Intellia Therapeutics, Inc.

Hello, and welcome to Intelia Therapeutics' second quarter conference call. My name is Chloe, and I will be your conference operator today. Please be advised that today's call is being recorded. I would now like to turn the call over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intelia. Please proceed.

Thank you, operator, and hello, everyone. Earlier this morning, we issued a press release outlining recent business updates in our second quarter financial results. This document can be found on the Investors and Media section of Intelia's website at inteliatx.com. At this time, I would like to take a minute to remind listeners that during this call, Intelia management may make certain forward-looking statements. We ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intelia undertakes no duty to update this information unless required by law. Joining me on the call are John Leonard, our chief executive officer, and Ed Dulac, our chief financial officer. With that, I'll now turn the call over to John to begin our business discussion.

Thank you, Jason, and good morning, everyone. We're excited to be speaking with you to recap the tremendous progress we made in our phase three development programs of Flamvozi in hereditary angioedema, or HAE, and Nexi in trans-thyretin amyloidosis, or ATTR. The full results of our Phase 3 HALO trial in HAE position us very well for potential approval and launch of the world's first in vivo gene editing product in the first half of next year. We also have gained important new genomic insights that further our understanding of NEXE's profile and could help position us even more favorably within a large and dynamic ATTR market. Let's begin with Lombosi. Simply put, the second quarter was a momentous period for this program. In April, we reported positive top-line results from HALO and got our rolling BLA submission underway with the FDA. This was followed by our late-breaking oral presentation at IACI and a concurrent publication in the New England Journal of Medicine, Intelia's sixth manuscript in this prestigious journal. HALO was an unequivocal success as we achieved statistical significance for the primary and all key secondary endpoints. More specifically, during the six-month primary observation period, we reported an 87% reduction in mean monthly attacks for Lombozy versus placebo. 62% of patients were entirely attack-free and therapy-free in the Lombozy arm. A 23-point improvement was observed for the Lavoisier arm in the total angioedema quality of life score from baseline. For context, a change of just six points is considered to be clinically meaningful. The New England Journal manuscript also contained compelling figures and analyses underscoring the unique value proposition that could be afforded by this one-time therapy if it's approved. For instance, patient-level data demonstrated that all patients in the Lombosi arm experienced attack rate reductions from baseline from weeks 5 to 28. In other words, every single patient received a clinical benefit, including those who are not yet fully attack-free during that six-month period. A subgroup analysis demonstrated meaningful attack rate reductions in the Lombosi arm regardless of age, sex, race, weight, geography, baseline attack rate, or prior therapy. The publication also included a figure depicting the mean number of HE attacks over time. It traced patients from when they were on prior therapies before screening through the entire efficacy evaluation period and into crossover. And it showed that mean attack rates for the longvose yarn dropped well below the prescreening attack rates by week four. Attacks continued to decline in the months that followed and approach zero in the crossover period after week 28. In the placebo arm, not surprisingly, mean attack rates didn't drop below prescreening levels until patients crossed over to Lombosi. At that point, they dropped steeply and approached zero within a few months. Also, notably, all patients who received Lombosi at baseline or in crossover remained free from long-term prophylaxis therapy as of the data cutoff. and finally, favorable safety and tolerability data were observed. The most common treatment emergent adverse events were infusion-related reactions, headache and fatigue. All treatment emergent adverse events were grade one or grade two and there were no serious adverse events observed in the Lombosi arm as of the data cutoff. These results are unsurpassed by chronic long-term prophylaxis therapies or LTPs. We believe it is clear, moreover, that they truly stand alone in the HEE space given that this is a one-time treatment. Most patients were attack-free and therapy-free for the entire six-month efficacy observation period following a single long-pollution dose. Based on our preclinical work and observations from our Phase 1-2 trial, our expectation is that this percentage will increase further over time as patients who have lived with HAE their entire lives adjust to their new normal. So what's next for us? Well, we expect to be in a position to announce the FDA's acceptance of a BLA filing for Lanvozie by the end of this year. In the meantime, our pre-commercial readiness efforts are advancing well as we prepare for a potential U.S. launch in the first half of next year. Most of these efforts are well underway, including work streams across medical engagement, payer outreach, for their work on treatment center readiness, distribution planning, and access strategy. We've completed hiring for our field medical, reimbursement, and strategic accounts teams, and they're now engaging with treatment centers around the country to ensure they are well prepared to address patient needs shortly after approval. We're also building awareness of the many burdens associated with HAE. During the second quarter, we launched haereframe.com, a disease awareness initiative designed to elevate understanding of the challenges patients face, including those related to lifelong chronic therapy. Together, these efforts reflect meaningful progress in building the infrastructure, awareness, and access pathways needed to support our planned launch. So let's turn to the progress we made with Nexi, our potential one-time treatment for patients with ATTR cardiomyopathy and polyneuropathy. We were pleased to have resolved the clinical holds on our Phase 3 trials quite rapidly earlier this year, and I'm excited to report today that we were able to resume enrollment and dosing in both trials in Q2. Investigator engagement and enthusiasm remain high, and our screening rate is rapidly increasing globally once again. ATTR is a large, growing, and highly underdiagnosed market with significant omit needs. Today, patients are predominantly served by stabilizers, silencers, or a combination of the two. About a month ago, disappointing top-line results were shared from CardioTransform, the pivotal trial of eplantersin, a TTR silencer, for patients with ATTR cardiomyopathy. Since then, there's been some debate about whether a silencer can work on top of a stabilizer. We and others believe the negative outcome is specific to eplantersin in this particular trial, and it does not speak to combination outcomes in general. We remain firm believers that combination therapy will work, but only with the right agent. This belief is based empirically on clinical evidence. First, we would point to the fact that another chronically-dosed silencer, ritrizarin, has already shown a directional benefit on top of stabilizers in a well-controlled trial. But even more importantly, we would point to what was observed in the monotherapy data for each of the chronically dosed stabilizers and silencers. If you go back and look at the readouts for approved stabilizers like tefamidus and acaramidus and approved silencers like aplentersin and fritrizorid, you'll see that patients continue to progress while they're on those therapies. Why is that? Well, we and others are convinced it's because they inadequately reduce or control TTR protein. Focusing in on the approved silencers, you'll see that mean TTR reductions for each of them are about 80%. However, the details behind that number matter. For instance, it takes many months for those silencers to achieve their 80% data of reduction. There's significant variability and TTR from patient to patient, with some achieving a 90% knockdown and many others receiving reductions of only 50 or 60%. And even within an individual patient, the knockdown fluctuates due to issues with PK and issues with dose interruptions and adherence, whether due to patient behavior or toxicity. Simply put, it appears today's silencers and stabilizers are leaving efficacy on the table and a progressive disease with high mortality like ATTR-CM every day and every microgram per milliliter of TTR counts. MEXE has demonstrated its ability to deliver an unsurpassed knockdown of TTR protein for patients in both relative and absolute terms. Our phase one data demonstrated a mean TTR reduction of 90%. While that percentage is impressive, We believe the absolute TTR reduction is even more clinically relevant. When Nexi is provided as monotherapy, mean serum TTR with less than 20 micrograms per milliliter, about one-third of the absolute level seen with the leading chronic silencer. That knockdown was achieved rapidly within one month of the infusion, and it was extremely consistent across all patients. Best of all, Patients began receiving therapeutic doses of Nexi in 2021, and as of our latest data cutoff, intrapatient TTR control was constant and was maintained across all patients following their one-time Nexi treatment. We look forward to presenting updated long-term durability data at future Congresses. We believe Nexi's distinct TTR knockdown is why disease stabilization or reversal is observed in most patients in our Phase I while our would-be competitors have observed disease progression. Additionally, the response has been consistent across patients of all New York Heart Association classes, those with either variant or wild-fed disease, and it also includes patients who have progressed on past silencers. And so, we continue to have significant confidence in our ability to show a benefit on top of typhanitis and magnitude. Additionally, unlike CardioTransform, which was a time-bound study, Magnitude's primary endpoint is strictly event-based. We've enrolled well over 650 patients in Magnitude. We've been accruing events for quite some time, and those events continued unabated through the clinical hold. While still premature for us to guide us to data timing, what it can say today is that the blinded event rate in a trial remains within the range we've projected internally. We're looking forward to reviewing the detailed Cardiotransform data later this month at ESC. And of course, we have the opportunity to consider changes that further optimize magnitudes design based on what we learn. Now let's move on to one other encouraging update we're able to share today related to Nexi. As we reported late last year, grade four liver transaminase elevations had been observed in less than 1% of patients enrolled in magnitude. These were transient, and in most cases, they resolved without any intervention. Based in part on the fact that the observations consistently occurred two to five weeks after dosing, we hypothesized they were caused by an adaptive immune response. As a result, we implemented mitigation measures to enhance monitoring for transaminase elevations and intervene if they are observed. These measures are very straightforward. and could easily be implemented in a real-world commercial setting if required. We also went further. Working with Regeneron and other external experts, we sequenced and analyzed data from over 600 patient samples across all MEXC clinical trials to date. Our goal was to understand if there were subpopulations that might be most susceptible to higher-grade transaminase elevations. This work focused on HLAs, which are proteins on the surface of cells that play a key role in regulating the immune system and helping to distinguish native and foreign peptides. This blinded analysis revealed one statistically significant finding. Patients carrying one specific HLA allele that's known as C0501 had a significantly higher rate of grade three or greater transaminase elevations than the broader population. In fact, each of the five highest elevations observed following dosing occurred in patients carrying this allele. Now, some important context on what this does and doesn't mean. Only 12% of the 600-plus samples we analyzed carry this allele, and the strong majority of CO501 positive patients did not experience severe transaminase elevations. So we continue to see the potential for a favorable benefit-risk profile even in the subgroup, particularly with the mitigation strategy that is now in place. What the finding gives us is valuable, a mechanistic explanation for a general signal we'd already flagged and a way to identify patients who are more likely to be affected before it happens. In doing so, it further increases our confidence in Nexi's ability to deliver on its long-recognized potential. So here are our next steps. We're engaging with FDA to review the findings. In the meantime, we already have updated our protocols, investigators' brochures, and informed consents to incorporate HLA typing for all patients in the phase three trials. These documents are in the process of being rolled out to regulatory authorities, IRBs, and sites globally. Following the reviews, investigators and patients will be informed about the HLA results during screening or prior to crossover so they can make more informed treatment decisions. And so to close, I'm exceedingly proud of all the team continues to accomplish here at Intelia. We're marching towards the world's first potential launch of an in vivo gene editing therapy with Launvosy. We're on track to complete enrollment magnitude two later this year. and we're demonstrating precision medicine at its finest with our HLA work on Nexi. These achievements layer on top of all the other pioneering work we've undertaken as we seek to harness the power of machine editing to deliver optimal treatment outcomes for patients with just one dose. So with that, let's now turn the call over to Ed to share some financial color.