Adicet Bio, Inc. (ACET) Earnings Call Transcript & Summary

Thanks, everyone, for joining us. On the call today from Adicet are Chen Schor, President and Executive Officer; Dr. Francesco Galimi, Chief Medical Officer; Nick Harvey, Chief Financial Officer; and Dr. Blake Aftab, Chief Scientific Officer. Before we begin, I'd like to remind you that various remarks that we make on this call contain forward-looking statements that are made under the safe harbor provisions of the securities laws, including, but not limited to, express or implied statements regarding the potential safety, durability, tolerability and efficacy of ADI-001. Due to progress of ADI-001 in patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma, or NHL, including selection of a recommended Phase II dose, expectations regarding future discussions with regulators and regulatory filings for product candidates in the company's pipeline and timing for the potentially pivotal Phase II study of ADI-001 in post CAR T LBCL patients. In addition to our prepared remarks, we may make forward-looking statements in response to questions, including, for example, statements regarding potential future trials, our financial position and that positive interim results from a clinical study may not necessarily be predictive of the results of future or ongoing clinical studies. Any statements made in this call that are not statements of historical fact may be deemed to be forward-looking statements. Forward-looking statements involve risks and uncertainties that could cause Adicet's actual results to differ significantly from those projected including, without limitation, the risks and uncertainties detailed in Adicet's most recent annual report on Form 10-K and subsequent filings with the SEC. We issued a press release today outlining results of our Phase I clinical trial of ADI-001 in patients with aggressive NHL. The press release and the accompanying presentation can be found on the Investors section of Adicet's website. This call is the property of Adicet, and any replay of this conference call cannot be made without Adicet's express written permission. With that, I'll turn the call over to Chen Schor, President and CEO of Adicet. Chen?

Thanks, Anne, and thank you all for joining us on this call to discuss our latest data cut from the Phase I clinical study of ADI-001 and in patients with aggressive non-Hodgkin lymphoma. Let me walk you through the agenda for today's call. I will begin with an overview of the data and provide a comparison of durable CR rates in aggressive NHL for autologous CAR T, Bispecifics and ADI-001. I will then hand it over to Dr. Francesco Galimi, our Chief Medical Officer, to provide a more detailed overview of the Phase I data. I'll close with a short summary of the market opportunity for ADI-001's first potential indication in our near-term corporate milestones, before we open up the call for Q&A with the rest of Adicet team. Let's go ahead and get started. Let's go to Slide 5. We're excited about the ADI-001 data we announced this afternoon from our Phase I study, demonstrating strong efficacy and favorable safety in 24 patients with aggressive, relapsed or refractory B-cell non-Hodgkin lymphoma. The data is especially impressive given that these patients were heavily pre-treated with a median of 4 prior lines of therapy and 50% of the patients had progressed on prior autologous CAR T therapy. The overall response rate we observed in the study was 71% and the CR rate was 63% in the efficacy of evaluable patients across all doses. In post-autologous CD19 CAR T patients, the overall response rate was 83% and the CR rate was 67%. We have observed strong durability with ADI-001, with a 6-month CR rate consistent with autologous CD19 CAR T therapies. We continue to observe a favorable safety profile with no significant incidence of CRS or ICANS, and let me remind you that ADI-001 is off-the-shelf and rapidly available to patients. We selected DL4 as a recommended Phase II dose. At this dose level, the Cmax and Day 28 persistence of ADI-001 exceed, there of approved CD19 autologous cell therapies. Last month, we completed our Type B meeting with FDA. We plan to transition the ADI-001 program into a potentially pivotal Phase II study in post CAR T LBCL patients in the first half of 2024 under an accelerated approval cap. There is a significant and growing market opportunity for this potential indication that we will outline on a separate slide. We believe the data you'll see today provides a strong foundation for our growing pipeline of engineered gamma-delta T cell therapies. Let's review the efficacy of the currently approved autologous cell therapies in Bispecifics -- Bispecifics in aggressive NHL so we can put some context to ADI-001 efficacy. Let's go to the next slide. If you look at published data in the The New England Journal of Medicine, you'll see that CRs to cell therapies, which last 6 months, are a strongly indicative of long-term remission in contrast to the Bispecifics. The graph in green on the left is from axi-cel's ZUMA-1 trial published in the New England Journal of Medicine, showing duration of complete response. As you can see, the 6-month CR rate represents a long tail of durable CR rate. The graph in blue on the right is from Glofitamab trial published also in The New England Journal of Medicine. As you can see, there is a significant erosion in Glofit's CR rate over time, and there is still no tail to the CR rate. What's the actual durable CR rate for Glofitamab? What we do know is that at least 50% of the CRs progress. Let's move to the next slide. So you can see the durable CR rates when you layer the number of prior lines of therapies across autologous CAR Ts and Bispecifics. This slide shows the efficacy data from the different trials at the recommended Phase II dose. In purple, we plotted the Durable CR rate for the ZUMA studies which investigated axi-cel in the first, second and third line setting. As you can see, the Durable CR rate defined in cell therapies as the 6-month CR rate decreases from 69% in first line to 46% in second line to 33% in patients with a median of 3 lines of prior therapy. The ZUMA studies have been conducted by definition in CAR T patients. In gray, Bispecific antibodies, Glofitamab and Epcoritamab, both had the same median of 3 prior lines of therapy in their pivotal studies as the ZUMA-1 study. Both Bispecifics have shown an approximately 20% Durable CR rate, given that the initial CR rate was approximately 40% and at least 50% of CRs progress is published in the New England Journal of Medicine. As a reminder, ADI-001 was evaluated in patients with the median of 4 prior lines of therapy and 50% of the patients progressed on prior autologous CAR T. Now let's layer on our ADI-001 data on the next slide to see where we stack up. Next slide, please. As you can see here on the slide, the data for ADI-001 is outlined in the blue boxes on the right, as we tested ADI-001 in later-line patients with a median of 4 lines of therapy. If you look at the bottom blue box for all patients dosed -- for all patient dosed at a recommended Phase II dose cohort which included 38 of patients that previously progressed on CAR T, the Durable CR rate in this group was 25%. If you look at the top box in post CAR T patients at the recommended Phase II dose, the Durable CR rate was higher at 33%. While we have a smaller N at the recommended Phase II dose, the bottom line is that ADI-001 seems to be in the same ballpark when compared to autologous cell therapies with lower incidence of CRS and ICANS and it's off-the-shelf rapidly available to patients. Overall, we're very pleased with the strong Durable CR rate demonstrated by ADI-001 in these late-line NHL patients. Now let's turn our attention to ADI-001, Durable CR rate in the post-CAR T setting. Next slide, please. The CD20 Bispecifics have demonstrated a CR rate of approximately 34% to 35% in the post-CAR T setting. But given that at least 50% of the CRs progress with the Bispecifics, the Durable CR rate in the post-CAR T setting is estimated at 17% or less. With ADI-001, when you look at all doses combined, we have seen a higher complete response rate and a comparable Durable CR rate as indicated in the middle funnel. At the recommended Phase II dose on the right, both the CR rate and the Durable CR rate are more favorable to available therapies. In particular, although a smaller N for ADI-001, the CR rate for ADI-001 may be double that of the Bispecifics and the Durable CR rate comparable and more likely favorable at a recommended Phase II dose. Additionally, it's important to point out that treatment with Bispecifics required frequent infusions. For example, for Epco, the first 24 doses are provided weekly or biweekly in the hospital or clinical setting for the first 9 months, tying up the patients for hours at a time for each of those 24 infusions, followed by once-a-month infusion regimen. In the case of ADI-001, we provide a onetime treatment infusion liberating patients from the need of frequent visits to the hospital. I'll now turn the call over to Francesco to talk about the ADI-001 data in greater detail. Francesco?

Thank you, Chen. Hello, everyone, and thank you for joining us today to review the latest data cut from our Phase I study, evaluating ADI-001 in aggressive B-cell malignancies. I will now review the main findings which we believe continue to be very encouraging and share our preliminary plans for our first potentially pivotal Phase II study. Let's first give you a quick reminder of the first in-human study design on Slide 11. The dose escalation included 4 dose levels starting at a flat dose of 30 million CAR+ Cells and continuing to 100 million, 300 million and 1 billion CAR+ cells. Each enrolled patient received a 5-day Lympho-depletion regimen. We have explored 2 different Lympho-depletion regimens shown on the slide, both based on fludarabine and cyclophosphamide. One exploratory section of the protocol, not shown on the diagram, which we call Part 1b, included patients receiving a single Lympho-depletion in 2 infusions of dose level 3 on day 1 and day 7 for a total of 600 million CAR+ Cells. Let's go to patient characteristics on the next slide. As of the May 4 cutoff date, the trial enrolled 23 patients with aggressive B-cell lymphoma. 18 patients had large B-cell lymphoma and 5 had mantle cell lymphoma. One additional patient was enrolled with follicular lymphoma for a total of 24 evaluable patients. Most patients were heavily pretreated with a median of 4 prior lines of therapy, relatively high tumor burden and a poor prognostic outlook. Approximately 70% of patients were refractory to their last course of systemic therapy and the remaining had relapsed. 12 patients, 50% of the total, had progressed following approved autologous anti-CD19 CAR T cell therapies, including axi-cel, liso-cel and brexu-cel. Let's go to efficacy data for ADI-001 on the next slide. This chart summarizes the efficacy for ADI-001 as of the May data cut date. Let's focus on DL4, the recommended Phase II dose, as shown on the first 2 rows on this slide. You can see that the 6-month CR rate is in the same ballpark as autologous in spite of the high prior lines of therapy in the percentage of post-CAR T patients. In dose level 4, patients had a median of 4 lines of prior therapy with approximately 38% post-CAR T. This group achieved an overall response rate of 75% with 6 responders out of 8 patients. The complete response rate was 62.5% and the 6-month complete response rate was 25%. Importantly, at the recommended Phase II dose in patients with prior CAR T, the group achieved a 100% overall response rate. The complete response rate was 67% and the 6-month complete response rate was 33%. Let's go to the next slide. This slide shows our response data on a swim lane plot for all 24 evaluable patients as of the May 4 data cut date. Let me remind you that our patients are heavily pretreated with a median of 4 prior lines, including prior treatment with autologous CAR Ts in 50% of them. In the boxes on the right, for each cohort, we break out the median number of prior lines of therapy and highlighting yellow, the percentage of post CAR T patients. As we saw on an earlier slide, our recommended Phase II dose DL4 included 38% of post-CAR T patients. The overall response rate was 75%, complete response rate was 63%, and the 6-month CR rate was 25%. If we look across all those levels, which included 50% of post-CAR T patients, the overall response rate was 71%, CR rate was 63%, and the 6-month CR rate was 17%. A total of 21% of patients remain cancer-free if we include the first patient in dose level 1 who had a local skin relapse, was managed with local radiation, and remains disease-free without any systemic therapy for over 20 months. We consider this patient, one of the success stories for this Phase I trial, even though we have to count him as a progression for Lugano criteria. Overall, the preliminary efficacy data of this trial to date have shown high response rates comparable to the clinical experience with approved CAR Ts and comparable durability despite the high number of prior lines of therapy and percentage of post-CAR T patients. Let's now focus on the post-CAR T patients shown on the next slide. This slide shows our response data on a swim lane plot, focusing on patients who have previously progressed on autologous CD19 CAR T therapies, which included 12 of the 24 total evaluable patients. Across all those levels, the post-CAR T patients had a median of 4 lines of prior therapy and saw an overall response rate of 83%, a complete response rate of 67%. A 6-month complete response rate of 17% with 25% cancer-free patients if we include the patient with a skin lesion that I discussed earlier. The 25% of cancer-free patients include 3 out of the 12 post autologous CAR T patients. 2 were large B-cell lymphoma and one was mantle cell lymphoma. Given that there were 10 large B-cell lymphomas in 2 mantle cell lymphomas post autologous CAR T patients, while this is a very small N, this suggests that 20% of the large B-cell lymphoma post autologous patients and 50% of the mantle cell lymphoma post autologous post-CAR T patients remain cancer-free at 6 months. As you can see at dose level 4, a recommended Phase II dose, patients had an overall response rate of 100%, with a complete response rate of 67% and a 6-month complete response rate of 33%. Let's move to the next slide to talk about PK. Slide 16 depicts the PK analysis of blood samples using 2 different techniques: Flow Cytometry for CAR+ Cells on the left and ddPCR for the CAR transgene on the right. For the latter, at this point, we have data only for dose level 4. By both methods, Cmax and D28 persistence exceed levels reported for approved autologous CD19 CAR Ts like axi-cel, [ diso-cel ], liso-cel. Also similar where the peak values for ADI-001, occurring between day 7 and 10. Persistence at Dose Level 4 was also clearly detectable at high levels through day 28. Of note, both Cmax and persistence in dose Level 4 were much higher than dose Level 3 and dose level 3 x2, providing supporting data to our recommended Phase II dose selection. Also please note that this PK measured in peripheral blood may be only the tip of the iceberg considering gamma-delta 1 cells tropism for tissues. Altogether, we believe these are the most compelling pharmacokinetic data reported to date for any allogenic CAR T platform. This data set is also very promising for its implications for our upcoming pipeline programs. Let's go to the next slide. This slide shows a summary of key safety data collected so far. There was one CRS and one ICANS reported in Grade 3 or above in dose Level 3 and dose level 3 x2 respectively. We have not seen any event of graft versus host or any dose limiting toxicities. The occurrence of infection in the study appears to be rather low in spite of the use of enhanced lympho-depletion. Overall, ADI-001 was remarkably well tolerated throughout the dose escalation, including patients, those at dose level 4, especially in comparison with the safety profile of approved autologous CD19 CAR Ts. Let's go to the next slide. Let me show you this diagram again, which visualizes how we describe the lay of the land when it comes to recent advances in Non-Hodgkin lymphoma immunotherapy. As you can see, ADI-001, shown by the blue dots compares well to both the axi-cel experience shown in purple and the 2 recent accelerated approvals of Bispecifics shown in gray. We are convinced that our data set bodes well for further characterization in our future clinical program. Let's move to the next slide. Last month, we met with the FDA for our Type B meeting, and we are now advancing our plan to initiate our potentially pivotal Phase II study in post-CAR T large B-cell lymphoma. The Phase II study will evaluate a single infusion of ADI-001 at our recommended Phase II dose of 1 billion CAR+ cells in a single-arm clinical trial in post-CAR T large B-cell lymphoma patients. We expect to enroll approximately 100 evaluable patients. The primary endpoint of the trial is expected to be complete response. Manufacturing is underway to supply clinical material for our potentially pivotal Phase II study, which we plan to initiate in the first half of 2024. In addition, given the highly favorable data we have observed in post-CAR T mantle cell lymphoma patients, we're also evaluating our plans for this indication. In summary, we are very pleased with the CR rate, durability and safety data demonstrated with ADI-001 in this study. With that, I thank you all for your attention, and I'll turn it back over to Chen.

Thanks, Francesco. We believe the latest clinical data set provides us with a strong foundation for future development. The data we've shown you to date demonstrate that ADI-001 had a high CR rate at least comparable to approved CD19 autologous CAR T therapies. ADI-001 showed strong durability in late-line patients with high percent of post-CAR T and the Cmax and D28 persistence exceeds the value reported for approved CD19 autologous CAR T. We've already published the superior cell-killing potency of ADI-001 compared to the alpha-beta CAR T. And finally, a favorable safety profile with no significant incidence of CRS and ICANS, which is expected to enable dosing in outpatient setting. Let's move to the next slide to discuss the market opportunity. Autologous CD19 CAR T market is estimated at over $2.2 billion annual run-rate. And the market is expected to grow significantly given the recent approval of autologous CD19 CAR T therapies in the second line setting. Yet in the second line and third line setting, 60% to 70% of patients progress following autologous CD19 CAR T. We believe this provides a significant opportunity for Adicet and for ADI-001. Let's go to the next slide to talk about the near-term milestones. Looking ahead, we're well funded and have significant near-term milestones ahead. Based on these first-in-human findings, we expect to initiate a potentially pivotal Phase II study for ADI-001 in post-CAR-T LBCL in the first half of 2024. We plan to provide a clinical update from additional post-CAR-T LBCL patients, including efficacy, 6 months CR rate and safety data in the second half of 2024. We also expect to evaluate opportunities for a second pivotal study. Our second pipeline candidate is ADI-925, which we believe has the potential to introduce a fundamental advance to the fields of cell therapy and innate immunity by significantly enhancing the intrinsic innate and adaptive antitumor activity of our gamma-delta 1 T cells. We continue to expect to submit an IND for ADI-925 in the second half of this year and initiate a Phase I clinical study in AML in the first half of next year. Our third pipeline candidate, ADI-270, for which we expect to submit an IND next year provides multiple levels of differentiation for CD expressing tumors such as renal cell carcinoma. One, our CAR construct uses CD27 to bind to CD70, enabling us to target tumors with low antigen density at very high specificity. Two, gamma-delta 1 T cells have tissue tropism to the renal tissue unlike other immune cell types. And three, the innate antitumor activity inherent in our gamma-delta T cell platform may help address tumor heterogeneity in renal cell carcinoma. We're excited about the data we discussed today, which demonstrate that ADI-001 has the potential to generate meaningful responses in patients where other treatments have failed. We're developing a pipeline of programs targeting additional hematologic and solid tumors. We appreciate your continued support and look forward to updating you on our progress. And with that, I'll turn it back to the operator to open it up for Q&A. Operator?

[Operator Instructions]. Please note that this call is being recorded. [Operator Instructions]. Our first question comes from John Newman from Canaccord.

Congrats on the continued progress here. I just wanted to confirm the pivotal study will only be enrolling large B-cell lymphoma patients. And I'm also wondering if you considered at all perhaps enrolling patients that had prior exposure to CD19 Bispecifics or a few -- at this time, it's just going to be prior CAR T exposure?

Yes, absolutely. Francesco, why don't you take this one?

Yes. Thank you, John. So yes, to answer your first question, yes, we plan to enroll patients with post CAR-T large B-cell lymphoma. And in terms of CD19 Bispecifics, you are alluding to the agents in development or do you have anything in mind in particular?

Yes.

Yes, so we don't plan to exclude patients with prior exposure to anti-CD19 Bispecifics. That's not our current plan.

John, just to add to that. The same is for CD20. CD20 is quite a stable antigen, so also these patients will be allowed to the pivotal study.

And then if I could ask just one additional question. Over time for development of the CAR T therapies, the FDA has generally required somewhere around 6 months follow-up. Just to get a sense of durability. I've noted that your primary endpoint here will be complete response. And should we assume that you'll be following the patients for say, 6 to 12 months also to get a sense of the durability there as well?

Yes, John, you're right. It's very, very traditional for the FDA in cell therapies to ask for follow-up with the 6 months. So indeed, the primary endpoint is expected to be a complete response, and we expect to file with a follow-up data of 6 months for patients in the study. Absolutely.

Our next question comes from Asthika Goonewardene.

Congrats on the progress as well. So I just want a couple of clarification questions here on the pivotal study here. Chen, I believe I heard you say that you might have preliminary data in the second half of 2024. I just want to clarify, did I hear that correctly or was there whack to my ears.

Yes, yes, absolutely. Let me separate. So regarding the initiation of the potentially pivotal Phase II, we expect to initiate it in the first half of '24. So that's number one. Regarding the clinical update with additional post-CAR-T LBCL patients, this will include efficacy, 6-month CR rate as well as safety. This update, we expect it to be provided in the second half of next year. It will include additional post-CAR-T LBCL that we will enroll into the currently ongoing Phase I as well as patients that will be enrolled to the expected pivotal study.

So can you maybe parse out how you will be prioritizing recruiting patients if you have both of these sort of ongoing? Or would you kind of have it at you'll continue enrolling patients into the Phase I all the way until you really kick off the Phase II study?

Francesco?

Yes. We will continue enrolling patients in our existing Phase I, and we will also start enrolling patients in our upcoming Phase II, which we are currently writing and finalizing. So the answer is yes, we'll be doing both.

And Francesco can I ask -- maybe give a little bit of color on maybe some of the differences in the baseline factors all sort of like the inclusion and exclusion criteria we can expect to see for the pivotal study compared to what was for the Phase I? And how do you think that would impact outcomes?

Yes. So let me rephrase my answer. So we will add more patients through the ongoing Phase I. And then at some point, of course, we'll switch to a Phase II, which we are currently finalizing. The eligibility criteria for the existing Phase I, as you know, are broader in the Phase II, we'll focus, as we said, in the post-CAR T population of large b-cell lymphoma patients.

And then just the last one. How would you define prior CAR T exposure? Would you define any takeaway like maybe patients should have had a prior response to CAR T or will you allow patients who have best response of [ PT ] to prior CAR T?

Yes, we don't -- so let's talk about semantics for just a minute. So we call patients who did not respond to their prior autologous CAR T experience. We call those primary refractory. And we don't expect to enroll a significant number of those in the upcoming pivotal study. The broader definition of refractory in the literature is patients who relapsed within 6 months from their prior CAR T experience. And we do have quite a few of those already in our Phase I, and we plan to have some of those in the upcoming pivotal. So some of it has to do with the definition that is used in the literature to define the refractory population.

Our next question comes from Reni Benjamin from JMP.

A couple here. Just you had a nice comparison between the Bispecifics and 001 in terms of Durable CR. Can you comment a little bit about the median duration of response for both assets?

I'll start and Francesco might be able to comment. It's tougher to compare median duration of response because when you look at the Bispecifics, you can see this very significant erosion in the CR rate. So when you think about eventually people are looking for a cure, you're trying to understand what percent of the patients are actually cured. And you look at cell therapy, you look at the 6-month CR rate and that gives you a sense of what are the percent of patients that can get a cure. So that is the best way for us to try to calculate it. Of course, when we expand the study and we'll have many more patients in DL4, we can start understanding that better. So that's what I can share so far. Yes. I don't think we have anything to add.

Okay. And then how do you strategically plan to evaluate patients with lesser lines of prior therapies? And are you -- because we're hearing, obviously, the CAR T therapy moving up in terms of administration, right, sometimes in the second line. Is there a way to -- as you continually point out that in your set of patients, they've had at least 4 prior lines. Is there any way in your ongoing pivotal study to move that up and you increase your criteria to have only 2 or 3 lines of prior study and potential get your CR rate higher?

Absolutely. Reni, I think this is a great question. Actually, there's nothing that we need to do. Because so far, most of the patients we've seen in this study were a median of 4 line of therapies. When you think about it, something happened relatively recently and it's the autologous CAR Ts got approved in the second-line setting and are really becoming the standard of care in the second-line setting. So effectively, in this upcoming potentially pivotal study, it would not be surprising if most of the patients would progress on 2 lines of therapies, including post autologous CAR T and we'll see ADI-001 in the third-line setting. So from that perspective, it's really not a result of our effort, but rather a result of the nice data that the autologous CD19 have shown in the second-line setting.