Are necessary for a successful SMARCA2 directed agent? Obviously, it sounds like degrader or inhibitor is one of the things. What are some of the key properties you think are necessary for this kind of agent to be successful?
Yeah, so we know from our pre-clinical models that if you hit both four and two, that you have quite a bit of toxicity. The degradation of two allows and selectivity and potency for two actually allows you to be able to have a wider therapeutic index as well as the ability to avoid off-target toxicity.
OK. You do have two SMARCA2 degraders in the clinic. One's oral, one's IV. How do these two agents kind of compare and contrast given the same target? How do you think then about the best role for each of them?
Yeah, the IV went into the clinic first, and it's the one we had available to go to the clinic. It's a VHL-based versus Cereblon. Those are slightly different molecules, the IV and the oral. I think the IV has provided really nice proof of concept for the pathway because this is a novel pathway. We showed responses using the IV. There are some patient populations where the IV may be more applicable, for instance, where we showed activity in upper GI where people might have trouble swallowing pills, those areas. I think they're complementary. Of course, if the oral catches up, which we are rapidly advancing due to our knowledge that we gained from the IV, we will be able to think about what is the best way to deploy one or both.
OK. Maybe let's start then to dig a little deeper on each of those agents. PRT3789, I believe, is the IV. Dose escalation is still ongoing. There's been, I think, 11 doses in the clinic to date. Can you talk to us about that pretty extensive dose escalation program?
Yeah, so we actually just completed a selection of the dose. We went through up to 10 doses, and then we did not do the 11th. Because it was a novel epigenetic mechanism, first in class, we were required by the health authorities to go very slow because it was through a Fibonacci sequence of dose escalation. You could not do your 67% steps. From that, we really just went into the clinic quite quickly. But the.
Maybe just to add to that, you know, if there was toxicity, like with some other agents that were seen, then you would stop, right? In this case, because the way that the molecules were designed to be very, very selective for two, we did not see the toxicity that allowed us to continue to push the doses to see, you know, to try to get the maximum degradation possible.
Yeah, so you know we selected our dose recently that was announced this last quarter at 500 per meter squared, which is dose level nine, not the top dose. We actually just stopped not because of DLTs, but because we looked at the totality of data and thought that 500 would give us the maximum benefit.
OK. Maybe to follow up on that, what were you using to judge kind of like the maximum level of benefit? What are the key kind of properties of the drug that you saw that gave you confidence in moving forward to the 500?
Yeah, we looked at tissue degradation of SMARCA2 as well as peripheral blood, the PK properties, the safety properties, and activity.
OK. You've reported some early efficacy across a number of tumor types. Maybe you could walk through the efficacy data to date.
Yeah, so the important part to recognize is when we started the program, we went a little bit broad. We looked at all SMARCA4 mutations because there was very little known. It's possible that there's two types, class 1 and class 2. Class one are known to be loss of function of the SMARCA4 protein. Class two's, you can detect the protein, and it may or may not be loss of function. We wanted to understand the whole landscape. As we narrowed in in our backfill cohorts, we looked specifically at loss of function. We see that the activity is in the upper GI and non-small cell lung cancer tumor types. That's not to say that there might not be other activity in other tumor types, but that's where we saw it.
In the other tumor types, for instance, we had a couple of breast cancer patients that were enrolled, but they were like ninth or tenth line. In a phase 1 for us, you know, lowest hanging fruit is to really hone in on the upper GI and lung cancer.
OK. I think you reported an objective response rate around 23% at some of the higher dose levels. How does this compare to kind of expectations for this patient population? As you mentioned, this is a phase 1 study, so pretty beat-up patients usually.
Yeah, so for lung cancer, as I mentioned, docetaxel would have been what the patients would have gotten. Docetaxel at best is a 15% response rate. That is all comers, including those that do not harbor a SMARCA4 mutation. Based on my discussions with the investigators, you know, the target overall response rate would be around 5%-10%. A 23% response rate we are very encouraged by.
OK. You mentioned that you selected a dose now. Maybe you can talk to us about the next steps for the monotherapy study here. What sort of data should we be expecting over the intermediate term?
Yeah, we will report on the full data set toward the end of the year in terms of the outcomes and the efficacy and activity based on the dose that we selected. In terms of there's also a chemo combo as part of it with docetaxel that we'll report out on around 10-15 patients' worth of data in the specific population, looking really down at the loss of function, lung, and upper GI. As I sort of alluded to and Kris alluded to, the oral is really catching up quite quickly because we just went into the clinic in October. We're at the sixth dose cohort now. We have learned so much from the IV that we were able to really focus in not only on the investigators, but also the patient population. Able to accelerate that.
If the oral catches up, we'll have some decisions to make on how we want to develop.
OK. We're going to move to the oral in a second. Let me just put a bow on the conversation around the IV. As we think about the data that is coming, I guess, what would you think are metrics for success that give you additional confidence in moving forward with either one of the programs given the same mechanism?
Yeah, even though the overall historical control, let's say, would be guessed to be around 5%-10%, you want a comfortable margin, right? You want to see at least 30%, 30%-40% in a reasonable number of patients to be able to move it for single arm towards registration. That would be the typical bar.
OK. Maybe we can talk about the oral then. Let's talk first about the key features of the oral program. What are the advantages you see between this and IV?
Yeah, certainly because of targeted therapies that are out there right now, I'm still seeing patients in the clinic. I know that the patients far prefer the oral. You don't use chair time, et cetera. You don't have to come back to the clinic every week, which is the IV. The oral as a convenience, as well as in addition to having the convenience, you also have the ability to really target SMARCA2 on a daily basis. You really inhibit it 24/7, basically, or degrade it 24/7 and drive those levels even lower, thus potentially increasing the activity even further.
Can you talk about the key technical features or challenges that you had to overcome to get an oral with the right properties versus an IV?
Maybe Kris can take that.
Yeah, I can take that. When we started the program, oral was not an afterthought. We wanted to actually go with both VHL and Cereblon-based degraders or like ends. The reason for that is that VHLs are very big molecules, right? It is hard to get oral viability. There are really no known VHL-based degraders that actually have good oral viability. We went down the path of Cereblon. It is actually because the technology leverages the sort of ubiquitization of lysine, it is a significant challenge to design a Cereblon-based molecule that only ubiquitinated SMARCA2, but not SMARCA4, right? That took longer than VHL. We were able to crack that with VHL first. That allowed us to identify specific lysines that we iterated on using the Cereblon. Once the binders are, you know, we understood the properties.
Getting oral viability is another challenge because these are very large molecules, right? On the positive side, because you're degrading, as Jane was saying, you are actually—it's not like an inhibitor where you need it to cover. We do want to cover around the clock. We want to take it out as much as possible. As in the case of epigenetic mechanisms, you know, the more, the better, right? It gave us an opportunity with the oral, like daily dosing, you know, even though it is a large molecule, we don't need enormous concentrations in the blood to be able to really achieve our intended pharmacology and target engagement. That's kind of how we thought about it. We're very, very pleased with the molecule our team was able to design and come up with, the 7732.
Perfect. Maybe you could spend some time on the development program. As you mentioned, it's sort of catching up. Where are we today in terms of development? What should we expect to see in terms of data over the near term?
Yeah, so we're in dose escalation, as I mentioned, at 60 milligrams for the oral, which is approaching the DC50 that you want to achieve. If we're at this same clip, assuming we have the same safety profile as we continue to dose escalate, we should be able to select our dose by the end of the year and then decide on what our registration path would be.
What are the patient populations included in these early studies? How should we think about when you do report data, like the number of patients, the time on therapy? What are the key things to understand about that?
Yeah, so while the design is very similar where we allow more patients, you know, because when you're trying to go through dose escalation, you do want to amass as much safety information as you can. Really, we are trying to focus in on the lung upper GI loss of function patients. And so we'll have a pretty robust data set around that.
You've mentioned a couple of times that one of the keys for these types of drugs is to keep pretty good kind of target coverage over the dosing, like over the treatment period. How do you then think about dose selection, making sure that you don't have doses where dose reductions or any sort of holds, et cetera, are required to keep patients on therapy?
The beauty of our molecule being a specific degrader right now is that we're having a very clean safety profile. We haven't seen any cumulative toxicity. If you look at the IV, you can see that our adverse event profile is really quite good as monotherapy in terms of there were no DLTs. From the oral, we're progressing so rapidly, you can basically ascertain that we have a very similar safety profile. From that perspective, I think we feel quite good that we should not have to have that many dose reductions. This is a sick population. Naturally, as you go into earlier lines, you would expect less and less dose holds, for instance, for drug holds.
OK. Once you have the dose selection, I guess, what is the path forward in terms of is there like an accelerated approval path? Or what's the kind of registrational plan for this kind of program?
Yeah, certainly while we haven't had those discussions yet with the health authorities, we have certainly thought about this being a biomarker-selected population really lends itself towards a faster pathway because there's no other really good options for this. It is an aggressive disease. A potential would be to pick a tumor type and do the single arm accelerated approval pathway.
OK. In terms of combination strategies, are there any combinations that are kind of like make a lot of sense with this mechanism? Could you speak to that?
Yeah, preclinically, we did see combinatorial synergies in terms of both immunotherapies. We tested pembrolizumab preclinically. We saw that you had increased T- Cell engagement and that you could turn the cold tumors hot, essentially, is how I think about it. Knowing that these patients have specifically SMARCA4 loss of function, patients often have low PD-L1. That could be a reason that they're not responding as well to frontline therapy with chemoimmunotherapy. We certainly for the IV actually have an ongoing study looking at the combination with pembrolizumab. With chemotherapy, there also is thought to be synergistic activity if you combine. Those are the two things that we would be looking at quite carefully.
Is the role of combinations in your view, I guess, will that kind of be in specific patient populations, whether it's line of therapy or different tumor types? Or is this going to be kind of like where you move with the whole program?
Yeah, I think the natural progression would be to target frontline non-small cell lung cancer. Knowing that the progression-free survival in these patients is 2.7 months, we need to get to the front line as quickly as possible because there really are we didn't cover overlapping co-mutations. Really, there are no other overlapping targetable co-mutations. EGFR is non-overlapping. KRAS is a very small percentage. ALK, none of them overlap. This would be a very specific patient population for us to go after.
OK, understood. Anything else you want us to understand about this program before I spend a few minutes on CDK6?
No, we're just happy about the progress we've made and looking forward to the completion of the phase one toward the end of the year.
Just strategically, you know, as Jane said, that because of the attractiveness of the oral as an approach for these and other patients and the progress we've made and based on the learnings from IV and the POC from IV, we are planning to make a decision on which one, prioritize one over the other, or relatively soon. I think we're almost there.
On the CDK6 degrader, you did allude to this earlier, but let's go back. It's been an emerging target of some interest. Maybe first you can speak to the proposed mechanism of action and sort of the tumor types that are going to be most sensitive to it.
Yeah, so you know this is a, I mean, this is CDK6 as a target, which is an epigenetic target. And there's been observed reported amplifications in CDK6 here, which is what originally got people to be interested to look at this. Pfizer actually generated the first clinical data with an inhibitor that there is A and B, just like everything seems to be. There are no more than one family members. In this case, there is A and B. And there are others. Some people are targeting CDK7, for instance. There are a number of these proteins that are part of the large complex. When we saw, I mean, we've been interested in it from the standpoint of, again, as a precision oncology company targeting amplifications that could potentially allow us to go after tumors or cancers that have no good therapies.
We saw that we have been working on it as a degrader approach because we have built a lot of expertise on degraders internally. When we first looked at this as a target, we felt that we could actually go after this and be selective for one versus the other. That was our initial hope. When the clinical data came out, and in fact, Pfizer's work kind of narrowed it down to positive breast cancer. The jury is still out there with regard to other tumor types where there is also CDK6 amplification and what happens, or can you target those. For now, the focus from everybody is positive breast cancer because high response rates when you combine with fellow students, 37% response rate that they have just recently reported at ASCO.
From a biology standpoint, what we've been able to show, and we had a recent publication or presentation at AACR, that we were able to design CDK6A selective molecules. What's interesting is, although there is genetic evidence pointing to potential role for both of them, A and B in bone marrow function, when we were able to selectively target A, we were able to show in vitro and preclinically less impact on bone marrow. Obviously, this has to be proven further. At the moment, there is a therapeutic rationale of going selectively after A as an approach to reducing one of the key toxicities of the Pfizer compound, which is neutropenia. That's kind of the idea.
The team has been able to make really good progress in terms of not only identifying highly selective, exquisitely selective A degraders, but also coming up with really attractive molecules that have all the other properties you want, not just biochemical cellular properties, but the PK and PD and all the safety profiles. That is kind of where we are with that program.
OK. I think you mentioned this, but the degrader versus inhibitor advantages, maybe you can just quickly enumerate those?
Yeah, so again, like SMARCA, in some ways, there are certain similarities with our SMARCA2 and SMARCA4 program here. These proteins are fairly similar, right? Designing an inhibitor is a challenge. I'm not saying it can't be done, but it looks like some people are trying to do that. I think from our standpoint, there are two benefits. We were able to design degraders that are exquisitely selective for A. That is one benefit. We were able to prove preclinically targeting A was sufficient, meaning you have similar or even better activity than dual inhibitors by just only selective but degrading. That is the second benefit. Just in terms of overall target coverage with the degraders, that is the reason why many companies have gone after or are going after degraders, because you are taking the protein out.
Your pharmacology is based on how fast the protein regenerates rather than whether you're able to keep the levels around the clock. It just gives you a little bit more flexibility in terms of the target doses and target concentration.
OK. Maybe quickly, the next steps for this program?
As I said, not only do we have good preclinical POC, but we actually have molecules that we think are pretty attractive as development candidates. We're evaluating those. Depending on the amount of capital that we're able to allocate or other ways of funding it, we would like to take this into the IND next year. Sometimes it does happen.
You also have an ADC pipeline. You mentioned this earlier. I guess why think about moving into ADCs? You've already got this kind of like degrader technology. So why is that attractive?
Yeah, again, this is all kind of built around the same theme, right? As I said in the very beginning, our approach in building the company and our vision is to come up with novel treatment options for patients with highly aggressive cancers. The same mechanism is not obviously going to be effective in all tumor types, depending on what's driving it. We've already seen how powerful ADCs with the cytotoxic chemotherapy payloads are. What it allowed us to do is to combine the technologies, like the degrader technology that we've developed internally. Now we have SMARCA2, SMARCA4, two different molecules moving forward with CDK6 behind.
All the learning, we just asked the question, can you deliver degraders that are otherwise not tolerated systemically directly to tumors where you can take advantage of the tumor specificity and be able to target the pathways you could not otherwise target systemically? We presented some data at, I think, a triple meeting last year. We are collaborating with AbCellera. We are not an antibody company. AbCellera is obviously a very, very powerful antibody discovery company. We discussed this potential collaboration. It seemed very logical to be able to actually kind of expand the reach of the SMARCA2, IV. We talked about how you could not tolerate II and IV, taking II and IV out, right? There are tumor types where they are very, very dependent on both of them.
We made picomolar II, IV dual degraders that we could not give systemically orally or IV. We were able to put them on antibody and safely deliver two drugs. We are not doing all of this on our own. We are really working with a very, very capable company in the antibody space. We see a great future in this space. Obviously, we are very early stages. It does allow us to potentially bring in some interesting collaboration BD opportunities as well, having this technology in our possession.
Maybe we can wrap with a quick question on cash runway. What's the current balance sheet and runway? What activities are embedded in that?
Sure. Our cash position, as recently reported in our Q1 press release, is $103 million. That takes us into Q2 of 2026. Everything that Jane and Chris has been talking about as it relates to SMARCA, oral, CDK6, our collaboration with AbCellera are all zoomed and sub-zoomed, if you will, in that number.
Perfect. I think that probably brings me to the end of my questions. It was great having you guys here this morning, great chatting with you. Love learning about the story. Thanks to everyone who joined us here and online. Thank you.
Thanks. Appreciate the opportunity and look forward to reporting the progress in the next coming months.
Beautiful. Beautiful. Thank you.
Thank you.