Okay, I guess we're ready to start. Good afternoon, everyone. I'm Janani Sundararajan, and I'm happy to introduce our next guest for today's session, Dr. Tim Lu, co-founder and CEO of Senti Biosciences. Thank you for joining us today.
Thanks.
The format for this session is a fireside chat, roughly about twenty-five minutes, and during the session, if anybody in the audience has questions, please raise your hand. Okay, so to begin with, could you please provide a brief overview of Senti for those that are new to the story and highlight on upcoming catalysts?
Sure, yeah. So thanks a lot for the opportunity to be here. I'm really excited to share some of what we're doing at Senti, as well as some of the upcoming news that's coming out. So, Senti is a biotech company I co-founded with a variety of sort of leaders in the synthetic biology space, really focused on introducing control, specificity, and ultimately greater efficacy in cell and gene therapies, broadly speaking. We're based out in South San Francisco, California. We have a pipeline of internal cell therapy programs at this point, focused on oncology, really trying to solve the issues of target selection and specificity and efficacy.
At the same time, we've done partnerships with other companies outside of the space of oncology, including with Spark, around designing very specific promoters for AAV gene therapy, as well as with BlueRock around engineering iPSC-derived cells, so at the core of what Senti does, it's really what we call a gene circuit engineering company, very much focused on introducing greater control into cell and gene therapies, and what we've been focused on over the last couple of years is driving our lead programs into the clinic. I think we've guided externally that we will release data on our lead program, SENTI-202, this year, and we're certainly making great progress in the clinic and looking forward to that.
Great, thank you. So before we touch on all these different, you know, topics that you just mentioned, can you walk us through your gene circuits technology platform and help us understand how it addresses current limitations in the space?
Yeah. So I think one of the main areas that we focus on is that current therapeutics, especially for cancer, are essentially, at this point, limited by targets. We have a lot of great modalities like T-cell engagers, ADCs, CAR-Ts, CAR NK cells, that can recognize a single target really well and kill everything that expresses that target. So at the end of the day, we only have so many, you know, clean, single targets available to us in cancer. There's not that many targets that are only expressed on cancer cells and not expressed anywhere else. And so what Senti is really focused on in the oncology space is broadening out the target space.
Instead of relying on just a single target to differentiate cancer cells versus healthy cells, why not build a product that can recognize two or three targets and use some combination of those targets as the sign that this is a cancer cell and this is a healthy cell? By doing that, we think we can really introduce a new way of thinking about targeting cancer that's multimodal, multi-target, in nature.
Great. So now let's jump to your lead program, SENTI-202, and talk about how it, you know, incorporates some of these aspects.
Yeah.
So SENTI-202 is targeting hematologic malignancies, including AML. So let's start off by, you know, understanding a little bit of a background on AML and, you know, why this is a good lead indication-
Yeah
... to start with.
SENTI-202 is currently in a phase I study in relapsed refractory AML. That's an indication that, unfortunately, has very poor prognosis for patients, median survival, about five months or so for patients that have relapsed on upfront therapy. And AML is one of those classic cancers where there is not a single clean target available to it. So unlike, you know, CD19 or BCMA and other hematological malignancies, where you can go in and wipe out all the cells that express that particular target, AML doesn't have a target like that. All the targets in AML that we know of on the cell surface are expressed not just on AML, but they're also expressed on some component of the healthy body, including the healthy stem cells. And so what SENTI-202 is really designed to do is to try to tackle this problem.
It's a CAR NK product, allogeneic, that's designed to recognize two cancer targets, CD33 and FLT3. Both of these are really well known in the space. You know, there's an ADC Mylotarg that goes after CD33. So by going after both CD33 and FLT3, we can hopefully drive deeper responses, attack AML blasts, and leukemic stem cells. This seems like a kind of an obvious idea. Why haven't people done this before? It turns out it's because these targets are found on healthy cells. So how do we protect against that? We've used our gene circuit technology to essentially identify those healthy stem cells through another target called Endomucin. Endomucin is highly expressed on the healthy cells. It's not found on the cancer cells, and that basically serves as a "don't eat me" signal to our product.
So we've engineered a, basically a second inhibitory receptor that recognizes endomucin and basically tells the CAR NK cell, you know, "Don't touch those cells, and sort of stay off of it." So what we hope to be able to demonstrate is that this allows us to drive, you know, deep, durable responses in patients with AML while mitigating the toxicities that we've seen with other AML-targeted products.
Great. And so you touched on this a little bit, but why CD33 and FLT3?
Yeah
... you know, specifically from all the other possible-
Yeah
... targets?
We really wanted to start off with ideally validated targets in this space.
Mm-hmm.
CD33 is a proven target in AML. It's also known clearly to be expressed off-target on healthy stem cells. FLT3 is also a known target in AML. You know, there's FLT3 small molecule inhibitors that target the intracellular side of FLT3. However, you know, the extracellular side of FLT3 is actually a very intriguing target that many companies have been trying to attack in the past with conventional strategies, including CAR-Ts or T-cell engagers. However, FLT3 is a very good marker for hematopoietic stem cells as well. We believe that going after CD33 and FLT3 will allow us to drive deeper responses in a heterogeneous disease, especially by being able to attack AML blasts and leukemic stem cells at the same time.
Mm-hmm.
And so by hitting these two targets, you can get a broader coverage, but we have to solve the problem of the, you know, off-target expression, off-tumor expression on the stem cells.
... Got it. So another aspect of SENTI-202, which you also mentioned, which is that it's a CAR NK product.
Yeah.
So why specifically go, you know-
Yeah.
Use NK cells here, as opposed to other cell sources?
Our gene circuit technology actually works really broadly.
Mm-hmm
Across cell types. So we've shown that this logic gate approach works in T cells, it works in NK cells. And I think depending on the indication, you may choose one cell type versus another. Specifically for AML, we chose to use NKs for a variety of reasons. We know that NK cells on their own have, you know, good basal killing activity against AML, so you have a baseline of anti-AML activity through the NK approach. You can make allogeneic NK cells and deliver them to patients with AML. That's been shown to be pretty safe in the past. And frankly speaking, it's pretty challenging oftentimes to make good CAR T products from patients with AML.
You know, they're coming from a background of, you know, being treated with chemotherapy or sort of just having sort of poor quality cells in many cases. So we think an off-the-shelf allogeneic approach using NK that basically has this baseline AML killing, and boosting it with the ability to go after CD33 FLT3 makes a lot of sense here.
Got it. And so just pivoting a little bit, because you spoke about how your platform can be applicable across many different cell types and not just NK cells.
Yeah.
So can you speak a little bit about any data that you've generated, you know, to this aspect?
Yeah.
And what some applications of
Sure
... this could be?
Yeah, we've shown that with our most optimized logic gate, what we call the NOT gate, do not eat, you know, do not kill this healthy cell, that's the sort of the idea. We can achieve, you know, 90% or higher protection of healthy cells in a variety of models. So we've looked at doing that in the AML setting, we've done that for a variety of solid tumor targets as well. So for example, we've previously described a CAR T or as well as CAR NK product, we actually built both versions of this, that go after CEA, which is a known target for colorectal cancer. CEA is actually known to also be expressed on healthy epithelial cells.
And so what we did there in both NK as well as in T cells is we showed that we could kill CEA-expressing cancer cells by using our NOT gate, our logic gate. We could actually protect the healthy cells by recognizing another target, in this case called VSIG2. And so that has a lot of promise, I think, for expanding this platform. As we hope to be successful in AML, there's a lot of use cases in the solid tumor space, where there are clean targets, sorry, lack of clean targets in specific areas, and we can use CAR T products, CAR NK products, or other cell types that may come about in the future.
Okay.
Yeah.
So let's come back to SENTI-202. So can you first start off by describing any preclinical data that you've generated that gives you most confidence of-
Yeah
... success in the clinic?
I think one of the first things we did when we were developing this program is to look at, along what you said, what combination of target antigens should we go after? Should we do CD33/FLT3, CLL1, CD123, et cetera? One of the core principles of what we wanted to do at Senti was not only target the blasts, but also the leukemic stem cells, which is a rare population in AML that oftentimes is missed by a lot of therapies and can regrow in these patients. We started looking for what combination of markers could help us cover both populations quite well.
Mm-hmm.
And again, it turns out there's no single target that can do that. But you know, looking at you know, RNA sequencing as well as patient-derived samples, it turned out that FLT3 and CD33 complemented each other really well. CD33 is usually highly expressed on the blasts and some of the leukemic stem cells. FLT3 is very highly expressed on leukemic stem cells. And so by going after these two targets, we tested across a variety of patient-derived samples, showing that we could eradicate or significantly suppress models of AML from a variety of backgrounds across different subtypes of AML. We showed that in vivo we could get significant extension of survival in mice, you know, up to 200 days when the sort of standard treatment in mice was like 50. And then we also looked at protection.
Protection of healthy human hematopoietic stem cells, both in vitro as well as in vivo, and we showed that our logic gate system could actually protect those cells from being killed. That gave us a lot of confidence that this product was working as intended and could have the potential therapeutic activity in humans.
Great. So based on this, I mean, you've moved your SENTI-202 into the clinic now.
Yeah.
Earlier this year, you started dosing patients in a phase I trial. So based on the preclinical data, can you describe kind of like how you've structured your phase I trial, the patients that you're-
Okay
... looking at, and the trial endpoints?
Yeah. So yeah, we have a phase 1 trial open both here in the U.S. as well as in Australia. I think we're seeing a lot of great PI enthusiasm for the program, so we're really excited to have a lot of interest in what we're doing. We are going after a relapsed refractory AML population. We're starting with patients that are being treated essentially first with a lymphodepletion step using Flu/Ara-C as a lymphodepletion to clear some space out for the cells. We can then give three doses of the cells. We're currently dosing at day zero, day seven, and day 14, so one week apart, and then we assess for response at 28 days. In the protocol, we have the ability to do repeat cycles if the patient is showing evidence of response.
And that's essentially the structure of the trial. We do have the ability to dose escalate, so this is designed as a three by three, you know, standard study. You know, we're starting off with the one billion cells per dose cohort.
Mm-hmm.
Then, you know, after doing that, we're gonna dose escalate to 1.5 and look at those patients, and ultimately, hopefully find our, you know, recommended phase II dose going forward.
Great. And so what are the trial endpoints that you'll be evaluating?
Yeah.
You know, can you expand a little about what relevant benchmarks in these patients-
Sure
... you know, that you'll be comparing them against?
So as a phase I study, we're obviously looking at, you know, standard things like safety. We wanna look at PK/PD, what are the cells doing, is repeat administration feasible? All those sort of baseline studies. But being an open label trial and certainly going directly into patients, we are looking for signs of efficacy.
Mm-hmm.
This is gonna be monitored both in terms of, you know, standard response criteria, as well as looking at about MRD status in these patients afterwards. You know, if they are responding, you know, how deep is that response? 'Cause we know the depth of response correlates with potential durability, downstream. So those are some of the sort of parameters that we're looking at. We are also looking to do some correlative studies of these patients, you know, looking at, you know, if we take the bone marrow, what subpopulations of cells can we see? Are we able to detect protection of the healthy cells? Is that manifesting itself in any way in terms of how these patients their normal blood counts rebound after LD? We're looking at all of those aspects together.
Great. So you've guided to releasing initial clinical data by the end of this year. So what can we expect to see in that data release?
Right. Yeah, so I think in AML there's sort of two aspects that we're interested in exploring. Certainly, the upfront depth of the responses that we're seeing and in what sort of patient backgrounds. You know, if we're seeing patients that have high blast counts come in and we're seeing good responses there, even MRD negative responses, we'd be really happy to see that.
Mm.
'Cause that, like I said, does correlate to the ability to, for example, take patients into transplant, which is, you know, a major next step for some of these patients in terms of curative therapy. There's also the opportunity to assess for long-term durability on our own product characteristics. So I think what we're looking at probably this year, just given timing, is be able to look at least the first patient cohort of the one billion cells per dose patients. We should have a sense of, you know, are we seeing responses there? And then we hope to, you know, next year, as we collect more data, have more time look at, you know, higher dose level cohorts and also durability of responses.
Mm. Great.
Yeah.
Okay, and so then after that, like, what are the next steps in this trial, and bigger picture, what is the regulatory pathway?
Yeah
... in this space?
It's an area of high medical need for sure. We're starting with relapsed refractory, but we have the ability potentially to expand into other indications. Our current protocol actually lets us explore in MDS, which is a related disease.
Mm-hmm
... to AML, so that's one potential direction we could go in. Certainly pediatric AML is another area that could be of interest, and also moving this into newly diagnosed AML populations is an area that, where we'd be interested in exploring in terms of expanding the commercial opportunity for the program. We do hope that if we see, you know, good, durable, deep responses with evidence of durability, that we can have a conversation with the FDA about what a pivotal study could look like, and we could then move into that, you know, downstream.
Okay, great. So before we move on, anything else that you would like to highlight about SENTI-202?
You know, it's taken us a bit of time to get here in terms of optimizing the gene circuit technology, but we're actually really excited to be in the clinic. I think we're seeing really a lot of excitement from the clinical side, especially the investigators who are working together with us. So, you know, we appreciate the patience from everyone, and we're really trying to get data out to the marketplace once it's ready to come out. Yeah.
Great. Look forward to seeing it.
Yeah.
So now moving on to your next program, SENTI-301A.
Yeah.
Can you briefly describe the design here and how it addresses the unmet need in the hepatocellular carcinoma space?
Sure. Yeah, so SENTI-301A is our next program. We've guided to that. Program is really focused, it's a, it is an allogeneic CAR NK cell going after GPC3 as a target, for liver cancer, as well as other solid tumors. I think some of you may know, earlier this year, there was some data that came out from AZ around GPC3 CAR T cells that was quite promising in terms of seeing responses. We like GPC3 as a target.
In this particular case, we also felt NK made sense as a potential chassis to use, in part because NK cells actually traffic to the liver quite effectively, and two, in prior GPC3 CAR T trials, there's actually been a pretty significant overhang of toxicity in many of those patients, and we think the NK chassis has the potential to be potentially much safer in this population as well. So we've partnered with a company in China called Celest Therapeutics. They're in the process of, you know, getting that first patient started. We hope to have that done this year, in terms of an IIT trial in China.
Okay, and so when can we expect to see initial data from this program?
Yeah, I think we're looking at that in 2025.
2025.
Yeah.
What will that potentially entail?
It's, you know, open-label study in the area. I think we have the ability to look at efficacy, so we're certainly looking for signs of that in addition to the routine, you know, safety and PK sort of profile of these programs.
Okay. I also want to briefly touch on your other collaborations, ongoing collaborations with Roche, Spark Therapeutics-
Yeah
... and Bayer BlueRock Therapeutics, on which you've presented data previously, so can you give us a brief update on how that's going?
Yeah, so just a little bit of context. I think I mentioned in the beginning, like, part of, really at the core of what Senti does is design cellular gene therapies with greater specificity or control built into them. Our internal program, we think, you know, makes a lot of sense for oncology applications, but there's actually a lot of uses for this. I'll mention with Spark and Roche, basically what that collaboration was focused on when it started was that, our partner had some great AAVs, some great biology they wanted to go after. But those AAVs didn't necessarily give them the level of specificity for certain-
Mm
... cell types, for example, in the eye or in the brain, or in other tissues. And it was difficult for them to... And I think this is a problem field-wide, is, you know, how do you engineer capsids to be so specific? It's actually quite challenging to do. So what we did for them is actually design promoters inside of the gene therapy that could complement the specificity of the AAV, and these promoters gave us, you know, 10,000-fold or greater specificity for specific cell types in the body. So we're really excited to have worked with Spark on that.
We've entered into the second phase of that collaboration, where they're now taking some of those lead candidates forward and testing it in their proprietary models, and we hope that, as those progress, then they have the ability to opt in to those promoters that they like and take those programs forward. For BlueRock/Bayer, that collaboration, as many of you may know, BlueRock is working on iPSC-derived cells for neuro as well as other areas. iPSC-derived cells, very exciting, but once you've implanted these in the body, you wanna be able to control them. You might wanna control their phenotype, what they're expressing in terms of payloads, especially if you're operating in the confines of the brain.
So similarly, we designed the genetic circuitry that goes into those products, handed them over to BlueRock for testing, and then they're planning to take those forward into a variety of downstream applications. Okay. Oh, that's a sign.
Okay.
Trying to get me off the stage.
Yeah.
May I have your attention please? May I have your attention please. This is your safety director. We are investigating the cause of the alarm. Please stand by for further information. Once again, this is your safety director. We are investigating the cause of the alarm. Please stand by for further information. Thank you.
Okay.
Icebreaker there.
Okay. Assuming that no one's going to speak for a little bit, can you, you know, one quick question on manufacturing?
Sure.
You know, we know you, you executed a transaction last year that established an independent contract manufacturing-
Yeah
... facility, GeneFab. So can you briefly touch on how this is going to be incorporated in your pipeline?
Yeah. So GeneFab was actually the spinout of the company GeneFab from Senti actually took over our manufacturing facility and is operating now as an independent CDMO. So they're the CDMO that we're using for our product. Actually, many of the Senti colleagues that were at Senti before are now actually at that facility, so they have a lot of experience with the program. You know, we've been very grateful to them continuing to help support the program. And certainly, as we go forward, as we continue to scale our process, we intend to continue to use the GeneFab facility for the foreseeable future.
Great. And so I also wanna tie in a question on your cash position-
Yeah
... and runway, and talk about, you know, can you talk about how that aligns with your overall strategy?
Sure
... for advancing SENTI-202 and your other programs?
Yeah. We were very fortunate, earlier this year actually, to receive a non-dilutive grant of $8 million from the California Institute for Regenerative Medicine, for the SENTI-202 program. It was funny because when we looked back at the scores, actually, I think we received the top scores in there, and, you know, it's very hard to get scientists to agree on anything. So we're really excited to, you know, have that support from CIRM. That was very helpful in terms of a cash infusion for the company. I think as we look forward to this year, as we're starting to collect data as an open-label trial, we certainly anticipate that that data, assuming it's positive, may serve as a catalyst for the company, for, you know, downstream financing as well.
We've previously guided to cash runway into the first half of 2025.
Okay. I wanna see if there are any questions from the audience, and if not, I wanna ask you a final question. So what would you say investors are missing about the Senti story?
Yeah, I think Senti, when we went public, I think we sort of ran into the perfect headwinds of a variety of things. We did go public through a De-SPAC process and sort of caught the tail end of that. Two, we were a preclinical company, you know, a very exciting one, but, you know, a couple of years away from the clinic at the time and, you know, certainly, I think investors today are looking for clinical data. And thirdly, I think there were examples of other cell therapies that may or may not have been doing well in the clinic. There was nothing really specific to Senti, but we caught the headwinds of all those. And so what I would say is, we are actually at a very unique time now.
I think, you know, we're valued at a very, very low price right now, an attractive entry point for investors. And actually, we're on the cusp of really starting to release data that will really tell us, you know, does this platform work? And if so, we very much believe in the transformative nature of the programs, not just for AML, but actually for a variety of solid tumors and even autoimmune diseases, where a single target on its own is just not sufficient. And we think this is an area where cell therapy is truly differentiated from, like an ADC or T-cell engager, where it's very hard to build a protein that actually recognizes multiple targets and turns on or off, depending on what's there.
So I think this is a sweet spot for cell therapy, and if we can demonstrate that this product works in the clinic, there's a really bright future for the company going forward.
Great. And so with that, we've come to the-