Okay. Good afternoon, everyone. Thank you so much for joining us on day three of the UBS Global Healthcare Conference. I'm Eliana Merle. I'm one of the biotech analysts here at UBS. Very happy to have Gossamer Bio here with us for a fireside chat. Joining us from Gossamer Bio is Bryan Giraudo, Chief Financial Officer, and Richard Aranda, Chief Medical Officer. Thank you guys so much for joining. Maybe before we jump into the specific programs, if you could, frame for us some of the history of Gossamer, as well as high level, how you're thinking about the strategy, asset prioritizations, and key milestones from here.
Absolutely. Ellie, thank you for having us, and to the UBS team, grateful to be part of your first in-person conference back again.
Mm-hmm.
For healthcare. Gossamer was founded in January of 2018 with a mission to really find differentiated programs for a variety of immunologic conditions. We started with a fairly broad portfolio of a number of different compounds for a variety of different diseases. Over time, through both the attrition and the process of clinical development, we've come down to two programs that we will hope to have significant data here in both calendar year 2022 and early 2023, which is Seralutinib, our program for pulmonary arterial hypertension, and GB5121, a brain-penetrant homegrown BTK for the treatment of primary CNS lymphoma. We're located in San Diego, California, and myopically focused on bringing these therapies to patients as quickly as possible.
Mm-hmm. Awesome. Maybe starting with Seralutinib and PAH. First, frame for us what we learned from the IMPRES trial and some of the motivation for this program and how you're able to harness this biology through Seralutinib.
Sure. Well, I think one of the key things we've learned from the IMPRES trial is that a drug like Gleevec or imatinib was efficacious both in a phase II study and a phase III study, and some data in an open-label extension of that program. However, it was encumbered by certain safety liabilities around tolerability, as well as some subdural hematomas that occurred in patients with concomitant anticoagulation. Seralutinib was developed taking the best of that experience, while trying to avoid those liabilities.
We focused on a drug that has better kinase specificity around the PDGF, the CSF1R and c-Kit pathways, and then we packaged it to be delivered through the inhaled route of administration, which then delivers the drug more specifically to the site of disease, while also limiting systemic exposure. With that profile, we're hoping to approach the treatment of PAH with a drug that would be efficacious with a better therapeutic index.
Can you tell us a little bit more about the mechanism of action? I think, you know, a common investor question I get is, "Hey, there's a lot of approved drugs for PAH, including, you know, other novel mechanisms and developments, such as Sotatercept. What's the mechanism of action of Seralutinib or Gleevec in PAH, and how is this different from some of the other options, both approved and in development?
Yeah. I would start off by saying that I think we're entering very exciting times in PAH, really an era that we're going to see some hopefully some advances for patients. Right now, with current therapies, which are more directed as vasodilators, mortality still remains at five years close to 50%, so very dismal outcomes. Seralutinib is in a class, a new class of drugs that could be potentially disease modifying by impacting the underlying disease process, which is basically a hyperproliferation of the cells that line the blood vessels in the lung, which then prevents blood flowing through it and then causes right heart failure. That's what fundamentally kills patients. The mechanism of Seralutinib specifically addresses, through the PDGF pathway, the hyperproliferation of these cells.
By targeting CSF1 and c-Kit, we impact the inflammatory or the immune component of PAH as well as the fibrotic component. It is distinct from vasodilators, and it is distinct from a drug like Sotatercept, which acts through the activin pathways.
Well, that certainly makes sense in terms of both the unmet need as well as the unique mechanism of action. Turning to some of the clinical data, as well as what we've learned about the profile so far, I guess, maybe just starting first with the molecule. In terms of the kinase selectivity, can you tell us a little bit more around the design? Specifically, you mentioned enhanced selectivity for certain receptors relative to Gleevec. Can you tell us a little bit about that and maybe what we've learned from any of the initial clinical data so far?
Sure. We, as I mentioned or alluded to, we hit the PDGF pathways, and there's two isoforms that we hit, and that's both alpha and beta. imatinib similarly hits alpha but has less potency on beta. That is one advantage that Seralutinib has. In addition, while imatinib does impact c-Kit and CSF1R, we're actually much more potent on those two pathways. We have animal model data that shows through the inhaled route of administration in the typical PH models, Sugen/hypoxia monocrotaline models, that we have good outcomes both in hemodynamics and histopathology.
We have conducted a phase I trial in PH-PAH patients, demonstrating good tolerability, good safety, as well as some preliminary, you know, albeit very limited sample size that we do seem to be having good pharmacodynamic effect on such biomarkers such as NT-proBNP, for example.
Can you tell us a little bit about this initial clinical study number of patients, you know, duration of follow-up and, you know, more detail on what we learned?
Sure. This was a phase Ib study in which we enrolled PH patients. They were included based on having a diagnosis of PH. They could have been on background double or triple therapy. We did not require them to have a right heart cath because since it was only a phase 1b, and the intent of this study was to get initial PK safety and some biomarker information. We began the study actually at the beginning or right before the COVID pandemic hit us. We, as a company and as a team, we persevered and got through that. When everything was said and done, obviously, we were impacted by the pandemic, but we're pleased to see that we're able to enroll a total of eight patients.
With two of those went on to an open label extension. The two that entered the open label extension entered the trial once the pandemic restrictions were lifted. Otherwise, we would have had much more. When our initial six patients, we had to put a pause on the study since many sites were not conducting research. A total of eight patients. We were able to demonstrate good PK profile following the inhaled route of administration. Really what we would expect to see with the inhaled route, meaning a good or quick systemic administration through the inhaled route with a very rapid clearance in the systemic circulation.
We had some CSF1 target engagement biomarker in the blood that indicated that we were hitting the target. In addition, we had very good safety and tolerability with cough and headache being the predominant adverse events experienced by these patients. As I mentioned, we had those two patients that continued for additional six months, and we saw improvements in NT-proBNP and at least maintenance of a six-minute walk, if not some improvement.
Those two patients were really important to us from a confidence perspective that the therapy could be tolerated over a longer period of time, and really underwrote our confidence that we could have patients on the current phase II TORREY study for that extended period of time. It was a real important confidence booster for us on safety and tolerability.
Mm-hmm. Absolutely. I mean, you know, I'm probably oversimplifying, but, you know, what we learned from IMPRES was that this is a clinically active target, but just systemically, maybe not so tolerable. I guess that raises the question of if we can be confident in target engagement and successful inhaled delivery. I think that, you know, lends to a certain degree of, you know, biological already proof of concept. How are you confident in the target engagement in the lung? Now, you mentioned some, you know, markers in the blood, but can you maybe elaborate a bit more in terms of how you're delivering to the lung and how you're measuring the target engagement there and what we've learned from the initial clinical experience?
Sure. Well, let me start off by saying that we have a formulation that's been designed to have a particle size that delivers drug to the deep part of the lung, and this is really based on a lot of background in science on how to optimize drug delivery to the lung. First of all, we deliver it through a dry powder inhaler device, which is very convenient for patients. That package then gives us the confidence that that route of administration is quite suitable for this disease, which is basically a disease of the small blood vessels within the lung. How we...
Our confidence around the exposure that we're going to get in the lung is really through a combination of looking at animal model data, doing some scaling and allometric modeling, if you will, from both animal models to humans, and also taking into consideration that, as you mentioned, we do have the human experience with oral imatinib. We could actually fold that into our modeling considerations. That combination of data inputs gives us the confidence that the doses that we're currently taking forward in our phase II are the relevant doses to study.
Mm-hmm. Is there any color that you can give us on the doses you selected?
Sure. In our phase 1B, we studied a dose of 45 mg -90 mg twice a day. In our phase II, our goal is to study 90 mg twice a day. We have an initial starting dose of 60 mg, and during the first two weeks, we have patients dose titrate up to 90 mg twice a day, where they stay on that dose for the duration of a 24-week trial.
Mm-hmm.
We also give patients or the physicians the option to down dose if they need to. I think as we're now, you know, fully enrolled with the TORREY study, we've been very pleased to see that substantially all of the patients are able to get to 90 and maintain 90. The episodes where they've had to down dose are because they get a cold, little things like that. Ultimately, that first two-week experience of the patient with the physician getting to the maximum dose has been a very successful proposition for us.
Can you give us any color on sort of the choice of inhaler and how you're thinking about that? Is it, like, what's the reason, if so?
We-
Down dose?
Ours is a Plastiape inhaler. Thousands and thousands of patient experiences, mostly in Europe. Sandoz utilizes it for some COPD drugs. We wanted to make sure, one, it was easy, small, convenient for patient. We wanted zero regulatory risk. Again, that was hugely important. We wanted to make sure that the actual way that patients could load drug onto the inhaler was very, very easy. That accomplished all of those and at a cost that is quite attractive.
Got it. That's, it's very helpful. Just going back to kind of the experience with imatinib, is there any? You know, when you thought about dose selection and doing really extensive sort of exposure modeling, I mean, how much are these receptors being inhibited relative to the systemic dose levels used in the IMPRES trial, and how should we think about that in terms of the overall exposure and, I guess, the relevant, you know, pulmonary tissues?
Yeah. I would say that the advantage of Seralutinib is we're predominantly having exposure of these pathways in the lung versus the systemic circulation. Hence, that, we hope, will drive the efficacy. In contrast, imatinib, you actually have a lot more systemic exposure relative to the dose that you're given and what is going on in the lung following oral administration. We do feel confident that with giving it directly to the lung that over a 24-hour dosing cycle, that's why we give it twice a day.
Mm-hmm.
Because our modeling tells us that in order to fully cover the PDGF and CSF1R and c-Kit pathways, we do need twice-a-day dosing.
Makes sense. Turning to the TORREY study, can you tell us a bit about the design and, you know, how, I guess, the study management is going given, I mean, I guess, we're sort of out of the pandemic, but not fully, and just all the puts and takes involved in running a trial.
Well, I think Bryan likes to say that we've completed enrollment. I'll start off with that.
Exactly.
And, uh, so, uh-
Yeah. I would say, you know, we, as you know, Eliana, we had to push guidance in the fourth quarter of last year to the second half. That was really a function of the Delta variant, where many of our investigators and their nursing staff were pulled away from their PH practices to work in ICUs and take care of COVID patients. Fortunately, as we've all seen, despite rising infections, hospitalization rates have not changed. That was very important for us through Omicron. It's also been very important for us as now we're in that period where physicians, or where patients are coming in for their week 24 right heart cath and the rest.
The fact that infrastructure is still open and operating, and the sites are able to manage some of the nursing challenges and the rest much better than they could, say, in September of last year, we remain very, very confident that we'll have our top line data in the fourth quarter. We've been guiding to around the mid to late November timeframe. Very, very excited to be able to have those results here in the not-too-distant future.
Before or after Thanksgiving? I'm kidding. I'm kidding. That's not a real question.
What's your vacation schedule like?
Can you talk about it later?
I could go through a little bit about the trial design if that.
Yeah. A little bit. Yeah.
If that's what you would like me to do. Yeah, it's a 24-week trial. We're targeting functional class two and three group one PH patients. We're allowing patients to come on double or triple therapy, including IV prostacyclins. We do have an entry criteria of a baseline pulmonary vascular resistance of at least 400 or greater. Our primary endpoint, as expected, would be a pulmonary vascular resistance reduction or improvement at week 24, and we do have a six-minute walk as our secondary endpoint, although we're not powered for six-minute walk. We're powered primarily for our PVR.
What is good data from this study? We're looking at the PVR and six-minute walk data from the IMPRES trial, also some data from sotatercept. What are you looking to see, and how should we think about any important differences in the patient populations across these trials?
Yeah. What I would say is our expectations of a profile that we would like to see is really anchored, to some extent, on what IMPRES demonstrated and what Sotatercept demonstrated. If you look at the PVR data, IMPRES in their phase II and phase III showed approximately a 20% and 32% improvement in PVR. Then Sotatercept similarly showed, I believe 18% and a 30-ish%, their low and high dose on PVR. We would similarly like to see. You know, those are the guideposts for us. We would like to see a PVR placebo-adjusted improvement somewhere within that range. Obviously, our underlying thesis is we're going to have an improved therapeutic profile or safety profile relative to an oral kinase inhibitor.
We're hoping to see improved tolerability and safety profile. We're already, I would say, given our completion rate, if you will, in the double-blind to date and sort of roll over into our open label extension, quite encouraged by, you know, I think the tolerability.
Mm-hmm.
That patients seem to be experiencing.
Mm-hmm. Makes sense. Can you comment to the extent you've disclosed on the patient baseline and any differences you're expecting versus, say, the Sotatercept PULSAR study or even going way back to the IMPRES study?
Yeah. I would say we're likely going to be much closer to Sotatercept in terms of baseline characteristics. Our inclusion criteria are very similar. You know, IMPRES was done, what, 13-14 years ago. You know, patients are more treated now with more triple therapy. Overall, they're just treated more, you know, more intensely.
Any expectation in terms of the proportion on triple therapy in TORREY?
Once again, it's sort of similar to Sotatercept, so probably be like 50/50.
Mm-hmm.
Ish.
Got it. Makes sense. You alluded to you're encouraged by the tolerability seen so far and the number maybe entering the open label extension. To the extent you can comment, can you provide more color on maybe some of what you're learning, any, you know, interesting takeaways from what you're seeing in the open label extension?
Yeah. What I would say is that we continue to be encouraged that both physician and patients are going into the OLE. That speaks to, I think, the safety and tolerability. We've disclosed that nearly 95% of the patients who have completed the 24 weeks are going into the OLE. I think that that speaks to physician and patient comfort with the molecule. That, again, is a, I think, a very good sign that, you know, again, a DPI presentation, where there has been history, albeit with a different molecule, of some side effects, that we're well through that and people are really looking towards, you know, extended exposure to the compound.
Got it. Well, it's an exciting readout. We look forward to it before or after Thanksgiving. Perhaps that timeframe. Maybe just thinking in terms of the bar to move forward now, I know we're looking at, you know, comparing to data that was, you know, systemic administration. Given the unique mechanism of action, potential for combination, I guess, what's sort of the bare minimum efficacy that you think about in needing to see before moving forward into a larger trial, even if say a combination? Like, could it potentially be lower since you could combine it with other mechanisms? How are you thinking about that?
I think we have to see the totality of the data, Ellie. I think from our perspective, right, as Richard says, we can be somewhere between the low dose of Sotatercept and PULSAR and the high dose, right? Our thought leaders and investigators have said that that's something that is really interesting for us. Ultimately, you know, the forward projection of where those therapies could be commercially, I think, you know, just coming out of the American Thoracic Society meeting last week, there's a lot of excitement about combination, right? You have two different mechanisms, two different targets. Two different ways of presentation, DPI versus injection. You know, could we, in combination, get to a terrific place for patients?
Obviously, that data in the works is on the way, but if Seralutinib performs somewhere between where Sotatercept did with PULSAR, and we continue with the totality of data to have the safety profile we're experiencing today, that would be something that would be very encouraging for us to move forward to phase III.
Mm-hmm. Great. Looking forward to it. Moving on to the BTK inhibitor franchise. I've heard you say in the past that this could potentially be the first Gossamer product on the market. Tell us a bit more about the strategy here and when we could expect to learn more from the initial clinical readouts.
Well, I'll let Rich talk a little bit about the clinical plan, but I'm happy to say that we dosed our first patient actually two days ago.
Oh, congratulations.
in New Zealand. That was a big milestone for the program. We have a very, very active and aggressive enrollment plan throughout the globe for just what is a terrible disease. Primary CNS lymphoma, no approved treatments, off-label use of ibrutinib at very high levels, you know, methotrexate, just a place where there is such a high unmet medical need that we think GB5121 could really be a powerful entrant for patients in this disease. But Rich, you want to talk a little bit about the clinical plan?
Right now, you know, we're conducting our phase I dose escalation expansion. It's actually a phase I, II. We're getting through our dose escalation and then expansion to figure out what our phase II dose is going to be. We'll go into a registrational phase II trial design. As Bryan indicated, we're on our way, given that we've dosed our first patient with a CNS lymphoma.
When it comes to GB5121 and the CNS lymphomas, can you help us understand, I guess, what we do know about the efficacy from ibrutinib so far of BTK inhibitors in these patients, as well as maybe the, you know, added benefit or the increased CNS penetrance that you're getting from GB5121?
Yeah, sure. You know, ibrutinib is generally quite effective. However, you have to go up as high as 840 mg, which is at least double the dose that is typically used. In that scenario, the studies have shown at least an ORR of between 50%-80%. But because of the tolerability concerns, the progression-free survival is very limited and on average is somewhere between, you know, three months to four months. Having a drug like GB5121 with superior CNS penetrance properties allow us to utilize a lower dose to get better CNS drug levels, which then covers the target much more profoundly over a dosing cycle.
In addition, we have greater kinase specificity that even with some systemic exposure, we're going to limit some of the side effect profile that generally is associated with BTKs. The thesis here is that with greater CNS penetrance, we should see very good ORR, but a potential advantage is we're going to have better durability of response because we're going to cover the target, the BTK target in the brain or in the tumor, I should say, better. There's less chance of escape mutants, and we're just going to have better durability of responses.
Mm-hmm. Can you help us understand maybe the, you know, current standard of care in this patient population, and the size of the patient population here?
In the U.S., there's about 1,500 or so patients, similarly in Europe. First-line therapy generally is high-dose IV methotrexate, and that's because methotrexate does get into the brain. Although with the high dose you do get tolerability and hematologic issues. With first line there is good ORR, but once again, because of the tolerability issue, patients relapse or they get refractory to that treatment. The next level up is either radiation therapy to the brain or various investigators or experts in the field have tried various combinations of either methotrexate or ibrutinib and Rituxan or ibrutinib and chemotherapy, you know, trying to find the right combination of therapies.
Despite all of that, our investigators are quite excited about the potential profile of GB5121. You know, given the challenges that I described, the opportunity or the promise that it could offer for their patients. I would just add that while we're focusing on primarily CNS lymphoma, there's also secondary lymphoma that gets into the brain. We're also going to be studying vitreoretinal lymphoma, that's a lymphoma that affects the eye, and it could be a component of CNS lymphoma. There's some other relapses of more hematologic malignancies that also go into the brain that, you know, that we could potentially expand beyond the primary CNS lymphoma that we're currently studying.
Mm-hmm. Interesting. Maybe first starting with primary CNS lymphoma, what are you looking to see in the phase Ib data? You've mentioned starting a potentially registrational phase II next year. I guess, first, what are you looking to see in the initial phase Ib? Then when you think about a registrational design, I guess, what's the hurdle from a regulatory perspective, either from an ORR or perhaps durability and PFS perspective?
What, you know, the nice thing about BTK inhibitors in a way is that we have receptor occupancy, right?
Mm-hmm
In the periphery, and we can model that in the brain, so to speak. What we want to see in the dose escalation is to rapidly move through that and get to a good dose, recommended dose for phase II, and then get additional safety experience through the expansion phase. Through that experience, you know, there are standard criteria that measure success in PCNSL, and that's through MRI imaging, as well as some biomarkers that you could detect in the CSF or cerebrospinal fluid of these patients. In principle, what we like to see is a good response based on MRI, and there's clear-cut criteria that determine success for that.
What we would then do is take the phase II dose selection into our pivotal trial with the MRI endpoint as a clear endpoint. Ideally, what we like to see is at least an ORR somewhere in between 50%-80%, you know, because that's what was seen with ibrutinib. More specifically, ideally, we like to see the durability of response longer than the three months to four months that patients on average currently see and extend that beyond six months or longer.
Mm-hmm. Makes sense. Are we going to get any response rate data this year, or is this more of a 2023-type readout once you get to the right dose level?
Yeah. I think we'll get some preliminary, you know, albeit limited data in our initial escalation cohorts, you know, maybe two to three cohorts by the end of the year. Yeah, absolutely. I think the more robust data will be coming out next year.
Mm-hmm. Okay. Well, we'll stay tuned for that. Exciting 2023. Just quickly before I move on to the MS programs, you mentioned a couple other indications like secondary CNS lymphoma that, you know, expands to the eye and then, you know, other malignancies that go into the CNS. Can you tell us a little bit more about some of the patient numbers behind this, as well as the timeframe for when you could move into these, you know, broader CNS implicated tumor types?
Yeah. Well, we're actually, as part of our expansion escalation, we're actually integrating those tumor types in our current trial.
Okay.
We will get some experience in those populations to see if we can move the needle, so to speak. Obviously, all these lymphomas are quite rare. Collectively, I think there's a big unmet medical need and, you know, Bryan could talk to more of the other potential that we see.
Well, I think this is, you know. Again, if you're getting a very potent anti-cancer agent into the brain, there's a lot of places you can go, or especially with, you know, the dose levels that we're looking at. Primary CNS lymphoma, second line, lymphoma of the eye are just the beginning of what could be a nice franchise in the brain for this program.
Mm-hmm. Absolutely. Well, we're excited to learn more. Turning to, you know, moving the CNS penetrant BTK programs into MS, can you tell us a bit more about that program and the timelines there?
We did announce that we are shifting that timeline a bit, and that's really around capital allocation and preservation. We had a series of fairly expansive and expensive tox studies, as well as contemplating first in human work in the second half of this year. We made a decision with our board that we should just hit a pause on that to see Seralutinib through, and understand where the company will be and where 5121 is before we make those additional investments. We still absolutely love the program.
There are some attributes to GB7208 that are differentiated from GB5121 that may lend itself to more utility in neuroinflammatory conditions. We all live in the marketplace that we're in right now, and so we felt it prudent to extend cash as far as we could and being able to make some other operational changes around the company, as well as this pause with GB7208 really allows us to drive runway into the second quarter of 2024, which we thought very appropriate, as we're approaching a very important readout with Seralutinib, but then a series of readouts that we would expect next year on GB5121, which will really shape where the company goes.
Mm-hmm. Can you tell us more about that in terms of thinking about the cash runway, how you get to that projection in terms of 2024 and, you know, strategic decisions around which assets to develop yourself around that?
Yeah. You know, it was very straightforward, Eliana. I mean, I think, you know, when you have a clinical setback, and thus a lack of an opportunity to raise additional capital, you know, you have to do what I think any responsible company does, which is tighten your belt a bit, which is what we did. Throughout the clinical program and our research program, you know, we really wanted to focus on doing what needs to be done versus what's nice to do, what is going to continue to advance our programs and create shareholder value versus having, you know, things that would be interesting but not mission-critical.
We were able to, with both, you know, mothballing, some activities, as well as being very smart about how we were utilizing contractors and consultants, as well as just putting off some, you know, expensive work. Safety studies for potential MS, clinical work are not for the faint of heart when it comes to the size and scale of those. Really what our focus was is let's understand where Seralutinib is and what it could be. We also wanted to make sure that we could make some of the appropriate phase III investments, prior to the data. What does that mean?
That means starting to work with vendors on phase III drug supply, talking to potential CROs, engaging with the right level of advocacy in areas so that we can have a very rapid transition after positive TORREY data into the phase III. When you have to balance what's going to have the greatest bang for our buck, if you will, it was making sure that we could have Seralutinib in a good place, GB5121 in a good place, and have the right rationalization of runway elongation.
Mm-hmm. Absolutely. Makes sense. Well, with that, Richard, Bryan, it was so great chatting with you, and very much looking forward to a rich year ahead with a lot of data readouts.
Thank you very much, Eliana. It's great to be here.
Thank you, Ellie.