Good afternoon, and thank you for joining us. With me on today's call from Alpine are Dr. Mitchell Gold, Executive Chairman and Chief Executive Officer, Dr. Stanford Peng Peng, President and Head of Research and Development, Paul Rickey, Chief Financial Officer, and Dr. Remy Durand, Chief Business Officer. Also participating in today's call are Dr. Vibeke Strand, a pharmaceutical consultant and adjunct clinical professor from Stanford Peng University, and Dr. Kathryn E. Beckermann Thank you, Tamara. Today's R&D day will start with Stanford Peng providing an overview of ALPN-303, a highly potent, potentially best-in-class inhibitor of two critical B-cell cytokines, BAFF and APRIL. This will be our first major data disclosure from the phase 1 healthy volunteer study, RUBY-1. Results of the study support a differentiated, potentially best-in-class profile for ALPN-303 and enable the launch of a broad development plan for the program, including a phase 2 study in lupus and the initiation of three basket studies in renal, hematologic, and dermatologic diseases. Dr. Vibeke Strand will provide a detailed overview of the current treatment landscape and the clinical rationale for targeting BAFF and APRIL in lupus in particular, as well as other B-cell-mediated inflammatory diseases. Second half of the R&D day will shift to immuno-oncology, where Stanford Peng will provide the first look at data from our NEON-2 study of davoceticept, ALPN-202, in combination with pembrolizumab. Davoceticept is our first-in-class conditional CD28 costimulator and dual checkpoint inhibitor that has shown encouraging clinical activity, particularly in renal cell carcinoma, both as a monotherapy and in combination with pembrolizumab. Dr. Kathryn E. Beckermann will then cover the additional rationale for targeting CD28 in oncology and renal cell carcinoma in particular. Before we dive into the data, it's worth stepping back to understand the company's history and how productive our directed evolution platform has been. In 2015, through our fund, the Alpine BioVentures, we incubated and provided seed funding to the company with the goal of creating novel protein therapeutics that could work against multiple targets within the immune synapse. We quickly brought in two blue chip investors, OrbiMed, Frazier Healthcare Partners, and went public in 2017 via reverse merger to support our rapidly growing pipeline in both oncology and immunology. Follow-on offerings led by both Cowen and Omega allowed us to advance three molecules from de novo discovery to the clinic within six years of our inception. External interest in our platform and our team of more than 120 Alpinists has also been the foundation of our collaborations with top-tier pharmaceutical companies, including AbbVie in 2020, and more recently, Horizon Therapeutics. Currently, Alpine has three distinct programs that are in the clinic. acazicolceptan, or ALPN-101, is a dual inhibitor of two T-cell costimulatory receptors, CD28 and ICOS. In 2020, we announced a transformational option and license agreement with AbbVie around this program, which is currently in a phase 2 study in lupus, known as Synergy. Today's presentation will focus on Alpine's two wholly-owned programs. ALPN-303 is a highly potent, potentially best-in-class inhibitor of two B-cell cytokines, BAFF and APRIL, a cytokine pathway that plays key roles in B-cell development, differentiation, and survival. Together contributes to the pathogenesis of multiple autoimmune diseases like lupus and many other autoantibody related inflammatory diseases. This molecule is particularly exciting as our data suggests that it may be the first true dual BAFF-APRIL inhibitor in development. Davoceticept or ALPN-202, our lead immuno-oncology program, is a conditional CD28 costimulator and dual checkpoint inhibitor. Davoceticept works by localizing to the tumor microenvironment, where it binds to PD-L1, cross-linking CD28 to thereby activating T-cells. As a result, it subverts PD-L1 and turns it into a costimulatory ligand in addition to preventing its interaction with PD-1. We continue to be excited about this molecule and its potential as a significant value creator for the company. There is increasing external interest in CD28, particularly in prostate cancer, as well as the emerging data by us and others in renal cell carcinoma. Looking forward, we set a clear vision for the company to become a leading protein engineering platform with the goal of achieving proof of concept for Alpine 303 and advancing all three of our development candidates into pivotal or registrational studies by 2025, either on our own or with our potential partners. Importantly, we are building an efficient organizational infrastructure capable of supporting these key studies. In parallel, we will continue to leverage our productive directed evolution platform with the goal of identifying three novel development candidates, both independently and through our collaborations, in particular our Horizon Therapeutics collaboration as well as our collaboration with Adaptimmune. With that, I now hand the call over to Stanford. Thank you, Mitch. We'll begin by reviewing our most recent development program,ALPN-303. ALPN-303 is a dual inhibitor of two B cell cytokines, BAFF and APRIL, in development for lupus and other autoantibody-related diseases. It's been engineered for high affinity against these targets and has demonstrated superior efficacy in preclinical studies in comparison to other tested inhibitors of BAFF and/or APRIL. The first-in-human study in healthy adult volunteers has been mostly completed, and the initial data is highly encouraging, enabling us now to plan multiple patient studies such as in lupus and other autoimmune diseases in other therapeutic areas. In its present form, the drug may be administered subcutaneously or intravenously, and based on our current PKPD modeling, at least every four weeks. As a reminder, the BAFF/APRIL cytokine system includes three receptors, TACI and BCMA, which bind both BAFF and APRIL, and BAFF-R, which binds only BAFF. Currently, there is only one approved drug in this pathway, belimumab or Benlysta, which is a monoclonal antibody against BAFF, approved for systemic lupus erythematosus and lupus nephritis. Alpine 303, in contrast, blocks both BAFF and APRIL. BAFF and APRIL play complementary and partially overlapping roles in B cell development and activation, as illustrated in this figure, which depicts the expression pattern of their three receptors during B cell development. Early on, BAFF plays a dominant role related to BAFF-R expression, while the later stages are APRIL and/or BAFF dependent, related to TACI and BCMA expression. Important to note that APRIL and BAFF responsiveness continues well into the B cell stages that produce antibodies, in particular, plasmablasts In contrast, receptors such as CD20, the target of rituximab, are fully expressed in plasmablasts Similar to atacicept and telitacicept, Alpine three zero three is also an Fc fusion, but its TACI domain is a smaller variant TACI domain based upon only one of the six cysteine domains. Engineering of this domain was focused on increasing the affinity of TACI against both BAFF and APRIL. APRIL was of particular interest because wild-type TACI appears to be a relatively weaker inhibitor of APRIL. Here, the sensorgrams of surface plasmon resonance analyses are shown. In this case, using commercial telitacicept as a source of wild-type TACI. Note that while wild-type TACI does bind APRIL, it appears to have poor retention, and APRIL falls off relatively rapidly. In contrast, Alpine three zero three demonstrates significantly improved retention, more akin to what you might expect or desire from a high-affinity inhibitor. Overall, ALPN-303 appears to have improved the affinity of TACI against BAFF, each tenfold and dramatically improved the affinity against APRIL. These attributes correlate with significantly improved efficacy in multiple preclinical models. For instance, in a sheep red blood cell challenge model on the left, ALPN-303 in green has the most potent effect on antibody responses as well as plasma cell formation compared to wild-type TACI in blue, single inhibitors of BAFF or APRIL in orange and red, or the combination of the two BAFF and APRIL-specific biologics in purple. These types of studies demonstrate that inhibition of both BAFF and APRIL might be required in many target diseases since they can have non-overlapping functions. Indeed, previous studies in a New Zealand black-white spontaneous model of lupus, shown in part on the right, demonstrate superiority of dual inhibition to the mouse TACI Fc fusion, which inhibits both mouse BAFF and mouse APRIL, in comparison to inhibition of either cytokine alone. ALPN-303 similarly exerts potent efficacy in the New Zealand lupus model, suppressing anti-DNA autoantibodies, nephritis, and proteinuria, as well as salivary gland inflammation or sialadenitis. To summarize the preclinical data, ALPN-303 is an Fc fusion of an engineered TACI domain with significantly improved potency against BAFF and particularly APRIL. It demonstrates superiority against BAFF or APRIL-only inhibitors as well as wild-type TACI in preclinical disease models. Not shown is that ALPN-303 has been well-tolerated in repeated toxicology studies in rats and cynos, the latter up to six months. Anticipated pharmacodynamic effects such as reduction in serum immunoglobulins were observed, supporting advancement to clinical studies. RUBY-1 is the first-in-human study of ALPN-303 in healthy adult volunteers. It is a single ascending dose study exploring both intravenous and subcutaneous routes of administration, as shown on the left. Endpoints of particular interest besides safety include pharmacodynamic effects on circulating immunoglobulins, since prior drug candidates have published benchmarks thereof. Circulating B cells were also of interest. Prior candidates have not reported reductions in B cell populations when administered at single doses to healthy adults, but they are of interest with ALPN-303 since they were observed preclinically and may provide additional biological differentiation. Today's presentation reflects our initial analyses with a data cutoff of July twenty-ninth, at which time all presenting participants had completed at least four weeks of follow-up. Overall, ALPN-303 has been well tolerated. This table shows the overall treatment emergent adverse event rates for all participants treated with placebo or ALPN-303. There is a slight numerical excess of AEs in the ALPN-303 group, although mostly grade one. Importantly, no administration-related reactions were noted except for mild injection site pain, and there were no severe infections or severe hypogammaglobulinemia. Here, the left table lists the most common adverse events reported with ALPN-303. These included generally mild headache, dizziness, or back pain. Mild hypogammaglobulinemia was noted in some subjects, but importantly, none were associated with infections. Adverse events of infections are shown on the right. The overall rate of these events was, if anything, lower with ALPN-303 compared to placebo. ALPN-303 demonstrates dose-dependent pharmacokinetics as shown for the IV doses on the left and subcutaneous doses on the right. The 80- and 240-mg dose levels are of particular interest as we anticipate these to be the primary phase 2 doses. In both cases, the bioavailability appears scalable. ALPN-303 also exerts dose-dependent target coverage as assessed by circulating free APRIL levels. Note that at 240 mg in green or higher, free APRIL is essentially completely suppressed throughout the four week observation period. 80 mg in red is also effective for at leasttwo to three weeks. ALPN-303 also exerts dose-dependent effects upon circulating serum Ig levels. Shown here are the three main isotypes, IgA, IgG, and IgM, for the IV cohorts along the top versus subcutaneous cohorts along the bottom. Note that at 80 milligrams or higher, the rate of reduction of Ig, particularly for IgA and IgM, does not appear to increase. In other words, the effect appears to be saturated at doses of 80 mg or higher. The less dramatic effect upon IgG is consistent with the longer half-life of IgG, typically estimated to be around three weeks. Interestingly and importantly, Alpine 303 also exerts dose-dependent effects on circulating B cell subsets, particularly the antibody-secreting cell CD38 high plasma cell subset within the CD19 positive, CD27 positive, IgD negative memory B cell population. As you'll recall, this is of particular note since, as previously mentioned, this population is thought to contribute significantly to pathogenic autoantibody production in various diseases, and to our knowledge, has not been previously reported by other BAFF and APRIL inhibitors, at least after single doses to healthy adults. Similar to the effects upon Ig, this effect appears to be saturated at dose levels of 80 milligrams IV and higher. It's of interest to compare Alpine 303's effects with those previously seen with wild-type TACI and the anti-APRIL antibodies. These graphs all show the 80 mg subcu Alpine 303 dose now in green and the placebo comparator from the RUBY-1 study in black. Each of these columns overlays published data on the confirmed or anticipated pivotal doses of four different comparators, Atacicept and Telitacicept on the left and two clinical-phase APRIL antibodies on the right. It's notable that Alpine 303 appears to result in greater Ig reductions than Atacicept or Telitacicept versus comparable or perhaps slightly greater Ig reductions versus the APRIL antibodies. Overall, these findings suggest two things. One, APRIL appears to play a more dominant role than BAFF in circulating Ig levels, at least in healthy adults. Two, the observations with Alpine 303 are consistent with its improved APRIL activity compared to wild-type TACI. To summarize the phase 1 to date, Alpine 303 appears to be well tolerated with highly encouraging PK/PD. Based upon these findings, a dose regimen of 80-240 milligrams subcutaneously every four or more weeks is being proposed for future development. Based on these results, we anticipate moving forward with a broad development plan pursuing systemic lupus in the long term while conducting signal-seeking basket studies in other therapeutic areas with high rationale, including renal, hematology, and dermatology. The rationale for each of these indications is based upon known correlations for each of these diseases with specific pathogenic autoantibodies which can be followed during treatment with Alpine 303. In addition, these indications have objective and/or clear endpoints that should facilitate confirmation of activity in a small open-label study. The next few slides outline the planned trial designs for these studies. The lupus proof of concept trial will be a randomized, placebo-controlled, dose-ranging, parallel-arm study of adults with systemic lupus erythematosus, modeled after the telitacicept phase 2 design. It will enroll subjects with at least moderate disease activity and utilize standard efficacy endpoints of 48 weeks, such as SRI-4 or BICLA. The renal basket study will enroll subjects with proteinuria, IgA nephropathy, lupus nephritis, or primary membranous nephropathy in small disease and dose-specific cohorts for up to 48 weeks. Endpoints will include changes in disease-specific autoantibodies as well as proteinuria, eGFR, and various definitions of renal response. The hematology basket study will enroll subjects with immune thrombocytopenia, warm autoimmune hemolytic anemia, or cold agglutinin disease in disease-specific cohorts using a two-stage Fleming design for up to 48 weeks. Subjects must have active cytopenia, and endpoints will include standard definitions of response, such as durable endpoints and durable responses. Changes in antiplatelet or anti-red blood cell autoantibodies will also be followed. Dermatology basket will enroll subjects with pemphigus or pemphigoid in a design similar to the renal basket. Subjects must have active cutaneous disease and positive disease-associated autoantibodies for enrollment and will be assessed by various standard methods for disease activity. Altogether, we anticipate that these studies will provide significant insight into the ALPN-303's activity in the near term as the phase 2 lupus study is initiating and progressing. Each of these indications also has its own medical and development rationale as well, many of which include potentially accelerated and/or highly efficient development plans. We therefore anticipate pursuing one or more of such accelerated approval pathways in the 2024 timeframe, likely based upon discussion of our data with, and guided by, health authorities. In summary, ALPN-303 is a phase 2-ready potent dual inhibitor of the BAFF and APRIL cytokines. We think it could be best-in-class based on the preliminary preclinical and early phase 1 data, which demonstrates to be well tolerated with on-target effects on circulating Ig and antibody-secreting cells, enabling a convenient dose regimen. A broad development plan is about to be initiated in multiple therapeutic areas. With that, let me turn the presentation over to Dr. Vibeke Strand, who will provide additional commentary on these targets and this program. Hello, I am Vibeke Strand, and I am a consultant in new product development in rheumatology, but also an adjunct clinical professor in the Division of Immunology and Rheumatology at Stanford. Systemic lupus erythematosus is perhaps one of the most complicated diseases that we treat in rheumatology. It is relapsing and remitting, but it's very heterogeneous. It's systemic, an autoimmune disease that can range from mild to life-threatening manifestations. Multisystem involvement is its character. Arthritis, rash, oral ulcers, and alopecia are very common at any time the disease is active, but also internal organ involvement such as pleuritis, pericarditis, peritonitis, nephritis, even CNS manifestations. It's associated with profound fatigue and impaired health-related quality of life. There are about 400,000 patients in the U.S., and our current treatments revolve around polypharmacy. These patients are taking multiple oral therapies and oftentimes injections at the same time or infusions. Glucocorticoids are very effective in lupus, but they have toxicity. Hydroxychloroquine has been approved for years and is used as background therapy and does decrease the severity of the manifestations of lupus and may also prevent flares. Immunosuppressants are what we classically use. mycophenolate mofetil and azathioprine and methotrexate and leflunomide are used in RA as well.. Also mycophenolate mofetil becomes really our most preferred immunosuppressive in lupus. None of these have been approved use in lupus, nor has cyclophosphamide or rituximab, which are used when it's severe. We recently have two biologics that are approved, belimumab or Benlysta, anifrolumab or Saphnelo ALPN-303 basket studies are really linked as potential manifestations of lupus because looking at these applications in other diseases, glomerulonephritis and cytopenias and blistering skin disease are very relevant to the manifestations we see in lupus. Currently approved therapies in lupus do include. Belimumab has actually been approved first in 2011 for treatment of lupus and more recently for treatment of lupus nephritis. It is a monoclonal antibody to BLyS or BAFF. It's given IV or subQ, and the approval for lupus nephritis occurred in 2020. The two phase 3 trials for lupus approval actually included essentially many patients. One in lupus nephritis, and subsequently there have been five phase 4 trials of which four met their primary endpoint, indicating we have a lot of data with this product that indicate it is efficacious and it has a good treatment profile, well-tolerated and fairly safe considering the disease itself. The SRI-4 or the systemic lupus responder index, which is based on the SLEDAI or disease activity score, was derived from the phase 2 trials in with belimumab and then validated in their phase 3 trials. We recognize well, and this has now been seen subsequently, that there are better effects in patients with high disease activity. In other words, those are the patients who are anti-double stranded DNA antibody positive and often have low complement levels, either C3 and/or C4, and that BLyS levels do correlate with lupus disease activity and these titers of antibodies in many patients. This has validated BLyS as a clinically relevant target in lupus. Although, as I said before, we have a persistent need for additional effective therapies. Recently approved was anifrolumab, which is a fully human monoclonal antibody to the type one interferon alpha receptor. This was in 2021. Currently, it is given IV every four weeks, and there is work on using it sub-Q. Their primary endpoint in their first phase 3 trial was the SRI-4, and it actually did not meet the endpoint, and so they switched to a BILAG-based Composite Lupus Assessment called the BICLA, and they maintained approval with two phase 3 trials based on the BICLA. Interestingly, there is discordance between SRI-4 responders in lupus and BICLA responders, and that just underscores the heterogeneity of the disease. Again, we've seen much better effects in patients with high disease activity, and we learned some more about trials in lupus. This time statistical superiority to standard of care was demonstrated because there was no change in background therapy. Therefore also could be seen that there were no fewer severe lupus flares. Furthermore, with stable background therapy, required glucocorticoid tapering could be accomplished with the goal of less than or equal to 7.5 milligrams daily, which is considered a physiologic dose and has been an accepted goal of therapy by FDA. The tapering regimen can be flexible, tailored to the patient with the goal of reaching this dose at a certain time point. Again, we need definitions for treatment failure to allow early rescue of patients who aren't going to be responders and do need further treatment. Further, we've learned with a phase 2 trial that did not succeed with anifrolumab that dosing requirements are much higher in lupus nephritis because of proteinuria and therefore loss of drug substance. A confirmatory trial with anifrolumab is currently underway. The next product I wanna tell you about is not specifically a B-cell targeted therapy, but it's known as voclosporin or Lupkynis, and is quite similar to other calcineurin inhibitors that have been used orally for treatment of lupus and lupus nephritis. Interestingly enough, both the belimumab and the voclosporin trials have now confirmed lupus nephritis endpoints of what we call complete or CRR and partial or PRR renal responses, which are based on measures of urine protein creatinine ratios, which are a sensitive measure of renal function. We saw with voclosporin rapid responses that the urine protein creatinine reductions, which we like to see, were reduced by 50% even within as fast as 30 days versus about 60 days with standard of care. This product was only studied with mycophenolate mofetil. They accomplished rapid glucocorticoid tapering to 2.5 milligrams by week 16 in these two trials, a phase 2 and a phase 3. Again, you still must monitor for calcineurin effects. We worry about hypertension, dyslipidemia, new onset diabetes, and electrolyte changes. But unlike other calcineurin inhibitors, voclosporin has very predictive pharmacokinetics, and so one can reduce or dose increase based on renal function. Trial design learnings we got from them. Again, confirmation of the lupus nephritis endpoints that I just spoke about. Again, successful glucocorticoid tapering, but this time to really low doses that had been unprecedented previously in lupus. The fact that it was very well-tolerated and was able to be monitored for adverse events. Now if we talk about the lupus pipeline, I simply want to show you that we have a lot to look forward to as well as the ones that we've been using. If you look, you can see that there are selected agents that are specifically approved in red. That's hydroxychloroquine and anifrolumab on the left and voclosporin in the center and belimumab on the right. There are a lot of products in yellow which have been the products that we have used in lupus treatment but are not specifically approved. In blue, you can see the various types of therapies that have been investigated in lupus, including the JAK inhibitors, none of which are yet approved. We can see that along with atacicept and telitacicept that has been talked about, ALPN-303, of course, is a promising product. Again, if we look at this list of therapies, we can see according to the targets, this is a very busy slide, and it shows you how much interest there is in the development of therapies for lupus. This has been going on for a long time, and as of now, we have these four products. Given that lupus is a lifetime disease, and given that there are so many flares, maybe some remissions, and the fact that the disease does change over time, we are representing a very long-term unmet need for something that for which we certainly do not have any cures. Why are BAFF and APRIL compelling targets in lupus nephritis, and other autoimmune disease? They're clinically validated as B-cell modulatory pathways. Certainly, I've told you about belimumab. You can see here now an example with and without atacicept. The role of B cells in lupus and lupus nephritis has been well-validated over the last 20-plus years, which is one of the reasons why we use a B-cell depleting agent such as rituximab. Specifically, BAFF and APRIL both support B cell development, differentiation, and survival. We know that plasma cells require both BAFF and APRIL to survive. When you co-neutralize BAFF plus APRIL, you dramatically reduce B cell function, including autoantibody production, as you can see here in the figure. Now, if we go back to atacicept, wild-type TACI-Fc dual BAFF/APRIL inhibitor r, this is high disease activity in enriched population. I've talked to you before about looking at those patients who have double-stranded DNA antibodies and low complement C3 or C4 levels. These are the patients here that I'm showing you. On the left is the responder rate by the SRI-4. One can see that there's nice differentiation between atacicept and placebo. Then on the right, I'm showing those patients who attain what we call the lupus low disease activity score, which I'll show you in the next slide, which is a meaningful clinical definition of, should we say, close to remission. In other words, disease still under treatment, but tolerable and controlled. If we now look at this slide, we're looking at different definitions of what we would call low disease activity or remission in lupus. This is a post-hoc analysis of the trial that I showed you above. We had the SRI-4 as a responder criteria. If you ask for an SRI-6, which is more improvement with no new flares and no worsening in patient global physician global assessment and patient global assessment, you can see that outlines in the far out about half the patients. If you then look at low disease activity, simply saying that the SLEDAI score is less than or equal to 2, then you can see that's about 27% of the patients in blue. LLDAS, which I showed you above, is a SLEDAI-2K score of less than or equal to 4 without major organ activity. No new disease activity versus the previous visit. A physician global of less than equal to 1, which means low disease activity. Again, prednisone at that equivalent of a what we call physiologic dose of less than or equal to 7.5 milligrams daily and stable immunosuppressants. That's 19% of these patients. Then finally, remission, which is really a stringent definition, essentially meaning no disease activity. You can see that's 11%. These are attainable measures, and these are important measures, but they are hard to see in patients over the long term. Then if we look at another wild-type TACI-Fc product, which is telitacicept that you saw before, that was developed in China and studied in China in this study, you can see that there's very nice statistical significance with a dose response. In fact, this IgG fusion protein has now been, as we mentioned, conditionally approved for use in China and is currently underway in an international phase 3 trial, multinational, which is important. This product is similar to atacicept, but it does have a different amino acid sequence. In conclusion, BAFF and APRIL are really clinically validated targets in lupus, and we have successful precedents to say that they are relevant. We have responder indices now that are well-validated. We know that they should be supported by clinically meaningful outcomes. FDA has endorsed the use of patient-reported outcomes, such as health-related quality of life measures by SF-36 and LupusQoL and fatigue by FACIT-F. These are important to indicate that patients are also feeling improved when essentially their disease activity is improved. We have the successful precedent now for product approvals in lupus and lupus nephritis. Belimumab certainly confirmed the importance of the BAFF pathway inhibition in both lupus and lupus nephritis. Although not approved, the supportive data with both atacicept and telitacicept, both described as BAFF/APRIL inhibitors, but less effective APRIL inhibition, as we know, than Alpine three-oh-three. Alpine 303 is a potentially best-in-class therapy, which are targeting clinically validated cytokines. Clearly, this is applicability in lupus and lupus nephritis and other B-cell mediated autoimmune diseases, as I discussed. Every 4 weeks sub-Q dosing would be a substantial improvement for patient convenience versus the current therapies that we have, and look forward to seeing the effects of Alpine 303, both in lupus and in these other B-cell mediated diseases. Thank you. Thank you, Dr. Vibeke Strand. Let's now move on to davoceticept. Davoceticept was created as a way to provide CD28 co-stimulation as a means to overcome checkpoint inhibitor resistance. As a reminder, CD28 is a key T-cell costimulatory receptor which has two activating ligands, CD80 and CD86. Immune checkpoints like PD-1 and CTLA-4 interfere with CD28 signaling by antagonizing the latter's signaling and/or competing for binding with CD80 and CD86. As a result, checkpoint inhibitors like anti-PD-1 antibodies release the brakes on CD28, but do not provide any activating gas. The immunosuppressive tumor microenvironment often lacks expression of CD80 or CD86, potentially fostering tumor immune escape by leaving CD28 unactivated. Activation of the CD28 pathway may therefore overcome at least some forms of checkpoint inhibitor resistance. Davoceticept was designed to address this. It is an Fc fusion protein of an engineered CD80 domain with high affinity to PD-L1 while retaining binding to CD28 and CTLA-4. It's meant to localize to the tumor microenvironment by binding to PD-L1, and in so doing cross-link and co-stimulate CD28. It also blocks interactions between PD-1 and PD-L1, as well as between CTLA-4 and CD80, CD86. It is the PD-L1-dependent CD28 costimulatory mechanism that is the most unique and, to our assessment, the most biologically dominant contributor to the drug. In preclinical studies, davoceticept demonstrated superiority to and/or important combinability with checkpoint inhibitors. On the left is a study in the MC38 tumor model in which davoceticept demonstrates superiority to monotherapy with durvalumab, a PD-L1 inhibitor. These responses were associated with enhanced intratumoral immunity as well as increased TCR clonality and richness in the tumor and lymph node. On the right is a combination study in the B16 tumor model demonstrating that a combination of davoceticept PD-1 inhibitor can be particularly efficacious. This combination strategy is meant to take advantage of the known ability of PD-1 antibodies to upregulate PD-L1 in the tumor microenvironment. That, in effect, would provide additional PD-L1 substrate for davoceticept CD28 costimulatory activity. At this year's ASCO and AACR, recent presentations were made on the NEON-1 study exploring dose escalation with davoceticept monotherapy. As a reminder, two dose regimens, Q1W and Q3W, have been explored in advanced solid tumors, with expansion cohorts recently opened and focusing on the 1 and 3 mg per kg Q3W dose regimens. I'll briefly run through the next few slides as a reminder of the NEON-1 data and refer you to the more detailed presentations at AACR and ASCO for the details. Overall, monotherapy has been well-tolerated through 10 mg per kg with early signs of antitumor activity. The most common adverse events have been immune-related, mostly grade 1 and 2, particularly of the skin, thyroid, and gastrointestinal systems. Despite heavy pretreatment of the enrolled subjects as a whole, clinical benefit as defined as best objective response, stable disease or better, were observed in approximately one-half of subjects. The most deep antitumor activity was observed in a subject with papillary renal cell carcinoma, uncertain and IMDC poor risk at baseline. PD-L1 was low to negative. During treatment with davoceticept, the subject achieved a concurrent PR with a maximal percent change in SLD of -60% compared to baseline. NEON-2 is a study of davoceticept in combination with pembrolizumab in advanced melanoma disease. Like NEON-1, it is initially a dose escalation study exploring two dose regimens of davoceticept, Q1W and Q3W, in combination with the standard dose regimen ofpembrolizumab. Today's presentation reflects a data cutoff of August 16, at which time 19 subjects have been enrolled to this study, distributed among the 0.1 and 0.3 mg/kg dose levels as indicated. The median age of enrolled subjects is 61, mostly male and Caucasian. Many of the enrolled subjects had previously progressed after treatment with the PD-1 inhibitor, and the majority had low or undetectable levels of PD-L1 on archival tissue. Colorectal has been the most common tumor type so far. The safety of the combination remains satisfactory overall, with adverse events of grade three or higher occurring in 37.37% of participants to date. Of particular note are the immune-related adverse events summarized on the right table. Notable events include a grade 5 cardiogenic shock, clinically suspected to be myocarditis, as well as a grade 3 biopsy-proven tubulointerstitial nephritis, both occurring in subjects assigned to 0.3 mg per kg davoceticept at Q3W. Both of these events qualified as a DLT. Some of you will recall that it was the cardiogenic shock event that prompted a partial clinical hold by FDA, although that has since been removed after appropriate safety updates to the investigator brochure, protocol, and other essential documents. At the same time, preliminary efficacy analyses suggest early signs of interesting antitumor activity. Please note in particular the 3 subjects on the right side of this waterfall plot, including two with renal cell carcinoma as well as prostate carcinoma, third from the right. A prior plot of the target lesions provides additional perspective. This subject was a 69-year-old man with castrate-resistant prostate carcinoma, whose archival PD-L1 expression was low to negative. He received davoceticept and pembrolizumab as 7th-line therapy and received only two doses before developing neurocognitive functional decline and hospice placement. However, in the meantime, his target lesions had reduced by approximately 14%, associated with an approximately 40% reduction in PSA. This seems a notable improvement, particularly given the line of therapy, and is reminiscent of the recently announced activity of Regeneron's PSMA×CD28 bispecific prostate cancer, which was also dosed in combination with a PD-1 inhibitor. This subject is a 58-year-old man with poorly differentiated renal cell carcinoma with primary resistance to pembrolizumab and axitinib. He received davoceticept in combination with pembrolizumab as 2nd-line therapy, and so far has a documented tumor volume reduction of 25%. This is of particular note given the prior regimen involving pembrolizumab. The dotted line represents our knowledge that the subject remains on treatment in cycle 9, although the scan data has not yet been updated. The second subject with renal cell carcinoma is a 58-year-old man with clear cell enrolled for seventh-line of therapy with davoceticept and pembrolizumab. A prior line of therapy included nivolumab twice, most recent with primary resistance. He achieved a confirmed PR about 5- 6 months into therapy and remains on treatment in cycle 21. We have been particularly interested in the responses seen in renal cells that we have observed in both trials. This table summarizes the experience across both studies. Although the numbers remain small at N of five, it's notable that all subjects to date have achieved stable disease or better, even though most have been PD-1 resistant. This 40% PR rate, if it continues to hold up in a larger population, could be a highly clinically meaningful outcome. Next steps for the program are therefore to consolidate this potential efficacy signal as efficiently as possible. The NEON-1 monotherapy study has two open expansion cohorts, including renal cell, melanoma, and PD-L1-positive tumors. The NEON-2 combination study will continue dose exploration and hopefully will be prepared to enter expansion cohorts in the near future. There, cohorts will likely include renal cell as well, although further review of the data may be informative. In summary, davoceticept is a potentially first-in-class PD-L1-dependent CD28 costimulator and dual checkpoint inhibitor, which preclinically has demonstrated superiority to or combinability with checkpoint inhibitors. As monotherapy, it appears to be well-tolerated with early signs of antitumor activity. In combination with pembrolizumab, it appears to exhibit more overall activity, encouragingly in PD-1-resistant tumors. Further exploration, either as expansion cohorts into monotherapy or ongoing dose exploration and combination, is warranted. Based upon the preliminary data, renal cell carcinoma may be of particular interest for davoceticept development. Let me now inviteDr. Katy Beckermann to speak on the role of CD28 in cancer immunity, as well as its relevance to renal cell and the renal cell disease space in general. Hi, thank you so much for the inclusion. I'm excited to chat with you all about how I think about treating kidney cancer and the role I think that intervening on CD28 might have for benefit in kidney cancer. I'll ask for next slide. You know, when I think about kidney cancer, you know, I think about where are we right now? How do we treat kidney cancer? What are the standards of care? And there's so much left that I think we can improve upon. What are the current unmet needs? Why do I specifically think that we can target CD28 in kidney cancer? And you've heard a little bit of data already on that. I'm gonna describe some more preclinical data, some rationale, and then where I think that davoceticept can really fit in to meet some of the needs that we have in metastatic kidney cancer. Next slide, please. So here on the left, you're seeing an overall survival curve, and you'll see that there's three different curves. These were made for patients who had metastatic kidney cancer undergoing treatment with what was then the standard of care, oral targeted kinase inhibitors. This is still a mainstay of treatment through which we use and sequence patients with kidney cancer. We've known historically that kidney cancer can be responsive to immune therapies, things like high-dose IL-2 and checkpoint inhibitors. I'm showing this overall survival curve just to give you a sense that while the biology is broad for kidney cancer, that some patients do well, there in the blue line, and some patients do less well with poor overall survival. There is still a huge need that unfortunately, with 75,000 new diagnoses every year and 15,000 patients dying every year from metastatic kidney cancer, while we have a lot and have made a lot of great advances in kidney cancer, there's still I think a lot of work to be done. On the right, this table I'm showing is because, you know, the I always explain to my patients when I think about how do we target kidney cancer, it's thought to be chemo-refractory, and really historically, we've used a lot of tyrosine kinase inhibitors, that oral therapy, to block blood vessel growth and angiogenesis. We don't have a way to understand or predict which patients yet will respond to immune checkpoint inhibition. Here on the right, when I think of which tumor types in general are responsive to immune therapies such as checkpoint inhibitors, that's typically been credited to high mutational burden. You know, for example, on the top right of the line there, you'll see melanoma. You know, we think of that as coming about from mutations from UV rays and having a high response rate to immune activating medicines. Kidney cancer that I've highlighted here in the red box does not have subsequently a high mutation burden, but as you can see, being above the line there, it does have a higher objective response rate to checkpoint inhibition and high-dose IL-2. So with that knowledge, I'll go to next slide that shows the current approved treatments in metastatic kidney cancer. You know, looking at these boxes, I think the first thing that you look at and see is look, there's a lot of different treatment options. And that's wonderful. It's wonderful to have that, to be able to say to my patients, "I have a toolkit," and in my toolbox, you know, we have a number of different agents. What I'll draw your attention to is whether a patient has favorable or poor and intermediate risk disease, really we still are in the same two methods of treating. We either can treat with oral TKIs, those, angiogenesis inhibitors, or we have PD-1 and CTLA-4 blockade. I think, again, that we've certainly made many significant advances with combination therapies on the frontline treatment for patients with metastatic clear cell renal cell carcinoma. I think there's still a lot of need here. I'll go to next slide. Showing you probably the longest and best overall survival data that we have. This was from CheckMate 214, which looked at PD-1 and CTLA-4 combination. The two checkpoint inhibitors were compared to what was then the standard of care in the gray line being sunitinib, that oral, VEGF angiogenesis inhibitor that we'd been using and, primarily before that. What you can see here is that at five years, so the curves on the left are overall survival, curves on the right are progression-free survival. This is the first time ever that we've been able to say for patients who got PD-1 and CTLA-4, that almost 50% of patients were alive at five years, which again is wonderful. While I certainly present it as a glass half full, I think unfortunately we know that 20% of patients don't respond to PD-1 and CTLA-4. As you can see on the right there, progression-free survival curves suggest that unfortunately many of our patients, even who have initial response, unfortunately go on to progress later on. I'll go to next slide, please. Why think about targeting CD28 in kidney cancer, RCC here? I think it's already been said in this presentation, but I have shown you data. We know that PD-1 and CTLA-4 can be beneficial in kidney cancer. It can take off the brakes of the immune cells to allow them to be active against tumor. I think what we're missing is that sometimes we take off those brakes, but there's no gas in the tank. Those T-cells can sit there, but without the stimulation that CD28 can provide, they're essentially inactive. You know, I think that's the preclinical data I have that has shown. If we'll go to next slide. Again, this is just a reminder slide of showing it in a slightly different way from the Nature Communications paper that looked at, you know, Alpine 202 or davoceticept here, again, showing that this molecule can provide a PD-L1-dependent blockage of that checkpoint inhibitor interaction, while also giving CD28 co-stimulation, allowing the signal to tell the T-cell to rev up its engine to produce effector function. We'll go to next slide. This next slide is some of the preclinical data that I've had the opportunity to be a part of. Our studies have basically shown that we know if we take patients' tumors at time of nephrectomy, so they're undergoing surgery to have their kidney cancer removed, and we take those samples, and we dissociate them, and we put them in culture, and we've looked, and we've shown that those T-cells from a patient's kidney tumor is inactive. They're exhausted, and they're mostly showing in that pictorial representation. They're the cells on the left. They're resting, they're not active against the cancer, and they're dependent on mitochondrial energy, so the TCA cycle. What they need to do is they need to be activated, whether that's with, here, I'll show CD28 in order to increase their effector function to divide cells and produce interferon gamma to essentially kill off the cancer cells. That is all dependent, what our work has shown, is on glycolysis, essentially, again, having that energy in the cell to be able to have this effector function. The bars on the right, the graphs on the right then in gray shows just a resting cancer cell fresh out of a patient's kidney tumor. The black lines represent those same cancer cells, but trying to stimulate the T-cell with CD3, an antigen presentation or engaging the T-cell receptor, essentially. The red line, which I think you can see dramatically improves metabolism here with an increase to just upright increase in glycolysis is CD28 applied in that same co-culture. Cancer cells are there, T-cells are there, and if you give CD28 stimulation, you can allow these cells to have energy and produce effector function. In the bottom left-hand corner, I've pulled some data from the preclinical data, again, from this Nature Communications paper, specifically with davoceticept. I'm sorry this line is small, but what I wanna get across is that essentially increasing from bottom to top is the amount of interferon gamma or what you wanna see a T-cell to produce to kill off cancer cells. The black line at the very bottom is the control line. The line right up above that is just engaging CD3, so T-cell receptor only. What you'll see with subsequent treatments where they've tried with CTLA-4 blockade, here in red line and in the orange line, the PD-1 blockade, that you do see a little bit of activation of the T cells, but really Alpine 202 or CD28 co-stimulation is what is enabling the T cell to rev up and to produce interferon gamma that would enable tumor killing properties. That's the same thing that we saw in our preclinical data from patients with kidney cancer where we take the kidney tumors out. Again, IL-7 being that black, just the cell sitting there, and then co-stimulation with the red. So if it shifts to the right, that means interferon gamma is increased. We found that, again, that was dependent on glycolysis 'cause we add this glycolysis inhibitor, a metabolic inhibitor, and the lines all shift down, all that interferon gamma production is abrogated if the cell can't undergo glycolysis and produce the energy that it needs. Then there, the last bars there on the right, what you'll see is the shift is to the left. This is when cells are dividing, they dilute out the dye that's integrated into the DNA. The red, when you stimulate with CD28, the dye is getting diluted out. That means those T-cells in the kidney cancer co-culture are dividing. They're rapidly dividing, they're producing interferon gamma, and they have the potential to have tumor-killing activity. I'll ask for next slide. You know, here's the, you know, where do we think about CD28 co-stimulation with davoceticept? Where would that fit into metastatic renal cell carcinoma? I would say the first, you know, an ideal place that we have this huge unmet need is that we don't know how to treat patients who can't or don't or progress on checkpoint inhibition. This box I'm showing is just these are the subsequent options that we have for treatment, but most of these are VEGF-TKI, oral angiogenesis inhibitors, not developed specifically to target checkpoint inhibition. If you go to next slide, this is kind of a summary table of what has not been effective when we have tried to target checkpoint inhibition specifically. These are five different trials, maybe all done slightly differently, but what you'll see there underneath the timing box is that many of these trials took PD-1 blockade, and if a patient either progressed or had only stable disease, then those patients, in order to try to rescue or to try to get more clinical benefit, the addition of CTLA-4 blockade was added. What you'll see, what I've highlighted there below in the red box, is that the objective response rates, unfortunately, were not overwhelming, ranging really from what we all kind of clinically say as being at best, you know, kind of 4%-10%, depending on the trial that was, the way the trial was conducted and what the inclusion and exclusion criteria were. Just to keep in mind, at the bottom of that slide, that's to compare to, you know, an objective response rate at best of PD-1 and CTLA-4 in the frontline setting of 40%. If we go to the next slide, you know, I think CD28 from the data that we've seen here and from the preclinical rationale does have that ability to address checkpoint inhibitor resistance that if a patient isn't responding to PD-1 and CTLA-4, perhaps it's because although the brakes are released off the car, there's no gas in the engine and CD28 could provide that. I think that, you know, first it makes very good or rational sense, I guess, to try it in the refractory setting because that is where our biggest need is. I could also see moving it to, you know, really actually the frontline setting that combining it with checkpoint inhibition, providing this additional co-stimulation might be helpful in the upfront setting. It's a novel mechanism, and I think what you've seen and what I've again highlighted here on the slide is that already, in some of the early data, some of the exciting data, that patients who've been refractory to checkpoint inhibition and have metastatic renal cell carcinoma are having responses to CD28. So, with that, I'll pass it back. Thanks very much, Dr. Beckermann. Thanks for that review of renal cell carcinoma space as well as the opportunity for targeting CD28. Thank you, Stanford and Dr. Strand. Today's data update had what we believe to be significant potential with ALPN-303 and davoceticept to improve the lives of patients suffering from severe autoimmune disease and cancer. As you heard from both Stanford and from Dr. Strand, today's data support and position ALPN-303 as the only truly potent inhibitor of both the BAFF and APRIL cytokines, and position us potentially best in its class. ALPN-303 has been well tolerated in healthy volunteers and demonstrates on-target effects on key biomarkers, which support a highly competitive therapeutic profile with at least once every four-week dosing. Phase 1 profile enables the launch of a broad development plan for lupus, as well as basket studies in renal, hematologic, and dermatologic autoimmune diseases, with expected preliminary readouts from the baskets in the second half of 2023. For davoceticept, our conditional CD28 costimulator and dual checkpoint inhibitor, preliminary data from the NEON-2 study in combination with pembrolizumab are highly encouraging, in particular, the responses in renal cell carcinoma and prostate cancer. The totality of our data in monotherapy and in combination strongly support the continued advancement of the program in solid tumors. Given the preliminary response that we've observed, we're particularly interested in exploring the potential for davoceticept in renal cell carcinoma. In addition, initial data from Regeneron in prostate cancer is intriguing and provides early support for targeting CD28 in immuno-oncology. We are continuing enrollment in both NEON-2 and in NEON-1 expansion cohorts with an anticipated initial readout in the second half of 2023. In closing, we've set a clear path for the company with the goal of achieving proof of concept for ALPN-303 and advancing all three of our development assets into pivotal or registrational studies by 2025. Importantly, we are building an efficient organizational infrastructure capable of supporting our programs, and in parallel, we will leverage our productive directed evolution platform. We believe we have laid a strong foundation to launch the next phase of growth for Alpine as we execute our plans and development plans in both autoimmune inflammatory diseases as well as in immuno-oncology. Operator, we'll now open the phones for questions. Thank you,Mitchell Gold. We'll now pause as we wait for questions from the audience. As a reminder to ask the question, you will need to press star one on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from the line of Mark Breidenbach with Oppenheimer & Co. Your line is open. Hey, guys. Good afternoon, and thanks for taking the questions. Thanks for putting this event together. Just a few from me. Kinda I'll maybe ask a couple on three oh three and then maybe a couple on davoceticept as well. First of all, I guess I'm wondering what the effects you've seen on overall B-cell counts with three oh three have been in your SAD dosing cohorts. You know, looking at a broader population besides the CD38 high plasma cells. And then kind of a related question is why no plans to do MAD dosing cohorts in healthy volunteers before going straight into patients? Side question to that is, where are you guys right now in terms of finalizing the trial protocols for those additional RUBY studies that you outlined in the presentation today? You wanna address those, and then I'll ask a couple davoceticept questions as well. Sure. Regarding total B cells, we've not seen a gross reduction or low, you know, B-cell leukopenia in the healthy volunteers. However, as you may know, in chronic dosing with telitacicept and belimumab and atacicept in disease population, there may be reductions in total B-cell population. That's something we'll be observing and tracking as we go forward, but it was not observed in the healthy volunteer study. Regarding the protocol finalization, those are protocols that we're actively finishing. I would say, you know, we expect it to be done in the very near future, you know, perhaps in the next month or so. That will, that's simply a matter of completing the design and finishing some of the writing. Okay. That's helpful. You had a question also about multiple ascending or considering a multiple ascending dose. We actually have found that does not appear to be necessary, in part given the precedent of these pathway molecules in development. I might draw your attention to the fact that we have dosed all the way up to 960 milligrams in the single ascending dose, which actually provides very extended “TACI” coverage with regard to exposure versus our anticipated therapeutic dose. These are also based on some of our initial pre-IND discussions with health authorities. We are confident that we can move directly into multi-dose studies as we've described. Okay. Then just shifting over to the oncology program, I'm not sure if Dr. Beckermann is still on and can take questions, but I'm wondering if she can offer any thoughts as to why conditional CD8, the CD28 co-stimulation seems to be working a little bit better in renal cell carcinoma versus a tumor type like melanoma where we've also seen really great data from PD-1 CTLA-4 checkpoint combinations. That's one question. Then with regard to the prostate cancer patient, I was just wondering if you could tell us what the immediately prior treatment before receiving davo was for this patient, and if they were characterized to have any specific AR mutations or driver splice variant. Splicing variants that would maybe explain progression on the prior therapy. I guess what I'm getting at is this, if there's any chance that the PSA decline that you're seeing is simply a function of anti-androgen withdrawal in this case. Thanks for taking this question. Dr. Beckermann, do you wanna take the first half of that? Yeah, sure. You know, I think of kidney cancer as being a very metabolically driven, but also immune responsive tumor. You know, my preclinical data would suggest that it is very responsive to co-stimulation in the sense that it kind of gives the dysfunctional T-cells in the RCC tumor microenvironment that capacity that they're lacking as far as fuel and metabolism. I think that. I'm still excited to see what the NEON-1 expansion cohorts and melanoma do to see if that opportunity is also, you know. I could see that CD28 essentially could provide similar fuel for T-cells across tumor types. Okay. Not ruling melanoma out quite yet, just that small numbers. Exactly. Yeah. Exactly. Thank you. Mm-hmm. Stanford, you wanna take Mark Breidenbach's question on AR resistance mutations? Yeah. I'd say we don't have that information in front of us. We'd have to get back to you on confirming what prior treatments there were. That would be pretty unlikely, Mark, just to see like a almost 40% reduction in PSA with that type of mechanism. I think that's a little bit speculative on your part, just given what we've seen in, you know, metastatic cancer versus the prostate cancer space historically. It's an interesting scientific question. All right. Thanks. This patient I think was in seventh or ninth line of treatment. Yeah. Yeah. Highly refractory patient. All right. Understood. Thank you for taking the question. Thank you. Please stand by for our next question. Our next question comes from the line of Boris Peaker with Cowen. Your line is open. Great. Thanks. I wanna add my thanks for doing this event, very helpful. Let me just jump in with my questions. Maybe let's start with three of three. What is the objective when deciding on the optimal dose? Is there a target antibody level reduction that you're looking at? Is it finding maximum tolerated dose? How should we be thinking about, given this mechanism, the objective and dose optimization? The way we see this at a first review is we'd like to cover the cytokine targets throughout the dosing interval. You may recall the figure that we showed of pro-APRIL coverage or pro-APRIL targeting. We'd like a dose that is not higher than necessary to cover the dosing interval that we'll be using. For example, the 240 milligram dose level appeared to effectively cover APRIL for at least that 4-week observation period. That being said, we know that the potency of this mechanism is greater than simply the APRIL target coverage. Even though the 80 milligram dose level seemed to cover APRIL for only 2- 3 weeks, we saw already maximal pharmacodynamic effects, at least based on the immunoglobulin and antibody secreting cell pharmacodynamic analyses. That suggests to us. Some of that is modeled, and also looking at the precedent seen with how telitacicept and atacicept looked in their healthy volunteer study translating to the lupus programs that they ran. That's part of the rationale for considering the 80 and 240. That is, the 240 will almost surely cover the cytokine targets, but it's probably more than necessary, and the 80 milligrams dose level is, you know, a half log lower. Got it. Also on 303, for the RUBY-2 trial, is there an interim look planned before 2026? 2026 is our final target, Alpine data. No, I understand that. I'm just asking if there's anything interim from that trial before then. That is something we're actually actively discussing right now. Although, you know, part of the way we look at this opportunity is that there has already been proof of concept with this mechanism. In the interest of moving as quickly as possible, our tendency is to consider no interim. Got it. Maybe lastly, ondavoceticept. When we think about the ideal tumor types for this drug, I'm just curious, how important is the sensitivity to PD-1 drugs or biomarkers like tumor-infiltrating lymphocytes or tumor mutational burden? 'Cause, I mean, at the end of the day, I think you're probably gonna have several patients in different tumor types, maybe not enough to draw a conclusion based on the patient observation. I'm just thinking theoretically, what's the ideal tumor type for this drug? Yeah, I mean, I think as you know from our previous discussions, that's something that we've been looking at, and it's been particularly interesting, for example, to see the concordance of our own data and external data such as Dr. Beckermann's around renal cell, that there seems to be a particular biological rationale for CD28 in that tumor type, and that's correlating with at least the preliminary data that we're seeing so far. There are a couple of other tumor types in the literature that have been suggested for which CD28 has been suggested to play a role in activation of T cells in the tumor microenvironment. you know, at the same time, we continue to explore additional tumor types, you know, through our dose escalation strategy and expansion cohorts. Got it. Well, thank you very much for taking my questions. Thanks, Boris. Thank you. I'm not showing any further phone questions. We will now take questions submitted via the online webcast. Great. Our first question submitted through the webcast. Did the reduction in pathogenic B cells correlate with their expected maturation? For example, TACI and APRIL are more highly expressed on further differentiated B cells. Yes. As far as the most differentiated B cells are, of course, the plasma cell and perhaps plasmablast populations, and that is where we're seeing the reduction so far. We do have ongoing analyses, however, so I would say in terms of where the maximal effect is seen, we still have yet to finally determine. Next question. Do you find the lack of activity in immune hot indications, for example, melanoma, non-small cell lung cancer surprising? I wouldn't say it's surprising in that if there really were no response there, it would be curious. At the same time, I think we're talking about only one subject in each of those indications. So far, at least in the NEON-2 study. That's, I think it's maybe premature to draw conclusions on that. Are there any combination results for Alpine 202, PD-1 in patients who had initially responded to a CPI? Well, as far as we know, for example, there was the second renal cell patient we described, that had previously had a response to nivolumab, but then when they received their second treatment with nivolumab, was primarily resistant. I would say, though, we have not formally looked at patients who had formally responded to a CPI and then come on the trial. To my recollection, these are patients who failed, mostly. If they had responded previously, they've already been retreated before coming on the trial. Jumping back to ALPN-303, there's a question. How were the basket indications for ALPN-303 selected? Well, the basket, there's maybe three different aspects that we looked at in considering these indications. One is that they all have a clear pathogenic autoantibody that is known to correlate clinically with disease activity. Given the mechanism of action of ALPN-303, we anticipate that those autoantibodies will be reduced, and we can follow that as a pharmacodynamic marker. In addition, each of the basket indications has a clearly defined clinical endpoint, either based on objective markers or clearly observable markers such as skin lesions in the derm basket. Finally, many of the indications in the basket trials have had precedented development paths that are either small or accelerated, which are attractive opportunities for us, you know, once we start to see signals from those trials. I think that's an important point, Stanford, which is while lupus is our anchor indication. The baskets will give us our earliest readout in a disease patient population and also give us opportunities for an accelerated approval path, depending on the data and our discussions with regulatory authorities. We do think the baskets allow us to really speed up the development path for the program beyond lupus. Next question submitted, what data specifically support a best-in-class profile versus other molecules in development targeting the BAFF/APRIL pathway? I'd say there may be two points here. One is the potency of the molecule. As we've shown, the pharmacodynamic effects of the molecule appear to be more potent than precedent molecules in this pathway, particularly as judged by Ig reduction, at least as judged by the B-cell changes not just seen before in healthy volunteers for the second time. In addition, the dosing regimen of the drug appears to be very convenient. If we are correct and 80 milligrams turns out to be the therapeutic dose, that would be a very easily administered dose, over the course of, you know, with a four-week dosing interval. In contrast, we understand that other molecules in this pathway either are dosed weekly, or sometimes biweekly, but with a large dose volume. The thing I would say on that is Dr. Strand highlighted the importance of blocking both BAFF and APRIL, in terms of blocking antibody-secreting cells. It's pretty clear from the data that we presented today that it's the first only true inhibitor of both those two B-cell cytokines of both BAFF, which we think is gonna continue to play out for the premise in our BAFF indications for this. Another question on 303. In your basket, are there limits for each population in the basket, or will you just take all patients that come? Well, the numbers that you saw in this, but I know we went through them quickly, but the numbers you saw on the slide are the additional enrollment targets for the different trials. There certainly is the option to continue to enroll into those studies, depending on what we might want to estimate need for estimation of safety and efficacy. Last question on 303. What sort of decline in Ig levels do you think you'll need to achieve to potentially show efficacy in patients? Well, one way to answer that is to look at what's happened with the other therapeutics in diseases such as lupus. Belimumab results in Ig reduction of about 15%, whereas, atacicept and telitacicept result in Ig reduction of about 20%-25%. That being said, in healthy volunteers, as we've shown or cited, in our slides, there isn't much Ig reduction in healthy volunteers with either of those drugs. Our observation or comparison that we appear to have deeper reductions in Ig already suggests that we should easily achieve that type of reduction in disease. At this point, there are no further questions. This brings us to the end of our time for questions. Dr. Gold, I'll turn the call back over to you. Thanks, Paul. I'd like to thank everyone that participated in today's call, especially for those in attendance, our investigators, and the volunteers and patients participating in our clinical trials. As you can tell, we're very highly enthusiastic about the potential of our programs to meaningfully impact patients' lives. We look forward to providing clinical updates on both studies in the months ahead. Thank you for joining us today. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.