Gossamer Bio, Inc. (GOSS) Earnings Call Transcript & Summary

Good afternoon. I'm Andrea Tan from the biotechnology team at Goldman Sachs, and I'm pleased to be joined by Gossamer Bio. With us, we have Sheila Gujrathi, CEO; and Bryan Giraudo, CFO. Thanks for joining us today. Sheila, I'll turn it over to you for some opening remarks.

Well, thank you so much for inviting us to the Goldman Healthcare Conference. We're really pleased to be here and looking forward to jumping into Q&A, and I have some slides here I can present along the way. But thank you, again, for including us.

Perfect. So maybe to start, can you provide a high-level overview of the company and some thoughts on how the company has advanced in the year plus since your IPO?

Yes. Sure. So we are very proud of what we've created at Gossamer Bio. So I cofounded this company with Faheem Hasnain. In January 2018, we actually officially kicked off the company, and we did our IPO, as you know, in the first quarter of last year. So we are a year plus since the IPO. And the real premise of this company was to kind of build on a lot of lessons learned we had from Receptos and other past experiences to build a truly, what we consider, next-generation biotech company. So we want to be a disruptive R&D engine. We do have expertise within the immunology area, translational immunology research, which can play out in different autoimmune disorders, inflammatory conditions as well as immuno-oncology. And when we first started the company, we really focused on having a clinical pipeline and bringing together a clinical pipeline that would have near-term value inflection point readouts in parallel, while we were building up our research portfolio and engine, and that's really where we are today. So we're so pleased to have 4 assets in clinical development in different disease areas that have actually inflections -- value inflection point in the next 12 to 24 months. So I'll be walking you through. And we really have this world-class team from Receptos, BMS, Genentech, a lot of people that we worked with extensively in the past that had significant proven track record and a lot of expertise in bringing drugs to market. So that's where we -- that's kind of the premise of the company. And we also have a lot of optionality on how we can pursue any given program.

Perfect. So you touched a little bit on upcoming milestones. So maybe we can start there. What milestones are you expecting for this year? And as the COVID-19 pandemic has played out, have you seen any impact to these trials or to your business? And what steps are you doing to mitigate these impacts?

Sure. So I have a couple of slides here just to help walk people through our portfolio. So we have 4 programs in the clinic. So these are our 4 programs on the slide. These are all small molecules. We have oral small molecule, GB001, which is against the DP2 receptor antagonist. We've taken it forward into 2 Phase II clinical trials. One is in moderate severe eosinophilic asthma. And one is in chronic rhinositis breathing without nasal polyps. These trials had completed their enrollment prior to the COVID pandemic and are on track to read out in the second half of the year. So we are on track for those final Phase II read-outs for both studies. GB002 is an inhaled PDGF receptor inhibitor. Very similar to imatinib, but more selective and potent than imatinib, which had some previous Phase III data with PAH, but had a lot of systemic toxicity. So we've taken this forward into a Phase Ib trial in PAH and we are about to launch a Phase II study in PAH. Here, we have had some more COVID impact where we had to pause a Phase Ib. But we are restarting that study with an open-label extension, and we are, again, ready to kick off the Phase II, a lot of PAH sites are opening up. So that looks like that will be getting started soon. So we will have Phase Ib data at -- second half of this year, and the Phase II trial will be getting off the ground. GB004 is an oral small molecule, which has got targeted -- targeting the HIF-1 alpha stabilizer mechanism, really leading to epithelial barrier repair and function, so increased mucosal healing as well as effects on the immune system. We completed a Phase Ib study here, which we showed a recent data on, which I'm excited to share with everyone. And we have a Phase II plan that we're also getting off the ground. And it looks like these sites are opening up as well. So I think that is also not as affected by COVID, which is great. In fact, we think we could be differentiating here because we have a non-immunosuppressant mechanism. So a lot of the sites we're talking to seem to be very excited about our approach. So I hope -- hopefully, we'll -- it will be a trial of choice. That's what we're trying to aim for. And lastly, we have a small molecule in immuno-oncology space, which is targeting a CD11b integrin. So it's a CD11b modulator, and we've taken it forward in select tumor types, really very minimal impact here from COVID, that trial is enrolling very well. We had some interesting data we presented at ASCO recently, and we'll have more clinical data on this program by year-end. So just a tremendous amount of progress that the team has made, both in the clinical setting as well as the research portfolio, we have about 9 preclinical programs, many of them are going to be advancing to the pre-IND and IND stages in the next year or 2 that we're excited to be talking about. So the team has been very productive. And so just to summarize, these are some of our near-term milestones. We have a lot going on in the second half of this year that's upcoming across all of our programs. And again, the biggest impact we had with COVID was on our PAH Phase Ib. But everything else is really quite on track. And again, the PAH Phase Ib is restarting as well.

Okay. So maybe let's just start diving into these programs. Your lead asset 01 is DP2 antagonist. Maybe just to start with, can you walk us through the mechanistic rationale for targeting DP2, the unmet need here? And what gives you continued confidence in this class of drug, just given others have failed in similar indications?

Yes. Of course, I'd be happy to walk you through that. So why don't I just jump into a little bit more of the background 001. Yes, so it's really around the unmet need in asthma, and I have a lot of experience in this because of my clinical training, I worked on Xolair, helping to launch the first biologic in asthma. We also have Hector Ortega with us who actually led the development of mepolizumab, now known as Nucala from GSK in moderate to severe eosinophilic asthma. And so we have a lot of understanding of unmet need and evolution in drug development in this area. So asthma, as you know, is a very difficult disease to control, especially for moderate to severe asthmatic. 50% of patients remain uncontrolled today. And there's also a distinct phenotype that's defined by what we call high eosinophilia or TH2-high disease. And so this is the unmet need we're really trying to go after. Patients who have moderate to severe disease, who need a robust anti-inflammatory to control their disease. We're really looking at asthma control. And the way we measure that is through the clinical effect of the reduction of exacerbations or asthma attacks. And we know that while about 3 million of just U.S. asthmatics have severe disease, half of those patients have high eosinophil disease and are really uncontrolled today. And the mechanism here is very important. We think DP2 receptors are expressed on a number of important cell types in that TH2 inflammatory cascade. And so they express on TH2 cells, ILC2 cells. As you can see on the top of this slide, which leads to the production of TH2 cytokines, and we now know that many of these cytokine blockers, if you will, through the biologics have shown proof-of-concept and validation within moderate to severe high-eosinophilic asthma patients. We also have effects on eosinophil within basophils as well as epithelial cells and airways with muscle cells. So again, a lot of data here from prior clinical trials that we've run as well as mechanistically to show the DP2 receptors can be very important. And the unmet need, again, here, what we're trying to address is really going after patients who have moderate to severe disease, who don't want to go on to biologics. So while there are great biologics, again, I worked on Xolair, and it's a really great drug as well as the anti IL-5 therapies and dupilumab. They're still going to be segmented in that really severe asthmatic population. And as we've seen with multiple disease areas, there's a real high desire for orals, and to have an oral controller medication. To go on after patients are continuing to have disease activity despite being on background controller medications. And this is the way we've designed our clinical trial. So here the patients are on inhaled corticosteroids as well as long-acting beta agonists and usually another controller medication, whether that's montelukast or another inhaler. But they are, again, remaining very active in disease. So it's the ability to have an oral that could be positioned prebiologic in this moderate to severe segment is very significant unmet need and a lot of opportunity for us. And in terms of your questions on prior DP2 receptor and what's happened in this class, I think, we've had a lot of learnings here. One is around the molecule itself. We do believe we have the best-in-class DP2 receptor antagonist. We have data now profiling our drug compared to other drugs in the class, including fevipiprant as well as the earlier DP2 receptor antagonists that were studied in asthma. We have a very long receptor residence time. In our latest studies, we show a receptor residence time of about 4.5 hours compared to about an hour for fevipiprant and less than 10 minutes for the earlier DP2 receptor antagonist. So we do think we have a truly differentiated profile that we've seen in our in vitro and preclinical characterization. In addition, we've learned a lot about how to do asthma study. So what we really know is we have to go after moderate to severe disease. And we have to go after the right endpoint. So we have to enrich for disease activity. We have to enrich for TH2 high disease. And then we want to go after clinical exacerbations, not just bronchodilator endpoints because these drugs aren't bronchodilators. So again, we've learned a lot in this space. And the earlier trials were going after more mild disease, looking at FEV1 and even the anti-IL-5s really failed in those -- in that type of trial setting until they went into moderate to severe high eosinophils looking at exacerbation reduction. So again, a lot that we've learned, and that's the way we've designed our leader trial. Here where we've taken 3 doses forward against placebo, looking at, again, clinical effects over a 24-week period. So we have reduction in asthma worsening, which is our 24-week end point. One of the components of this primary endpoint is looking at asthma attacks or exacerbations themselves, which is the Phase III endpoint that we typically look at with the biologics. And that is a key secondary endpoint for us in this study. We did do an interim analysis of this trial earlier this year, and we were encouraged by the data that we saw, looking at our clinical effects. And so we presented that to our independent data monitoring committee. They recommended to proceed without any modifications. And so we're very excited to continue with this trial and read it out second half of this year.

That's a great segue to maybe, if you don't mind, explaining more just what you did. What findings were coming out of the [ presa ] side interim analysis. And just as a backdrop to that, what was the strategy and thought process as you were designing and incorporating that into your trial?

Yes, it's a good question. We really were responding somewhat to a couple of factors. One was, as you and others may know, we did have a competitor in this space. Novartis has a drug, fevipiprant, that was ahead of us. That was in several Phase III trials, and we were very aware of that. Of course, that they were ahead of us, and we were looking at ways to accelerate our program. Similar to a strategy we employed in multiple sclerosis with our Radiance trial when we were at Receptos, where we did an interim analysis and were able to jump-start a lot of our Phase III efforts. Another factor here was looking at our IP runway, both for fevipiprant as well as our own program. And that was also something that we were really being mindful of just to understand what would our commercial runway be. We have since, since fevipiprant, really had more mixed data and didn't advance their program forward. That is no longer an issue for us as well as their IP. We are not locked to that IP runway. And then we actually had a U.S. patent issue that was able to extend our IP runway after 2037. So we're in a much better place. But having -- obviously, since we planned this interim analysis as an administrative analysis, so we didn't take an alpha hit. We went ahead and did an interim analysis. We have started some Phase III planning activities which are going to be very helpful to keep us -- to get us in the right position to be able to launch Phase III as quickly as we can. That it mainly consists of clinical pharmacology, CMC-type efforts. And then we'll take a look at the full data set and have regulatory interactions and be able to move forward, hopefully, if the data supports a real robust reduction in clinical exacerbations. And in our market research for an oral, that's been looking at around 25% to 30%. That's really what we're trying to get confidence around in terms of what we've seen in our interim and what we hope to see in our final data readout.

Perfect. That's really helpful. So you also have 2 other programs with the same asset. Maybe if you could walk us through those and then what the treatment paradigm looks like in each of those indications. And where this molecule could fit?

Yes. So the other indication that we really prioritize is chronic rhinositis with and without polyps. It's, again, a very significant unmet need for patients who have failed intranasal steroids. These patients tend to have recurrent surgeries to try to get rid of their polyps, and they have a lot of morbidity in terms of all the symptoms that you see here in the middle of the slide. There's also significant overlap of these patients, especially with polyps that have high eosinophilic disease and who overlap with moderate to severe eosinophilic asthma patients. And so on the biology, I think it could be overlapping between these 2 disease areas. So similar positioning from our perspective in terms of what we're trying to do with chronic rhinositis, again, with and without polyps. In the patient population with polyps, as you probably know, there are biologics that have been approved here, including dupilumab and other biologics who have shown promising Phase III data, including the anti-IL-5 and Xolair. But again, what we're trying to do here is really position before the biologics. So these are patients who have failed intranasal steroids, also saline irrigation, which is a common technique that we use to treat these patients, both with polyps and without polyps, and then see if they would really like to go on to an oral before going into a biologic. And without polyps, that patient population -- biologics have not been studied there. So that's an area of high unmet need, which is relatively pretty wide open. And these patients just really, unfortunately, just have to go to surgeries and multiple surgeries. So that's the way we designed the study, again, to look at a prebiologic. So we have a Phase II trial here, TITAN, which is a 4-month study, 16 weeks, which we're going to be reading out second half of this year. Looking at the SNOT-22 outcome measures as well as really CT scans and looking at the nasal polyp score. So that's our second study. And for chronic spontaneous urticaria, we are very excited about that indication. We are doing some more exploratory work to try to understand what segment of the population would this mechanism makes the most sense in. And so more to come on that disease area. But really, for now, we've prioritized these other 2 indications first.

Excellent. And then with these data that are expected for the TITAN study later this year, what would be clinically meaningful here?

Yes. So in terms of looking at the biologics and looking at the SNOT-22 questionnaire, and we chose that as our primary endpoint because 2/3 of this population will have polyps and 1/3 will not have polyps. So we needed an endpoint that would traverse both endpoints and then the reduction in nasal polyp scores are a key secondary endpoint. The biologics have shown anywhere from 30% to 45% reduction or improvement in this endpoint. Now we don't think we need to have a great improvement as the biologics, we think we can be less than that and still be a very meaningful therapy, but that's to kind of give you some ballpark figures of what other folks have shown, looking at SNOT-22.

Got it. Perfect. And then maybe moving to your program 004. Maybe if you could walk us through that, the mechanism of action for this molecule and the rationale for using a stabilizer versus an anti-inflammatory agent or immunosuppressant. That is typically used in these types of indications.

Yes. So this is a truly differentiated mechanism. And as you know, we know this disease area well, having brought forward ozanimod in ulcerative colitis and Crohn's disease, and I've worked on a number of IBD programs, and we have a really terrific team that have come over from Receptos and who have a lot of experience, including 3 gastroenterologists who are at our company. So when we saw this mechanism of really going after epithelial barrier and repair through HIF-1 alpha stabilization. We thought this is really truly differentiated and could be transformational for these patients because patients with ulcerative colitis and Crohn's disease, hallmark of the disease is having a disrupted epithelial lining, which we see here on this figure. And that leads to chronic inflammation and entry of microbes as well as inflammatory cells. And what we're doing with the HIF-1 alpha stabilizer is we're really leading to the healing of this epithelial cell layer, which is so important. And then there's a crosstalk between the immune mechanisms, including effects on neutrophils as well as other inflammatory cells that we see. So we're not only, again, impacting epithelial lining, we're also having affects on the immune system. So the idea here is could we treat patients, especially with moderate disease early and their treatment algorithm, lead to this lining and also potentially be able to be combined with other therapies in a safe manner. Because really no immunosuppressants have been able to really be combined safely without significant infection risk. So we are looking forward to again showing good monotherapy data as well as potential combination. And so we designed our Phase Ib study here to really assess this mechanism. So we have to look at the impact on the epithelial lining as well as the histology here, looking at reduction in inflammatory cells. So that's, again, a really differentiated mechanism compared to other immunosuppressants that we've seen in this space today. And so we're really going after mucosal healing as the unmet need. And this has evolved in the IBD disease landscape. Typically, in the past, mucosal healing was really defined by looking at endoscopy alone. And looking at the Mayo endoscopy subscore and looking to -- at the mucosal appearance. But what we've seen over time is that even for patients who have endoscopic resolution. If they still have active histology, they are in high risk for disease relapse. And so this has got to be the true remission is looking at because [ you feel like ] where you have significant histologic remission as well as a [ static ] remission, and that's more predictive of long-term remission and disease control. So that's really what we're focused on today. We've seen a dramatic improvement preclinically and looking at histologic remission as shown by this histo graph as well as effects on immune cells, looking at the reduction of proinflammatory cytokines. So we designed our study to enroll and [ enrich ] for patients who have active histologic inflammation, including the presence of neutrophils in the Phase Ib study. And then this is representative of the type of improvement we're seeing in the Phase Ib, where we're looking at a nice histologic remission in these endpoints. And so this is what we've really focused on. And so we are looking at patients who have active histology as represented by this top histo graph. And then looking at the nice inflammation coming down below. And so -- and to have histologic remission, you need to have a total score of less than or equal to 3, the Robarts Histopathology Index has a scoring system from 0 to 33. You also have to have a 0 on both neutrophil subscores. So it's a very high bar. And then just to go through some of the Phase Ib data, here we show really nice improvement on mucosal healing as well as histologic remission. So here we have in this Phase Ib trial, which is about 34 patients, 2/3 on treatment, 1/3 on placebo. We had 17% of patients who -- again, [ not ] that high bar of mucosal healing 4 out of 23 compared to 0 out of 11 patients. And for histologic remission, we have 43% of patients or 10 out of 23 patients compared to 18% of patients in placebo or 2 out of 11 who actually showed that nice improvement on the histology. And we even had nice improvement on clinical outcomes, looking at clinical response, improvement in rectal bleeding as well as 1 patient who had clinical remission within 28 days, which is very comparable to what we're seeing with other immunosuppressants and biologics in a 28-day type of trial period. So this is, again, very exciting, encouraging data. There's actually more data that I had when I started the ozanimod Phase II program. And we're really looking forward to presenting this data in more detail in a medical meeting. The other piece that's very differentiating about this program is that it's very gut targeted. So we have low systemic exposure, as you can see from the PK profile from our Phase Ib with very high colonic concentrations. And that's what we wanted to achieve with this profile. So we want to have, again, low systemic exposure, no effects on systemic EPO or VEGF and really -- a nice tolerability profile with rapid clearance systemically. So we have been able to achieve that and a nice improvement in the biomarker profile looking at tight junction protein in claudin-1, which really goes after epithelial healing and barrier repair. So when we think about this program, we think it could be actually, again, a foundational therapy for IBD patients. So for patients who failed 5-ASAs or are on 5-ASAs, who continue to have disease activity in the -- mild to moderate, even moderate to severe segment, we think GB004 can be added to 5-ASA [ granule ] patients and then also potentially have other therapies added to GB004 as we go on. And that's the way we're designing our Phase II program to look at moderate -- mild to moderate patients. And again, we're getting very nice receptivity from investigators because it's not an immunosuppressant. And they really like this differentiated mechanism in the differentiated trial that we're going after. So we do think this could be, again, a potential transformational therapy for IBD and ulcerative colitis to begin with.

Great. So from that interim data and that early look. How do they compare to other traditional methods of efficacy that are measured in these types of trials? Just maybe if you could help put that into context compared to other current standard of care therapies?

Yes. You can -- I encourage folks to obviously look into this more. So mucosal healing is a very high bar and as you know, in the past, most trials really looked at the old definition of mucosal healing, which is only endoscopy. So I do caution people when they do their research to understand and just make sure they understand when they use mucosal healing in the older trials, are they looking at endoscopy alone or endoscopy plus histology. But some of the newer trials that have read out with a mucosal healing, you're seeing really anywhere from a 10% to 20% type of improvement with mucosal healing. So we're really right in line with what's been seen. And given that this is just a 4-week end point, a lot of those other trials are reading out at 6, 8 or 12 weeks, we are very, again, encouraged that we're seeing this type of improvement just in a 28-day study. And this is true for biologics as well as the gut targeted JAK, there's a theravance paper that outlines a lot of these outcome measures. So you can see that we stack up very favorably to a lot of the approved therapies and other therapies that are in development right now.

Got it. And so maybe on that point that this was a 4-week study, and you've seen already very encouraging data here. How do you think that this would play out over the longer term.

Yes. So as I was mentioning, for us, it's really around what can we do with this type of profile and with this differentiated mechanism, this is where -- our next steps here is to develop -- we've designed our Phase II program to really go after this type of broader patient population, mild to moderate to severe for adding on -- active -- patients who have active ulcerative colitis despite being on 5-ASA therapies. That's really the patient populations we're going after, which is again, a pretty broad group of patients. And to show good monotherapy data and then also be able to see whether we can combine -- if the patients progress through our therapy, if we could combine biologics and other orals that are coming into the space that are more potent immunosuppressants to show that we can combine safely with those other therapies in a synergistic fashion because we're, again, focusing on the epithelia barrier repair and immune effect that will be complementary to the immune suppressant effects of those other mechanisms. And again, no therapies have really been able to combine safely with these potent immunosuppressants because of safety issues and infection risk issues. So again, to have a prebiologic therapy and preoral immunosuppressant therapy as monotherapy, and then go and see if we can have combination approaches as well. So a really nice, again, broad, long-term view of this program is that it could be, again, very transformational.

Perfect. And then as you've developed this tablet formulation. Maybe just talk about the rationale and the strategy. You talked a little bit about orals being used in this field. But how much confidence do you have just from this Phase I healthy volunteer study? Is that sufficient basis for moving this tablet forward?

Yes. We -- when we first did the deal with Aerpio, we got a liquid formulation. So the goal here was always to have a tablet. So while we did a Phase Ib with a liquid b in parallel, did a lot of tablet formulation working, we actually did normal healthy volunteer studies with the tablet that not only include peripheral measurements of PK, but also we did colonic biopsies. So we actually have a good idea of the colonic tissue concentrations with our tablet formulation. So based on all the great data we got for PK and PD and clinical data coming out of the liquid formulation 1B and the normal healthy volunteer tablet formulation, we're in a very good position now to take forward our tablets into the Phase II. And the other very promising thing about this is that we think we're actually at the low end of the range here with 120 milligrams of the liquid formulation. And so we think we have a nice room to improve upon the efficacy here in terms of our preclinical work that we've done, and looking at our target PD and what we're trying to achieve, again, with these higher doses of the tablet formulation that has a better tolerability profile than the liquid. So we're moving in the right direction in all these fronts, which is, again, very exciting for the program.

Great. So maybe if we move to the 002 program. If you can walk us through this program and then how it's differentiated from other PDGFR inhibitors.

Yes. So again, very exciting. I think we know PAH is really a disease of vascular remodeling now, not just basal constriction. And we see this here in this figure. And we do think there's so much data supporting the role of PDGFR alpha as well as PDGFR beta. And that's really a key point of differentiation of our therapy. Where -- and it's just imatinib data looking at reduction in PBR and significant improvement in exercise tolerance or 6-minute walk distance from their IMPRESS trial. But getting to your question, we have a really great molecule in GB002. It is more potent than imatinib and more selective than imatinib on PDGFR beta as well as other kinases that we'll be coming out to talk about and more selective than imatinib in that it really avoids BCR-ABL, which we think could be involved in cardiac toxicity in PAH patients. We also, of course, have developed the inhalation formulation, so we have significant lung exposure and minimal systemic exposure. And we saw with imatinib, there's a lot of GI side effects, [indiscernible] effects and of course, the CNS bleeds that occurred in the PAH program. So with any kinase inhibitor, systemically, it's always going to be a challenge for PAH patients. They're very brittle, and you have to combine the vasodilators. So you really need to minimize systemic toxicities. And then we were really pleased to show better efficacy in our preclinical models of imatinib, we saw a great reduction in right reticular systolic pressure as well as a significant improvement in BMPR6 healing in -- as well as a significant reduction in the periphery. So improvement and increase in the lung, BMPR signaling as well as decrease systemically, which again, is a sign of potential improvements in right heart function. So that's, again, all very encouraging and better than imatinib in all these different respects. So -- and here are some of our preclinical data histologically, looking at the clearance of the inflammatory cell infiltrate as well as the clearance of the occlusion in these blood vessels. So very excited. We think we have great preclinical data, we have excellent scientific rationale, we have differentiation to imatinib, will hopefully lead to good efficacy in the clinic. And so this is our Phase Ib data. It is a 2-week study, but we have an open-label extension. So we're hoping to enroll more patients into this and look at OLE effects over time, especially looking at biomarkers such as proBNP levels systemically and looking to read that data out in second half of this year. And we're starting our Phase II study, which will be a 24-week PVR trial as well as looking at 6-minute walk distance. And that will be starting this year, hopefully the second half of this year. And we want to start reading out data in the 2021 time frame.

So maybe just staying on this Phase Ib study then, when you do report these initial results? What should we be looking for, again, like maybe level set for us, what would be clinically meaningful? And what would be exciting to see for you?

Yes. So the 2-week component is really focused on PK, PD and safety. Because we wanted to get this experience before starting our Phase II 24-week trial in PAH patients, and we want to get experience in PAH patients. And so we already have some data in hand, which is very helpful for us to start our Phase II efforts. So we want to continue to expand upon that. And so from this portion, I think looking at pharmacodynamic and target engagement data in addition to again, PK and safety will be important. And hopefully, if we can continue to dose these patients in OLE now, again, we were on a very good clip here in the beginning of the year on this trial. But unfortunately, we did have to pause enrollment because of COVID. So if we're looking to jump-start this again and then if we're able to get patients in the OLE and keep them on drug, that's where we could potentially look at changes in biomarkers as well as potential imaging changes. But I do want to manage expectations just given the COVID environment and where we are today, we -- this is why we've kind of accelerated our plans for Phase II and want to get that study off the ground.

Perfect. So with the OLE and as you watch these biomarkers such as NT-proBNP, as you mentioned, what levels of reduction would you be looking for there to give you confidence to move forward?

Yes. I think it's really any reduction in proBNP. I think there is variability around this measurement. And of course, these aren't going to be large trial. And we do see that imatinib has effects on proBNP. We saw effects as early as 3 months or 12 weeks. So I think we'll just be looking at any improvement compared to patients' baseline. So that's something that we'll continue to characterize and get a sense about, but yes, that's -- we consider that a more objective marker. So any improvement there will be promising and encouraging for us.

Got it. And then finally, maybe on your GB1275 program. If you could walk us through that, the mechanism of action, how you're thinking about its utility, moving forward?

Yes. This is, again, a really novel differentiated mechanism. It is on -- the effects are mainly on the myeloid cell lines. So specifically on myeloid derived suppressor cells or MDSCs, both the monocytic and the granulocytic component as well as the tumor-associated macrophages or TAMs, as we call them, that are obviously very present in highly -- checkpoint resistant in immunosuppressive tumors. So what we saw with this mechanism is multiple mechanisms that were involved with CD11b modulation, where we can actually block the migration of MDSCs and TAMs to the tumors themselves as well as enhance the immunostimulatory or M1 phenotype of the TAMs and repolarize them against this M2 immunosuppressive phenotype. So -- and what we also like about this mechanism is that it seems to be more broadly acting on multiple cell types and cell lines and the myeloid cells because there is redundancy, we think. And so while we thought there is some evidence of clinical activity, when you look at CSF1R, CCR2, 5 as well as CXCR2 inhibitors, we think with CD11b modulation, you actually get better blockade and a more comprehensive blockade on TAMs, again, MDSCs as well as the avoidance of effect on T reg cells. So we think that this could be, again, very important to see better efficacy than some of the other agents we've seen. And so -- and this is what we've seen bearing out in our preclinical studies where we see a nice reduction in macrophages and granular sites and an improvement in dendritic cells as well as CD8 T cell expression within the tumor cells and the tumor microenvironment cells and very good data looking at both monotherapy as well as combination therapy with chemotherapy as well as with -- in combination with checkpoints, anti-PD-1s, looking at nice improvement in survival in very severe, difficult-to-treat pancreatic tumor models as well as, again, monotherapy data. So we're really very pleased with this mechanism in terms of the differentiation compared to other myeloid suppressor type mechanisms. So we designed our Phase I/II to enroll a number of different tumor types that do have evidence of CD11b upregulation and these -- evidence of these myeloid cells being involved either as -- in also primary or secondary checkpoint resistance. So we're looking at castrate-resistant prostate cancer, pancreatic disease, gastric, esophageal, triple-negative breast and colorectal cancer, especially, microsatellite stable colorectal cancer. And we're looking at monotherapy and combination therapy with anti-PD-1 and chemotherapy. And then we have expansion cohorts planned based on signals that we see. And then when we had some nice data, we think, presented at ASCO this year. We had 14 patients that we have studied as of March -- end of March. And we did see some nice data, both in terms of biomarker improvement, especially looking at the reduction in peripheral MDSCs, both granulocytic and monocytic, again, supporting this mechanism of action as well as improvement in biomarkers that we think are very pertinent disease. And then importantly, we did see clinical activity in the metastatic castrate resistant prostate cancer patients where we saw a 52% decrease from baseline and PSA. So this patient had very high baseline PSA, and this has considered to be very meaningful in talking to our prostate cancer experts as well as a 52% reduction looking at that baseline and neutrophil to lymphocyte ratio, again, considered to be a pretty good prognostic factor. And this patient was quite sick in that -- had previously progressed on multiple different therapies, including atezolizumab, and a PARP inhibitor. So again, interesting data, we'll have more clinical data by the end of the year. So more to come on this program.

All right. Well, a very full portfolio. Is there anything else in your pipeline? What else are you working on? And what are you most excited by?

Yes. So we have a whole research pipeline that we have not even spoken about. So we will start talking about that research pipeline. We are hoping to start having these molecules go into the clinic. Starting next year, our goal is to have 1 or 2 INDs coming out every year. It's a mix of what we think are validated mechanisms, points of differentiation in areas that we know well. And that we can really execute on in a development fashion, hopefully with excellence, which is what we really pride ourselves on. So more to come on the preclinical programs that we'll be entering into the clinic. And we think we're in a really strong position from a cash balance runway. We just completed a large financing where we raised $325 million, which really allows us to underwrite our clinical portfolio as well as our research portfolio and gives us a cash runway in a success scenario where we're moving many of these programs forward out to 2024. So you can see we have $642 million, and we actually have a debt facility of another $120 million. So again, we feel like we're in a very strong position financially to underwrite all of this with a nice runway, which is at least 18 months out post these Phase II data readouts for 2 and 4. So a good place to be.

Great. So with -- maybe just one last question then, following up on that. With your current cash balance and a very full and robust pipeline, how are you thinking about capital allocation, which programs to advance on the forward?

Yes. No, we -- our focus is really maximizing the value of our programs in the sense that we want to take these programs through truly meaningful value inflection readouts. And so that's what we're doing with each one of these programs. So we have that for 001, 2, 4 and 1275 here. So we are really advancing this to the top line data readouts for 1 in asthma and chronic rhinositis. We are very focused on executing the Phase II trials for 002 and 004, and really jump-starting and accelerating our operational efforts here to try to get these trials to read out as soon as possible. We want data coming out of these studies next year. So that's our stretch goal that we're really trying to go after and the latest would be first half of 2022. So again, that's what we're focused on as well as, again, characterizing signals coming out of 1275. So that's another thing that we're focusing on. So really, it's around capital allocation to try to get to these truly meaningful value inflection time points on each program and then seeing the research programs to get them into the clinic. And we can do all that with our current cash runway. And so any one of these programs is so substantial in terms of, I think, blockbuster potential, and again, meeting true unmet need for patients. So we think we have a lot of shots on goal here.

Perfect. And with that, thank you for your time. Thanks so much for joining us.

Thank you.