Beam Therapeutics Inc. (BEAM) Earnings Call Transcript & Summary

Good morning, and welcome to Beam Therapeutics Conference Call. [Operator Instructions] 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 Investors 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, an investigator in the Beam-302 trial; and Dr. 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 Factors 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 onetime genetic medicines that precisely correct disease-causing mutations and address disease at its source. The promise of our base setting 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'll 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 D&A. 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're seeing with Beam-302 reflects these fundamental advantages we set out to achieve with base editing. The power predictability is more than a scientific concept. It's 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 1 to the next. Our goal is not simply to develop a single successful medicine. It's to create a repeatable model for advancing precision genetic medicines efficiently, predictably and at scale. We are already applying that model across 3 major areas of opportunity, each with large addressable underserved patient populations and blockbuster potential for differentiated onetime 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 onetime 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-302 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 3 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 8. 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 a metabolic disease which aims to correct the severe R83C mutation in glycogen storage disease 1a 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 onetime treatment to address both lung and liver manifestations of AATD through direct correction of the disease-causing mutation. With follow-up now out to 2 years, treatment with Beam-302 has demonstrated durable restoration of normal AATD physiology, including production of corrected AAT for the first time that is both functional and under normal physiologic control in response to inflammation. A single dose of 60 milligrams 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 onetime treatment for AATD. With that, I'll turn the call over to Amy.

Thanks, Tom. 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 [indiscernible] AAT accumulates in the liver, while 2 little functional AAT reaches the circulation. This creates 2 distinct consequences progressive liver disease from the accumulation of the toxic ZAAT protein in 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 circulate [indiscernible] but does not address the underlying production of mutant 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 manifestations of AATD. Clinical Genetics gives us an invaluable benchmark for what meaningful correction could look like. Patients with severe PIDV 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, and MV and most SV carriers generally have AAT levels above the 11 micromolar 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 Serfina1, converting the disease-causing PIC 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 MAAT 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 inflammation. Taken together, these objectives have the potential to address both the lung and liver manifestations of AATD. And 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 a line with the FDA on a potential accelerated approval pathway for Beam-302 and with the primary end point 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 CMC 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 in Part B evaluated patients with mild to severe liver disease with or without long disease. As of August 17, 20260, patients were dosed with BAM 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 Beam-302 in the dose escalation portion of the study, including 21 patients in Part A and 8 from Part B. He will also provide additional data that was not presented in the corresponding ERS poster, which builds on the late-breaking presentation. Data from patients in the Part A multidose cohort and the Part A expansion cohort were not included. -- global pivotal cohort known as Part C is now dosing patients across an established network of more than 14 sites in 6 countries. With that, I'm pleased to introduce Dr. Gerry McElvaneyi, 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 center for genetic lung disease at Beaumont Hospital in Dublin and Founder of the Alpha One 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. McElvaneyi.

Thank you, Amy. Today, I'm very pleased to share updated data from the Phase I/II study of Beam-302 and that were reported at the ERS Congress earlier this morning in both an oral presentation and [indiscernible] . 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 BIM and CO2, 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 to 70 years with homozygous ZZ mutation, and sufficient lung function with alpha-1 antitrypsin levels lower than the protective threshold 11 micromolar were enrolled. In Part A patients with a clinical diagnosis of emphysema, but no liver disease were enrolled in the dose cohort of 15 milligrams up to 75 milligrams Beam-302. In Part 2, patients with a clinical diagnosis of alpha-1-related liver disease and fibrosis without cirrhosis received at 30 or 60-milligram doses. The key study endpoints other bits of treatment-emergent adverse events, including serious events, drug levels of total and mutant [indiscernible] including polymer disease and [indiscernible] function of AAT and other measures of disease activity and treatment efficacy. As of the June 24, 2026 data cut off debt, 21 patients have been enrolled Part A and 8 patients in Part B. And 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 lipid nanoparticle-based therapies with grade 1 to 2 infusion reactions and predominantly grade 1 elevations in liver transaminases in the most common adverse events related to treatment. There was one grade 3 elevation of liver transaminases that occurred in Part B in a patient with underlying alpha-1 antitrypsin efficiency liver disease that was without a normal 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 protection. In the 60-milligram cohort, main total alpetrypson increased from 5 micromolar at baseline to a steady state mean of 14.4 micromolar, and a median of 15.2 micromolar. The increases in total [indiscernible] were durable with the longest follow-up up about 18 months. Similarly, in Part B, the posttreatment steady state surfing total [indiscernible] and medians were $13.5 million and 13.8 micro, respectively, compared to a baseline of 4.7 micromolar. These measures were above to protect the structure. Importantly, increased total alpha in circulation was functional. The functional levels of Alpha 1 increased in a dose-dependent manner up to 60 milligrams and those increases were durable throughout follow-up. Cumulative [indiscernible] levels decreased in a dose proportionate manner also. Mutant Z-AAT [indiscernible] was significantly and durably reduced after treatment being 30 with a nearly 4% reduction in circulating G1 in both Part A and Part B 60-milligram cohort. Treatment with Beam-302 also led to a significant decrease in circuit GF-1 protein aggregates referred to as Z polymers from baseline in the 60-milligram cohort. This reduction in Z Polymers was to levels at or below that found in the MG genotype as seen with [indiscernible] Circulating polymers have been shown the correlated liver disease severity and also to amplify lung inflammation by inducing neutral recruitment. Following treatment with Beam-302 newly produced corrected MR1 antitrypsin comprised the majority of Alpha-1 in circulation. The proportion of [indiscernible] at steady state was 93%, following treatment with 60 milligrams in both Part A and Part B, exceeding the approximately 80% MR100tpportion associated with the MD genotype. Here, we demonstrated that following Beam-302 treatment, R-105 protein production remained under normal physiologic controls, as evidenced by the induciblity of Alpha-1 in a patient who experienced a respiratory infection roughly 8 months after treatment. This patient has been dosed with 60 milligrams of Beam-302 in Part A and achieved a steady state mean total [indiscernible] level of about 14 micromolar through month 6. At an unscheduled visit around Monde, the patient presented with a respiratory infection, resulting in elevated CRP and a concomitant increase in total alp00tryption level, which is upregulated to protect the loans from damage proteus. As the infection resolved the total [indiscernible] levels trended back down along with the CRP values by the month 9 scheduled visits, importantly with patients' favorable apatiptiun composition of approximately 95% and alpha 1 was maintained before, during and after the respiratory [indiscernible] In conclusion, Beam-302 the first therapy in pivotal development to correct a disease-causing mutation offers a potential onetime treatment for both the lung and liver manifestations of alpha iteration deficiency by restoring SERPINA1 function. BIMCO2 at 60 milligrams in Parts A and B was well tolerated with many transient grade 1 transaminase elevations and mild to moderate infusion-related reactions. It achieved durable increases in total [indiscernible] the threshold of protection. It increased function of 100 levels and decreased due to lasters activity. It reduced ZR-1008tandZ polymer levels and induced M100 triptan production in circulation. It led to an increase in alphanandetryptin during our respiratory infection, indicated that A4s protein production remains under normal physiological control. a pivotal cohort of patients with alpha-1 associated lung disease with or without liver disease is now currently dosing patients globally using 60 milligrams of Beam-302. As a decision, my idea of the ideal treatment for ARF-10tryption deficiency. We'll have the potential to meaningfully change the disease course for patients by addressing the following key aspects. It should elevate total alpha have triptan above the protective threshold to margin decreased risk of emphysema and liver disease in those without additional risk factors. It should improve the composition of Rattrypsin by producing high levels of functioning Mphantitrypton, where it's also reducing toxic Z and Z polymer alpha antitrypsin, which is associated with disease. And finally, it should enable further induction of MR 100 trips during acute inflammation when it's needed to contain tissue damaging props. What is encouraging about the Beam-302 data is that we are seeing evidence of all these effects. For a longer follow-up and additional clinical experience are in part -- these findings suggest that BAM 302 has the potential to move patients towards a biology that more closer examples that are carriers with substantially lower disease risk. With that, I'd like to thank all the patients, investigators and study teams have considered to this work.

Thank you, Dr. McElvaney. It is a pleasure to have you here with us today. As you've heard, the robust dose escalation data generated with Beam-302 continue to support its potential to address the critical aspects of ATD, including correction of the underlying mutation, restoration of AAT function, reduction of disease driving mutant Z-AAT and durable treatment with a onetime therapy. Taken together, this final strengthened our confidence in Beam-302 as we focus on execution of the pivotal development program. At Beam, our commitment to the AT 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, CPA1 consortium with the FDA to help identify clinically clinical efficacy end points. Our work with the Alpha-1 Foundation and Alpha One Europe Alliance to incorporate patient perspectives into clinical development and our support of Alpha detect to help improve detection and diagnosis. Together, these efforts reflect our long-term commitment to advance in care for the AATD community. More broadly, we're entering an important period of execution across beam. As you've heard today, executing the pivotal cohort for Beam-302 is a key priority, along with the submission of the BLA for risk to sell as early as the end of the year. At the same time, we're advancing the next wave of the pipeline with Beam 304 study start-up activities underway, initial Beam-301 data expected by year-end and continued progress in our no HSC editing program. And we're doing this from a position of financial strength with $1.2 billion in cash as of June 30 and an expected runway into mid 2029, supporting the anticipated Risto-cel launch, Beam-302-pivotal development and clinical proof of concept of Beam. To close, everything we do at Beam is ultimately about the people who could benefit from these medicines. I want to thank the entire BIM team for the work that Beam through to this point as well as our investigators, clinical sites, partners and advocacy organization around the world. Most importantly, we're 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.

[Operator Instructions] And our first question will come from Yanan Zhu with Wells Fargo.

This is Jeff on for Yanan. Congrats on the data. for the on Part D patient with Grade 3 liver enzyme elevations that 60 mg were the timing and resolution consistent, what you would expect from an LMP liver enzyme elevation -- and just a quick clarification. For this debt was measured by turbidimetry rather than LCMS, which was used in previous data this which assay will you be using in the pivotal Part C cohort and then data disclosures going forward.

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 and 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 3 to day 14 as the start of those elevations and then typically would start to decrease or recover by 2 to 4 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 is something very familiar to clinicians. So we felt like, especially at a medical meeting, something that was very useful to do. We will continue to report turbidimetry and we will also be optimizing LCMS for our pivotal cohort. 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 is actually measuring the mass of approaching -- and so we may still wind up doing both the assays. And going forward in our presentations, it's TBD, how we will present them.

And the next question is going to come from Maury Raycroft with Jefferies.

Just wondering, in the prior cutoff, the mean steady state total AT 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 increase from 3 to 5. Can you clarify whether this reflects a longitudinal decline in AAT levels with 1 follow-up or differences in assay methodology or the steady-state calculation?

Yes. Thank you. Amy, do 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. And so we think this difference between $14.4 million versus 16 is within the kind of normal variability you might see and feel that this is not a significant change.

Got it. And can you confirm the proportion of patients treated with 60 mg in Part A and Part B who remained above the 11 micromolar protective threshold through the latest follow-up, including in month 12?

Everyone has been above the 11 micromolar protective threshold.

And the next question will come from Alec Stranahan with Bank of America.

Good to see the progress. I guess just from a regulatory perspective, do you think Z or AAT levels are more -- most important to show for an impact on disease. And when you think about enrollment. Is the 50 -- is the targeted U.S. exclusive? Or do you plan to open ex U.S. sites as well to help expedite global submissions?

Yes. Thank you. So just covering the latter one. So this is a global cohort. So we're 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. I mean, the bottom line is, of course, we think the critical piece of this drug is to be achieving carrier status where you're well into the teens, you're above the protective threshold. You have the the MZ composition that we like and the 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're pursuing. Pino, do you want to talk to how we think about the specific endpoints within that push with the FDA?

Yes, sure. As you pointed out, it's important to demonstrate the entire physiology. And clearly, total levels about 11 micromolars are an important data point. But they don't describe the full extent of the correction that we're making. And obviously, the ratio between MNV and importantly, the reduction of Z is very important to show also a potential benefit to deliver in addition to the lung and as Dr. McElvaney has pointed out, the reduction of the 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 end point is going to be the primary versus secondary, frankly, we have not disclose that as it -- as you can imagine, this will be a competitive piece of information that we obviously hold through. And eventually, there will be also a complimentary trial been discussing very actively with the FDA exactly what the design and importantly, which endpoint we will be using as part of that.

And the next question comes from Eric Schmidt with Cantor.

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 AD? And then are you actually doing [indiscernible] or any other measurements in Part C that could support full approval.

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. And so 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. So in this case, we want to be able to have both and show that we have efficacy across the broad disease manifestations. As far as you asked about and sensitometry. Those are involved in all of our studies. So we'll be collecting CT sensitometry in our Phase I/II studies. We'll be collecting [indiscernible] as well in the pivotal study.