I guess my question for you is, has it been established the extent to which BTK activity is associated with or even drives pathogenic microglial activity in MS, and is more BTK knockdown better, period, or could there be a critical threshold that you want to exceed but then not go too far beyond in case a certain basal level of BTK is good for some reason? I think some of the data that we shared with you today, as well as data in the literature, really supports the role of BTK in the inflammatory functions of microglia. As with all myeloid cells, there's multiple populations of those cells, both in the CNS as well as in the periphery. I think the field is still working through the many subsets of these and the extent to which they are BTK-dependent. What we and others have clearly shown is some of the very pro-inflammatory functions of the microglia in terms of their proliferation, their activation, their production of pro-inflammatory mediators does appear to be BTK-dependent. I can add to that a little bit, Joseph, by saying that there have been a series of studies over the past half a decade that look at positron emission tomography, which is essentially trying to evaluate the role of microglia. Even though those studies have predominantly used peripheral drugs like the S1Ps, they've shown an impact on active microglia and a reduction. Whether there is a threshold effect remains to be seen, and that is something we'll have to explore in the clinic. Thanks again. There are no further questions at this time. I'll turn the call over to Mr. Faheem Hasnain. All right. Well, thank you very much. We at Gossamer are very excited to have had the opportunity to talk to you about these two new programs into the clinic. We're very excited about the potential for patients, and I just want to thank the Gossamer team for their incredible passion and diligence and focus on bringing these programs forward. Thank you all, and we look forward to answering any questions over time that you may have. You know where to reach us. Thanks, everybody. This concludes today's conference call. Thank you for participating. You may now disconnect.