Acumen Pharmaceuticals - Q4 2022

Transcript

Operator (participant)

Thank you for standing by. Welcome to Acumen Pharmaceuticals' full-year 2022 conference call and webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Alex Braun, Head of Investor Relations. Please go ahead.

Alex Braun (Head of Investor Relations)

Thank you, Michelle. Good morning, and welcome to the Acumen conference call to discuss our business update and financial results for the year ended December 31st, 2022. With me today are Dan O'Connell, our Chief Executive Officer, Dr. Eric Siemers, our Chief Medical Officer, and Matt Zuga, our Chief Financial Officer and Chief Business Officer. Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this morning and related slide presentation that we'll discuss today. 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. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements.

Please see slide two of the accompanying presentation. Our press release issued this morning and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments. After our prepared remarks, we will open the call for Q&A. I'll turn the call over to Dan.

Daniel O'Connell (President and CEO)

Thank you, Alex. Good morning, thank you everyone for joining us today. 2022 was a pivotal year for Acumen, marked by significant progress in advancing the critical development of ACU193, the first monoclonal antibody tested in Alzheimer's patients that was discovered and developed to selectively target soluble amyloid beta oligomers. Over the course of the year, we received Fast Track designation from the FDA, added experienced and talented members to our team to guide our development plan, and completed important CMC work to scale production in anticipation of upcoming phase 2 study. In February of this year, we announced the completion of enrollment in our phase 1 INTERCEPT-AD trial, which sets us up to report top-line results in the third quarter.

The INTERCEPT-AD results are anticipated to provide important proof-of-mechanism information for ACU193, including safety, pharmacokinetic, and target engagement data that Eric will speak to in greater detail shortly. Thus far, we are encouraged by preliminary PK and blinded safety data observed to date, which supports our thesis that at appropriate dose levels an antibody selected for Aβ oligomers such as ACU193 may provide a differentiated product profile in the fight against Alzheimer's disease. I want to briefly comment on the protocol amendment we disclosed in early February, just prior to completion of enrollment. Based on the preliminary CSF PK data observed that indicated that ACU193 antibody concentrations were in excess of reported Aβ oligomer concentrations.

Considering the blinded case of ARIA-E observed in the cohort 4 at the time, we opted to amend the trial's protocol to reduce the dose level in Cohort 7, our last cohort, to 25 milligrams per kilogram every 2 weeks. We believe the 25 milligrams per kilogram dose every 2 weeks in Cohort 7 will provide us with more meaningful dose-ranging, safety and target engagement information in support of establishing clinical proof of mechanism for ACU193 in this study. Looking ahead, we are actively preparing for phase 2-3 activities in anticipation of successful results from our phase 1 study in the third quarter.

We will request an end-of-phase 2 meeting with the FDA to be held in the fourth quarter to discuss the design of our phase 2-3 study, a design that incorporates an interim decision to expand the study, from a phase 2 size to a phase 3 study. On the CMC front, we remain well positioned to scale manufacturing to have sufficient drug supply to meet requirements of our current development plan. In addition, we have made meaningful progress in assessing various options for potential development of a subcutaneous formulation as part of our ACU193 product development plans. We intend to continue to explore such options based on data generated in our phase 1 study. On a final note, I would like to acknowledge the significant change in the overall treatment landscape for Alzheimer's disease over the past year.

The positive Clarity AD results from lecanemab in the fall of 2022 meaningfully advanced the field. Because it is a protofibril-targeting antibody, lecanemab has driven renewed interest in the role that soluble aggregated A-beta species, such as Aβ oligomers and A-beta protofibrils may play in the pathology of Alzheimer's, and how targeting these species can contribute to safe and beneficial treatment options for patients. The negative GRADUATE study results for gantenerumab, a plaque-targeting antibody, support the hypothesis that for plaque-targeting antibodies, clinical efficacy can only be achieved with the near complete removal of amyloid plaque.

Most recently, the negative A4 results for solanezumab, an Aβ monomer-targeting antibody, reinforced the evidence that targeting monomers may not be a viable means to produce clinical benefit even when intervening at the earliest stages of disease. Aside from these clinical datasets, the field is also seeing advancement with both fluid and imaging biomarkers, which continue to develop rapidly and could offer a diverse set of future alternatives that are predictive of effects in AD beyond amyloid PET imaging. Given the size of the disease burden, we are encouraged by these additional clarity these data have provided to the field, and look forward to additional upcoming data from many companies with differing approaches. At Acumen, we recognize the importance of these advances and strive to use the learnings to inform our approach to developing ACU193 as a potential disease-modifying therapy in early Alzheimer's patient population.

To this end, we look forward to sharing our INTERCEPT-AD top line data with you in the third quarter, a dataset we believe will be informative from a safety target engagement and dose ranging perspective. With that, I'll hand the call over to Dr. Siemers. Eric?

Dr. Eric Siemers (CMO)

Thanks, Dan. Good morning, everyone from Gothenburg, Sweden, where I arrived today to attend the AD/PD™ meeting that's happening this week. We are delighted to have completed enrollment of our phase 1 INTERCEPT-AD trial as we announced in February. This is a true testament to the hard work and dedication shown by our team and by the investigators, the site personnel, our CRO, and most importantly, the patients, families, and their study partners. I would like to thank them for their ongoing support in advancing our understanding of the potential of ACU193. With top line results now expected in the third quarter, I'd like to take a few minutes to provide some context around our expectations for those results. Our phase 1 study is a randomized, placebo-controlled first-in-humans SAD/MAD study with 65 patients enrolled with early Alzheimer's disease.

The objectives of the trial are to evaluate safety and tolerability, evaluate PK, and establish target engagement for ACU193 administered intravenously. The primary trial endpoints are focused on safety and PK. In support of our protocol amendment disclosure in February, we announced that we had seen two cases of asymptomatic ARIA-E as of January 31st in this blinded trial. Based on the preclinical data, we had expected less ARIA than that seen with some other monoclonal antibodies at their highest doses, and the preliminary blinded cases we observed in the first quarter were aligned with that expectation. We remain encouraged that the safety profile of ACU193 to date will support targeting soluble amyloid beta oligomers. We also note that ARIA-E cases do provide evidence of central pharmacology that ACU193 crosses the blood-brain barrier in sufficient quantity central effect.

Keep in mind as well that Cohort 6 is ongoing at a dose of 60 milligrams per kilogram every four hours, which is considerably higher than doses pursued by several other antibodies, including aducanumab, lecanemab, and donanemab. The preliminary PK data we disclosed support this line of thinking. We know that preliminary CSF PK data from our 25 milligram per kilogram cohort showed ACU193 levels that were substantially above the levels reported for oligomers. Oligomer concentrations in CSF are generally reported to be less than two picomolar, which is a very low concentration compared to other soluble species such as A-beta monomers. If this is the case, a dose of 25 milligrams per kilogram every four weeks could be a viable dose to test in the next phase of our program for ACU193.

Turning to target engagement, as many of you know, the assay for our target engagement is designed to measure the complex of Aβ oligomers bound to ACU193 in CSF. Simply detecting that complex after administration will satisfy the target engagement threshold. In non-clinical studies, Merck was able to measure these complexes in brains from transgenic mice after ACU193 administration using an immunoassay. Acumen is developing a conceptually similar methodology for the INTERCEPT-AD trial to look at CSF using proprietary materials that increase the assay's specificity for both ACU193 and Aβ oligomers, and thus specificity for the ACU193 oligomer complex. Importantly, we will be performing test runs of this assay prior to our database block to ensure the sensitivity is optimized.

Exploratory measures that are built into our phase 1 study include computerized cognitive testing for signs of early effects and arterial spin labeling with MRI scans to understand if cerebral blood flow is increased. While these analyses are exploratory and are unlikely to result in a statistically significant signal in this small study with a short treatment duration, the detection of a potential signal would suggest important central pharmacodynamic effects. Depending on our phase 1 results, these measures may be employed in subsequent clinical trials using ACU193. Turning toward our upcoming phase 2/3 clinical study, the team has been working diligently to develop an algorithm that would include evaluations by the Data Monitoring Committee of clinical measures Computerized cognitive testing and biomarkers to enable a go/no-go decision to scale a phase 2 study to a phase 3 study.

We are confident that the algorithm we finalize will provide a rigorous method to allow a go/no-go decision to expand from phase 2 to phase 3. With that, I'll turn the call over to Matt.

Matt Zuga (CFO and CBO)

Thank you, Eric. Good morning, everyone. Our complete year-end 2022 financial results are available in the press release we issued this morning and in our 10-K that will be filed later this afternoon. We ended 2022 with approximately $193 million in cash and marketable securities on the balance sheet. We continue to expect that cash runway to last through 2025. R&D expenses were approximately $32.4 million in 2022. The increase over the prior year was primarily due to the increased activity in the ongoing INTERCEPT-AD trial. G&A expenses were $12.9 million in 2022. The increase over the prior year, primarily the result of increased headcount. This led to a loss from operations of $45.2 million in 2022.

Regarding our exposure to Silicon Valley Bank, we had approximately $1.7 million in cash in our operating accounts there as of March 10, 2023, all of which has been moved to another institution. In conclusion, we remain well-resourced to execute against our strategic priorities over the next few years. We look forward to reporting top-line data for INTERCEPT-AD in the third quarter of 2023. We'll remain financially disciplined as we use our capital to advance our clinical program for ACU193 and deliver value to patients and shareholders. With that, we can open the call for Q&A. Operator?

Operator (participant)

As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. First question comes from Paul Matteis with Stifel. Your line is now open.

Paul Matteis (Managing Director, Head of Biotech Research)

Hey, thanks so much. On the interim analysis that you're planning, how is this similar or different to just your typical interim where a blinded group looks at the data, recommends sample size adjustments or if it stop the study? Then I have one follow-up. Thank you.

Daniel O'Connell (President and CEO)

Hey, thanks, Paul. I was gonna invite Eric to comment on that. I mean, there's a simple explanation, I think.

Dr. Eric Siemers (CMO)

Right. Yeah. Well, of course, you're right. A lot of times interim analyses are done to adjust sample sizes, and usually that's based on, you know, purely a statistical look at the data. One thing I should just emphasize is it's not a futility analysis. Everyone should be clear about that. The interim analysis itself is actually quite a bit more complex than the sort of thing that's done just to adjust sample size. In other words, we and as I discussed, we're developing the algorithm. We'll look at the clinical measures. I mean, we have things like the CDR-SB in the trial. In a little study like this, it would be surprising to see a drug effect there. We'll look at those things.

We'll look at the ADAS-Cog, and again, we'll look at our computerized cognitive testing and some of the MRI results, and also some biomarkers. We will develop this algorithm to give to the DMC. The DMC, if the algorithm is successful, so to speak, then the study will be scaled up to the size of phase 3 study. If it doesn't fulfill the algorithm, then it will be completed as a phase 2 study. At a minimum, we'll complete the next study as a phase 2 study.

Paul Matteis (Managing Director, Head of Biotech Research)

Okay, thanks.

And-

You've talked a little bit more about enthusiasm... Oh, sorry, Dan. Go ahead.

Daniel O'Connell (President and CEO)

Well, I was just gonna say, and Paul, of course, the two three design is really intended to be the fastest path to a potential, you know, registration for the product, you know, hypothetically. If that's not obvious-

Paul Matteis (Managing Director, Head of Biotech Research)

Okay.

Daniel O'Connell (President and CEO)

I just wanna make that comment.

Paul Matteis (Managing Director, Head of Biotech Research)

No, that's clear. Thank you. Then you've talked more about confidence in this 25 mg/kg dose. Is that based on anything you're seeing? I guess what if, what if you don't see a clear dose response on a target engagement assay? Does that mean you might take forward a lower dose? Like, how are you guys thinking about these scenarios in the second half of this year? Thank you.

Daniel O'Connell (President and CEO)

Yeah. Thanks, Paul. I mean, I'll just comment. I think, you know, we really made the amendment to the protocol amendment in February based on some observations in the study, including the PK and the, and the ARIA. I don't think we're, you know, we're not in a position to continue to roll out information till the third quarter. I do think that when we made the decision to modify the cohort seven dose level, it became sort of obvious to us at the time, given that might be a viable dose in terms of just the overall drug required to dose at that 25 mgs versus 60 every couple of weeks, which was the original concept for Cohort 7.

I think we're really encouraged that, you know, sort of the overall thesis for the ACU193.

It's very much intact and are confident that the modification for Cohort 7 in particular gives us more information, kind of with a mid dose level between the 10 mgs per kg and the 60 mgs per kg that's ongoing in Cohort 6.

Paul Matteis (Managing Director, Head of Biotech Research)

Thank you.

Daniel O'Connell (President and CEO)

Yeah.

Operator (participant)

Please stand by. Please stand by for our next question. The next question comes from Thomas Shrader with BTIG. Your line is now open.

Thomas Shrader (Managing Director, Healthcare Analyst)

Thanks. If you had more to say, it's almost the same question anyways. I have a little bit of a question about the world of plaque removal. There's still some controversy about how important it is. I think we might call it confusion, but what's your sense about where the FDA is on that issue and how important that would be in an interim look? Are they gonna be okay with a trial that is ignoring plaque removal, or is that kind of all your own business? Given that it's kind of unknown how important it is, how much do you have to think about it going into a trial with a, with an interim look? Thanks.

Dr. Eric Siemers (CMO)

Maybe I can try that. From an FDA standpoint in the plaque reduction, that was for an accelerated approval. In other words, FDA considered plaque reduction to be, quote, "reasonably likely to predict a clinical effect." That led then to the accelerated approval. One of the things that I think has become even more clear, I think it was clear before, but, as Dan mentioned, if you're going to target plaque, you have to essentially get rid of all of it to have any clinical efficacy. I think the gantenerumab GRADUATE studies demonstrated that very well. In our case, this interim analysis that we're doing is not really in anticipation of an accelerated approval or any sort of a regulatory approval.

It's for our internal decision making in terms of this phase 2 study and then scaling it up to a phase 3 study. There really isn't a regulatory piece to the interim analysis as we're doing it.

Thomas Shrader (Managing Director, Healthcare Analyst)

All right, great. Thank you.

Daniel O'Connell (President and CEO)

I think, Thom, just to, you know, we are doing analytic that in the current study and would anticipate doing it. Not that we would expect to see it move dramatically, but just as a kind of the convention standard practice.

Thomas Shrader (Managing Director, Healthcare Analyst)

Okay, great. Thanks for the answer.

Operator (participant)

Please stand by for our next question. Our next question comes from Colin Bristow with UBS. Your line is now open.

Ting Ong (Research Associate)

Morning, everyone. This is Ting for Colin. Thanks for taking our question. We have two questions and a follow-up, if we may do. The first question is for patients in the Cohort 6 in MAD. In our last correspondence, you noted they have not yet received MRI scans. Just wondering if they have received by now, and if so, could you provide any safety updates? The second question is more general. Do you think there's a general correlation to dose a oligomer targeted antibody more frequently than those core plaque targeted ones, given the faster turnover kinetics here? Thank you.

Daniel O'Connell (President and CEO)

Hi, Ting. Thanks for your question. I think on the first one, as I mentioned, and as Eric mentioned, you know, we've been disclosed the ARIA cases back in February in conjunction with the protocol amendment. We and Eric just noted that cohort six continues to proceed per protocol. We haven't provided any other information in terms of ARIA cases and so forth. I think maybe I would turn it to Eric in terms of the dosing frequency question with respect to an oligomer antibody. I mean, I think, yeah, Eric, maybe you would care to comment on that aspect of Ting's question.

Dr. Eric Siemers (CMO)

Yeah. It's a really interesting question. I think what you're really asking is that for an antibody that targets plaque, the antibody binds to the plaque. It actually starts an inflammatory response with microglia. It's not necessarily so dependent on the PK that you would see even in spinal fluid at any given time, since once it's found a plaque, it's obviously not gonna show up in spinal fluid. In our case, it may be a little bit more straightforward in that we do wanna show that we're in antibody excess. In other words, that you have more antibody there than you have oligomers.

That was one of the reasons why the preliminary data, CSF PK data in Cohort 3, which is 25 mgs per kg, really was so exciting for us, is that we were in antibody excess. The situation is a little bit different, you're right. I think in our case, again, I think the important thing is to show that we're in antibody excess.

Ting Ong (Research Associate)

Thank you much. Sorry. Yeah, sorry. Thank you for providing all the colors. Really helpful. We have a follow-up question, which kind of like echoing Thom's earlier question, also what Dan has mentioned in a prepared remark on A4. We understood, solanezumab is primarily sorry, primarily a monomer targeting, but it has some capacity to oligomers, although it does not touch any plaques. There were some concerns following solanezumab's completely failure that maybe some level of plaque clearance are still needed for the best treatment efficacy. We are curious if, to hear your thoughts, and if you could provide any colors to us would be greatly appreciated. Thank you so much.

Dr. Eric Siemers (CMO)

Well, Dan, you want me to go ahead and take that since I have a bit of familiarity with solanezumab. First of all, for the A4 resolve, of course, there's really just been press releases. We'll need to see all the data. What for me was a bit surprising and interesting is that actually, even though there were no statistical differences, the trends actually favored placebo over drug. That was at a dose of 1,600 mg every 4 weeks. Well, when solanezumab was given to people with mild Alzheimer's disease at 400 mg every 4 weeks, the trends were very consistent in terms of favoring drug.

Why you didn't see that with the higher dose of solanezumab is a bit of a mystery, and I think we'll have to see all the data to understand that. You know, again, our thesis has always been that if you wanna target plaque, you really have to get rid of it. You know, certainly gantenerumab and also going all the way back to bapineuzumab has taught the field that a little bit of plaque reduction doesn't really get you anywhere. I don't think that you could approach this as saying, "Well, let's target monomers, and then we need a little bit of plaque reduction." I think that probably would not end up being successful.

Daniel O'Connell (President and CEO)

Eric, to your knowledge, just to clarify, are you aware of any oligomer binding properties for solanezumab? I mean, it's almost a pure monomer targeting antibody to my understanding.

Dr. Eric Siemers (CMO)

Well, that's always been my. You know, you can always find publications where somebody shows a little binding to this or to that. Typically those are in, you know, in vitro studies, they're kind of artificial conditions. All the data that I'm aware of has really been quite consistent that actually solanezumab is remarkably specific for monomers.

Really, 193 has been developed to principally target oligomers and not have much interactions with monomer. I mean, yeah.

Ting Ong (Research Associate)

Oh, understood. Thank you so much.

Operator (participant)

Please stand by for our next question. Next question comes from Judah Frommer with Credit Suisse. Your line is now open.

Judah Frommer (Managing Director, Senoir Equity Research Analyst)

Yeah. Hi, good morning, guys. Thanks for taking the question. Just getting back to the protocol amendment and probably the key question we got around that. You know, how are you thinking about potential impact to a commercial profile and I guess a reimbursement profile for ACU193? Does this change the story in some way in that, you know, you might need MRI monitoring when you thought you might not have needed that prior? You know, have you had any preliminary discussions with payers on sort of, you know, acceptable levels of ARIA, how that might compare to lecanemab or anything else that comes between now and then?

Daniel O'Connell (President and CEO)

Yeah. No, thanks, Judah. Good question. I think, you know, in terms of Lot wrapped into that. I think in terms of the safety profile, you know, we continue to believe that oligomer-targeting antibodies such as ACU193, you know, may offer an attractive safety profile relative to plaque-targeting antibodies. You know, well, lecanemab does have a rate of ARIA-E in 12.5%. That's sort of a safety benchmark that we use internally. In terms of dropping the 25 mg/kg, you know, that becomes a dose level but that may be more amenable to a subcutaneous formulation.

That was actually part of the consideration in early February as we contemplated what to do really with Cohort 7, like what made the most sense from a programmatic standpoint. As I mentioned earlier on the call, we've looked at a couple of different options as to moving 193 at some point into a subcutaneous format. That modified dose for Cohort 7 does provide important PK information that will help inform the prospects of that. We haven't had any payer interactions per se. I do think that as we've envisioned the next study, we've always anticipated, you know, routine MRI scans for safety and other, you know, for general development purposes.

I think that study is much more likely to be instructive as to what would be required commercially. We just won't have enough, you know, product exposure in the INTERCEPT-AD study to definitively say what's required from a safety and really what's required from the overall. You know, this is a phase 1 study in terms of the overall ARIA rates.

Judah Frommer (Managing Director, Senoir Equity Research Analyst)

Got it. Thank you.

Operator (participant)

As a reminder, to ask a question, please press star one one on your telephone. Stand by for our next question. I show no further questions at this time. I would now like to turn the conference back to Alex for closing remarks.

Alex Braun (Head of Investor Relations)

Thanks, Michelle. Thanks everyone for joining us today. As always, we're available for follow-ups should you have any additional questions. Please reach out to us at the company, and have a great Monday.

Operator (participant)

This concludes today's conference call. Thank you for participating. You may now disconnect.