Beam Therapeutics Inc. Common Stock Status update

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 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 metabolic disease, which aims to correct the severe R83C mutation in glycogen storage disease type 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 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 MAAT 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, 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 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 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.