Well, welcome everyone and thank you for joining us at another great session at the 2021 Jefferies Global Healthcare Conference. Really happy to have here with us on this fireside chat, the President and CEO of ALX Oncology, John May Pons and also with us, the Chief Medical Officer, Sophia Randolph. Thank you for joining us today. We were briefly just chatting, of course, about so many things going on. I know Sofia is quite busy with so many trials getting up and running.
But I would just love to just start off first with a bit of a high level question that I think is on the minds of many investors, maybe to Jamey is trying to sort of parse out the CD47 landscape because there has been a lot of different companies sort of popping up. And I would just love to sort of briefly hear about why you think ALX is differentiated from some of those others that we're hearing about? That would be a great place to start off.
Yes. So thank you, Michael. I can't talk about that for a long time. So we'll try to be brief. C47, I think it's a good target.
Not already expressing cancer cells, so not because it's a tumor associated antigen. I think it's a good target because it's a checkpoint modulator in the native system. It is a checkpoint modulator for dendritic cells and macrophages. And I think the company is split a little bit in the way that they approach this duality. So many companies are choosing to make molecules that have an active Fc and therefore directly can bind and directly kill cancer cells.
So they are using C47 as a tumor associated antigen. That will be great if CD47 were only expressed on cancer cells, but that's not the case. CD47 is also expressed in most normal cells. So it's expressing rapid cells, platelets, microfibers, actually any single normal cell in the body is a market of cells. So I think this approach has brought to many compromises in terms of which effector punches they use, which affinity they pick with the result that at the end they don't have single agent activity or not a strong single agent activity and they have to develop the assessing combination.
I was just saying, do you feel that they're I don't want to use the term hand waving, but other companies who claim to just have a different epitope and claim to still be able to have an active Fc that they think that's good, but have somehow gotten around anemia and some of those companies have partnered, etcetera, and that's what they're saying. And they have some data, but it's hard to interpret. Is that do you think that ultimately will still not be as good?
Yes. So I would say that even in those cases those cells those molecules do bind normal cells and they have shown in their own data all these molecules do bind normal cells, maybe they bind less red blood cells, but they still bind bloodlets, for example, or the cells or other normal cells. And also in those cases, they are taking compromises either in the Fc function, so IgG4, which is less potent than IgG1. So it's not able to produce full activity or picking a low affinity molecule that actually is less able to block the pathway. So still in those cases, they are producing compromises in the site of single agent activity.
And again, they have to be developed in combination. We designed the molecule to be used and developed in combination to completely focus in CF-forty 7 as a checkpoint modulator. And we believe that in that setting, in the combination setting as a checkpoint, we have a superior molecule.
Right. The other issue with the combination approach, which is required is potential additive toxicity, so teasing out the therapeutic window. Do you think that ultimately will become an issue because a lot of these companies are still against single agents just to get safety before you can go to Congress. What do
you think? Yes. I think there's an essential difference. Our molecule has already shown in the clinic that can be combined with multi agent cytotoxic therapies that nobody else has shown, combined with checkpoints, combined with anti cancer antibodies and not only use technology shows safety, also we have shown efficacy in the solid tumor setting in where we are completely unique as well. So I think the C57 is a checkpoint moderator.
We have the best molecule. And I do parallel to that with PD-one and PD L1 molecules. Of all of them of all the PD-one, PD L1 molecules, there's only 1 with a vector function. That's a better map. But All the other ones choose to treat PD-onePD L1 as a checkpoint, not a tumor associated antigen.
Adelomab choose to try to do both and avelumab is not the best of that PD-one molecules.
That's interesting. So that's another example of where they would have wanted to dial it out as an inhibitor, right?
Yes. My guess is that they wanted to have both, wanted to have a checkpoint and effector function against cancer cells with the result that it didn't work as well, I just had a pure checkpoint modulator like pembrolizumab.
Right.
So that philosophy and that specific strategy has played out now in data. So let's talk about the gastric cancer data and the head and neck data, maybe we take each 1 of those separately And talk about why you were excited about that data, small numbers of patients, but why you're excited and where that takes you for the next update.
I don't know
if that's a good place for you or for Sofia to talk about.
That's a bit for Sofia.
Yes. Sure, sure. No problem. Yeah, so the data that we have in head and neck and gastric, and I'll start with the gastric, is really exciting for us. And all of these data coming from our first in human study has propelled us into our mid development program.
So in terms of gastric cancer first, so most recently, we presented at SITC this past year. There we presented some initial data in 14 patients of our drug, plus trastuzumab, on top of the standard of care rambucirumab plus paclitaxel in patients with second line HER2 positive gastric cancer. And there we saw an objective response rate of 64.3% in those 14 patients. And at that time, we had a median follow-up of about 5.3 months. So this was extremely exciting for us.
The benchmark there, rainbow study, is about 28% and then overall response rate. And then even the more recent Phase 3 within HER2 in patients who have failed 1 prior TRAS, objective response rates there were about 41%. So the data of ours, 64.3 percent was exciting and early. So now coming up at ESMO GI, this July 3, we'll be presenting an update on that now fully enrolled cohort of approximately roughly around 20 patients. And so we're excited to see now response rates across that full cohort as well as the longer median follow-up.
So to look at So those
shows, I'd say, a quadruple combination, but 2 of those rami cirumab and chemo are a standard option for patients with second line gastric cancer. And you're saying that people had, was it 28% response rates in general?
So they actually with the quadruplet, we had a 64% response rate. The backbone of RamPlat would be the 28%.
Exactly, right. So that's really exciting because you're doubling it. Now if you were to say, oh, well, is the Perceptin do anything, and your answer was, we'll look at something like it can hurt you, I think is what you said, And go ahead with that. And that was higher, but that's just that's as a single agent. So that wouldn't explain it either.
Yes. I mean, even when you look at in HER2, which is antibody drug conjugate, So trastuzumab hooked on to a direct satikan chemotherapy payload. There you're seeing an objective response rate of about 41%. With the direct cytotoxic
antibody. Right.
But what we did do, it is a question that we get, which is, well, you have a 4 drug regimen, how do you know what your drug is adding into that mix? And so what we had done, and we also presented at SITC this past year, was this updated data from a cohort looking at ALX plus trastuzumab, so a chemo free regimen in the same second line setting. And so there, we saw out of 19 patients, a 21% response rate. And this is significant because as we've just discussed earlier, our drug isn't anticipated to have much monotherapy activity by design based off of the design of the molecule. But when we combine it with an antibody like trastuzumab, which is also known and already has been published to have minimal activity in the second line settings.
So these are patients who have already failed prior trastuzumab. That activity via ErbB2 signaling, patients just don't respond very well to it beyond chemotherapy.
Yes. So if you were to parse those pieces out, there's certainly no data to suggest that it should be this robust. And so, therefore, you feel good that the hypothesis of the mechanism is playing out. Now, well, given that we'll have more patients, I guess, presented and more follow-up, what is good data? What do you come away saying is good?
Is that consistently high response rates? Is that a specific PFS that's better than ramucirumab? How do we benchmark that to give us confidence in the next step?
Yes. So the first thing that you definitely we would want to look at is objective response rates. And certainly, we've talked about the benchmarks already for that. Durability of response is important. Rainbow is the backbone, was about 4.4 months as well as its median PFS.
So anything significantly above that would be exciting for us. And then of course, ultimately, the gold standard is always overall survival. But in this Phase 1 cohort, the primary thing that we'd be looking at in addition to safety would be objective response rate and the durability.
Okay. Now just to be clear, it's 6 more patients, so it's 14 now going
to 20, is that what you said? Yes, we'll see we'll be presenting it mid year, but approximately 2020.
Okay. So it's 6 more incremental patients. So it's not like there should be huge swings of the data, right, because it's just
And I do want to it's approximate, so approximately that. Okay. And yes, but we'll have so a few handful of additional patients to look at response, but then also the longer durability of those who are already on.
And are those all at a higher dose, those new patients presumably, so you should feel good about that?
Right. So all of the patients with the quadruplet therapy, the majority of those patients will be looking at ALX at 15 mgs per kgqweek. And then there's a smaller group at 10 mgs per kgqweek.
Have you decided we'll get to head and neck in a second. Have you decided what you want to do? Are we going to hear an update or is there an analyst call after that data or how will we hear about what you want to do next?
In terms go ahead,
gentlemen. In terms of what we're going to do, obviously, in the poster we're going to describe, everything will be a press release. If we think it's necessary, we'll do an investor's call, but we have not decided yet. Okay. Would you want to
take it forward though? You want to take it into a Phase 2b kind of like head and neck?
Yes. We're completely ready to Phase 2b. So this will be starting shortly. So maybe Sofia can comment on that. Sofia, I think the number of patients is 18, right, for this?
But yes, the formal number at this point is 18.
Yes.
So we have 18 patients? Yes. Okay. So it's a small number more, but again, we will get more patients, it's more about follow-up. And does that inform you?
I mean, you've had some of the data since SITC just about what the next step is. I don't want to spend too much time because it's a smaller market, but does it inform about what the next step is? And I guess talking with the FDA, but you want to move forward?
Yes, absolutely. And so, yes, we will be working on a randomized Phase II study. And so we'll be looking at not only sort of definitively teasing out the contribution of ALX to a TRAS containing regimen, but then also ultimately looking at the randomization between that and ramasiram and paclitaxel.
So we'll waive that update. Now in the meantime, what was most intriguing to me was that you had some great head and neck data, but that that was discussed with the FDA already and that you guys have been able to, and I think the words are, say, potentially pivotal study. Maybe you could talk about that. I mean, have a potential pivotal study started now as a pretty big thing for small biotechs. So, maybe just talk about the head and neck data like you did with gastric, what the response rates were versus what you'd expect and what did the FDA say about this next study that you can review?
Right. So for head and neck, as you just mentioned, at SITC this past year, we presented 2 cohorts. I'm just going to highlight, these are the patients who are checkpoint naive. And so new data we had was in 4 patients who were first line checkpoint naive patients with head and neck cancer. In those first 4 patients, we had 2 PRs and 1 CR, obviously incredibly small numbers there.
And that is a group that we've now built out and will be presenting towards the end of this year. So there with those responders, we had interestingly responses in patients with CPS scores of 0 up to 50. The benchmark there is KEYNOTE-forty 8 objective response rate of 36%. And so that's the benchmark for our subsequent randomized Phase II that you alluded to. The other population that we updated at SITC was now second line head and neck patients who are checkpoint naive.
And there, we had 10 patients, previously reported 4 PRs, but a median PFS of 4.6 months, median overall survival of 22 months. CPS scores again in those responders ranging anywhere from 0 to 40. So the KEYNOTE-forty is a reference for those patients. Benchmark is an objective response rate of 15% that compares well with the 40% objective response rate that we saw. So again, small numbers, but provides the rationale for starting a second Phase II study, which we've now enrolled our first patient already.
And that will be looking in the first line setting, checkpoint naive, looking at our drug plus pembrolizumab versus pembrolizumab alone.
Okay. So you if I remember that right, doubled the response rates in the first line, doubled the response rates in second line and again feel that that should validate the mechanism again, right, both because they have, I guess, you were applying low checkpoint scores, but also because it follows along the gastric data. So it's really multiple things combined here that are putting together restoring. Is that fair to say?
Very fair to say.
Okay.
So what did the FDA say? You showed in this data and I'm personally surprised that 3 out of 4 patients, although I guess there's more coming later this year, is that 10 or 15 patients? How many patients?
Yes. By the end of the year, we'll have when we report, we've completely accrued. This was a Phase 1 dose escalation cohort. So we have a total of 13 patients. So we'll be presenting that data.
The data around in support of our fast track designation as well as in support of the Phase II is really the totality of the data from our Phase I
study. Okay. So you have gone ahead and
started a first line study, is that correct? Correct. So we have 2 Phase 2 randomized studies. The first 1 is the 1 I just mentioned, ASPEN-three. So our drug plus pembro versus pembro alone, and that has dosed its first patient.
The second trial, looking similar population, but here it is in patients with any CPS score. And there we'll be looking at ALX plus pembro plus chemotherapy as a standard versus pembro plus chemo. In first line. Both of those are in first line. Right, right, right, right.
So if you have low scores, you get the chemo added on.
Yes. So it'll be interesting to see how I mean, this is all built off of the label for pembrolizumab. So if you're pembro positive, the label supports a backbone of pembro monotherapy. If you're CPS score agnostic, meaning any CPS score, so including being PD L1 negative, you can get the added on chemo.
So that's exciting because, look, this could be so just to clarify, what did the FDA say specifically And it will take some time, but you got to enroll and they get the data. That's a pretty big event. Maybe just talk about that.
So I mean, essentially what they've communicated to us is that this study is exactly that potentially registration. It obviously depends upon the data and discussions with them. But just from a structural standpoint, it is a trial that could support approval.
Yes, both of them.
Yes, both of them.
Both studies.
Right. And just to be clear, now both of them are designed similarly. To be honest, I think you would probably be surprised if 1 worked and 1 didn't. But right, I mean, the idea because I don't know how many patients it is, but I would be shocked if just 1 study served as an approval. Presumably, it's a combination of both.
But that totality of that those 2 would be more obvious to support an approval. Is that fair?
Again, we'll see how the data pans out in both, but certainly, their general stance is to, I think, well conducted randomized studies. So certainly, these are 2 well conducted randomized studies.
Okay, good. Now, let me kind of round that out because what everyone's really seen a lot of is MDS data. And that's, of course, what led to 47's acquisition by Gilead. And interestingly, Gilead is not committed yet to filing. They're supposed to announce something.
You're still waiting on that, but you're going to have your MDS data coming up. So maybe comment about how that study is going, it's Phase 1, you believe you're going to be at doses that are active, how do we look at this data and what you're going to get, tell us what we'll get and how do we compare that, how should people think about that versus just pulling the last MDS data from Gilead at ASH and we look at that? But that's not necessarily a fair comparison, right? You maybe talk to that.
Yes. So the structure of our MDS Phase it's a Phase III study. So the Phase I portion will we anticipate presenting that before the end of this year. In the Phase I portion, it's a traditional dose escalation. So and it's a population of both relapsed refractory MDS as well as patients with treatment naive higher risk MDS.
So it is a blended population. So that's 1. Whereas 47 was only first line? In their most recent data that they presented, yes, it's in the only in the treatment naive.
Right. On top of A society. So while the CRH were good, it was a first line, meaning, again, you'll have patients, we want to parse that out, right? Right.
So it's important to look at the patients, exactly.
And number 1, the patients, okay.
Right. And then also we're looking at 3 different dose levels. So we're looking at a 20q week, 30q week and then excuse me, 20 every other week, a 30 every other week and then a 60 mgs per kg Q4 weeks or Q month. And the idea there is that because of the exemplary safety profile that we've seen with ALX across the program, the idea is that we can increase the dose of the drug without really sacrificing toxicity. And in that way, we can stretch out the administration schedule to make it more convenient to dose with the monthly azacitidine.
That could
be interesting. So I guess in a really good world, the data would show high CR rates across these populations and across the doses and that there wouldn't be a fall off, I guess, at monthly dosing or how do you think about those scenarios?
Yes. So ideally, the 20 every other and is a slightly lower exposure level, right? That's more equivalent to 10 mgs per kgq week. But the 30 and the 60 should have similar exposure levels. And that's equivalent to a 15 mgs per 10Q week that we've used in the balance of the program.
So with the small numbers, I don't know if you'll see formal differences because the numbers per cohort are small. But overall, they are all active doses. And so we would hope to be able to see something in the way of complete responses in some of the patients.
The complete responses happened in a reasonable timeframe because I recall that Gilead's data got the CRs got deeper over time where PRs made so the CRH went up. And all I'm just saying is, if you're taking a first look at it, help me, is the 1st CR rates a snapshot and that I would investors should compare to the 1st snapshot of 47? Like do I got to go back to the
47 data from 2019? Yes. So for all of these, and really not just for MDS, but even across the program, we do see deepening over time with this class of agents, meaning in terms of responses. We see that also in the solid tumor setting as well. When it comes for MDS in particular, even the Aza label, it takes time for these agents to work.
So for example, patients have to be on for at least 6 cycles before you even or 6 weeks before you even evaluate them. So there is a timing about this as well. But as we look at the different individual patients, their individual histories as this is a Phase 1, just really looking to see improvements in those blast counts, whether or not that flips into an actual objective response rate, looking at transfusion dependence and independence as well, looking at durability of response, all of these metrics become super important as we evaluate these patients.
Well, look, I think we're going to Wall Street is going to go look at CRH from 2019 2020, I promise you. You also have a second line population, so that's not directly comparable, so that's its own apples. And then also, the anemia and all that wouldn't necessarily be so much, but you believe you should
have similar CR rates and possibly better dosing. Is that a fair statement? Yes, I think that's our hope. And in addition, once we get through this Phase 1, then we would be moving seamlessly into the randomized Phase 2 portion of the study, where the randomization obviously becomes important.
Would you expect and I ask this because people think it's going to impact ALX. Would you expect that Gilead probably should be able to file? And if they don't, should we read that as a problem, as an ability to be fast tracked here? It's a great question.
Yes. Hard to know based off what's in the public domain, but we do know that their pivotal study is approximately 500 patients. So it will take time for that to accrue and to read out. But either way, I mean, I think that they have shown proof of principle that this target is important in MDS. And I think that helps all CD47 targeted agents.
Well, if they don't, that's the point. It's going to go for a while. And so let's hear what they say. So I look forward to the updates. I know we're out of time and this was a quick gathering.
So thank you guys for joining with us. Data coming up, a lot of data coming up and we look forward to following you throughout the rest of this year.
Thank you, Michael. Great.
Thank you, Tommy. Thank you, Sophia. Thank you.