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spk04: Good day. Thank you for standing by, and welcome to the Acumen Pharmaceuticals second quarter 2022 update call. At this time, all participants are in a listen-only mode. There will be a brief overview followed by a question and answer session. To ask a question during the session, you will need to press star 1 1 on your telephone. Today's call is being recorded, and I would now like to turn the call over to John Wolford from Westwick. Please go ahead.
spk02: Thank you, Operator. Good afternoon. Thank you for joining us today to review Acumen's second quarter 2020 update on operational progress and financial results. Before we start, we encourage you to read the operational and financial results press release issued this afternoon, which is accessible on our website in the Investors section. Please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. All these statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Our actual results could differ materially due to a number of factors, including the extent and duration of the effects of the COVID-19 pandemic, geopolitical events such as the conflict between Russia and Ukraine and related sanctions, and macroeconomic conditions such as rising inflation and uncertain credit and financial markets. Please refer to our recent filings with the SEC for a full review of the risks and uncertainties associated with our business. Forward-looking statements speak only as of the date on which they are made, and Acumen undertakes no obligation to update or revise any forward-looking statement. Dan O'Connell, President and Chief Executive Officer, will begin today's call with a review of select second quarter 2022 business highlights. Dr. Eric Siemers, Chief Medical Officer, will then discuss the recent developments in the Alzheimer's disease field and provide an update on the ongoing Intercept AD trial. Finally, Matt Zuga, Chief Financial Officer and Chief Business Officer, will provide a brief financial update. We will then open the call for Q&A. I'll now hand the call over to Dan O'Connell, President and Chief Executive Officer. Dan?
spk06: Thank you, John. Good afternoon, and thank you to everyone joining the call today. I'm delighted to be here to review our second quarter and provide a business update. Picking up from the momentum generated in early 2022, we continue to make progress with our Intercept-AD clinical trial of ACU193, the first monoclonal antibody developed to selectively target soluble A-beta oligomers to enter the clinic. Regarding site activation enrollment, we are continuing to activate new clinical trial sites. Intercept-AD enrollment is now ongoing at 15 active sites, up from 11 active sites as reported in our first quarter conference call in May, Given our continued progress in the trial, we believe we remain on track to report top-line results in the first half of 2023. In parallel to conducting the Intercept AD trial, we have also made progress in preparing for a future Phase 2-3 trial of ACU193. The chronic GLP toxicity study is ongoing, and we expect our new drug substance production process and drug product formulation should be finalized in the near term. The Phase 2-3 study design and planning for an end-of-Phase 2 meeting with the FDA are underway. Our plan is to be prepared to initiate the next trial, a potential Phase 2-3 trial, after the results of the ongoing Intercept-AD trial are available and assuming they demonstrate proof of mechanism. As I highlighted during our last call, we continue to grow the organization and make key additions to the senior leadership positions. Most recently, we have appointed Leanne Schenck as our VP Head of CMC, who brings to Acumen over 25 years of pharmaceutical industry experience in biologics process development, manufacturing, and CMC project management. Leanne started her career at Lonza Biologics before spending more than 20 years at Eli Lillian Company in various CMC roles. In her most recent position, she served as Head of CMC Program Management at Novavax. Since 2016, she has been responsible for CMC delivery of three commercial products in connections with these positions. Leanne is leading our CMC efforts, working closely with Kent Iverson, who continues to serve as a senior consultant on CMC matters. Ensuring timely and economical clinical drug products for potential late-phase development is a strategic imperative for Acumen, and we are confident in Leanne and her colleagues' abilities on this front. On a different note, I do want to acknowledge the departure of Dr. Jeff Sevigny, the Chief Medical Officer of Prevail Therapeutics, which recently became a wholly owned subsidiary of Eli Lillian Company. Jeff has recently stepped off our board as was required by his current employer. Jeff joined Acumen's board in 2019 and has been a major contributor. I want to thank Jeff for his service and support of Acumen over the last three years. He will be missed. Our nomination in Corporate Governance Committee has initiated a search for a potential new director. As many of you know, there are a number of anticipated upcoming clinical and regulatory developments for the novel Alzheimer's disease programs in the coming quarters, including Phase III data readouts for Esai's leucanumab, Roche's gantanarumab, and Lilly's dinanumab. Two weeks ago, Acumen and others attended the AAIC meeting in San Diego. The meeting served as an informative event to gauge the latest developments in the AD research field. On that note, I'll now turn the call over to Eric to discuss some of these recent developments from AEIC, including our poster on a potential standardized assay for evaluating soluble A-beta ligament binding properties for monoclonal antibodies. Eric?
spk08: Thanks, Dan, and good afternoon to everyone. First, I wanted to highlight that Frontiers in Neuroscience published a review article in late April that outlined an extensive rationale for targeting soluble A-beta amyloid beta oligomers in early Alzheimer's disease, as well as the preclinical evidence to characterize ACU193's selectivity and differentiated profile. The article is entitled, ACU193, an immunotherapeutic poised to test the amyloid beta oligomer hypothesis of Alzheimer's disease. We have observed what we believe to be a broad and emerging scientific consensus that oligomers are the most toxic form of A-beta and that the development of a product that reduces the toxicity of oligomers is one of the most promising approaches for the potential treatment and prevention of the progression of Alzheimer's disease. As detailed in the publication, multiple studies suggest that A-beta oligomer-mediated neuronal toxicity is directly responsible for Alzheimer's-associated neurodegeneration, as well as memory and cognitive problems. A-beta oligomers have been found to interact with brain cells called neurons, and more specifically with the synapses that allow neurons to communicate with each other, leading to altered neuronal function. Additionally, A-beta oligomers appear to initiate and perpetuate the process of neurodegeneration ultimately leading to cell death. At the recent AIC meeting in San Diego, Acumen presented a poster detailing a method designed to assess antibody binding properties using amyloid-derived diffusible ligands, or ADLs. As you may recall, ADLs were used as the antigen leading to the eventual development of ACU193. We believe that the use of ADLs in the described method to characterize binding properties of ACV193 and other monoclonal antibodies has the potential to advance the field by providing a detailed description of how these experiments could be consistently executed. In addition, we also believe that this is an exciting time in the field of AD research broadly, particularly given the anticipated near-term data readouts expected from other companies in the field. As a quick reminder, ACU193 is unique and differentiated from other monoclonal antibodies studied in Alzheimer's disease, given its high selectivity for A-beta oligomers relative to other anti-amyloid or anti-A-beta monoclonal antibodies that are less selective or target different amyloid species, such as deposited A-beta amyloid plaques or a beta monomers. We hypothesize that this selectivity may lead to improved clinical efficacy compared to other monoclonal antibodies. Importantly, we expect a lack of ARIA-related safety concerns, which are seen with several other monoclonal antibodies. Based on laboratory data in animals, we believe there is a potential for possible cognitive improvement in addition to disease slowing with ACU193 treatment. Given this strong rationale and differentiation, we look forward to reporting top-line data from Intercept-AD in the first half of next year. As a reminder, Intercept-AD, a randomized placebo-controlled Phase Ia-B trial, has two portions as it as is common in drug development, including a single ascending dose portion and a multiple ascending dose portion. The trial design for the single ascending dose portion includes four cohorts with eight patients per cohort at doses of 2, 10, 25, and 60 milligrams per kilogram for placebo. The multiple ascending dose portion includes three cohorts to be given three administrations of ACU193 with 10 patients per cohort at doses of 10 milligrams per kilogram and 60 milligrams per kilogram dosed every four weeks and 60 milligrams per kilogram dosed every two weeks or placebo. For each of these cohorts, two patients are to be given placebo which will be pooled for data analysis. Included in the trial design is the ability to initiate the first cohort of the multiple ascending dose portion, assuming positive safety and tolerability in the second cohort of the single ascending dose portion. The trial is being conducted in patients with what is now frequently termed early Alzheimer's disease. In other words, those with mild cognitive impairment or mild dementia due to Alzheimer's pathology. To participate in the trial, patients must be amyloid positive as determined by PET scans. A key objective of the trial is to demonstrate target engagement and proof of mechanism as determined by demonstrating that ACU193 is bound to oligomers in cerebral spinal fluids. Other important objectives include the evaluation of safety and tolerability, pharmacokinetics, and measures of cognition. The trial is expected to provide a significant amount of data that we expect will be crucial in the design of our potential Phase 2-3 trial, as well as our regulatory strategy. Assuming Intercept-AD demonstrates an acceptable safety and tolerability profile, And assuming that ACU193 enters the central compartment and that target engagement is confirmed, we plan to advance the program into a Phase 2-3 study. With that, I will turn the call over to Matt Zuga, our Chief Financial Officer and Chief Business Officer.
spk09: Thank you, Eric, and thanks to everyone for joining the call. To start, I want to emphasize that as a result of planning and executing on our private and public financing strategy in 2020 and 2021, we believe we are well capitalized and have the resources to achieve multiple clinical development milestones. As of June 30th, we had approximately $210 million in cash and marketable securities on hand. Looking ahead, based on our current operating plan, we expect our cash runway to last through 2025. Our strong balance sheet is the result of the proceeds from Series B and IPO financings completed in 2021. Our complete financial results for the second quarter of 2022 are available in the press release we issued this afternoon and in our 10Q, which we expect to file shortly. I'm not going to review our results in detail, but I do want to highlight a few items. R&D expenses were approximately $7.3 million in the second quarter. The increase over the prior year period was primarily due to increased activity in the ongoing intercept AD trial compared to Q2 2021. G&A expenses were $3.1 million in the quarter with the increase over the prior year period primarily the result of increased headcount and the cost of going public and being a public company. This led to a loss from operations of $10.4 million in the second quarter. Note that our comprehensive loss for the quarter was $10.3 million in the second quarter, compared to $61.4 million in the prior year period. The loss in 2021 was primarily driven by a non-cash expense of $57.9 million that represented the changes in fair value of our Series B tranche liability and our Series A1 warrant liability. The tranche liability and the warrant liability were initially recorded at fair value as a liability on Acumen's balance sheet and are subsequently remeasured at fair value at the end of each reporting period. Both liabilities were extinguished by the conversion of our preferred shares and warrants to common shares at the IPO. We will continue to work hard over the coming quarters to enroll Intercept AD and look forward to reporting top-line data in the first half of 2023. Importantly, we will continue to operate Acumen efficiently and cost-effectively. We thank our shareholders and partners for their ongoing trust and support and will now open up the floor for questions.
spk04: Thank you. As a reminder, to ask a question at this time, please press star 1-1 on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from the line of Judah Farmer with Credit Suisse. Your line is open.
spk10: Hi, guys. Good afternoon. Thanks for taking the questions. Just a couple for us. First, I was just hoping maybe, Matt, can you help us with any assumptions underlying cash farm rate 325 and what that contemplates for maybe size of a phase 2-3 study. It sounds like that might start maybe middle of 23 potentially. And then of kind of the late stage A-beta MABs that we're going to have readouts on near term, you know, any thoughts on which could provide the best read across to 1-9-3 and why that might be? Thank you.
spk09: So why don't we let Dan take the second part of that question, and then I'll come back to the first.
spk06: Sure. Thanks, Jude. That's a good question. I think everybody's on the edge of their seat to see how these results play out. We don't anticipate any of these late-stage products being direct read-throughs to AC193, principally because AC193 was developed with a different purpose and through a different methodology. If you look at those products, I would say that Leucanumab is sort of the most comparable yet distinctly different from 193. And I think that's probably the next one to read out. And I think Eastside's got it for us, maybe September. And then we'll be looking at Gansanarumab and Denanumab data, Q4 and I think Q1. So, you know, we're hopeful that there will be some success to report on in the space. We think that's helpful, positive development for patients generally and for the field at large. And I can't really comment beyond what I've suggested in terms of read-throughs and relevance to 193.
spk09: And then just back to your cash question, Judah. So the way that we look at this, the earliest that we would start a Phase II study is the beginning of 2024, because even after we've reported data from Intercept AD, we would still need to go spend time with the FDA and agree on the final design of the study, et cetera. So we don't think we'd start until the beginning of 2024. That's a pretty big study as designed, about 550 patients. Now, as we've talked about with all of our shareholders in the past, we're setting this up to have an interim look so that we could potentially flip this into a phase two, three study. But we're going to start it as a phase two, if that's all we do, is run a phase two study.
spk00: Did we lose Matt's audio?
spk06: Can you not hear me, Dan?
spk09: Now I can't. I'm sorry.
spk10: Judah, did you hear any of that response? Yeah, I think we lost that. You'd start it as a Phase II.
spk09: Right. So we'd start it as a Phase II study with the goal being 550 patients. The question will be, when we do an interim look, does it make sense to roll it into a Phase III? you know, the way we look at it is we certainly would be well into the phase two study in 2024 and 2025. And then, you know, we would do that interim analysis prior to needing to finance, so to speak. Okay. That's really helpful.
spk10: And then maybe just to follow up on Dan's response, a question we get, just kind of the mechanistic potential for comboing ACU193 with with any of these late stage MEBs, presumably you're not gonna run a combo arm in the phase two or phase two, three, but how do you think about these drugs potentially being administered together?
spk06: Well, so, Joda, I think the way I'd respond to that question is, you know, we think that, you know, probably the best means of patient treatment and management in the future will involve combination approaches, and it's potentially, you know, multi-mechanistic in the approach. So I think the A-beta space is playing out. I think, you know, the late-stage assets have a primary effect on amyloid plaques as measured on A-beta PET. I think 193 is positioned as a selective antibody towards soluble A-beta oligomers. Whether you target oligomers and plaque is something that may be explored in the future. Whether you would target oligomers and a tau or an inflammatory mechanism with another agent is something that we also think has a possibility in the future. So for us right now, I think the important thing is to demonstrate the proof of mechanism in this intercept AD study, establish the initial safety profile, PK, and target engagement. And that does set us up, we think, for the phase 2-3 and future possibilities of combination strategies that, again, might offer increased patient safety and potential benefit. Great. Thank you.
spk04: Thank you. Our next question comes from the line of Jeff Meacham with Bank of America. Your line is now open.
spk01: Good afternoon. This is Hao calling in for Jeff Meacham. Thank you very much for the question. So I think my question is really for the phase one study, you said you're going to test the concentration of antibody 193 binding to the oligomers. So it will be tested. Just wanted to Give a sense about how sensitive is that test and what level of bonding that you think may be transferred to good therapeutic effect in human testing. Thank you.
spk08: Yeah, well, this is Eric. I think I can take that one. So the assay, which is being refined at this point, will look at the concentration of the antibody down to oligolers. So in other words, really by definition, target engagement. For most monoclonals and actually drug development in general, as long as you have safety, the more target engagement you can have, the better off you will be. So there's no strict number that we've determined that's a cutoff. We need to show some target engagement. But assuming that we continue to see good safety, more target engagement will be better. So hopefully to answer your question a little bit, there isn't a firm number that we've determined that's a cutoff. We need to show that it's there. But again, as long as you have safety, more target engagement is better.
spk01: And how about the sensitivity of the test?
spk08: Well, I can't give you a number right now. Based on some projections made based on the laboratory studies of PK, what we expect to see in spinal fluid in terms of drug concentrations versus the concentrations of oligomers in spinal fluid we're at sufficient sensitivity sensitivity right now that we think we'll be able to show that in our trial now we're actually working on methods to make the assay even more sensitive so that we may be able to pick that up at even lower doses than we might with current assay but we certainly feel like We have the assay developed to the point where we can make the measurement now. And by the way, we won't need to do this until the study ends. So we have some months before we actually need to run this. But we are working on some other methods to either increase the sensitivity of this method or even use a different method that would be more exploratory, like mass spec, has the potential to give you even more sensitivity, but that would be more of an exploratory approach. But right now, based on the laboratory data and the animal data, we have an assay currently that has sufficient sensitivity, and we expect the sensitivity will be even better by the time we actually need to run the assay.
spk01: Awesome. Great. Thank you so much.
spk04: Thank you. Our next question comes from the line of Paul Matias with Stifel. Your line is now open.
spk05: Hi, this is James. I'm for Paul. Thanks for taking our questions. Maybe just a couple quick ones. One, as the trial has continued to enroll, have you guys taken any sort of look at blinded safety data? I guess, is there any color there you can share around any signals of ARIA that have been seen so far? And then two, can you remind us just are you taking one dose forward into the phase two, three, or multiple? I guess, again, just trying to understand kind of the decision criteria as you guys are thinking about taking a dose forward. And I know you've addressed it some, but outside of the assay, is there any other kind of data points that you're going to look to to help give you kind of confidence that you're taking the right dose forward? Thanks so much.
spk06: Eric, do you want to comment on that?
spk00: Yeah.
spk08: Yeah, sure. So, Yeah, one thing just to point out is that as we advance through the various cohorts, at the end of each cohort, we actually do a pretty extensive safety review, blinded, of course. So, yeah, that's just part of the criteria for advancing through this study. And we have been looking at that. Now, we've elected, we're not going to disclose real specific results for each cohort while the study is ongoing. We don't think that would be appropriate, but I think what I can tell you is so far so good. The study is going well, and we look at the safety data very carefully.
spk06: And on the dosing, on phase two, three, I think we do anticipate launching the phase two with two-dose arms, the level of which will be determined coming out of the intercept AD study. Is that correct, Eric?
spk08: Yeah, right. So two active and one placebo, so three total arms. And that, of course, will depend on the results that we see in the phase one study, but at least that's what we're planning right now. When we do the interim for the phase two, three, it's possible that we would drop one of the arms depending on what the data show us. But at least to start with, what we're envisioning is a total of three arms with two active and one placebo. Great. Thank you so much.
spk04: Thank you. Our next question comes from the line of Tom Schrader with BTIG. Your line is now open.
spk07: Good afternoon. Thanks for taking the questions. I have some formulation questions. How sub-Q friendly is 193? Do you have a sense of what concentration you could get to, and do you think it's attractive if you don't need it for safety? I mean, one of the other companies is doing it probably for a C-max reason, but is it an attractive route overall?
spk08: Yeah, so maybe I can take that, and Dan, you might want to follow up, too. So... As you enter Phase I, well, let's say before you enter Phase I, you don't really know enough about the pharmacokinetics to know whether or not it's feasible to go sub-Q. So, where will be IV in this first study? Now, if it turns out that the dose that's required is low enough that that would become a possibility, I don't know that we would immediately change that for the Phase 2-3, but certainly we would look at that down the line. But at least to start with, I think it's important that you don't sort of make too many assumptions and over-index. And actually, in terms of a lot of discussions we've had, I'm not sure that sub-Q is as much of an advantage as a lot of people do versus, you know, a once-a-month IV infusion at a clinic. So we'll be actively tracking that, but for right now it's IV. The one other thing, a good point that you brought up was the way that's ASI that's looking at sub-Q because they think that they can get less aria with that. So in our case, you know, we don't expect to see aria. and so I don't think we're going to have to deal with this CMEX versus AUC issue. And so, you know, we'll wait and see what the data show, but I think there's, at least based on what we've seen so far, there's good reason to think that ARIA won't be an issue for us, and so we won't have to deal with that AUC versus CMEX issue.
spk06: And, Eric, I will follow on that. And, Tom, just to note that as was announced in our earnings release, we've just designated Lee and Shank as our VP of CMC. So future manufacturing formulation types of opportunities for us are very much part of the way we kind of wrote up, map out the product roadmap, if you will. And so We're paying attention, but don't see an immediate, obvious need to move to a sub-Q formulation based on the information we have right now.
spk07: If I can ask Eric one nerdy follow-up. How toxic is your preparation? How toxic are your ADDLs? Do they approach in vivo isolated particles? And do you understand why the stuff isolated from human brains is so much more toxic? Is that a big area of effort for this assay?
spk08: Well, no, it's a great question, and it's one we've talked about a fair amount recently. So we know that the adult preparation that was used to create the antibody, ACU193, we know based on various studies that those are very toxic to neurons. In terms of the oligomers that are in the brains of humans with Alzheimer's disease, it's a it's a little bit more difficult to do those experiments. And actually, we've just recently been talking about the comparison between adults and what you actually see in the human brain. So those are experiments that are a little bit difficult to do, but it's a good question and it's under discussion. Great. Thank you.
spk04: Thank you. Our next question comes from the line of Colin Bristow with UBS. Your line is now open.
spk03: Hi. Good afternoon. This is Ting for Colin. So we have a question about the intercept AD, the upcoming readout. So one thing we have discussed before is that you'll be looking at the potential increase in blood flow. So could you provide more colors here? Is it the increase in the cerebral blood flow you'll be detecting or the blood flow in the brain? And we have two follow-up questions. Thank you.
spk08: So maybe I'll start off with the blood flow question. So just for others who might not be as familiar with the study, the patients are having MRI scans done in the study, actually primarily to look for arias. But there's also what's called a pulse sequence that can be used in an MRI scan that has sort of advanced fairly rapidly in the field recently. It's called ASL or arterial spin labeling. And what that enables you to do is look at changes in cerebral blood flow. So this is sort of a total amount of blood flow that goes to the brain. So there's long history of research in Alzheimer's disease showing that there's decreased blood flow in patients with Alzheimer's and that decrease continues to get worse with disease progression. So it's really part of the disease. So if, and we don't know that this will happen, but if we see some more immediate effects from ACU193, which is possible, one of the effects that you might see would be an increase or an improvement in cerebral blood flow. And so really the thought was these patients need to have the MRIs anyway, but let's get this pulse sequence that can give us some information on blood flow and see if we do have one of these more immediate effects of ACU193, even in a phase 1B study.
spk03: Thank you. That's really helpful. And we have a separate question. So you also mentioned there's a computerized cognitive test, which will be used over Intercept-AD. We're wondering, is it a daily self-testing assay just for patients? Or can you just provide more details about this test? Thank you.
spk08: Yeah, sure. So we work with the... a small company called Cogstate, who actually for a long time has been involved in computerized cognitive testing. They were one of the first companies to actually do that. I think one of the things you might be asking in that question is there's a lot of ongoing research now about people doing cognitive testing at home just on their computer over the Internet. We're not willing to be doing that in this study. All the... computerized testing will be done in the clinic in the SAD portion in the single dose portion actually patients are briefly in the hospital for a couple of days but one of the advantages of this computerized testing is you can do it multiple times there should be less variability in it than with sort of traditional scales like say the ADOS-COG and Alzheimer's disease and so it gives It gives us the opportunity to, again, if there should be some immediate effect of the drug, to pick that up. We will do all the traditional scales, the ADAS-COG and the CDR and the ones you heard about before. But in a study this small, I think it's just almost impossible to pick up a signal with those scales. But with this computerized battery, again, it's not a sure thing. but it gives you the potential to pick up an immediate or relatively immediate effective drug if that should happen.
spk03: Thank you. And we have a follow-up question. So in your recent clinicaltrial.gov update, you made one minor change of the enrollment criteria, which is on the MMFE score of 20 to 30, and then you lowered to 18 to 38. So could you provide more details? What's the rationale for this change? Thank you.
spk08: Yeah, that's a very good question. As we started to enroll people and screen people for the study, again, our study population is what people are calling early Alzheimer's disease, which consists of people with MCI and do Alzheimer's disease, so they have to have a positive amyloid cut scan, but MCI or mild dementia. Exactly where the cutoff is between mild and moderate dementia is you'll see different cutoffs used in different studies, basically. But as we got some experience with this trial, there were certain people that had a mini-mental of, say, 19 or even 18 that really seem to have mild dementia. I mean, in the clinician's view, these people really had mild dementia. And we didn't really think it was appropriate to exclude them from our study based on a somewhat arbitrary cutoff. I mean, it's a cutoff of 20 that's used in other studies. But as we got some experience with this, we just thought it was more appropriate to actually lower it just a little bit Because these people, after all, really did have mild dementia, and there's no reason to exclude them from our study.
spk03: That's really helpful. Thank you.
spk04: Thank you. And I'm currently showing no further questions at this time. I'll turn the call back over to Dan O'Connell for closing remarks.
spk06: Thank you. And thank you, everyone, for joining today's call. We look forward to updating you again later this year in what is a Promising to be an exciting and hopefully successful period for the field and for us as we continue to push forward on AC193 and the intercept AD trial. So thank you very much. That concludes our call.
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