Akero Therapeutics, Inc. (AKRO) Earnings Call Transcript & Summary

Good day, and welcome to the Akero 96-week Phase IIb SYMMETRY data presentation. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Bill White, Chief Financial Officer and Head of Corporate Development. Please go ahead.

Before we begin, I ask that you please read the disclaimers presented on Slide 2. And I'd like to remind you that various statements that we may make during this call will include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including expressed or implied statements regarding implications of this analysis of the Phase IIb SYMMETRY study of efruxifermin or EFX, which are preliminary top line results that are subject to audit and verification procedures and additional data that can result in material changes in the final data, our future plans, including our plans around the development of EFX, prospects and strategy, financial goals and guidance, product attributes and pipeline, drivers of growth and other statements that are not historical fact. Such forward-looking statements are not guarantees of future performance, and therefore, you should not put undue reliance upon them. Management's assumptions, expectations and opinions reflected in these forward-looking statements are subject to risks and uncertainties that may cause actual results and/or performance to differ materially from any future results, performance or achievements discussed in or implied by such forward-looking statements, and the company can give no assurance they will provide -- they will prove to be correct, and will not provide any further guidance or updates on our performance during the quarter, unless we do so in a public forum. Please refer to the press release we issued this morning and risk factors included in the company's filings with the Securities and Exchange Commission for a discussion of important facts that may cause actual events or results to differ materially from those contained in our forward-looking statements. Prior to this call, we issued a press release regarding the top line preliminary 96-week data from our Phase IIb SYMMETRY trial, which is available on our website at akerotx.com under Press Releases in the Investor Relations section. The presentation we'll walk through on today's call will be available immediately afterwards under Events and Presentations in the Investor Relations section of our website. I will now turn the call over to Kitty Yale, Akero's Chief Development Officer.

Thank you, Bill, and good morning, everybody. Today, I'm pleased to present new and unprecedented data for our Phase IIb SYMMETRY study of EFX, which we're developing as a treatment for MASH, included compensated cirrhosis due to MASH. Patients with cirrhosis due to MASH face a poor prognosis. As seen here on Slide 3, the overall 5-year survival rate without transplantation amongst F4 patients is about 50%. Patients with compensated cirrhosis are at risk of decompensation and liver failure. Liver failure manifest as clinical events such as jaundice, fluid buildup in the abdomen, known as ascites, presence of enlarged esophageal vein, known as varices, and impaired brain function known as hepatic encephalopathy. The first therapy to treat precirrhotic MASH was approved in March 2024. There's still no approved therapies to treat MASH cirrhosis. We believe an agent that reverse cirrhosis due to MASH would represent a major medical advance, with the potential to meaningfully improve outcomes, and transform patient life. Treatments capable of effectively treating cirrhosis due to MASH have proven elusive to date. Slide 4 shows the landscape of some of the leading programs that have evaluated the different mechanisms of Phase IIb or Phase III randomized placebo-controlled studies in patients with cirrhosis due to MASH. Over the past decade, no compound has been shown to statistically significantly reverse cirrhosis. We are excited about EFX potential to be the first treatment option for patients with compensated cirrhosis due to MASH, pending Phase III trial results and if approved by regulatory agencies. On Slide 5, shown is the SYMMETRY study design, which was a Phase IIb randomized, double-blind, placebo-controlled multicenter, dose-ranging trial. All patients had biopsy-proven compensated cirrhosis, fibrosis Stage 4, Child-Pugh Class A due to MASH. The study enrolled 182 patients, with approximately 60 in each treatment group who were randomized to receive once-weekly subcutaneous doses of either 28 or 50 milligrams of EFX or placebo. The primary endpoint was the proportion of subjects who achieved at least the 1-stage improvement in fibrosis, without worsening of MASH at week 36. Patients continued on blinded treatment with EFX or placebo for up to 96 weeks, at which point a second on-treatment biopsy was taken. This design enabled us to assess how quickly EFX could be expected to show a treatment response, and to evaluate the degree to which treatment response would be sustained and expanded after longer treatment duration. The secondary measures at week 96 are listed at the top right. On Slide 6, we review the baseline demographics, which we have reported previously. This was a patient population with advanced compensated cirrhosis reflected in liver stiffness values of 24 to 25-kilopascals. Approximately 80% of patients have type 2 diabetes, including approximately 1/4 of patients taking GLP-1. On Slide 7, we provide updated patient disposition from baseline to week 96. As shown here, 87% of patients for whom biopsies were collected at week 36 remained on study, with collection of 134 biopsies at week 96. This included retention of 82% placebo patients, 89% 28-milligram patients, and 90% of 50-milligram patients. Throughout the remainder of this presentation, we will focus on the results for the 50-milligram EFX group, as it's the only dose being evaluated in our Phase III SYNCHRONY study in patients with compensated cirrhosis due to MASH. As seen here on Slide 8, the main histology analysis is the week 96 liver biopsy analysis set, which comprised of 134 patients with baseline and week 96 biopsies. A corresponding ITT analysis of the histology results is based on the full analysis set of 181 patients and treated any missing liver biopsies of failures. This is a conservative approach to ITT analysis and aligns with the statistical analysis of Phase III data employed in product labeling. On Slide 9, we report the results for the proportion of patients who achieved fibrosis improvement of one or more stages without worsening of MASH, which was observed in 39% of patients in the 50-milligram dose group. This reversal of cirrhosis for 50-milligram compares to only 15% for placebo. This result at 50 milligrams was statistically significant at P less than 0.01. Statistical significance was maintained under ITT analysis, with 29% of patients achieving cirrhosis reversal without worsening of MASH compared to 12% for placebo. As a reminder, we used a conservative ITT definition where missing biopsies were treated at failures. Given the clear dose-related response with improvement in fibrosis, only statistically significant for 50 milligrams by either completer or ITT analysis, we believe the greater therapeutic activity of 50 milligrams is required to maximize cirrhosis reversal. Slide 10 highlights how the response to EFX was sustained and expanded with increasing duration of treatment. As shown here in the chart at left, there were 9 new responders for 50 milligrams compared to 3 for placebo. Moving to the table at the top right, amongst patients who completed 96 weeks of treatment, the proportion of week 36 responders to sustained fibrosis improvement through 96 weeks, with 75% for 50 milligrams compared to 50% for placebo. Moving to the table beneath. The proportion of nonresponders at week 36 who developed a response by week 96 was 26% for the 50-milligram group, 3x greater than placebo. Slide 11 shows that baseline GLP-1 therapy did not impact the cirrhosis reversal results we reported to date. As a reminder, amongst all patients with baseline and week 96 biopsies, we observed a treatment response of 39% for 50 milligrams compared to 15% for placebo. Looking to the chart on the right, we see the response rate amongst the subgroup of patients who were treated with 50 milligrams who were not taking a GLP-1 at baseline with 45% compared to 17% for placebo. This result remains statistically significant at P less than 0.01. Slide 12 reports the results for the proportion of patients who achieved MASH resolution. The rate of MASH resolution for 50 milligrams was 55%, about 3x the placebo rate. This result remains statistically significant using ITT analysis. Let's shift now to safety and tolerability. Slide 13 reports adverse events on a cumulative baselines from baseline through week 96. Starting at the top of the table. There were no deaths with EFX treatment, but one death prior to week 36 occurred in a placebo patient who developed pneumonia. There were 41 SAEs reported over the full 96 weeks of treatment. But shown in the row below, there were no SAEs that were determined to be drug-related by clinical investigators. Overall, these SAEs generally reflect the advanced disease status of these patients carrying multiple comorbidities. Moving down the table, we provided the total number of adverse events that lead to discontinuation over 96 weeks. We've also added 2 sub-rows to characterize the types of discontinuations that occurred from weeks 37 to 96. There were 2 discontinuations due to cirrhosis related clinical events. One 28-milligram patient experienced ascites and one 50-milligram patient experienced hepatic encephalopathy. As I mentioned earlier, these 2 events are associated with disease progression. There was only one additional discontinuation from week 37 to 96. This was a discontinuation due to diarrhea that occurred in the 50-milligram dose group. The bottom half of the table presents an overview of the drug-related adverse events on a cumulative basis from baseline through week 96. Consistent with previous evaluations of EFX, the most frequent adverse events were transient, mild to moderate diarrhea, and nausea Grade 1 or 2. On Slide 14, we provide an overview of additional safety parameters at week 96. Here again, we focus on the 50-milligram dose group, which is the dose being evaluated in our Phase III study in patients with compensated cirrhosis due to MASH relative to placebo. Based on nonclinical observation of impaired skeletal development, bone health is being monitored in all clinical studies with FGF21 analogs. 43% of 50-milligram and 41% of placebo patients had osteopenia at baseline, but only 3% of 50-milligram and 7% of placebo patients were being treated with bisphosphonates. Against this backdrop, bone mineral density adjusted for placebo declined to a small but significant extent, 5% for spine and hip regions over 96 weeks of treatment or 2% to 3% per year. For context, treatment with diabetic dose of GLP-1 was recently reported to be associated with about a 2% reduction in bone marrow density over 1 year. Importantly, after nearly 2 years of EFX treatment, there was an equal number of fractures in the 50-milligram and placebo groups. Overall, we consider these effects to be mild and manageable. And accordingly, we are monitoring for bone health at entry into our Phase III SYNCHRONY program and ensuring adherence to a consistent standard of care. There were no statistically significant changes observed for ECGs, heart rate or blood pressure for the 50-milligram group at week 96. Reductions of about 2% in body weight were observed for both the 50-milligram and placebo group. Markers of liver function and hemostasis, including bilirubin, MELD score, INR, platelet count, albumin, and Child-Pugh score remained stable or trended towards slight improvements for the 50-milligram group. I'll now turn the presentation over to our Chief Scientific Officer, Tim Rolph.

Thank you, Kitty, and good morning, everyone. As shown on Slide 15, the pattern of reductions in imaging and circulating biomarkers of fibrosis corroborate conventional pathology. Starting on the left, a significant reduction in ELF score of 50 milligrams relative to placebo was observed. Moving to the chart on the right, Again, for 50 milligrams, we see a statistically significant reduction in liver stiffness. The levels of reduction seen here for ELF and liver stiffness for the 50-milligram group has been associated with reduced progression to end-stage liver disease. Moving on. Slide 16 depicts time quarters of mean change from baseline for 2 markers of liver injury, ALT and AST. 50 milligrams of EFX consistently reduced levels of both ALT and AST through 96 weeks. Slide 17 depicts mean change from baseline in lipoproteins. Treatment with 50 milligrams showed a statistically significant reduction in triglyceride and in non-HDL cholesterol as well as a statistically significant increase in HDL cholesterol. LDL trended lower. Turning to parameters of whole body metabolic health among the SYMMETRY population, of which almost 80% were being treated for type 2 diabetes, including many receiving either insulin or insulin secretagogues. Slide 18 depicts mean change from baseline in markers of insulin sensitivity. Starting at left, we see statistically significant reductions in HOMA-IR of 4.1 for the 50-milligram group compared with an increase of 1.6for placebo. Treatment with 50 milligrams showed statistically significant reductions in serum levels of C-peptide, again, consistent with efruxifermin improving insulin sensitivity. Moving to the right-hand panel, circulating adiponectin not only indicates degree of insulin sensitivity, but also extensive activation by EFX of the FGF21 receptor, FGFR1c on adipose tissue. Although both 28 and 50-milligram doses significantly increased adiponectin at week 36, by week 96, only 50 milligrams showed a significant increase of 69% compared to 32% for 28 milligrams. The greater pharmacological response of 50 milligrams compared to 28 milligrams mirrors statistically significant reversal of cirrhosis, the larger reductions in markers of liver injury and fibrosis, and greater improvements in whole body metabolic health observed for 50 milligrams. Overall, this consistent pattern of differentiated dose response underlines the need for 50 milligrams of EFX to treat patients with compensated cirrhosis due to MASH. Finally, there was no meaningful change in hemoglobin A1c for 50 milligrams, which remained at its baseline level of 6.6 at week 96 compared to a slight increase from 6.8 to 7.0 for placebo. I will now hand over to Andrew, our CEO, to conclude the presentation.

Thank you, Tim. We are thrilled with the unprecedented level of cirrhosis reversal reported today. These results exceeded our expectations. As shown on Slide 19, we believe EFX stands apart as the first known compound to be associated with statistically significant reversal of cirrhosis in a placebo-controlled clinical trial. For patients with compensated cirrhosis due to MASH, these results offer hope that an effective treatment may soon be possible, pending the results of our Phase III studies and if EFX is approved. The trial design for our ongoing Phase III SYNCHRONY Outcome study in patients with compensated cirrhosis is shown on Slide 20. For all of the reasons mentioned by Tim and Kitty, we are only evaluating 50 milligrams of EFX against placebo in SYNCHRONY Outcomes. As shown here, there are 2 key endpoints for this study. All patients across 2 cohorts will be evaluated for clinical outcomes, which will be assessed as the time to first occurrence of protocol-specified clinical events. Cohort 1 also includes a primary histology endpoint, the proportion of patients who achieve at least a 1-stage improvement in fibrosis without worsening of MASH at week 96. The same time point evaluated in the SYMMETRY study. Before closing, I'd like to take a moment to extend our gratitude to all of the patients, investigators, and site staff participated in the SYMMETRY study, without whom, today's groundbreaking data would not have been possible. In totality, we believe today's results show unprecedented clinical activity for 50 milligrams of EFX with a favorable tolerability profile. Reversal of cirrhosis in less than 2 years as observed in SYMMETRY is reason for optimism about the future potential of EFX. I'd now like to turn things over to the operator for questions and answers. Thank you.

[Operator Instructions] Our first question comes from Michael Yee with Jefferies.

Congrats on this great data. We just wanted to ask, Andrew, maybe you could talk a little bit about the slide looking at new changes in fibrosis and sustained changes in fibrosis over 36 weeks and 96 weeks. Maybe talk to your conclusions around duration of efficacy and how you think about what's going on there and what would happen with longer efficacy, and talk to that also as it relates to the placebo because there were some people who were sustained and there were also some new ones there. And then maybe if you could take that and extrapolate that to the Phase III that you're running and maybe how many patients in the Phase III would be required for the primary endpoint because we'd love to see the data sooner rather than later.

Mike, thanks very much. So for that, I think we're thrilled in particular about that very slide that you called out because it really shows that longer dosing matters for this drug. And we saw that in the precirrhotic HARMONY study, which we released in Q1 '24. And again, with this drug, we see the same thing, that there is an equal growth in the number of responders that we're seeing the successes that are new after an additional 60 weeks. And I think you've really hit on a key point, that is longer dosing should continue to matter, that is that the fibrotic burden in cirrhotics is quite substantial. So I don't think that we've seen our maximal response yet. We've just seen the 2-year response, keeping in mind that our Phase III SYNCHRONY Outcome study is an event-driven study and may go on to anywhere from 3 to 5 years. So I think over time, we'll continue to see the benefit of the substantial efficacy. In terms of how we're going to adjust the study, I think these are really top line data, and we're still working through that now. So I don't have a very good answer for you right now. But thanks very much for your question.

Our next question comes from Eric Joseph with JPMorgan.

Let me add my congrats on the data and really impressive results. The -- really, the data here just in the significant level of cirrhosis reversal begs the question of whether an accelerated approval path in the F4 or the cirrhotic population is on the table. It's not really -- it's not currently considered within FDA guidance. To what extent have you engaged with FDA on the potential for an accelerated approval path in the F4 population, perhaps as it relates to SYNCHRONY Outcome trial? And then is there any potential here that actually the SYMMETRY results might be [ filable ]?

Eric, that's a really good question, especially given the huge unmet need for cirrhotics. So I would say, when you look back at the guidance, the guidance, really, as you outlined, focuses on clinical outcomes for cirrhotics. But when I read the first page of the guidance, it really highlights the fact that it begins with a sentences that states. Given the absence of any successful trials in histology, we have concluded and moved on. But now we're really challenging what we have a successful trial on histology. So I think we have breakthrough therapy designation, and we will work with the agency to review these data. But certainly, I'm unable to really make any comments about what that may come from that interaction. But certainly, we're hopeful given the effect size that we've seen here, both in completer as well as the intent-to-treat population that, that may be impactful with the division, but I think it's one of those stay tuned. But thanks very much.

Congrats again.

Our next question comes from Mike Ulz with Morgan Stanley.

Congratulations on the data as well. Maybe just a follow-up on one of the earlier questions just related to the ongoing Outcome study. Just wondering if you can maybe give us an update on the status of that study currently? And how does the data today impact the sort of enrollment? Do you expect a meaningful increase in the pace of enrollment here? And what does that mean for the timing of the Cohort 1 outcome?

Yes. So Mike, we announced in a press release last September that we enrolled our first patient. The sites that are up and running are primarily in the United States right now. We're really just getting the rest of the world going. We have Europe as well as Asia to bring on board still. So it's a slow process. But you can imagine with these kind of results, we've discussed these results with some of our investigators and the responses were uniformly positive. In fact, as Kitty and Tim nicely highlighted, these are the first results ever. And for investigators, it's a very, very compelling story, and we think that it can only help us as we roll these data out worldwide in terms of our impact on enrollment because it's very, very sought after to have these kind of results. So we're excited. And in terms of its impact on enrollment time, I think it's, again, a little bit of a TBD. But thank you for the question.

Makes sense. Congrats again.

We have time for one more question, which comes from Liisa Bayko of Evercore.

Congratulations on the transformational data. Mine is really a 3-part question. First of all, can you review the number of patients under care with cirrhosis in the U.S.? I've been fielding some questions on that. Also, I was wondering if you could talk about how your thinking may be evolving with respect to pricing of efruxifermin given this data in cirrhosis. Will you be coming at it from the cirrhosis angle or from the F2,F3 MASH angle, which may have -- as you can see from your mortality curve, has pretty significant implied benefit there. And then finally, any plans or thoughts about non-MASH cirrhosis and the potential for efruxifermin?

Thanks again, Liisa. It's pretty early out in California. So that one's -- I'll try to answer those that I can remember. I think going backwards, I think in terms of non-MASH cirrhosis, I think you've really hit on something that we're really thinking very actively about. That is that cirrhosis is a common pathway to unfortunately liver compromise, and yet it still has many on-ramps to get there. And we've just shown very compelling data in just one of those. It's due to MASH -- so I think as we think about other diseases that end up in cirrhosis, is something we're considering our optionality there. So thank you for raising that. The second question with regard to pricing. And of course, we're pretty far away. We're just starting enrolling our Phase III studies. We can't really give any meaningful details on pricing. But I would say that, as you can imagine, drugs that provide a mortality benefit often are priced differently than those that are priced for chronic diseases. And so I think you can imagine how it is, but we may look at this overall. And then in terms of the first one, which has something to do with the addressable market, that's a hard one for me. We don't really have a good handle on the number of people under care. We look at this as probably 2 million Americans having MASH cirrhosis. But in terms of the actual number of care, we don't have a good handle. I have seen some estimates somewhere in the 20% population. But again, that's a very rough estimate, it is where -- there's some degree of hearsay from that. So I wouldn't rely on that number.

That concludes our question-and-answer session. Thank you for your participation. You may now disconnect. Everyone, have a great day.