Hey, good morning, everyone. My name is Daniel Wally. I'm an analyst covering mid-cap biotech. Welcome to the 40th Annual JPMorgan Healthcare Conference. I'm joined today with President and CEO Jaume Pons of ALX Oncology. As a reminder, if you wanna ask questions, you can submit using the blue Ask a Question button through the question portal, and I'll be able to ask those questions. Without further ado, Jaume.
Thank you, Daniel. After the customary disclaimers in the slide one, let's move to slide two. Our main focus is evorpacept, a highly differentiated CD47 blocker that is now in phase II clinical trials for three solid tumor indications and also in at least clinical studies in two hematologic indications. Evorpacept is designed to be used in combination with a long list of anti-cancer therapies.
If we are successful, it can be a cornerstone of therapy. Evorpacept was designed to be used on top of the standard of care in combination. Continuing with the CD47 pathway, we have a CPG-conjugated CD47 antibody in IND-enabling studies in collaboration with Tallac Therapeutics. This is a CD47 blocker that directly activates dendritic cells using CPG as an agonistic molecule. This molecule will jumpstart the immune system against cancer.
This molecule is designed to have a very strong single agent activity to be used in combination and as a single agent when standard of care fails. In addition, we have early pipeline of anti cancer-activated antibody drug conjugates that will stand alone development and also will be able to combine with the evorpacept. Thanks to investors, also, we are in a very good cash position with $238 million as of September 30, 2021, with enough cash into 2024.
That includes all the fundamental studies that we are now running with the evorpacept. In slide number three, focusing on evorpacept. We have promising data in combination with antibodies, checkpoint inhibitors, and chemotherapy. It is the only CD47 blocker that has shown positive data both in solid tumors and hematological malignancies.
Evorpacept has a very good safety profile that enables high dosing and flexible dosing to match a combination with the drug that we want to combine with. The clinical trials we are running now are selected by mechanism. For example, in gastric cancer, we're combining with Herceptin as a test of mechanism of combination with anti-cancer antibodies.
In head and neck, we're combining with KEYTRUDA to test the mechanism of combination with checkpoint inhibitors. In MDS, we're combining with azacitidine and also NHL rituximab. From here, if the studies are successful, we can branch out into many other studies in other combinations and other indications using the same mechanism. From there, also we can go to other modalities like antibody drug conjugates, et cetera. In slide number four, you have a snapshot of our clinical pipeline.
We've done a very large phase I study testing the different mechanisms, and now we're running phase IIs in the mechanisms that we think evorpacept has shown activity. For example, based on our promising data in phase I in head and neck in combination with KEYTRUDA, we are now running two phase II studies, ASPEN-03 and ASPEN-04. ASPEN-03 in first-line head and neck in combination with KEYTRUDA. ASPEN-04 in combination with KEYTRUDA, 5-FU and platinum, also in first-line.
We have Fast Track designation, and we are running these studies in collaboration with Merck. Also, based on our positive data in gastric cancer in our phase I study, we are now initiating one phase II study. It's a randomized study that compares Herceptin, CYRAMZA, paclitaxel with evorpacept versus Herceptin, CYRAMZA, paclitaxel.
We also have faster drug designation for this indication, and we are running the study in collaboration with Lilly. Based on this positive data with Herceptin, we are now doing a collaboration with Zymeworks to test evorpacept with zanidatamab, a bispecific anti HER2 antibody. It is on breast cancer, high HER2, breast cancer, low HER2, and many other indications.
The hematological setting, our phase I show very good activity in NHL in combination with rituximab, and now this is being developed as a IST in combination with rituximab and lenalidomide. We're running studies in MDS and AML. In MDS in combination with azacitidine, and AML in combination azacitidine plus venetoclax. Based on this data, we're going to be moving into phase II studies, also randomized for these indications.
Focusing on evorpacept, ALX148, and this mechanism, on slide six, you have the CD47 is a target that is highly expressed in cancer. Here in the left panel you see the expression of CD47 in tumor in red, but also very highly expressed in normal tissues in black.
Therefore, if we want to design a molecule that kills all CD47 positive cells, it's not going to have a very good therapeutic window. What's interesting to me about CD47 is its function as a checkpoint modulator, in this case, for myeloid cells. On the right panel, you can see that CD47 is highly expressed on cancer cells and interacts with SIRPα on macrophages. This is an inhibitory signal called "Do Not Eat Me" signal. But macrophage, to be fully activated, requires a positive signal.
This positive signal can come from the Fc interaction of antibody with Fc gamma receptors or other kinds of damage to cancer cells. What's important to remember here is that blockade of CD47 SIRPα by itself will not activate macrophages. That's very similar to PD-1, PD-L1 on T-cells, where blockade of the PD-1, PD-L1 is not efficacious unless the T-cell already has a T-cell receptor that recognizes a MHC peptide on the cancer cell.
This mechanism is equivalent to PD-1, PD-L1, but instead of T-cells, we are now talking about myeloid cells, macrophages, and dendritic cells. In slide seven, this is actually the approach that we talk about modulating CD47 as a target. We wanted to design a molecule that highly potently blocks CD47 and prevents interaction with SIRPα, but does not provide the required positive signal of the Fc gamma receptor interacting with Fc receptors.
Why is that? It's because we do not want to target normal cells for destruction, for example, red blood cells. Evorpacept does bind red blood cells, but because the Fc does not interact with Fc gamma receptors, these red blood cells are not being destroyed. And therefore, we don't have anemia, thrombocytopenia, or neutropenia problems that other CD47s have shown in the clinic.
Because this property, we can dose very high, fully block the CD47 pathway, and then in combination with an anti-cancer antibody or other anti-cancer therapies that specifically target cancer cells, we can then get destruction of the cancer cells specifically and sparing normal cells. In slide number 8, you have the design of evorpacept. We paint it like antibody, but it's not an antibody. It's a fusion protein that comprises a binding domain that is a high-affinity SIRPα.
It's the extracellular domain of the receptor of CD47 that has been affinity matured to bind CD47 with very high affinity, with picomolar affinity. The normal or wild-type SIRPα binds CD47 with micromolar affinity, so we have thousands-fold higher affinity than the natural SIRPα. That is fused to a completely inactivated Fc domain that does not interact at all with Fc gamma receptors, but maintains the interaction with FcRn.
It has the same decay as an antibody. In our case, about 30 days half-life at a steady state. The molecular weight of this molecule is half of our antibody. Therefore, we have twice the number of molecules per gram. Our 10 mg per kg is equivalent to 20 mg per kg of an antibody. And that, of course, has a very significant stoichiometric advantages.
In addition, this smaller size may provide a better tumor penetration. What's quite unique about evorpacept is that we have cross-reactivity to human, monkey and mouse, so our animal models are more relevant of the clinical setting than other CD47 molecules. The manufacturing of evorpacept is completely antibody standard.
With our yields of 4.5 g per liter, and now we have a stability of more than two years at 40 degrees. It's a very well-behaved molecule. In slide number nine, you have the safety profile of evorpacept so far in combination with different agents. You can see that across multiple studies, including chemotherapy, checkpoint modulators, and anti-cancer antibodies, the safety profile has been really good.
The most common side effect is fatigue, low-grade, some rash, also low-grade, and the other, side effects are quite sporadic and single digit and mostly low-grade. We have never reached maximum tolerated dose with evorpacept, and we have dosed up to 60 mg per kg, which remember, that's equivalent to 100 mg-120 mg per kg of an antibody.
Now let's move to the different indications that evorpacept has been tested. In slide 10, we want to focus in, evorpacept in HER2-positive breast cancer. In slide 11, you have the mechanism of evorpacept in this setting. In this case, cancer cells express HER2 that can be recognized by Herceptin, and this interaction with Fc gamma receptors would activate macrophages. However, the CD47 SIRPα interaction prevents the activity of Herceptin in macrophages.
By blocking CD47 with evorpacept, we completely enable this mechanism of Herceptin that is usually not in use. In slide 12 is our data of evorpacept in combination with Herceptin, Xeloda, paclitaxel. You can see in this study that we have a very high response rate of 72%, so most patients do respond, including patients with lower HER2 expression, for example, 2+.
You can see that the duration of response is also very long. Most patients respond, and many patients stay for a very long time in the study. You can see the overall survival at 12 months is 79%. These two numbers, response rate and OS at 12 months, are much better than the benchmark of Xeloda paclitaxel of 28%.
With this positive data now, we are moving into a phase II study where we are comparing Herceptin CYRAMZA paclitaxel versus Herceptin CYRAMZA paclitaxel. This is to completely demonstrate the activity of evorpacept in this setting. Remember that the standard of care is not Herceptin CYRAMZA paclitaxel. It's actually CYRAMZA paclitaxel, because it has been shown that Herceptin does not add anything in the second line setting.
If this study is positive, we're going to move into a phase III, where we're going to do Herceptin CYRAMZA paclitaxel versus the regulatory benchmark, CYRAMZA paclitaxel. The endpoints will be response rate, OS, PFS, and duration of response. Next, I want to talk about evorpacept in head and neck, in this case, first line. In slide number 15, you have the mechanism of evorpacept in combination with checkpoint modulators. This mechanism is slightly different than the don't eat me signaling macrophages.
In this case, the regulatory function of CD47 is with SIRPα expressed on dendritic cells. The dendritic cells also express SIRPα, and we have shown that they are completely inhibited constantly by the CD47 interaction. By blocking CD47, we activate dendritic cells, and then they are able to present antigens to T-cells. T-cells, when they are unleashed by blocking PD-1, PD-L1 will directly kill cancer cells. In this case, the killing mode, the killing cell is a T-cell, not a macrophage.
Despite that, we have proven that in this setting, we compare M2 macrophages, that they are immunosuppressive, to M1 macrophages that have more anticancer. Which is another mechanism that plays part in combination with checkpoint modulators. We have run two studies in combination with KEYTRUDA. One that was in second line, evorpacept plus KEYTRUDA.
Only 10 patients, but we had a response rate of 40% and overall survival rate at 12 months of 80%. That compares very well with the results of KEYNOTE-040. Also, in the first-line head and neck, we combine evorpacept with KEYTRUDA and chemotherapy.
It's also a small study. In this case, the response rate is similar to the KEYNOTE-048 benchmark, but also again, the overall survival is much longer at 12 months than the KEYNOTE-048. With this positive data, we're now moving or actually in the middle of two phase II studies, as both of them randomized in first-line head and neck. In one, we are combining evorpacept with KEYTRUDA, and the other one, evorpacept with KEYTRUDA plus chemotherapy. That's the two labels of KEYTRUDA.
In one case, in the doublet, is for patients that have PD-1 score higher than one. While in the Keytruda chemotherapy is PD-L1 agnostic, so any patient can be enrolled in this study. The endpoint is 12 months overall survival and response rate. Moving to hematologic malignancies. In slide number 19, you have the mechanism of evorpacept in combination with azacitidine.
Azacitidine, when it gets internalized into cancer cells, upregulates calreticulin. Calreticulin is another eat-me signal that interacts with LRP, that's a receptor of macrophages, and provides the required positive signal. In this setting, blocking CD47 enables macrophages to eat cancer cells.
In slide number 20, you can see the study that we are running now, which is a dose escalation safety study, where we are both enrolling newly diagnosed MDS patients and relapsed refractory MDS patients. We're starting at 20 mg/kg every other week, 30 mg/kg every other week, and then we move to 60 mg/kg every four weeks to be able to conveniently combine with isatuximab that is dosed once a month. We have proven safety up to 60 mg/kg already, and now we have moved into dose expansion.
We can see on the right our patient characteristics that more than half of them are refractory, where, isatuximab is not expected to have much effect, and many of them has very complex cytogenetic status. For example, we have, an unusually high percentage of, TP53 patients that have a lower, prognostic.
In slide number 21, you can see the data of the part of the patients in the dose escalation safety study. You can see it is very small number of patients, but we have out of the TP53 patients, 2 CRs of the five. That compares very well with the data that has been shown for magrolimab, the Gilead molecule. Also is clearly higher than the expected response rate for isatuximab that is at 17%-20%. In the refractory setting, where decitabine is not expected to produce much of an effect and no other CD47 molecule has shown any data, you can see that we have five patients out of nine with a marrow CR. That is very interesting to us and for me is a clear proof that activity of evorpacept in this setting.
With this promising data, we are now running a dose expansion, dose optimization study following FDA guidelines of trying to find the dose before moving to randomized studies. Where we're comparing 40 mg/kg every four weeks with 60 mg/kg every four weeks. Both doses we believe has efficacious. Now, from there, we're going to move into a randomized study. We're going to compare evorpacept, azacitidine versus azacitidine.
The regulatory endpoint is complete response. I think the activity of evorpacept in the clinic is better seen when we compare all the studies together. In slide number 24, you have the data of solid tumor for evorpacept compared with regulatory benchmark on those indications. On the left, you see that second-line HER2-positive gastric cancer. The combination of evorpacept, Herceptin, Cyramza has a response rate of 72%, where the benchmark is 28%.
More importantly, the overall survival at 12 months of close to 80% doubles of what is seen as a benchmark of 40%. Also this data is superior to the data shown for the Enhertu in the DESTINY study, where response rate is 40% and overall survival at 12 months is about 50%. In head and neck, this slide, in combination with KEYTRUDA, 5-FU and platinum, the response rate is very similar. That is the same that was seen in the KEYNOTE-048, comparing KEYTRUDA chemotherapy versus the control arm in KEYNOTE-048, where the response rate was identical as well. KEYTRUDA was approved based on overall survival at 12 months.
If we focus in overall survival at 12 months, we see that in this very small study, overall survival for the evorpacept combination is 88% versus 53% in the KEYNOTE-048 KEYTRUDA arm. Same situation, second line, but here in absence of chemotherapy, we see some improvement in response rate with a 40% versus the benchmark of 15% in KEYNOTE-040. More importantly, we see a very significant improvement in OS rate at 12 months, 80% versus 37%.
This is with three years follow-up. In slide number 26, 25, we see the same for hematological malignancies, now comparing with magrolimab, the CD47 molecule of Gilead. As I said before, in the TP53 mutants, magrolimab had two CRs out of four. We have two out of five, so very similar. We have a much better safety profile.
As I mentioned before, magrolimab did not publish any data in refractory patients, where we have a very interesting activity. In NHL, in combination with rituximab, also the response rates and the CR rates are very similar between magrolimab and evorpacept. But again, in our case, with a much better safety profile, with clearly no dose-dependent cytopenias in our case, and very high rates of cytopenias in the case of magrolimab, like anemia, thrombocytopenia, and neutropenia.
Based on the data that I just showed you, I would believe that those indications are just the tip of the iceberg that every time that we prove one of these mechanisms in a randomized study, we'll be able to move into other combinations with other indications where those mechanisms are relevant.
In slide number 27, you can see that 2021 was a very busy year for us, with a lot of studies initiated and read out, and that continues in 2022, where we have interesting readouts. For example, the MDS dose optimization study and also initiation of many other studies and also data that can come from our ISTs and collaborations.
2023 is when things will get really interesting with the readout of our gastric trial, randomized, and also the AML study and the IND filing for our second compound, the SIRPα-CpG conjugate. In 2024, we will have also the results for the randomized study in head and neck. With that, thank you for your attention, and I want to introduce Dr. Sophia Randolph, our Chief Medical Officer, to answer any questions. Sophia.
Thank you for the presentation. As a reminder, if you wanna ask a question, please use the blue submit question box and I'll be able to ask question to the floor. There's a couple questions. Maybe to start with one of them. While acknowledging the rationale for combination approach, given the mechanism of action with different modalities, how would investors go about assessing the true value proposition of evorpacept as a monotherapy? What does it bring to the different treatment modalities that you're putting it into?
Evorpacept was designed to be used in combination to actually have a larger therapeutic window. We sacrifice the monotherapy part of it. Therefore, in every single study, we have to be combining with something that specifically target cancer cells.
How we evaluate that, you know, how investors can see the activity of evorpacept in this context, but you have to look at all the studies one by one and in context before we have randomized data. Of course, the real answer will come in the randomized studies. The way I see it as a drug developer is that the signs of activity that we have in five indications give me very good confidence that evorpacept is adding to these different studies. Maybe Sophia.
Just as you said, I think, once you get into the clinical studies, it's really comparing with historic controls, and seeing the improvement in clinical activity with the tolerability, compared to standards of care. Seeing that sort of reproducibly across different combinations, different tumor types, does give us the confidence that the drug is actually doing something positive in these different indications. True proof of concept will come in the randomized portion of the development that we've entered into now.
When looking at the gastric cancer landscape, and specifically the HER2+ gastric cancer in the second line or greater, with KEYTRUDA as part of the first line of standard of care, recently, you know, introduced, do you expect patients to respond differently in second line with evorpacept combination, when you start doing this randomized phase II, as opposed to earlier phase I studies when patients were not seeing that KEYTRUDA in the first line?
It's a great question. Certainly, there has been a sea change in the first-line setting, which is great for patients with the introduction of pembrolizumab in combination with trastuzumab, a fluoropyrimidine, and a platinum for HER2-positive disease.
The nice thing about the evorpacept studies that were done in the second-line or greater setting is we actually did enroll patients who had come off of some of the clinical trials that were underway exploring the pembrolizumab activity even before it was formally approved.
Within our second line or greater setting, when we were looking at evorpacept plus trastuzumab doublet, approximately half of patients had actually already seen a checkpoint inhibitor in the first line setting in combination with trastuzumab, and we were able to see partial responders in that population. Similarly, when we look at our four-drug regimen, ALX148 or evorpacept plus tras, CYRAMZA, paclitaxel, Herceptin, CYRAMZA, paclitaxel.
There too, although we only had two patients who had seen prior checkpoint inhibitor, one of those patients also achieved partial response. With the numbers that we've evaluated so far, and it makes sense from a mechanistic standpoint, we don't believe seeing checkpoint inhibitor in the first line study should impact evorpacept activity in the second line or greater setting.
Okay, great. You know, maybe continuing in this setting, what do you plan to see in the phase II ASPEN-06 study that would drive the advancement of the study into phase III?
The phase II portion of the study for ASPEN-06, as Jaume explained earlier, is really aimed at looking at the contribution of evorpacept to a trastuzumab-containing regimen. Because it is a four-drug regimen, and we wanna be able to sort of elicit what exactly is the evorpacept contribution to the three drug backbone.
For phase II, we'll be looking at evorpacept plus Herceptin, CYRAMZA pac versus Herceptin, CYRAMZA pac. There, we're looking for at least a 10% difference between the two arms. And then also, the study is powered to look at the comparisons of each arm to historical control Ram-Pac or CYRAMZA pac, which is the true global standard of care.
Those are sort of how the study is being powered, looking for a magnitude difference of 10% between both arms and then, ideally, looking at an improvement from a historical rate of approximately 28% or 30% for CYRAMZA paclitaxel, looking to get to about 50% response rate on the test arms. Given what we've seen in the ASPEN-01 first-in-human study in that cohort, where we've seen a 72% response rate, I think we're very encouraged that phase II will hopefully read out positive.
Okay, great. In MDS, you know, we have seen great efficacy in phase I that necessarily did not translate to separation in randomized studies as recently as last year. What are you trying to ensure, that, you know, when you go to randomized studies that efficacy, you know, will be able to continue to be interpreted as coming from the evorpacept combination, as you go from single study to a randomized controlled trials in MDS.
Yeah. For MDS, it's been interesting, you know, for the longest time, azacitidine was the only real or a hypomethylating agent was the only real active agents in this particular space. Those original studies, which showed in higher risk MDS patients a CR rate of about 17%. Those studies were done probably over a decade now at this point.
Recent studies, as you allude to, the azacitidine monotherapy activity has been bouncing around a little bit, kind of in the low 20s. Then most recently with the PANTHER study, there was a azacitidine monotherapy rate that was actually very high. It was around 30%, and that seems to be a bit of an outlier compared to other randomized studies that have been done recently.
A meta-analysis done in 2020 shows the azacitidine monotherapy rate to be netting out around 20%. I think KOLs, at least that we've spoken to, feel that that's a very reasonable benchmark. It does speak to the importance of randomization. Seeing the activity, and again, for us, it's very early days. The data that we presented at ASH was for TP53, again, five patients who were response evaluable at that point.
It does speak to the importance of randomization in when looking at proof of concept. In the phase I setting, it's appropriate to look at our activity versus historic control. We benchmarked azacitidine around 17%-20%.
As we go into the phase II setting, as Jaume described here, we'll be looking ultimately comparing evorpacept plus Aza versus Aza alone. It just has to do with the heterogeneity of the population, as well as I think just the duration and time from when those original studies with azacitidine were done. We'll be looking for an improvement ultimately over an azacitidine backbone, where the assumption of the Aza is about a 20% response rate.
HER2 breast cancer is a substantial opportunity. With recent collaboration with Zymeworks, I'm just wondering what you are looking for, you know. First of all, I guess, what was the rationale into, you know, forming that collaboration, particularly going to a study that also looks not only at high expression of HER2, but also low HER2 expression? What does, you know, evorpacept bring to the table that would allow you to be able to bring, you know, a differential efficacy measure?
Yes. As you know, most Herceptin works for blockade of the signaling. That's the main activity of Herceptin in the clinic, this HER2 signaling blockade. It doesn't have much of a ADCP activity. We pick a Zymeworks molecule because there is a bispecific molecule that has one epitope that binds the same epitope as Herceptin, and the other arm binds the same epitope as pertuzumab, which provide a much higher density of FCs on the cancer cell.
Providing that positive signal that we can enhance with the blockade of CD47. That would make sense in doing the low HER2 setting when you have less receptors. But now with this molecule, you can have twice the number of antibodies bound to those receptors, and it could be enhanced by the blockade of CD47.
that was the reason we pick that molecule to combine with everolimus. Maybe, Sophia, you have any clinical point of view?
Yeah, no, I think and just from a, you know, bucket in terms of a mechanism of action, I think based on our gastric data from our first-in-human as well, even in our non-Hodgkin's, where we're combining with anti-cancer targeted agents such as rituximab, this mechanism of action where we're enhancing that ADCP activity lends to other indications. Whether it be other indications where HER2, for example, is targeted or even other solid tumor indications where there may be other anti-cancer targeted antibodies. These are some of the additional indications that we're interested in expanding into.
Yeah. For example, colorectal. Right. We have an IST combined with cetuximab in colorectal.
Yep.
PD-1 and
Maybe bigger picture. As you think about future collaborations, what are some of the underlying drivers, both in terms of unlocking commercial value for evorpacept, but also in terms of the right mechanism of action that works, you know, as you think of the opportunity as also mechanistically works, you know, the best. How are you thinking about it as you know, when you think about future collaborations?
Yeah. We're trying to zero in the mechanisms and then expanding from there. I think the mechanism in combination with anti-cancer antibodies in our mind is very well validated. That's why we already have a collaboration with Zymeworks with HER2-positive, and we're going to be cetuximab, as I just mentioned, in the case of colorectal. We're going to be actually trying to do other collaborations, potentially in antibody drug conjugates as well, where I think it makes a lot of sense to combine.
The same with the checkpoints. We have now head and neck and the colorectal study I just mentioned, but we're going to be actively looking for other indications where checkpoints are used. In the case of small molecules like azacitidine, we have other studies in AML and MDS from there, we will see. Sophia.
Yeah, exactly that. When it comes to future studies, I think ADCs and solid tumor are ones that are a special interest to us. And then exploring a little bit more the combinations with the small molecules. We certainly not only with azacitidine but and even across our other studies where we've been combining with chemotherapy, you know, where we're seeing activity or potentially even radiation, that might be another area. I think for the short term, it's looking at these three mechanisms, anti-cancer antibodies, checkpoints, and then small molecules, and that's how we're moving it forward.
Great. Maybe we can bring that to a wrap. Again, thank you very much, Jaume and Sophia for your presentation and also for your thoughtful answers. And thank you, investors, for listening in. Thank you.
Thank you, Daniel.
Thank you.