Okay, welcome everybody. My name's Daina Graybosch . I'm the Senior Analyst here at Leerink Partners . I cover mostly immuno-oncology. Since the beginning of my time at Leerink , I've covered Affimed, and I'm happy to have their CEO, Shawn, here with me today. Thanks for joining.
Yes, thanks for having us.
We can jump right in. I only have 30 minutes and about 50 questions to get through. I have a hard-hitting one to start, but before that, maybe I'll just ask to introduce yourself because you're a new CEO at Affimed.
Sure.
So everybody knows you and where you're coming from.
Yeah, so Shawn Leland, I'm a PharmD by training. I've been in the industry for about 17 years. I joined Affimed in September of last year. Prior to that, I was CEO for a private company called Fore Bio. I helped them raise a $75 million Series D financing in August of 2023 and also brought their lead program into a phase II study with registrational intent. Prior to that, I was founder and CEO for Elevation Oncology, helped the company raise over $200 million worth of capital, took the company public in just two years' time, brought their lead program into a phase II study with registrational intent, and did a variety of other strategic transactions while there, including in-licensing of their Claudin 18.2 ADC, which is now their lead program. Prior to that, I've held mostly head of business development roles. I started my career at Eli Lilly.
I've been at Ariad Pharmaceuticals, Argos Therapeutics, and Verastem Oncology.
Awesome. Thank you. Okay, Affimed has three, what I think are promising clinical assets, but the next meaningful readouts are just at or beyond your cash runway.
Yep.
I think that's essentially maybe the hardest question I have for you today.
Sure.
What are your plans for getting the financing to take those programs forward?
Yeah, I mean, I think more and more in this day and age where you're in a challenging market, I mean, pipeline prioritization is top of mind for everyone. It's not an easy task in the situation of Affimed because, as you've mentioned, I mean, all three of these programs have clinical proof of concept, right? It's not necessarily easy to kill one of those programs. At the end of the day, I think the pipeline prioritization will be dictated by the investors that come into this next financing round. I mean, I think that will be the key driver. I mean, I think as you look at the portfolio of assets, with all three programs having clinical proof of concept, there's different commercial potential associated with those three assets and programs. I think the one with the smallest commercial potential happens to be the acimtamig program.
As you think about, if you have to make some tough choices, is that the program that ends up getting deprioritized just because it's got the smallest commercial potential? I think that these are the things that we will have to think about. Every investor that I've spoken with has their favorite kind of two programs, and you'll get different responses from all of those investors. Again, it's not an easy decision to make from that regard. I think the vast majority of our investor discussions, as well as partnering discussions, have really focused on AFM24. I mean, I think that data has been extremely encouraging. I think folks are really looking forward to seeing kind of how that data evolves, especially at the higher dose of 720 mg, given the post-hoc analysis. That's really kind of been the core focus.
There has also been a lot of interest in AFM28. I mean, obviously, AML is a huge unmet medical need. The clinical proof of concept and data we've shown in dose escalation there has been extremely promising as well.
Thank you. Can you talk about some of the conversations with partners versus investors? Are there any differences?
Sure.
Are they holding up any milestones or thresholds?
Yeah, I think honestly, the partner and investor feedback is quite similar. I don't think that there's a ton of disconnect between what the partners want to see and what investors want to see. I mean, I think kind of going through program by program, there are companies that are focused in hematologic malignancies, for example, that are looking for late-phase bolt-on programs where a program like acimtamig makes a lot of sense, right? There are folks that want to meet and talk about acimtamig because it's a late-phase development program. It's got compelling differentiated clinical data, and we have an agreed-upon path to registration there with the regulators. That program comes up in partnering discussions.
Obviously, AFM24 comes up in a number of partnering discussions as well, just because of the significant commercial opportunity, the unmet medical need that exists in kind of second, third line, and beyond non-small cell lung cancer. That is a hot topic of discussion. For the same reasons, CD123 is obviously a well-validated target in AML, but has been very difficult to pursue because of the narrow therapeutic index. Because of our unique approach with the NK cell engagers and being able to thread that therapeutic index, there's also been a lot of interest given the updates we've had around the AFM28 program.
Actually, one follow-up on acimtamig. You're partnered there with an NK cell therapy company, Artiva. How does that complicate partnering conversations or add to it?
Yeah, I mean, I think it's one of those things where there's clear synergy, right? I mean, obviously, we've tested acimtamig as a monotherapy, and I think you see encouraging response rates, but the durability piece seems to be lacking with the monotherapy approach. I think for acimtamig, the combination is necessary and has dramatically improved not only the overall response rate, but also the durability piece. I think it's an inherent necessity. I think where the partnership with Artiva becomes more complicated is the business relationship that exists, right? I mean, we own 2/3 of the economics, they own 1/3 of the economics. When you're talking about a market in double refractory Hodgkin's lymphoma, that's 2,500 patients to 3,500 patients a year, that becomes challenging when you have an economic split like that to make it work from a business perspective.
I mean, I think in order for someone to be interested, it's very important to be able to expand and show clinical proof of concept in relapse refractory PTCL, which would essentially triple that commercial opportunity.
Are you enrolling PTCL to that trial?
We have not started enrolling PTCL, but that would be a clear next step for that program because that is what will truly unlock the commercial potential for that program. Obviously, we've shown some monotherapy clinical proof of concept, so we know that there's activity of acimtamig. And if you look at the precedence of other CD30 targeted therapies like Adcetris, I mean, I think we feel highly confident that it's going to work in relapse refractory PTCL, but obviously, we're in a world and an environment where it's a show-me story, so.
Got it. Let's talk about AFM24. Your EGFR, CD16A, innate cell engager.
Yep.
You're focused on lung cancer.
Yes.
Even though you've seen activity in some other tumors.
Yes.
Starting that prioritization there, can you describe the activity you've observed there in mono and in combination with Roche's atezolizumab?
Yeah, so we've seen both monotherapy as well as combination activity. As a monotherapy in non-small cell lung cancer, the development was focused on EGFR mutant non-small cell lung cancer. As a monotherapy, we have not tested that program in EGFR wild type. There were 13 patients with EGFR mutations that were enrolled. These were refractory patients. One out of those 13 patients had a response, so about 7% overall response rate in that patient population. There was about a third of patients, a little bit over a third of patients that had tumor shrinkage, and there was about six out of those 13 patients that were on treatment for six months or longer. We did see benefit in patients, and some of those benefits that we saw were durable.
Where I think the data gets much more exciting is when you're leveraging both the innate and adaptive immune system with this combination with atezolizumab, or you could really use any checkpoint inhibitor. We have also shown really good additivity synergy with pembrolizumab, with the combination of acimtamig and pembrolizumab as well. We think that this additivity synergy isn't specific to just atezolizumab, for example. We think we can see this with any CPI. In the phase II combination study with atezolizumab, we have two cohorts. One cohort is patients with EGFR wild type. The other is patients with EGFR mutations. All of these patients have seen standard of care chemotherapy plus anti-PD-1, and all of these patients have documented progression on anti-PD-1 as well.
Wait, not the mutant patients? If indicated, they.
Yes, if indicated.
Yeah.
In the wild type patient population, we've released data on 33 patients, 21% overall response rate there. Preliminary PFS is at 5.6 months. I think that's quite encouraging. If you look at the PD-1 retreatment historical numbers, the overall response rates that you would expect in that patient population is about 5% to 10%, and the PFS is at two and a half months. I think what we're seeing is quite encouraging. Standard of care there in this setting would be docetaxel, which produces an overall response rate of about 10%, and a median PFS that's around four months. In the wild type, we seem to be seeing both an ORR as well as PFS signal. In the patients with EGFR mutations, in our last data released, there were 17 evaluable patients. There we're seeing a 24% overall response rate.
In the median PFS, there is also coincidentally 5.6 months. There is, interestingly, still about a 1/3 of patients that remain on treatment, and all of those patients have been on treatment for eight months and longer. There seems to be a very clear tail of the curve effect, which is what you would hope and want and expect to see with an immuno-oncology product.
You're currently, and you alluded to it earlier, enrolling a higher dose cohort.
Yes.
720 mg. Is there, just first, is there an efficacy threshold that you're looking to hit in this new cohort?
Yeah. Yeah, just for clarity, we haven't started enrolling the cohort yet. We're still waiting for the amendment to be approved to start enrolling patients at the 720 mg dose. The decision to move to the 720 mg dose was driven by a post-hoc analysis, which showed a very strong correlation between higher exposure and not only response rate, but also PFS and overall survival. Not only did we see this trend in non-small cell lung cancer, but as you alluded to, Daina, we also saw the same trend in the other tumor types that were enrolled. We've seen the same trend across our portfolio of NK cell engagers, where there's this clear correlation between higher doses and a response.
In terms of the threshold that we're looking to see, I mean, I think as you look at the competitive landscape for non-small cell lung cancer, I would say both in EGFR wild type as well as EGFR mutant patients, the overall response rates that we've been seeing are kind of in that 20% 30% range. PFS numbers are right around kind of that five-month to six-month range. I think what we're showing currently at the 480 mg weekly dose, I think is competitive with what others have shown. The question is, how can you be differentiated, right? What do people really want to see to get excited about this program?
I mean, I think internally and what we've heard from investors, what we've heard from partners is they want to see north of a 30% ORR, and they want to see ideally north of a seven-month median PFS. Those, I would say, are kind of the benchmarks of what folks are hoping to see. I think we've seen others produce that 20%-30% ORR and that median PFS in the five to six-month range, and then they go and spend $100 million to $150 million on a phase III registrational trial to go head-to-head versus docetaxel, and they end up falling short.
Are you still enrolling, all patients who are post-chemo and PD-1, d id you consider allowing just post-PD-1?
Yeah.
Is that maybe just get you a little bit easier patient population?
Yeah, I mean, the cohorts have enrolled quite rapidly, right? I mean, now that we have kind of all the sites up and running and active, enrollment has not been an issue or a challenge from that perspective. I mean, and when you think about kind of standard of care for these patients, I mean, the vast majority of patients are still seeing both chemo and anti-PD-1. I mean, maybe you have some elderly patients that are not suitable for chemotherapy where they would just get anti-PD-1, but I don't think we're losing a ton of patients by the inclusion criteria that we have.
I was just thinking maybe you could gain some patients that are not chemorefractory would you see just a kind of signal?
Yeah, I mean, I think it's a relevant question, right? I mean, especially given the prior taxane analysis that we've done, right? I mean, as part of the post-hoc analysis, not only did we see the correlation between higher exposure and better efficacy from an ORR, PFS, and OS standpoint, but we also looked and did an analysis to look at the impact of prior taxane exposure, and patients that did not see a prior taxane had a median PFS of 7.4 months versus those that did have prior taxane exposure had a median PFS of 4.4 months. Perhaps maybe you could further enrich by just allowing for patients who had anti-PD-1.
You are excluding prior taxane now, though, right?
In the next cohort, in the 720 milligram cohort, the plan is to exclude patients that had prior taxanes.
Got it.
Yeah, I mean, I think anything you can do to enrich for the PFS north of seven months, then clearly that's a signal that would allow us to do so.
Let's talk more about this dose. I mean, like I said, I covered Affimed for a long time. One, there's always worry that you're seeing a post-hoc signal because it's small, so there's a chance that it's not right. Also, there was a lot of work on picking the dose.
Yep.
It took a long time.
Yes.
There was a lot of pharmacokinetics, pharmacodynamics, these beautiful posters showing that you're fully saturating receptor occupancy, I believe, on the NK cell side at the 480 nm filter. Why did all that modeling work fall short?
Yeah, so I mean, your PD marker is only as good as the assay, and a lot of this is dependent upon where you're measuring those corresponding markers, right? The assay that was run in this scenario that you're describing for the PD marker is an NK cell-based assay in terms of receptor occupancy, but it's in the peripheral blood, right? It doesn't highlight how much drug is getting into the tumor microenvironment. It doesn't highlight, probably even more importantly, how much drug is actually getting into the tumor itself.
Even though we were reaching full saturation on the peripheral blood NK cell occupancy assay, I think the concern here with this post-hoc analysis was that that's not necessarily indicative of how much is getting into the microenvironment and how much is getting into the tumor because the post-hoc analysis that we've done, albeit with the caveats associated with the post-hoc analysis, it is a very robust analysis, and it's over 100 patients' worth of data. I think we feel quite confident in all of that data trends towards this suggestion that higher exposure correlates with the improved efficacy. Again, it's across all efficacy parameters. It's ORR, PFS, and OS.
You said over 100 patients?
Yes.
That's because you're pulling in all the other tumor types.
Correct. Yeah.
You did not share all that, right?
No, this data was shared as part of the post-hoc analysis.
Okay.
We did pool not only just the non-small cell lung cancer patients, but we also pooled the analysis around other solid tumors, and it includes both monotherapy as well as combination. That is where you get to over 100 patients' worth of data for the analysis.
I know it's early, and this is you have to get to the next step.
Yes.
How are you considering registration paths here in this setting, going to frontline? Is there a front-runner option here?
Yeah, so I mean, I think in terms of the registrational path, I mean, I think the registrational path in second, third-line non-small cell lung cancer really hasn't changed a lot in probably the past decade, if not close to two decades at this point, right? I mean, you will be required to run a phase III randomized study, and that comparator is docetaxel today. I mean, it has not changed. I think people are optimistic that maybe Trop-2 ADC would overcome docetaxel, but it was obviously unable to do so. So that would be the registrational path, and that would be true in either the EGFR wild type or the EGFR mutant patient population.
Do you need to show contribution in some ways, or have you talked to FDA about the PD-1?
Yeah, so I mean, I think you would rely on kind of the historical numbers with kind of the PD-1 rechallenge here. We haven't had any discussion with the agency around the contribution of parts. So it's something that I would imagine will come up in a discussion with the agency once we are ready and prepared to have that registrational phase III discussion with them.
How do you disentangle your development from atezolizumab and move it to a more validated PD-1 antagonist? We can debate if atezolizumab is worse or not, but I think it adds risk. I'd rather be with pembrolizumab, cemiplimab, or tislelizumab, any of them.
Yeah, I mean, I think the good thing here, and I think I mentioned this earlier, I mean, we have shown that this additive synergistic effect that we see between the innate immune system and the adaptive immune system is not just unique to atezolizumab, right? We have shown this with other NK cell engagers, most notably with acimtamig in combination with pembrolizumab, and that work was done in Hodgkin's lymphoma, where we meaningfully improved the overall response rate and probably more importantly in that setting improved the CR rate as well. I think we're highly confident that we should see good additivity in synergy with any of the anti-PD-1s. I think it's also important to note at this time, Roche is paying and contributing atezolizumab for free.
I mean, I think we're open to looking at other anti-PD-1s or L1s in this setting, but I don't think the results will change regardless of which anti-PD-1 or L1 you use.
So far to say you're open and that you're out there. You're just not willing to say you're out there actively thinking about it.
Sure.
Okay. I had forgotten until I was preparing for this session that there was a one-dose lead-in with AFM24.
Yes.
In the study before the combo, and you mentioned you had monotherapy activity alone. Did you look at anything?
Yes.
Is that enough time?
Yeah, I mean, I think as an expert in immuno-oncology, you know these things take time to work, right?
Yeah.
I mean, it's nice to have a one-week monotherapy activity, but it's just too short of a period to learn anything at that stage.
Let's move on to AFM28, which is the CD123 for AML. I wonder if you could just summarize the activity you've seen thus far and also, yeah, let's start with that.
Yeah, so I mean, I think the data has been quite encouraging. I mean, obviously, AML is a significant unmet medical need. Patients in the relapse refractory setting have a median overall survival expectation of about four months. We are currently dose-escalating. We started to see signs of clinical activity at dose level five. This was at the 200 mg dose level. We've seen increased activity at the current dose level, which is 300 mg so that's a 300 mg cohort. W e had an oral presentation of our data at ASH. There were 11 available patients at that point. What we were seeing is a 40% composite CR rate, so CR, CRi in patients, and those durations of response ranged anywhere from 2.5 months to 6.5 months.
When you think about recent regulatory precedents and how does that data stack up, you can look at the recent approval of the Syndax menin inhibitor, which was approved in patients with KMT2A translocations. That was approved based upon a 20% composite CR rate and a median duration of response of six months. Even though we're currently continuing to dose-escalate, I think we're seeing very encouraging signs of activity with that 40% composite CR rate and durations that range anywhere from 2.5 months to 6.5 months, which obviously stack up quite nicely against that recent regulatory precedence.
I think you're currently, and tell me if I have this right, treating 12 patients at a higher dose and five patients at the dose level six were still ongoing treatment as of ASH.
Yeah.
Is that right w hen will we see updated sort of outcomes from those cohorts?
Yep. We continue to follow the patients at dose level six. Patients are still ongoing there. Next step will be, as you just mentioned, to dose-escalate to dose level seven. We have not done that yet. That will be the clear next step, to go up to dose level seven and assess, does the higher dose lead to deeper and more durable responses. In terms of timeframe as it relates to data updates, we have not provided any formal guidance, but when you think about how enrollment has gone and how quickly data has kind of come in thereafter, I think once we start enrolling patients to dose level seven, I would imagine you would have data in that six to nine-month timeframe.
What's gating the enrollment?
There's nothing specific that's gating the enrollment. We're just looking to make sure that we have a good sense of the durability at dose level six before moving to the next dose level.
Is that for internal investment reasons or why?
Yes. Yeah, yeah. I mean, I think we want to make sure that not only are we seeing good response rates, but I mean, I think making sure that you're seeing durable responses is also critical. I mean, I think as you think about having the three programs, it's important that we are good stewards of investor capital, and I think making sure that we have as much information to make informed decisions is critical.
You mentioned earlier that a lot of CD123-directed approaches haven't worked, including a monoclonal antibody from J&J and T-cell engagers.
Yes.
Why is yours working? What's different about it? I guess we've also seen one working from Innate and Sanofi.
Yes.
What do we learn across those two programs?
Yeah, I mean, I think what we've learned is that this approach of using an NK cell engager is critical to navigate the narrow therapeutic index. I think when you look at kind of those historical studies that you've mentioned that have pursued targeting CD123, they've been TCEs, they've been CAR-Ts, they've been ADCs, they've been monoclonal antibodies, and those therapeutic modalities don't have the ability to differentiate that expression of normal healthy human tissue versus that on the tumor tissue, right? In turn, you have collateral damage, and that collateral damage with CD123 manifests as cytokine release syndrome, which is obviously a very challenging toxicity to deal with and manage.
For an NK cell engager approach, what is unique and differentiated about this is that in the normal healthy human tissue, the NK cell engager will bind, but it will not attack and kill those normal healthy human cells because in that microenvironment, you have NK inhibitory factor that basically tells the engager that you're in normal healthy human tissue and to not attack and kill those cells. That allows us to have a wider therapeutic index, and I think that's a key piece of the differentiation strategy. I mean, we see the same effect with AFM24 in terms of pursuing EGFR, for example. I mean, if you look at EGFR small molecule inhibitors, for example, or other therapeutic modalities against EGFR, you see that prototypical on-target skin toxicity and mucosal toxicity. We don't see that with AFM24. That is a key component here of the differentiation.
I think, again, Sanofi and Innate have seen the same thing. We seem to be showing slightly higher activity than what they have shown initially, but I think both of these approaches have validated that an NK cell engager approach could be optimal for pursuing a narrow therapeutic index target like CD123.
Maybe the last question on acimtamig. You mentioned the maybe challenging commercial situation, business situation with a partner and complexity of NK cell. I guess for me, if I just think about it from a clinical perspective, you had proof of concept with the MD Anderson investigator study, and you changed a lot of things.
Yes.
In the Artiva study by necessity versus what was done in a single site at MD Anderson.
Yeah.
I'd say for me, the updated data has a modest degradation in NK cell exposure, efficacy, and safety.
Yeah.
Still promising, but we saw it step down across the board. Is this luck or is there something about the new regimen that you would even consider testing as you have two dose arms in the registration study where you could test two different things?
Yeah. I mean, I think, I mean, we obviously tested a variety of different dose levels on the most recent data release that came out at ASH, right? We looked at two different doses of acimtamig and two different doses of allogeneic NK cells and small patient numbers, but I mean, there's no meaningful difference in the activity regardless of the dose of acimtamig or regardless of the dose of the allogeneic NK cells. I think it's important here to keep in mind the unmet medical need that exists, right? Patients with double refractory Hodgkin's lymphoma have already been through chemo. They've been through Adcetris. They've been through anti-PD-1. Really, the only option for these patients is to get additional chemotherapy, which in this double refractory setting would produce about a 10% overall response rate and unlikely to produce any CRs r egardless of whether it's kind of the MD Anderson regimen or the combination with Artiva's allogeneic NK cells
I mean, we're producing north of a 50% CR rate and an overall response rate that's north of 80% in both of those settings. I don't know if it's necessarily fair to say that there's a "modest degradation." I think the efficacy, safety, PK exposure are similar. I mean, I think really the devil will be in the details. I think it's important really to see how the durability piece plays out. I mean, once we have that data in the second half of this year, the PFS and durability I think will be the key components that folks will focus on.
Okay. I didn't ask and we're out of time, but I have to say.
Sure.
If it were me, I would, instead of testing the two higher NK cell doses as you did, a lot of companies have shown you get better exposure with bunched-up dosing.
Sure.
In MD Anderson, they had the advantage of changing donors.
Yeah.
With each dose. I would try to do one where I'd bunch the dosing up to try to give a better area under the curve, but are you considering that at all?
It's not something we have considered. I mean, I think commercial viability is also a key component, which drove our decision too. I mean, the MD Anderson cells were obviously not commercially viable. A big part of kind of the transition to partnering with Artiva was having access to commercially viable NK cells that could be accessible from a global standpoint. I mean, it's great that you could produce north of a 90% ORR and a really high CR rate, but if you can't get that to centers, that's a problem.
Yeah. Yeah. Awesome. Thank you very much. Thanks, everybody, for your attention.
Sounds good. Thanks, Anne.