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spk07: Thank you. Ladies and gentlemen, the conference is scheduled to start in a moment. Until that time, your lines will be placed on hold. Please continue to stand by. We thank you for your patience. Ladies and gentlemen, thank you for standing by and welcome to the Gossamer Bio Q3 2020 earnings call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0. I would now like to hand the conference over to your moderator today, Mr. Brian Jurado, Chief Financial Officer. Thank you. Please go ahead, sir.
spk03: Thank you, Operator, and thank you all for joining us this afternoon. I am joined on today's call by Gossamer Bio's Co-Founder and Chief Executive Officer, Dr. Sheila Gujarati, as well as our Chief Scientific Officer, Dr. Louisa Salter-Sidd. Earlier this afternoon, Gossamer Bio issued a press release announcing its financial results for the third quarter ended September 30, 2020, in addition to providing a corporate update. Please note that certain information discussed on the call today is covered under the safe harbor provision of the Private Securities Litigation Reform Act. We caution listeners that during this call, Gossamer Management will be making forward-looking statements. Actual results may differ materially from those stated or implied by these forward-looking statements due to the risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the statements contained in Gossamer's news releases and SEC filings, including in the annual report on Form 10-K and subsequent filings. This conference call also contains time-sensitive information that may only be accurate for a limited period of time. Our ability to meet our guidance, especially that related to the timely initiation and completion of clinical studies, in addition to our ability to release results from our clinical trials in a timely manner, may be adversely affected by the ongoing COVID-19 pandemic. Gossamer Bio undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Now I'd like to turn the call over to Sheila. Sheila?
spk06: Thank you, Brian, and good afternoon to everyone who is joining us on today's call. We appreciate you taking the time to hear about the progress Gossamer has made. Earlier this afternoon, Gossamer Bio was pleased to announce its financial results from the third quarter 2020, in addition to several updates to the status of our pipeline of clinical product candidates. Gossamer Bio was founded as an innovative research and development engine. to deliver values through the selection and development of a pipeline of multiple independent programs across the therapeutic areas of inflammation, immunology, and oncology. This engine is centered around an experienced team with a history of successful and efficient execution in these closely related therapeutic areas. Each program is backed by rigorous preclinical and clinical work to understand and de-risk the product candidates, focused on areas of high unmet need and a differentiated product profile that would be meaningful for patients. We are pleased to be advancing two independent molecules targeting two different indications into Phase II trials. We are also excited to discuss new clinical data from our immuno-oncology candidate, GB1275, as it continues to progress through its Phase I-II trial in solid tumors. All told, development progress from multiple candidates is a manifestation of Gossamer's purpose, the continual and simultaneous advancement of multiple high-potential programs through the execution of the proper experiments to create value for shareholders. First, I will briefly review the status of GB001, our once-daily oral DP2 antagonist for the treatment of moderate to severe asthma. In October, we read out the top line results of our Phase 2B LIDA study. While the primary endpoint of asthma worsening was not met, GB001 did demonstrate a consistent reduction of 32 to 35% in the proportion of patients exhibiting asthma worsening across all three active drug arms as compared to placebo. And in the key secondary endpoint of time-to-first asthma worsening, we saw statistically significant improvements in both the 20 milligram and the 60 milligram dose groups as compared to placebo. We are currently in the progress of engaging with global regulatory authorities about these results and the path forward. We hope to have clarity from these discussions in the first half of next year, which will help inform potential partnerships and strategic alternatives. Since the end of the third quarter, we have activated two value-deriving proof-of-concept Phase II clinical trials for our GB002 and GB004 programs, which I will touch upon before walking through the recent clinical data reported this week at SISTI from our oncology candidate, GB1275. After that, Brian will provide a financial update. GB002 is an inhaled PDGFR receptor inhibitor for the treatment of pulmonary arterial hypertension, or PAH. GB002 was designed to improve upon prior success observed with kinase inhibition in PAH by delivering a tyrosine kinase inhibitor with an optimized selectivity and potency profile directly to the site of disease by a convenient dry powder inhaler. GB002 is being studied on top of vasodilators with the hope of delivering a new standard of care that reverses pulmonary vascular remodeling and further improves patient outcomes. Our ongoing two-week Phase 1B study is meant to bridge the safety, PK, and PD results we saw in our Phase 1 studies in healthy volunteers to an initial experience in PH patients. While the two-week portion of the study is too short to evaluate changes in clinical endpoints, we have gathered important information on target engagement and biomarkers. These patients also have the option to roll onto a six-month open-label extension. We look forward to sharing the two-week data before year end at a GB002-focused investor event in December. As a reminder, this study's conduct was interrupted earlier this year by the COVID-19 pandemic. And now that the trial has restarted, we have enrolled new patients onto the study. We believe this Phase 1B impatience helped inform us how a PH trial needs to be conducted during the COVID pandemic. And while unanticipated, the lessons learned here in terms of protocol adjustments, operations, logistics, as well as the investigator and patient experience, are critical to moving this program forward in PAH. We are also excited to announce that we have activated multiple sites for our Phase II TORI study. We expect to begin enrollment of this trial in the fourth quarter. The TORI Phase II study is a 24-week, double-blind, placebo-controlled, multi-center clinical study to evaluate the efficacy and safety of GB002 in functional class II and III pH patients. This is an 80-patient study, and patients will be randomized evenly between drug and placebo. The primary endpoint is change in pulmonary vascular resistance from baseline at week 24, and the key secondary endpoint for this trial will be change in six-minute walk test distance. We expect to be able to read offline data from the Phase II TORI study in the first half of 2022. subject to further developments in the COVID-19 pandemic. We are working closely with sites, investigators, and study coordinators surrounding the obstacles posed by COVID-19 with a focus on patient health, and we believe we have put in place protocols and procedures to help mitigate that risk. In response to the inbound interest we have received on the GB002 program from investors, clinicians, and patient advocacy groups over the past few months, We will host a GB002 PAH focused webinar in December. During the call, we plan to discuss rationale for GB002 and PAH, initial results from our Phase 1b study, and give additional details on our Phase 2 study design, in addition to making some of our key external advisors available for Q&A. We hope you will join us on this call to learn more about the GB002 program. Please be on the lookout for details surrounding this virtual event in the coming weeks. Next, we will discuss our oral hip analysis stabilizer, GB004, which is being developed for the treatment of inflammatory bowel disease. As a reminder, GB004 is an oral gut targeted therapy with a unique mechanism of action that is intended to address the high disease burden and impaired quality of life in patients with IBD. Unlike traditional anti-inflammatory approaches to IBD, GB004 is believed to promote the healing of the mucosa, to achieve sustainable histologic, endoscopic, and clinical remission. GB004 has the potential to deliver meaningful patient benefit, both as a monotherapy and in combination with standard of care in patients across the disease continuum. We are so pleased to announce that we have begun dosing patients in a GB004 SHIFT-UC Phase II study in patients with active ulcerative colitis. The SHIFT-UC Phase II study is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, PK, and PD of GB004 in adult subjects with mild to moderate active ulcerative colitis. We expect to enroll about 195 UC patients who will be randomized evenly across two-dose groups and placebo. The primary endpoint for this trial is proportion of patients with clinical remission at week 12. Secondary endpoints include proportion of patients at week 12 with clinical response, histologic remission, endoscopic improvement, and mucosal healing. Patients will remain on background therapy, including 5AA phase and steroids, throughout the trial. We expect to be able to read out top line data from the phase 2 SHIFT-UC study in the first half of 2022, subject to further developments in the COVID-19 viral pandemic. In line with what I mentioned previously regarding the Torrey study in PH, we are working closely with SHIFT-UC sites to mitigate potential COVID-19-related disruption. Also, we believe there is a possibility that GB004's non-immunosuppressive mechanism may turn out to be a recruiting advantage in the recruitment of UC patients as compared to immunosuppressive therapies. We're commencing this Phase II induction study in UC after having completed a four-week Phase Ib trial in patients with active mild to moderate disease. In October at UEG Virtual Week 2020, Dr. Bill Sanborn of the University of California San Diego presented these data following Gossamer's top-line announcement in May of this year. We received a great deal of interest and positive feedback from KOLs and investigators following Dr. Sanborn's presentation, which is available on the posters and publication section of our website that is enabling us to hit the ground running with our Phase II trial. And finally, we will turn to GB1275, our oral CD11B modulator being developed for the treatment of solid tumors. We have a couple of updates on our Phase I-II Keynote A36 trial being shared at SISTI this week. Dr. Johanna Bendel is presenting poster number 388, which details some of the GB1275 clinical results from the ongoing dose escalation portion of Keynote A36, from both monotherapy and in combination with pembrolizumab. Dr. Wells Messerschmidt is presenting poster number 389, which dives into the relevant clinical biomarker data, which is also from this ongoing Phase I-II study in advanced solid tumors. Enrollment in the dose escalation phase continues, as no dose-limiting toxicity has been observed. Oral GB1275 has now been used to treat 40 patients with doses up to 1,200 milligrams twice daily. Safety data suggests that GB1275 both alone and in combination with pembrolizumab is well-tolerated. Despite being studied in tumor types that are known to be less responsive to checkpoint inhibitors, GB1275 has generated encouraging clinical and biologic activity especially in dose cohorts equal to or greater than 800 milligrams BID. In terms of clinical activity, 12 patients had an initial resist assessment of stable disease with a median duration of treatment of 102.5 days. Among those 12 patients, prolonged stable disease, stable disease greater than 84 days, was noted in seven patients who had microsatellite-stable colorectal metastatic carotid-persistent prostate cancer, triple negative breast cancer, and gastric cancer. Three of these patients received monotherapy in regimen A, and four of these patients received combination therapy in regimen B. Importantly, five of the seven involved doses greater than or equal to 800 mg BID, suggesting increased clinical activity at higher doses. Staple disease was also observed in two of the combination therapy patients who had previously been treated and progressed for the checkpoint inhibitor. We have seen one confirmed partial response in a patient with microsatellite-stable colorectal cancer who received 800 milligrams of GB1275 BID in combination with pembrolizumab. That patient had previously received five lines of therapy and is continuing on steady treatment. Published preclinical work suggests that GB1275 works by disrupting immunosuppressive myeloid cell biology. which allows for more T-cell infiltration and activation in tumors, potentially converting the tumor microenvironment to an inflamed phenotype. Our early biomarker findings support these aspects of GB1275's mechanism of action. Protein and gene signatures in blood show changes consistent with reduced myeloid-derived suppressor cells, which correlates with dose and pembrolizumab combinations. Myeloid-derived suppressor cells also decrease in dose-dependent manner after treatment with GB1275 or in combination with pembrolizumab. An increase in tumor-infiltrating T lymphocytes or TILs is observed in serial tumor biopsies following both the GB1275 monotherapy regimen as well as the combination therapy with pembrolizumab. CD8-positive T cells also increase with combination treatment. We next plan to further characterize GB1275 in an expansion cohort of up to 40 patients evaluating the recommended Phase II dose of GB1275 in combination with pembrolizumab. We will continue to report out clinical data from this ongoing trial in 2021. Please feel free to view these posters in their entirety on our website. The presentations from Drs. Bendel and Messer-Smith can be accessed on the SISI website as part of the SISI virtual conference. With that, I will hand it over to Gossamer Bios, Chief Financial Officer, Brian Jurado for a financial update. Brian?
spk03: Thank you, Sheila. We will now review the financial results for the third quarter of 2020. We ended the quarter with $555.4 million of cash and cash equivalents. We anticipate our cash and cash equivalents equivalents and marketable securities, along with access to our debt facility, will provide us sufficient capital resources to fund operations and capital expenditures into the second half of 2023. Research and development expenses in the third quarter of 2020 were approximately $41.8 million as compared to R&D expenses of $40.1 million for the same period in 2019. G&A expenses were $11.4 million in the third quarter of as compared to G&A expenses of $9.8 million for the same period in 2019. Our net loss for the quarter was $57.8 million, equating to 80 cents per share. For the same period in 2019, we reported a net loss of $48.5 million, which equated to 80 cents a share. The increase was primarily attributable to an increase in interest expense of $4 million and a decrease in investment income of $1.7 million. With that, I will turn the call back over to Sheila to offer some closing comments before we open the lineup for Q&A. Sheila?
spk06: Thank you, Brian. It has been an exceptionally busy quarter and year at Gossamer, especially as we advance multiple clinical and research programs during the COVID pandemic. I want to extend my personal appreciation to our patients, physicians, and partners who have helped us achieve the activation of Gossamer's third and fourth phase two trials to date. I would also like to extend my sincerest gratitude to the Gossamer team, who continue to bring their best selves and go beyond possible during these unprecedented times. With that, I will now turn the call over to the operator for questions. Operator?
spk07: Thank you so much. Ladies and gentlemen, we will open it up for question and answer session. If you wish to ask a question, please press star 1 on your telephone. If you wish to cancel your request, you may press the pound or hash key. Please stand by while we compile the Q&A roster. Your first question comes from the line of Tyler Van Buur. Your line is now open.
spk02: Hey, guys. Good afternoon. Thanks for taking the questions. I had a couple on GB002 and the PAH data coming up. I understand that it's more potent and selective than imatinib, but I guess I'm specifically interested in ratio of lung exposure given the route of delivery. Can you just, I guess, has there been any data in terms of ratio of lung exposure with imatinib that you could speak to and how much higher you think GB002 could be when we see the data? And then, Can you just confirm, will we see data from being planned patients? And did you mention a six-week OLE? Is it possible we could see data from that as well?
spk06: Great. I'll start, and then I'll ask Louisa, a soldier sitter, chief scientific officer, to add anything she would like. So, yes, we do have a several-fold higher exposure in the lungs to plasma. And, you know, we have done more characterization of this preclinically as well as in our normal healthy volunteer study in terms of measuring peripheral PK and then in our PH phase 1B trial. You know, it's important to understand that we designed this molecule specifically to have low systemic PK concentrations because clearly what we saw with the prior imatinib experience in the clinical phase 2 and 3 PH trials was really substantial issues around safety and tolerability, so that if you have high imatinib PK levels that hit, again, a number of kinases, that they were having a significant number of adverse events, serious adverse events, including GI side effects, as well as edematous events, and CNS subdural hematomas. So this was really critical that we would be able to ensure, again, low PK levels systemically in the periphery. And so GB002 is rapidly cleared and never reaches high levels systemically. So what you see are low levels from a C-max perspective and then rapid clearance. And we've shown this in our normal healthy volunteer trials, and we're confirming that profile in the pH population. So that's a really critical component to this profile where you, again, want very substantial lung exposures but very, you know, again, manageable systemic exposures to really improve upon the safety and tolerability. So that's critical. And so, you know, we'll continue to discuss that. And I think we can touch upon that in our webinar in December to go into more details on that. Regarding the Phase 1B experience, again, as I mentioned, this is a two-week study. We do have a six-month OLE available for these patients, unfortunately. We had patients in that OLC in the early part of this year, but because of COVID, they had to come out because we had to pause really the conduct of the study given the total shutdown at the sites, especially for the PH treating centers. So we will mainly be focused on two-week data in December. So again, focus on PK, safety tolerability, target engagement, and biomarkers, and continue to discuss the program. With that, Louis, did you have anything to add?
spk05: Yes, I think you pretty much covered it, but I think one other thing is not only just the exposure, but it's also the duration that really 002 has a high retention on target, and because of that, we have actually sustained exposure in the lung for a long period of time. So it's not just the PK distribution, but it's also also the way that 002 binds on target. And we have data from PD endpoints, such as BMPR2 and others, that really confirm this prolonged PD.
spk02: Great. Thank you.
spk06: Yeah, great. Thanks, Luisa. So I think we're going to look forward to really presenting a substantial amount of preclinical data and further characterization that we've done with our molecule to really show how we think it's truly best in class. and the right way, the right molecule for pH patients particularly.
spk07: Your next question comes from the line of Joseph Swartz. Your line is now open.
spk12: Hey guys, how are you doing? Thanks for taking my question. I also wanted to ask one on GB002 to start, and that has to do with Some comments I think I heard you say about how you might be able to look at some data from the ongoing Phase 1B patients and gauge some potential to bridge off of the effects that you've seen in healthy volunteers, if I'm not misunderstanding. I was just wondering if that was accurate, if you could expound on that. since this isn't a vasodilator per se, you know, at what point would you hope to see a signal and, you know, what would that signal be in terms of PD markers or, you know, how are you thinking about, you know, when you might start to see some interesting signs?
spk06: Yeah, great. I think my points were really – Josephette, we have a pretty substantial phase one experience. When you look at our SAD or multiple ascending dose studies in normal healthy volunteers across a range of doses and now with the phase one B and pH patients. So the totality of the clinical experience we have to date is great for where we are in the stage of development. I think we're taking all the right steps to make sure that we're going with the right design for the phase two trial. So I think what we'll be sharing in December really is the totality of our phase one experience. And so that's what I was mentioning in terms of being able to bridge and look at not only what we have generated in terms of data from the PH patients in the phase 1B, but also bridging that information back to normal healthy volunteers and seeing consistency and PK exposures and the like. So I think that was the point I was making. And secondly, on your question on, you know, time points for efficacy readouts, I think typically for PD, you know, our hope would be we could follow some patients over time and be able to look at changes in peripheral clinical disease biomarkers, such as pro-BMP levels, as well as potential changes on imaging, such as echocardiograms. If you're asking me about timing, if you look at some of the imatinib data, you know, they were able to see effects of, you know, really even in that 12-week timeframe. But of course, our phase two study is a 24-week study. And so that's looking at PBR. And we'll be also looking at imaging and some of these systemic markers as well for clinical disease as well as biomarkers. So I think it'll be a pretty robust data set coming out of the phase two. And again, unfortunately, just because of the COVID pandemic, you know, really impacted our ability to have the more robust phasal and beak springs we were hoping for. But nonetheless, I think we got very informative and impactful data for the program.
spk12: Cool. Well, stay tuned. So then on GB001, I was wondering if you could give us your thoughts or expectations for when we might be able to look forward to learning about what biomarkers you've found are associated with a better response in the LIDA trial?
spk06: Yeah, I think that for us, I think we're shooting towards that first half of next year to be able to kind of get the regulatory feedback. We're seeking, you know, we have to schedule these meetings and this is the same, you know, divisions that deal with COVID and other therapeutics that are out there being studied in the COVID patient population. So we're very mindful of that. But our hope is that we're going to get that regulatory feedback, and then we'll look forward to presenting more of the detailed data in our plan forward in that first half.
spk12: Sounds good. Thanks.
spk07: Your next question comes from the line of Jeff Mecham. Your line is now open.
spk04: Hey, guys. Thanks for taking the question. I had a couple. The first one is on O2. Is there a population in PEH that you feel like you could maximize the differences in PBR resistance? I guess maybe those not well controlled on combo therapy, for example? And then what types of effects, Sheila, would you say that you're aiming for in the study just as a proof of concept as you sort of get the, prepare for a larger study? And I have one follow-up on 001.
spk06: Yeah, that's really exactly the patient population we're going after, Jeff. We're looking at patients who continue to have higher PVRs and, you know, disease burden in symptomatology despite being on at least two classes of vasodilator therapies, if not three classes of vasodilator therapies. So they are on functional class two and three patients with, you know, again, a pretty substantial disease burden. And they are on background therapies that we're adding on to. So I think we're really enriching for kind of a higher disease activity population, which we think is the right population to be studying in this phase two trial. So I think that's, you know, very, very compelling unmet need. In terms of effect size, you know, if you look at the data from Imatinib from their IMPRESS trial, you know, they saw about a 32% reduction in PVR, like 30 to 32%, as well as improvement, about 30% improvement in six-minute walk distance. Now, that was done a while ago, you know, in terms of, when that study was conducted, you know, how sick those patients were. And then they were also on two or three classes of vasodilator therapy. So that's similar. That was also an add-on study design to those other classes of therapy. So that's really helpful to know that they saw that level of improvement despite being added on to vasodilators. And I think that's, again, very compelling rationale for our program. So I think, you know, obviously that would be terrific to be able to show that type of similar efficacy. Again, the question is how much are patients improved since then with their level of disease control? And so, you know, we're going to be, you know, talking, thinking more about that and talking more about that as we get our study off the ground.
spk04: Gotcha. Okay. That's helpful, Sheila. And then maybe one for you or for Brian, I know you're still getting feedback on 001 on next steps, but, you know, when you think about strategic options here or partnering, Is it a parallel process or do you have to have absolute clarity on, you know, phase three design as sort of a first step to negotiations? Thank you.
spk06: Yeah, I would say both, right? Because, I mean, we engage in discussions. It's, of course, a very critical piece for us to understand what is the regulatory and development path forward, right? So I think those are obviously very natural steps. things that we have to get information on. Brian, do you want to provide any commentary?
spk03: Yeah, I would. Thanks for the question, Jeff. I think our practical challenge is that while we have ideas around what a Phase 3 program could look like, really hard to engage in substantive discussions until we let regulators weigh in. That obviously has a direct read-through to the investment that any partner would have to make in Phase 3 and then what the really potential commercial presentation could be. So, you know, it is a little bit of a chicken and the egg conversation and we're working diligently to be able to get those answers because right now the only real reference point the strategic market has as to what a phase three with a DP2 antagonist looks like is what our friends at Novartis did. And so we're obviously trying to see if we can have, you know, a more streamlined and efficient plan. But until we have regulators weigh in on that, it's really hard to talk about what that financial as well as infrastructure commitment any partner would have to make. Okay. Thanks, guys.
spk04: Thanks, John.
spk07: Your next question comes from the line of Josh Shimmer. Your line is now open.
spk00: Thanks for taking the question. Again, on OO2, can you indicate when we might be able to get a first look at the effect on right-sided heart pressure and PBR specifically? Is that being measured in the Phase 1B, or is that going to have to wait for Phase 2? And Brian, I might have missed it in your prepared remarks, but how should we think about operating expenses going forward?
spk06: Yeah, so pulmonary vascular resistance and the you really see the data comes from right heart catheterization is really the primary endpoint of our phase two trial. So that's, again, the 24 week endpoint for phase two. And so that'll be, that's really when that will be robustly characterized. And so that's when you should plan to see that. From the phase one B, that is more around, again, clinical biomarkers, disease activity biomarkers, and potential echocardiographic imaging, but not really, you know, hemodynamic data. And then go ahead, Brian, operating expenses.
spk03: Yeah. So, Joshua, we said, we said in my remarks that, you know, all the capital available to Gossamer takes us into the second half of 2023. I'm cautious to give greater guidance than that, just because, you know, as we are kicking off these two important phase two trials against the backdrop of the pandemic, it's still too early for us to make predictions on enrollment timelines and thus costs, but we do feel very good based upon the totality of the book of work, shall we say, that we're doing at Gossamer that the capital we have takes us well into the back half of 2023. Thank you.
spk07: Your next question comes from the line of Carter Gold. Your line is now open.
spk10: Great. Thanks. Good afternoon. Thanks for taking the questions. I guess first, maybe to come back to 002, I know you guys have been engaging with a lot of KOLs and trying to understand the landscape. I appreciate you guys bringing up the imatinib experience in phase two, but I guess when you think about sort of the hurl for clinical meaningfulness, either in terms of PVR, six-minute walk distance, how do you think about that in this population kind of you know, what's the, I guess, lack of a better term, sort of floor and what you need to see. And then maybe on 1275, you know, the poster talked, you know, sort of delineated, you know, sort of 50 to 75% reduction on MDSCs. Can you maybe just help put that in context? And if there's a target or there's some sort of, you know, hurdle you guys are looking to to get, you know, to reach and, you know, just kind of help thinking about some of that biomarker data. Thank you.
spk06: Sure. Yes, I think, you know, it's really good. Your first question really gets to the unmet need of what we're trying to achieve here. So, you know, just as a reminder, you know, everyone knows there are these three classes of vasodilator therapies that have been improved. and PAH and better, you know, predominantly use a functional class 2, 3, and 4. And most patients are started off in a combination regimen, you know, usually, you know, with some type of PD5, ERA type and, you know, type coat combination. And, you know, then process cyclones are added, obviously, and, you know, depending on how severe the patient is could be added on even earlier in the debut stage. And then there really are no other approved treatment options, you know, beyond those three classes of vasodilator therapies. So for those patients who have a continued symptomatology, continued deterioration in their functional status, and real impairment on the hemodynamics leading to right heart failure and morbidity and mortality, you know, with a high rate of mortality, and there's a 50 to 75% mortality rate, for patients who are functional class three and four who aren't, you know, controlled or continue to progress, which is, you know, really rivals any oncology indication. These patients have no available therapies. So we're really looking to add on to these classes of therapy, you know, to these vasodilators and see if we can just, you know, really show any functional improvement as measured by six-minute walk distance, which is obviously very clinically important because we need to see that functional improvement And the objective parameter of looking at hemodynamic improvement is obviously very important and critical, especially at this stage of development, for us to get that type of information. That's why we put this as our primary endpoint for the Phase II trial. But we will also be measuring our impact on functional improvement as well. So that's really, you know, what we're looking. So, you know, we can answer the question about, you know, what's the level of improvement we want to see? You know, I would argue, and what we're hearing from our clinicians is they would obviously like to see any level of improvement here because it's, you know, just being able to add on to these vasodilators in such a sick population and show improvement in these outcome measures will be very meaningful because there just aren't any available treatment options. Having said that, you all know that Acceleron and Cetatercept is moving forward into this population as well, which is terrific that they could potentially be affording another type of treatment for these patients. And just to remind you, obviously, that is an injection that's given every three weeks in person because of the hematologic monitoring. Our commercial presentation for GB002 is really designed to be a very convenient dry powder inhaler that patients can carry around with them and really be able to live a normal life while having this DPI, just similar to what asthmatic patients do. They're also very familiar with different types of inhaler devices that before they had a pretty bulky nebulizer type system now that they've had to take up to four times a day so now with you know a type of dpi presentation and they're moving more to dpi it's very favorably received and it's a presentation and a delivery a system that is highly uh you know appreciated by the ph human community so i think that you know again showing really any improvement on functional uh symptomatology and improvement will be will be considered very very uh very favorably, given that there's really a lack of treatment options for these patients. And then moving on to 1275, I'll let Louisa comment on this as well. I mean, I think we've seen preclinically our ability to really disrupt myeloid cell biology. That means we've shown in preclinical tumors the reduction of myeloid-derived suppressor cell populations, both granulocytic and monocytic, as well as tumor infiltrating macrophages or tumor associated macrophages or TAMs, and the increase in the T cell populations, which is so critical for efficacy. So you see increase in tumor infiltrating lymphocytes and the CD8 positive T cells. So we've seen this preclinically. So it's really, you know, the combination of being able to reduce that immunosuppressive burden, both by blocking the recruitment and migration of these cells into the tumors themselves, and also repolarizing them from an M2 immunosuppressive phenotype to an M1 immunosimilatory phenotype, and then showing the resultant increase in the T cell biology to be able to then translate into clinical response. And so I think when you look at the totality of our biomarker data, when you see the reduction in MDSC cells, both in the peripheral compartment, both monocytic and granulocytic, in the monotherapy as well as the combination arms, especially if you look at the granulocytic MGSCs, as well as what we're seeing in the periphery on the proteomics and the transcriptomics that Louisa can speak more to. And then looking at the tumor biases themselves and seeing this influx of TILs and this influx of CD8 cells in the TILs, you see in monotherapy patients as well as combination therapy patients for the CD8, we're seeing it the limited samples we have in the combination treated patients i think that's what we're trying to get to your question of what level of mgsc or you know myeloid cell population targeting we have to get to to kind of you know show the increase in um t lymphocytes i mean i think that's a great question i don't know if we have enough data to answer that but let me turn it over to louisa to get her um you know more informed opinions about about these matters
spk05: Yes, absolutely. So that is a question for all therapies that people have grappled with. What is enough? And basically what I think most people, including us, have landed is it has to be going down in the right direction, and it has to be beyond just significant. So there is significance, so it's not just an haphazard observation. But as Sheila's point, what I think that other folks, and us including, have really zeroed in is, Do we have then proteomics biomarkers that go with it? You see significant change in cytokines, in chemokines, which we do, and that is really that you are impacting the biology. And then, as Sheila mentioned, at the end of the day, in the tumor, it is all about the T cells, specifically the CD8. And are you seeing an increase in CD8 in tumors infiltration? And we are. So I think it's the totality of the data rather than a specific number. That number just has to be consistent enough for us to know that it's not just a fluke. And that's, I think, what everybody else is doing with these MDSC modulating therapies.
spk06: Yeah, and I would just add... Getting back to the clinical data as well, you know, so this has been very reassuring to us that we're seeing these biomarker changes. Again, looking at the periphery, looking at the cells themselves, looking at the proteins, looking at the gene expressions for myeloid-derived genes, as well as inflammatory genes, if you look at interferon-type responses, and then the tumors themselves. And, you know, in the few patients we've been able to get biopsies, which has been a really great effort from our team. I want to thank our team because it's not been easy during the COVID pandemic to actually get paired biopsies. I think, you know, that's been incredibly productive and fruitful for us to be able to see that, you know, we are seeing this influx of TILs and CD8 positive T cells, which are, again, really critical for the mechanism and validation of that biologic activity. And then to see the clinical activity, just to remind everyone, I mean, you guys know this, that these are very sick patients. Most patients who are coming in all have at least two lines of therapy. Many of them have five or greater prior lines of therapy across very difficult to treat tumor types that have not shown good responses, either, you know, mostly secondary resistance to checkpoint inhibitors and also primary resistance to checkpoint inhibitors, as we've seen with patients who've been treated with CPIs and had, you know, about a two-month duration of response prior and then lost that. And then we're seeing, you know, responses in combination. So I think that, you know, in terms of loose stable disease, I should say, I think that is really encouraging. So to have, you know, again, five of the seven prolonged stable disease at the 800 milligram or greater is including, again, a confirmed PR at this point, given just the phase one experience we're in, we find really encouraging. And that's in about 16 evaluable patients. So if you're seeing five out of 16, that's really, I think, encouraging information for us.
spk07: Your next question comes from the line of Emma Nillen. Your line is now open.
spk01: Hi, thanks for taking the question. So turning to GB004 and UC, I mean, given some of the physician feedback from the recently presented phase one data, can you just speak to why the early profile is so potentially exciting to physicians in this mild to moderate setting and where it could fit into the evolving commercial landscape? And then just in terms of potential future combination work, are there any specific mechanisms that you think would be logical?
spk06: Yeah, I think it's just, The excitement really is such a differentiated mechanism. So as I've mentioned on the call, it's really not that typical immunosuppressant. And there are a number of, you know, effective therapies. Of course, most of them are biologics, but also some orals that are entering into the marketplace. We have the JAKs that are approved. I think the S1P receptor modulator, Xanamod, you know, has very exciting phase three data. And I think others will potentially be entering into the space, but those are really focused on targeting the immune system. This type of therapy is actually a therapy that clinicians have been looking for, both in terms of the differentiating mechanism focused on epithelial barrier function and repair, and the integrity of the mucosal lining and being able to heal that the mucosa in the gut for these IBD patients that have had a disrupted epithelial lining, which leads to further inflammation and continued disease symptomatology and severity. So I think that's really very exciting from, again, a differential mechanism that could be used alone, especially in earlier stages of disease, as well as in combination with some other immunosuppressants, hopefully in a safe and synergistic manner. as well as the ability then to take that and to target a earlier population in terms of really that more moderate disease, especially 5-ASA and steroid failure patients who have not progressed on to moderate to severe disease at this point. Because right now it's a pretty big leap of faith for patients to have to go from their 5-ASAs and steroids and maybe some other, you know, generic immunosuppressant therapies that are commonly used to a biologic. or to a really potent immunosuppressant oral that has the risk of infections, the risk of malignancies, and other monitoring that may be required. So it's a really big jump and leap of faith, and really patients and clinicians would prefer to have another therapy that could be in that gap to be able to use, such as a GB004. So I think it's really, again, that pre-biologic, that pre-moderate severe positioning, as well as the differentiated mechanisms that is resonating so powerfully and they're so excited about this type of approach, which makes really tremendous sense when you look at the biology of the disease area. And so I think that's really what we're focused on addressing with our trial design with the SHIFT-UC study to really capitalize on what we understand about the mechanism and who are the best patients to benefit. And I want to have Louisa add her thoughts on this as well, because we've been doing a lot of work on the mechanism. And then we could talk about, you know, the combination approaches too.
spk05: Yes, so we have really spent some time, because as Sheila mentioned, this is really the mechanism of action is self-complementary to the immunomodulators that are at the standard of care. So we have gathered a lot of data, both on translational endpoints with organoids and co-cultures, as well as in vivo models, including patient samples. And really, we are seeing that synergy, not just complementary, but also synergy in quite a few endpoints when you combine with specific therapies up there, including the JAK inhibitors as well as ITNFs. So more to come, and we will absolutely share the data. But I think, you know, not surprisingly, we are seeing very good synergy between these two approaches.
spk01: Great. Thank you very much.
spk07: Your next question comes from the line of David Huang. Your line is now open.
spk11: Hey, guys. Good afternoon. Thanks for fitting me in. So I just had two questions, one on PAH and then one for ulcerative colitis. So for PAH, I know that Acceleron with the Catercept, you know, they have a supportive phase two trial that's looking at cardiopulmonary exercise testing and really looking at peak oxygen consumption. Is that, you know, is that something that you would ever be interested in pursuing for O2? And, you know, do you think having that info would be informative or additive to the drugs profile?
spk06: Yeah, no, that's a very, obviously very interesting study. And, you know, we applaud them for taking those types of measurements. We have discussed this extensively with our investigators as well. We have not built in that type of detailed and rigorous, you know, in terms of intensive, I should say, assessments into some of these, our trials in our phase two study specifically. I think, you know, I think we're focused on the, we think the most relevant endpoints at this stage of development in terms of looking at pulmonary vascular resistance and the measurement on the hemodynamic parameters as well as right heart function. And that's, again, through, again, the Right Heart Tap data that we'll be getting, as well as echocardiogram imaging to really assess ejection fraction. So I think those are, you know, some of the areas that we, you know, I think we think that we're, that's the most relevant for where we are. The other biomarkers that we're assessing, again, around pro-BNP levels, this is a marker, Right Heart Strain, and you know, would be also very important. And then BMPR2 to really think about the mechanism in greater depth I think is important. But those are things that we are looking at potentially doing, you know, over time in supportive studies. We are looking at some other imaging modalities that I think will be very exciting to potentially try to get at what's happening in the vascular structure. you know, and the really in the vessels themselves in the lung. So those are things that we look forward to discussing again at our webinar in December. And I think those are some other novel techniques of imaging that we'll be employing in our program, which, you know, we have decided are probably the best at this time.
spk11: Got it. Great. And then just on ulcerative colitis, I know that some of the S1P receptor modulators are interested in moving, you know, earlier into the treatment paradigm. And so, for example, I've seen that, you know, Trasomod has a phase two trial in moderate patients. I think they're going from Mayo score four to six, endoscopic score of at least one. Now, is that, you know, is that a patient population that overlaps with who you're enrolling in your phase two or you know, will you guys be different or maybe even earlier in the treatment paradigm?
spk06: I would say that that would be an overlapping disease population. You know, if you look at the totality of the Mayo scores and the endoscopic scores, you know, I think the question will just be, you know, what is the profile for, you know, atrazumab long-term? I mean, we obviously know the profile for adenomod. You know, we know adenomod very well having developed the drugs. So, you know, I think that we know that, you know, the safety and other liabilities, you know, around monitoring for that therapy. And while we think it's a great therapy, I think there will be, you know, maybe potential challenges in their uptake, given some of the, you know, safety liabilities that drug and those treating clinicians will have to deal with, with S1P class. I think the question is, over time, what will the liabilities be for any S1P modulator, you know, completing their large development programs? We'd have to see that. And then how can they move up into the treatment algorithm? So I think that'll be a question in terms of how it's positioned and how it will be used by the clinical community and how it will be received by patients. You know, there is something around just significant lymphocyte reductions, which can be scary to clinicians, especially because they have had to deal with PML risk. With Tysabri, obviously they've gotten a lot more comfortable with that, with Entivio, with Avetaluzumab, looking at alpha-4, beta-7 targeting therapies. Having said that, that's always a risk in terms of thinking about potential infection risk when you have really reduced the number of circulating peripheral lymphocytes. So I think those things are real and will always have to be managed by clinicians and always thought about for patients. So the question is, how will that profile impair the ability to be treated and to be really used in that mild to moderate population versus a therapy that doesn't have a type of immune system effect and potential infection risk over time. So I think those are some of the things that we think about when we think about these other therapies and how they want to try to move up into the earlier lines of therapy. So that's one thing. And then the second thing is some of these other orals coming in, I don't really view them as so much competition as this could be great again, complimentary or synergistic combinations for us. So for us to have really powerful oral oral combinations, I think will be great for patients. And because we have such a orthogonal mechanism, you know, and we think we should be able to combine safely with these other therapies also, you know, to, to really focus on that we are gut targeted. So we have a very limited systemic pay. We have a lot of, you know, really focused on colonic exposure. I think that those would be very good for us to be able to, you know, mechanisms that we could potentially combine with. As Louisa is mentioning, we just started our work on the combination. And again, have oral combination approaches for patients is critical. You know, no one therapy is going to cure, you know, an ulcerative colitis patient or really any patient with any autoimmune disease is going to be a combination approach. So for us to figure out the best way to have safe combination regimens over time, I think is also important as we develop our therapies as individual therapies.
spk11: Got it. Thanks for the insights and taking my questions.
spk07: Your next question comes from the line of Patrick Truccio. Your line is now open.
spk08: Thanks. Good afternoon. Just a few follow-ups on GB004. So, you know, we've seen this shift in recent years in terms of regulatory guidance and endpoints for IBD with the preference for the measuring of mucosal healing that's confirmed by histologic analysis and the validated PRO measures. So, you know, with SHIFT-UC enrolling, I'm wondering how we should view the endpoints in IBD and UC particularly and with this mild and more moderate patient population? And do you believe the endpoints and regulatory bar is still shifting, or is it fairly stable as we look ahead to an eventual update in the SHIP-UC study? And then I have a few follow-ups.
spk06: Yeah, that's a great question. You know, for ulcerative colitis, I would say there's been, of course, a lot of regulatory dialogue on the proper endpoints, but it does seem to be more stable than, for example, Crohn's disease. which I think is still, you know, an evolving area and has additional challenges. I think the importance of clinical remission is still very relevant. So that is looking at really the Mayo score primarily, looking at, again, not only signs and symptoms, primarily stool frequency and rectal bleeding, but looking at the endoscopic improvement and looking at endoscopic remission to really be able to, you know, be counted as that clinical remitter. And so I think there's a lot of, you know, confidence in that endpoint, I think the higher bar is mucosal healing. And it really gets to, you know, as our medical leader at Levesque likes to say, and has spoken to many of you on the phone here, the tissue is the issue. So we do say that a lot at Gossamer. And we believe that greatly because it is very true that if you can show that histologic remission on top of the clinical remission and really get to mucosal healing, That's just such a meaningful endpoint. So if you can show resolution of inflammation, and again, as we define histologic remission, it's very, very detailed. You have to have, again, really absence of neutrophils and other inflammatory cell types in multiple layers of the colonic tissue. And so to be able to get to that high hurdle mucosal healing endpoint is, again, I think is definitely a higher bar. And it's something that we'll be measuring very closely. It's where we saw really the best data coming out of our Phase 1B. And so we're going to measure that in our Phase 2 trial. But I do think the provable endpoint of the clinical remission is, I feel, very solid. And so I don't think that's going to shift dramatically during our development program. I could be wrong. But I think having clinical remission as your primary endpoint and then looking at histologic remission as a very important secondary endpoint and then mucosal healing as well as important secondary endpoints to characterize your efficacy and getting at that ability to have sustained long-term remission will be very important to the regulators. It will also be very important to treating clinicians and to patients.
spk08: Got it. And then just regarding potential movement to Crohn's disease, would the plan be to wait for the outcome from shift UC before moving ahead in Crohn's disease or what would determine if 004 moves ahead in Crohn's?
spk06: That's currently the thinking that we have plans for Crohn's disease and believe, you know, based on rationale, the scientific rationale that it will work in Crohn's disease. Yeah, but I think right now, you know, our lead indication is ulcerative colitis and based on the data we see there and as we get more experience, you know, we'll be moving Crohn's forward.
spk08: That's helpful.
spk06: Thank you very much. Thanks, Patrick.
spk07: Once again, in order to ask a question, please press star 1 on your telephone. There are no further questions at this time, so you may continue.
spk06: Thank you so much for taking the time and asking us all these great questions around our portfolio. So pleased to be able to speak to you all today and looking forward to hopefully seeing you at the webinar in December and more discussions to come. So thank you again. Bye-bye.
spk07: Ladies and gentlemen, that does conclude today's conference call. Thank you for participating. You may now disconnect. Thank you. Thank you. Thank you. Thank you.
spk09: Thank you. Thank you. Thank you. Music Thank you. Thank you.
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