Good morning, and welcome to Beam Therapeutics' conference call. At this time, all participants are in a listen-only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at Beam's request. I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications. Please go ahead.
Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review updated clinical data from the phase I/II trial of BEAM-302 in patients with Alpha-1 Antitrypsin Deficiency presented today at the ERS Congress. You can access slides for today's call by going to the investor section of our website, beamtx.com. With me on the call today with prepared remarks are John Evans, our Chief Executive Officer, Dr. Amy Simon, our Chief Medical Officer, Dr. Gerry McElvaney, a physician from Beaumont Hospital and an investigator in the BEAM-302 trial, and Dr. Giuseppe Pino Ciaramella, our President. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.
Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the Risk Factor section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements, even if our views change. With that, I will turn the call over to John.
Thanks, Holly, and good morning, everyone. At Beam, our vision is to provide lifelong cures for patients with serious diseases. We are working to realize that vision by developing one-time genetic medicines that precisely correct disease-causing mutations and address disease at its source. The promise of our base editing technology is becoming increasingly tangible across our growing and maturing pipeline. Today, we're excited to share detailed and updated clinical data for BEAM-302, our lead liver-targeted genetic disease program and the most advanced genetic medicine in development for Alpha-1 Antitrypsin Deficiency, or AATD. For the first time, we are sharing BEAM-302 data at a major medical congress, and we're honored to bring these findings to the global AATD and respiratory communities gathered in Barcelona at the European Respiratory Society Congress, or ERS.
As you will hear shortly, this data set gives us even greater confidence in the differentiated profile of BEAM-302 and its potential to transform the treatment paradigm for people living with AATD. Beam was founded on the idea that precise changes to individual bases in DNA could fundamentally alter the treatment of serious genetic diseases. Base editing is designed to make those changes without creating double-strand breaks in DNA. This precision is intended to produce consistent gene sequence outcomes and durable correction following a single treatment with the potential for less genotoxicity than traditional gene editing approaches. Together, these attributes are central to what we call the power of predictability, the ability to design genetic medicines with precise and reproducible biological outcomes for patients. The profile we are seeing with BEAM-302 reflects these fundamental advantages we set out to achieve with base editing.
The power of predictability is more than a scientific concept. It is also our strategy for building a durable and scalable genetic medicines company. BEAM-302 is an example of that strategy in action. The same core capabilities that underpin BEAM-302, including our base editing platform, LNP delivery technology, and internal manufacturing expertise can be leveraged across current and future programs, increasing confidence and speed from one to the next. Our goal is not simply to develop a single successful medicine. It is to create a repeatable model for advancing precision genetic medicines efficiently, predictably, and at scale. We are already applying that model across three major areas of opportunity, each with large addressable underserved patient populations and blockbuster potential for differentiated one-time therapies.
Starting with sickle cell disease, our multi-wave approach begins with risto-cel, a potential best-in-class ex vivo transplant where we expect to file a BLA as early as the end of this year. With a differentiated clinical program and internal manufacturing capabilities, risto-cel is poised to enter an established market with significant demand. Behind it, we are applying our targeted LNP expertise to an in vivo sickle program that has the potential to reach the vast majority of sickle cell disease patients. In AATD, which is the focus of today's call, BEAM-302 is the only genetic medicine in pivotal development and has the potential to be the first one-time treatment addressing both the lung and liver manifestations of the disease. Our newest major program is in phenylketonuria, where we are taking a multi-mutation approach with BEAM-304 to address the majority of patients living with this disease.
PKU has few treatment options and an established regulatory pathway for approval. BEAM-304 leverages our industry-leading in vivo LNP capabilities to advance multiple base editors within a single clinical program and represents an important foundation for our growing interest in base editing for metabolic disorders. Together, these three programs demonstrate the breadth of what is possible with our base editing platform and represent multiple meaningful opportunities to create value for patients, physicians, and shareholders over the near term. Turning to slide eight, BEAM-302 is the lead program within our growing liver-targeted in vivo portfolio, where our platform capabilities create meaningful synergies across programs and have enabled us to efficiently advance multiple clinical programs in parallel. This portfolio also includes BEAM-301, another liver-directed base editor for metabolic disease, which aims to correct the severe R83C mutation in glycogen storage disease type Ia with first-in-human data expected later this year.
Before I turn it over to Amy to provide an overview of AATD and our BEAM-302 clinical program, I want to highlight a few key takeaways from the data shared at ERS today. First, BEAM-302 continues to demonstrate the potential to become the first one-time treatment to address both lung and liver manifestations of AATD through direct correction of the disease-causing mutation. With follow-up now out to two years, treatment with BEAM-302 has demonstrated durable restoration of normal AAT physiology, including production of corrected M-AAT for the first time that is both functional and under normal physiologic control in response to inflammation.
A single dose of 60 mg BEAM-302 led to total AAT levels above the protective threshold and substantial reductions in mutant Z-AAT and circulating Z-polymers. In addition, the safety profile remains consistent with our prior experience and expectations for LNP therapies. Taken together, these findings reinforce our confidence in BEAM-302 as a potential first-in-class, best-in-class, one-time treatment for AATD. With that, I'll turn the call over to Amy.
Thanks, John. Alpha-1 Antitrypsin Deficiency, or AATD, is a serious genetic disease caused by mutations in the SERPINA1 gene. In the most common severe form, the PiZZ genotype, mutant Z-AAT accumulates in the liver while too little functional AAT reaches the circulation. This creates two distinct consequences: progressive liver disease from the accumulation of the toxic Z-AAT protein and progressive lung disease from too little and poorly functioning AAT in circulation to protect the lungs. Despite affecting more than 100,000 people in the U.S., treatment options remain limited. Current augmentation therapy replaces circulating AAT but does not address the underlying production of mutant Z-AAT or restore the body's natural regulation of AAT. Weekly augmentation is intravenous and is the only approved therapy for lung disease. There are currently no approved treatments for the liver manifestation of AATD.
Clinical genetics gives us an invaluable benchmark for what meaningful correction could look like. Patients with severe PiZZ disease have very low AAT levels, well below the 11 micromolar protective threshold and substantially elevated risk of both emphysema and liver disease. By contrast, as shown here on slide 12, MZ and most SZ carriers generally have AAT levels above the 11 micromolar protective threshold and do not develop progressive disease without the presence of additional risk factors such as smoking or obesity. This provides a clear therapeutic goal. Move patients from the severe PiZZ phenotype towards a carrier-like state associated with substantially lower disease risk. BEAM-302 aims to do exactly that by correcting the disease at its genetic source.
Delivered to the liver through a lipid nanoparticle, or LNP, the BEAM-302 base editor is designed to directly correct the E342K mutation in SERPINA1, converting the disease-causing PiZ mutation to the normal PiM allele. Through that correction, our goal is to restore AAT function and address the full spectrum of AATD. That means providing functional M-AAT for the first time in circulation, increasing total AAT above the protective threshold, substantially reducing toxic Z-AAT, and restoring the body's ability to increase AAT naturally during periods of inflammation. Taken together, these objectives have the potential to address both the lung and liver manifestations of AATD. With base editing, we can potentially accomplish all of this with just one treatment providing durable long-term benefits. Importantly, the clinical and regulatory strategy has advanced alongside the clinical data.
Last year, we reached alignment with the FDA on a potential accelerated approval pathway for BEAM-302 with the primary endpoint expected to be based on AAT biomarkers evaluated over 12 months. To support that pathway, we plan to enroll approximately 50 additional patients in a pivotal cohort in the ongoing global phase I/II study. We continue to partner with the FDA on the confirmatory trial design and have also been accepted into the agency's Chemistry, Manufacturing, and Controls Development and Readiness Pilot Program. Our flexible phase I/II trial design allowed us to move rapidly from dose escalation into pivotal development. The open label dose exploration and dose expansion clinical trial was designed to investigate the safety, tolerability, pharmacodynamics, pharmacokinetics, and efficacy of BEAM-302. Part A evaluated patients with AATD-associated lung disease, and Part B evaluated patients with mild to severe liver disease with or without lung disease.
As of August 17th, 2026, 38 patients were dosed with BEAM-302 across Part A and Part B. As you'll hear from Dr. McElvaney in a moment, the ERS presentation included data from 29 patients treated with a single dose of BEAM-302 in the dose escalation portion of the study, including 21 patients from Part A and eight from Part B. He will also provide additional data that was not presented in the corresponding ERS-B poster, which builds on the late-breaking presentation. Data from patients in the Part A multi-dose cohort and the Part A expansion cohort were not included. A global pivotal cohort known as Part C is now dosing patients across an established network of more than 14 sites in six countries. With that, I'm pleased to introduce Dr. Gerry McElvaney, who currently serves as an investigator in the BEAM-302 trial.
Dr. McElvaney is a professor of medicine at the Royal College of Surgeons in Ireland, head of the Irish Centre for Genetic Lung Disease at Beaumont Hospital in Dublin, and founder of the Alpha-1 Foundation of Ireland. He is a world-leading expert in AATD research and translational medicine, and we're so honored to have him on the call with us today. Dr. McElvaney.
Thank you, Amy. Today, I am very pleased to share updated data from the phase I/II study of BEAM-302 that were reported at the ERS Congress earlier this morning in both an oral presentation and an e-poster. Having treated Alpha-1 patients and worked on Alpha-1 therapies for decades, this is really an exciting time for the field given the number of emerging transformative therapies such as BEAM-302, which are now available. BEAM-302 has been studied in a first-in-human phase I/II clinical study, enrolling patients with both the lung and the liver manifestations of Alpha-1 Antitrypsin Deficiency. Patients aged 18- 70 years with homozygous ZZ mutation and sufficient lung function with blood Alpha-1 Antitrypsin levels lower than the protective threshold of 11 micromolar were enrolled.
In Part A, patients with a clinical diagnosis of emphysema but no liver disease were enrolled into dose cohorts of 15 mg up to 75 mg BEAM-302. In Part 2, patients with a clinical diagnosis of Alpha-1-related liver disease and fibrosis without cirrhosis received 30 mg or 60 mg doses. The key study endpoints are the rates of treatment-emergent adverse events, including serious events, blood levels of total and mutant Z-AAT, including polymeric Z and M-AAT, functional AAT, and other measures of disease activity and treatment efficacy. As of the June 24, 2026, data cutoff date, 21 patients have been enrolled in Part A and eight patients in Part B. Now we report the safety and efficacy data for all 29 patients enrolled.
At the data cutoff, the safety profile of BEAM-302 was consistent with that of LNP-based therapies, with Grade one to two infusion reactions and predominantly Grade one elevations in liver transaminases being the most common adverse events related to treatment. There was one Grade three elevation of liver transaminases that occurred in Part B in a patient with underlying Alpha-1 Antitrypsin Deficiency liver disease that was without abnormal bilirubin and resolved completely without intervention. There were no serious adverse events related to BEAM-302. In Part A, a single dose of BEAM-302 led to sustained increases in total Alpha-1 Antitrypsin levels above the 11 micromolar protective threshold. In the 60 mg cohort, mean total Alpha-1 Antitrypsin increased from five micromolar at baseline to a steady-state mean of 14.4 micromolar and a median of 15.2 micromolar. The increases in total Alpha-1 Antitrypsin were durable, with the longest follow-up out to 18 months.
Similarly, in Part B, the post-treatment steady-state circulating total Alpha-1 Antitrypsin mean and medians were 13.5 and 13.8 micromolar, respectively, compared to a baseline of 4.7 micromolar. These measures were above the protective threshold. Importantly, increased total Alpha-1 Antitrypsin in circulation was functional. The functional levels of Alpha-1 increased in a dose-dependent manner up to 60 mg, and those increases were durable throughout follow-up. Human neutrophil elastase levels decreased in a dose-proportionate manner also. Mutant Z-AAT was significantly and durably reduced after treatment with BEAM-302, with an 84% reduction in circulating Z-AAT in both Part A and Part B 60 mg cohorts. Treatment with BEAM-302 also led to a significant decrease in circulating Z-AAT protein aggregates, referred to as Z-polymers, from baseline in the 60 mg cohort.
This reduction in Z-polymers was to levels at or below that found in the MZ genotype, as seen with dashed gray line. Circulating Z-polymers have been shown to correlate with liver disease severity and also to amplify lung inflammation by inducing neutrophil recruitment. Following treatment with BEAM-302, newly produced corrected M Alpha-1 antitrypsin comprised the majority of Alpha-1 in circulation. The proportion of M Alpha-1 antitrypsin at steady state was 93%, following treatment with 60 mg in both Part A and Part B, exceeding the approximately 80% M Alpha-1 antitrypsin portion associated with the MZ genotype. Here we demonstrate that following BEAM-302 treatment, Alpha-1 antitrypsin protein production remained under normal physiological controls, as evidenced by the inducibility of Alpha-1 in a patient who experienced a respiratory infection roughly eight months after treatment.
This patient had been dosed with 60 mg of BEAM-302 in Part A and achieved a steady-state mean total Alpha-1 antitrypsin level of about 14 micromolar through month six. At an unscheduled visit around month eight, the patient presented with a respiratory infection, resulting in elevated CRP and a concomitant increase in total Alpha-1 antitrypsin level, which is upregulated to protect the lungs from damaging proteases. As the infection resolved, the total Alpha-1 antitrypsin levels trended back down, along with the CRP values by the month nine scheduled visit. Importantly, the patient's favorable Alpha-1 antitrypsin composition of approximately 95% M Alpha-1 was maintained before, during, and after the respiratory infection. In conclusion, BEAM-302, the first therapy in pivotal development to correct a disease-causing mutation, offers a potential one-time treatment for both the lung and liver manifestations of Alpha-1 Antitrypsin Deficiency by restoring SERPINA1 or A1 function.
BEAM-302 at 60 mg in Parts A and B was well-tolerated, with mainly transient Grade one transaminase elevations and mild to moderate infusion-related reactions. It achieved durable increases in total Alpha-1 antitrypsin above the threshold of protection. It increased functional Alpha-1 antitrypsin levels and decreased neutrophil elastase activity. It reduced Z Alpha-1 antitrypsin and Z- polymer levels and induced M Alpha-1 antitrypsin production in circulation. It led to an increase in Alpha-1 antitrypsin during a respiratory infection, indicating that Alpha-1 antitrypsin protein production remains under normal physiological control. The pivotal cohort of patients with Alpha-1 associated lung disease, with or without liver disease, is now currently dosing patients globally using 60 mg of BEAM-302. As a physician, my idea of the ideal treatment for Alpha-1 Antitrypsin Deficiency would have the potential to meaningfully change the disease course for patients by addressing the following key aspects.
It should elevate total Alpha-1 antitrypsin above the protective threshold to markedly decrease the risk of emphysema and liver disease in those without additional risk factors. It should improve the composition of Alpha-1 antitrypsin by producing high levels of functioning M Alpha-1 antitrypsin, whilst also reducing toxic Z and Z- polymer Alpha-1 antitrypsin, which is associated with disease. Finally, it should enable further induction of M Alpha-1 antitrypsin during acute inflammation when it's needed to contain tissue-damaging proteases.
What is encouraging about the BEAM-302 data is that we are seeing evidence of all these effects. While longer follow-up and additional clinical experience are important, these findings suggest that BEAM-302 has the potential to move patients towards a biology that more closely resembles that of carriers with substantially lower disease risk. With that, I would like to thank all the patients, investigators, and study teams who have contributed to this work.
Thank you, Dr. McElvaney. It is a pleasure to have you here with us today. As you have heard, the robust dose escalation data generated with BEAM-302 continue to support its potential to address the critical aspects of AATD, including correction of the underlying mutation, restoration of AAT function, reduction of disease-driving mutant Z-AAT, and durable treatment with a one-time therapy. Taken together, these findings strengthen our confidence in BEAM-302 as we focus on execution of the pivotal development program. At Beam, our commitment to the AAT community extends well beyond BEAM-302. We continue to invest in life cycle opportunities while working alongside leading patient, research, and regulatory organizations to advance the broader field. That includes our participation in C-Path's CPA-1 consortium with the FDA to help identify clinical efficacy endpoints.
Our work with the Alpha-1 Foundation and Alpha-1 Europe Alliance to incorporate patient perspectives into clinical development, and our support of AlphaDetect to help improve detection and diagnosis. Together, these efforts reflect our long-term commitment to advancing care for the AATD community. More broadly, we are entering an important period of execution across Beam. As you have heard today, executing the pivotal cohort for BEAM-302 is a key priority, along with the submission of the BLA for risto-cel as early as the end of the year. At the same time, we are advancing the next wave of the pipeline with BEAM- 304 study startup activities underway, initial BEAM- 301 data expected by year-end, and continued progress in our in vivo HSC editing program.
We are doing this from a position of financial strength with $1.2 billion in cash as of June 30th, and an expected runway into mid-2029, supporting the anticipated risto-cel launch, BEAM-302 pivotal development, and clinical proof of concept of BEAM- 304. To close, everything we do at Beam is ultimately about the people who could benefit from these medicines. I want to thank the entire Beam team for the work that brought BEAM-302 to this point, as well as our investigators, clinical sites, partners, and advocacy organization around the world. Most importantly, we are grateful to the patients and caregivers who participate in our trials and make this progress possible. Thank you for joining us today. Operator, please open the line for questions.
You. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. We ask that you please limit to one question. Our first question will come from Yanan Zhu with Wells Fargo. Your line is open.
Hi, this is Jeff on for Yanan. Thanks for taking our questions and congrats on the data. For the one part B patient with a Grade three liver enzyme elevation, the 60 mg, were the timing and resolution consistent with what you would expect from an LNP-mediated liver enzyme elevation? Just a quick clarification. For this data, AAT was measured by turbidimetry rather than LC-MS, which was used in previous data disclosures. Which assay will you be using in the pivotal Part C cohort? Then data disclosures going forward. Thanks.
Yep. Thank you, Jeff. Amy, do you want to handle those two?
Yes. Thank you. The patient had, as you know, an underlying history of AAT-related liver disease. We saw that the LFT elevations began to increase around day 14 and peaked around day 28-ish, then recovered spontaneously. Again, nothing too out of the norm. We saw, in general, LFT elevations, if they were going to happen anywhere from day three to day 14 as the start of those elevations, and then typically would start to decrease or recover by two to four weeks post-treatment. As far as your question about turbidimetry, yes, we used turbidimetry this time, which is something that is used often in the clinic, and it is something very familiar to clinicians. So we felt like using that was something that, especially at a medical meeting, something that was very useful to do.
We will continue to report turbidimetry, we will also be optimizing LC-MS for our pivotal cohorts. I think that one may serve more for a regulatory function, which is that LC-MS is often something that is looked at as preferred by the regulatory authorities, given that it is actually measuring the mass of approach. We may still wind up doing both the assays, going forward in our presentations, it is TBD how we will present them.
Great. Thank you very much.
Thank you. The next question is going to come from Maury Raycroft with Jefferies. Your line is open.
Hi. Good morning. Thanks for taking my question. Just wondering in the prior cutoff, the mean steady state total AAT in the Part A, 60 mg cohort was 16.1 micromolar versus 14.4 in the new ERS analysis. As the number of patients reaching 12 months increased from three to five, can you clarify whether this reflects a longitudinal decline in AAT levels with longer follow-up or differences in assay methodology or the steady-state calculation?
Yep. Yeah. Thank you. Amy, you want to cover that again?
Sure. We actually think that in general, we've seen once patients go up after day 28, we tend to see quite durable Alpha-1 levels. As you know, Alpha-1 is not something that is kind of very rock solid. It's something that is fluctuating based on how patients' immune system is, whether there's inflammation. We think this difference between a 14.4 versus 16 is within the kind of normal variability you might see and feel that this is not a significant change.
Got it. Can you confirm the proportion of patients treated with 60 mgs in Part A and Part B who remained above the 11 micromolar protective threshold through their latest follow-up, including at month 12?
Everyone has been above the 11 micromolar protective threshold.
Got it. Okay. Thanks for taking my questions.
Thank you. The next question will come from Alec Stranahan with Bank of America. Your line is open.
Hey, guys. Good to see the progress, and thanks for taking my question. I guess just from a regulatory perspective, do you think Z or [inaudible] levels are most important to show for an impact on disease? When you think about enrollment, is the targeted 50 U.S. exclusive, or do you plan to open ex-U.S. sites as well to help expedite global submissions? Thank you.
Yeah. Thank you. Just covering the latter one. This is a global cohort, so we are absolutely in multiple countries and double-digit sites around the world to enroll this. On the question of endpoints, maybe Pino, if you want to talk a little bit. The bottom line is, of course, we think the critical piece of this drug is to be achieving carrier status where you are well into the teens, you are above the protective threshold, you have the M/Z composition that we like and the Z reduction. So those are all critical pieces of what we think is so predictive of clinical benefit here and therefore supportive of the approval pathway we are pursuing. Pino, do you want to talk to how we think about the specific endpoints within that push with the FDA?
Yeah, sure. Obviously, as you pointed out, it's important to demonstrate the entire physiology. Clearly, total AAT levels above the 11 micromolars are an important data point. But they don't describe the full extent of the correction that we're making. Obviously, the ratio between M and Z, and importantly, the reduction of Z is very important to show also a potential benefit to the liver in addition to the lung. As Dr. McElvaney Has pointed out, the reduction of Z-polymers are also very important. So we intend to measure all of those parameters and obviously provide a very complete picture about the effect of BEAM-302.
Exactly which endpoint is going to be the primary versus secondary, frankly, we have not disclosed that. As you can imagine, this will be a competitive piece of information that we obviously hold through. Eventually, there will be also a complementary trial. We're discussing very actively with the FDA exactly what the design and importantly, which endpoint we will be using as part of that.
Thank you.
Thank you. The next question comes from Eric Schmidt with Cantor. Your line's open.
Thanks and congrats on the consistency of these data sets here. Another question with regard to the pivotal cohort C. Can you talk about any differences in enrollment criteria between Parts C and A/B? Are you actually doing densitometry or any other measurements in part C that could support full approval? Thank you.
Sure. Amy, do you want to cover that?
Sure. Our inclusion criteria is really meant to encompass the spectrum of disease for Alpha-1 patients. In this regard, the criteria, you have to have evidence at least by CT scan of emphysema. You can have normal pulmonary function, so just some evidence of lung disease. You can also have liver disease. In this case, we want to be able to have both and show that we have efficacy across the broad disease manifestation. As far as you asked about-
Densitometry
Densitometry, those are involved in all of our studies. We will be collecting CT densitometry in our phase I/II studies. We will be collecting CT densitometry as well in the pivotal study.
Thank you.
Thank you. The next question comes from Samantha Semenkow with Citi. Your line is open.
Hi, good morning, and congratulations on the progress from me as well. I have another one on the pivotal cohort. I am wondering if you could just speak a bit to the enrollment cadence that you are seeing so far, particularly since there are several other trials that are enrolling patients or about to start enrolling patients within the overall development landscape. Then when do you think you will be in a position to guide on top-line data from the pivotal cohort? Thanks very much.
Yeah, that is a great question. Maybe, again, Amy, you can maybe expand on this. I think overall, the enthusiasm for the drug has been quite high, and we have seen that continue. So maybe, Amy, if you want to talk a little bit to what you are seeing, and we can also speak to no decisions made yet in terms of any top-line outcomes from the pivotal cohort. But go ahead, Amy.
Yeah. This is a global study, and I have to say the amount of enthusiasm for this has been outstanding. What we are hearing from are their lines from their own clinic. They are now getting calls from out of country, out of state, depending where they are, and they said they have never seen anything quite like this. We are getting to the point where people are demanding more slots, and obviously we are trying to do that. We have not seen a problem. I think we are first in pole position here because we have been in the clinic now for quite some time. I think that has been very helpful. We continue to expand the sites that we are opening because we know that, as mentioned before, a confirmatory trial is not that far behind. I think we have a lot of momentum.
Thank you. Our next question will come from Michael Yee with UBS. Your line is open.
Hi, good morning, guys. This is Matt on for Michael. Congrats on the update, and thanks for taking our questions. Just curious to any updates around your thinking on the requirements for a confirmatory study. I know those are an active conversation with the FDA, but thoughts around FEV versus functional outcomes, and then also just curious if you will need to do any kind of natural history work or any kind of controlled study down the line as well, and kind of your thoughts there, too. Thanks so much.
Yeah. I can just handle that. I think that is very much an active conversation with the FDA. We do anticipate needing to run a confirmatory trial given that the cohort C is an accelerated approval strategy. All of the endpoints you described, as well as things like CT densitometry, which we have talked about in the past, are of interest. That is something we will work through with the FDA. We have to be operationalizing that trial by the time of the filing for the accelerated approval, as you may know. That gives us some time to get it designed and up and running.
Obviously our operational focus right now is the cohort C, but we will have plenty of time to get that trial locked and then opened in time to then complement the study. Ultimately, we do know that the communities can be very interested in functional outcomes. Given our profile here, we are quite confident that we will be able to show stabilization of this disease over the long term, consistent with what we believe could be a functional cure.
Thank you. The next question comes from Cory Kasimov with Evercore. Your line is open.
Hey, guys. Thanks for taking the question. I wanted to ask about the 11 micromolar bar and your 60 mg steady-state medians were 13.8- 15.2. The poster out shows the per-patient minimums were 11.0 in Part A and 11.1 in Part B, so sitting right at what is thought to be that protective floor threshold. If the field's view of adequate AAT drifts higher post the upcoming SPARTA data, does your 60 mg dose still clear that patient by patient, or is it possibly you could potentially need dose headroom or look into dose further? Thank you.
Yeah, thanks. Maybe I will answer this to start, then I am wondering if maybe I could invite Gerry to say a few words about the profile we are achieving and how he sees this relative to what we need to do for patients. I think that might be a good opportunity. Just to answer the question, I think SPARTA, as you rightly point out, is testing standard augmentation versus high-dose augmentation. I would just remind people of the very different profile of augmentation. On augmentation, the number you care about is that trough level because you are not going to go up when you are sick. That is all you can get. That is not the case with us, right? These numbers are floors, and when you are sick, as we have shown, you will go up higher.
I actually think that high-dose SPARTA is probably a closer parallel to what we're achieving physiologically than the low dose. We do hope it shows some benefit. Also, of course, augmentation does nothing for the Z protein, which is still being produced by the body. So maybe with that preamble answer, I would invite Gerry to maybe just give some perspectives on how he views this profile and how it might compare to augmentation.
Thank you very much. I would certainly agree with what you have said there. I think one of the most interesting things about the Beam result is that it is mainly M Alpha-1 antitrypsin, a very small amount of Z Alpha-1 and phenomenally decreased polymer levels. That is really important because Z Alpha-1 is less efficient at inhibiting proteases. It is slower, and if it is in polymer form, it is unable to inhibit proteases. So the more M Alpha-1 you can get, the better. So put it another way, 11 micromoles in a Beam individual is much more effective as an anti-protease and anti-inflammatory than 11 micromoles in a person receiving augmentation therapy.
Thank you. The next question is going to come from Luca Issi with RBC. Your line is open.
Oh, great. Thanks so much for taking my question and congrats on the data. Maybe Amy or Giuseppe, just circling back on a prior question, can you talk about the kinetics of the ALT and AST post-infusion? When you compare and contrast those kinetics between patients with and without liver manifestations, are the curves generally superimposable with Cmax and area under curve generally comparable with one another? Or should we assume the patient with liver pathology tends to have a little bit of a higher level versus the patients without liver pathology? Again, just asking the questions in the context of obviously the Grade three being in patients on Part B. So any thought there, much appreciated. Thanks so much, guys.
Yeah. Amy, do you want to try to narrow on?
I mean, we really don't have that many patients to be able to comment fully about that. I do think that we know, and maybe after I'm done, I'll have Gerry comment, that once you have Alpha-1 Antitrypsin Deficiency and you have known liver involvement, that your response to medications and your liver can be quite susceptible to, I would say, almost kicks or inflammation. I think this is not that inconsistent with, number one, what we see with getting a lipid, and then number two, in someone who has Alpha-1 Antitrypsin Deficiency with known liver involvement of then having to process that lipid and having that inflammation occur as well.
Overall, this was a little bit higher than the typical Grade one. TBD what will happen with other liver patients, because right now we've only dosed, I think about five. But on the whole, we think the safety overall is largely still Grade one in the Part B patients that we've seen to date, with the exception of this patient. Maybe, Gerry, you can comment on what you see in your patients with underlying Alpha-1 Antitrypsin Deficiency-related liver disease.
Yeah. That is an important point, I think. People with Alpha-1 Antitrypsin Deficiency related liver disease tend to have a retention of Z-AAT or Z-polymers in the liver, and that makes them somewhat sensitive to certain inflammatory processes. For example, if you start an individual with Alpha-1 on an antibiotic, he may get a flare-up in his liver function tests as well, but it usually settles down. It's something that happens, but we don't see it as being a major contributor to the ongoing process in these patients. You'll notice that in Part B, none of the patients had cirrhosis, so they had a certain degree of liver disease, but not the really severe liver disease that we sometimes see.
Got it. Thanks so much.
Thank you. The next question is going to come from Sami Corwin with William Blair. Your line's open.
Thank you. Good morning, and congrats on the data. I guess I was curious that there was a change in Z that was dose-dependent, so it was greater in the patients treated at the high dose, but that didn't necessarily translate into a greater reduction in Z-polymers. I guess I was curious as to why and what the implications are for that. Dr. McElvaney, kind of continuing off from the messaging you've been saying, do you think that increasing these steady-state AAT levels would add further benefit, or does it not matter as long as the M-AAT is still increasing during periods of acute inflammation? Thank you.
Sure. Maybe, I guess, Amy and Gerry, if you want to talk a little bit about Z- polymer reduction, and then the question about raising from steady state.
Yeah. The Z- polymer story is one that's evolving, but there's some very interesting data coming out now. If you look at Z individuals and you get a person who's got the same level but less polymers, the people with less polymers have less inflammation. We've actually done a study comparing MZ individuals to SS individuals who got exactly the same levels of AAT, exactly the same antielastase capacity, but the SS individuals have no polymers. The less polymers you have, the less inflammation you have, and the less decrease in lung function you have.
We've good evidence now that polymers actually impact upon you in a number of different ways. Obviously, they impact upon the liver, but they're also pretty useless at inhibiting elastase or having an anti-inflammatory effect. Then on top of that, they're very potent, beautiful chemoattractants, so they're pro-inflammatory. Anything you can do to decrease polymers is a good thing.
Thank-.
Great. I wasn't quite sure I followed the question about increasing the steady state. I think the key point again there that we've highlighted is just that the AAT physiology, this is acute phase response protein. We want it to go up when people are sick, and we have shown that. Obviously, you get a higher level as a basal level with BEAM-302 treatment. Then when you're sick, it goes even higher. The key point is that you're maintaining the quality, let's say, of that AAT, the over 90% M, that's completely consistent between that new basal level and when it's upregulated, meaning you're getting almost all M production and not increasing Z. To Gerry's point, we think that the quality of the AAT we're producing is quite significant for the effect within the body.
Got it. Thank you.
Thank you. I am showing no further questions at this time. I will now turn the call back over to John Evans for closing remarks.
Thank you very much. Thanks for your attention this morning. Thank you, Gerry, for joining us and for your great insights. We are clearly very pleased with the consistency of the data here with what we have shown previously. Achieving what we believe is a protective level of AAT, normalization of the AAT profile towards M and Z, the natural regulation, and now the reduction of these harmful Z proteins, the aggregates, just showing the overall profile that we think is really as Dr. McElvaney said, the ideal profile that we are trying to deliver for patients suffering from this terrible disease. As well, very pleased with the operational momentum in the trial, moving deeper into our pivotal experiment here. I am looking forward to bringing this to patients as quickly as we can. Thank you again for your time, and look forward to speaking again soon.
This concludes today's conference call. Thank you for participating, and you may now disconnect.