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

Thank you for standing by. Welcome to the Akero Reports Data for 16-Week Study in Cirrhotic NASH patients. I am now handing over to William White, Chief Financial Officer and Head of Corporate Development at Akero Therapeutics.

Thank you, and good afternoon. Joining me on the call are Andrew Cheng, President and CEO of Akero; Kitty Yale, Chief Development Officer; and Tim Rolph, Chief Scientific Officer. Today, we will be sharing 16-week results from the expansion cohort, known as Cohort C of our balanced Phase IIa clinical study of efruxifermin, or EFX, for the treatment of NASH. Before we begin, I'd like to remind you that various statements that we may make during the call will include forward-looking statements as defined under applicable securities laws. Forward-looking statements include those regarding implications of this analysis of Cohort C of the BALANCED study, our future plans, including our plans around the development of EFX, prospects and strategy, the potential impact of COVID-19, financial goals and guidance, product attributes and pipeline, drivers of growth and other statements that are not historical fact. 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 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 today and risk factors included in the company's filings with the Securities and Exchange Commission for a discussion of important factors 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 data from our Phase IIa BALANCED study, which is available on our website at akerotx.com.com under Press Releases in the Investor Relations section. We also prepared a presentation, which we will reference during our remarks. This presentation will be available on our website under Events and Presentations in the Investor Relations section of our website. I will now turn the call over to Andrew Cheng, Akero's President and CEO.

Thank you, Bill, and thanks to all who have joined today's webcast. Today marks an important new milestone for Akero Therapeutics. We reported exciting new data from an expansion cohort of our Phase IIa BALANCED study in NASH patients, or Cohort C, which evaluated efruxifermin, or EFX, in the treatment of cirrhotic NASH patients with compensated disease. Most importantly, we reported that 33% of EFX patients achieved fibrosis improvement without worsening of NASH, and 25% achieved NASH resolution, in each case, compared to 0% for placebo. These encouraging results paved the way for us to expand EFX development into cirrhotic NASH patients, a group with the highest unmet medical need. On Slide 3, we review the strong foundation on which today's results are based. That foundation begins with our molecule, which we believe represents Amgen's innovation and protein engineering, an Fc fusion protein designed based on their [ MREL ] scaffold. EFX incorporates a modified sequence of human FGF21 with 2-point mutations that prevent degradation, as a result, extending half-life to 3 to 4 days, which supports once-weekly dosing. Based on clinical observations as well as in vitro pharmacology, we believe EFX's unique engineering delivers balanced potency across FGF21's receptors comparable to native human FGF21. Last year, we reported results for EFX in patients with NASH and F1 through F3 fibrosis. As shown on the right-hand side of the slide, these data showed EFX's potential to address all core facets of NASH with improvements in histology, including both fibrosis improvement and NASH resolution as well as liver fat, health score and Pro-C3, ALT and AST, lipoproteins, hemoglobin A1c and weight loss. Most notable among these improvements was 2-stage reversal of fibrosis in 11 of 22, or 50% of F2 and F3 patients. This magnitude of resolution of fibrosis after only 16 weeks of treatment suggests 2 distinct pathways are involved in EFX's therapeutic action. One, a metabolic effect that reduces steatosis and dampen's hepatocyte stress, in effect, exerting an indirect antifibrotic effect; the other, a direct antifibrotic effect. Before we dive further into the data, it's important to underscore that cirrhotic patients represent a distinct patient population, separate from the F2 and F3 population that is projected to be 11 million in 2030. As shown on Slide 4, FDA has issued draft guidance specific to F4 patients, a population projected to be 3.5 million Americans by 2030. As explained by FDA in its guidance, the treatment goals for cirrhotic patients differ from patients with less advanced fibrosis. The goals of treatment for compensated NASH cirrhosis are to halt or slow progression of fibrosis, prevent clinical decompensation and reduce the need for liver transplantation and improve survival. Slide 5 illustrates the poor prognosis of cirrhotic patients and shows why reversing fibrosis and improving survival should be the main objective for this patient population. Fibrosis stage, but no other histologic features, has been associated independently with increased mortality, transplantation and liver-related events. The Kaplan-Meier plot on the right demonstrates how liver-related mortality increases dramatically from F3 to F4 fibrosis, with approximately 60% of F4 patients dying within 5 years, absent the liver transplant. This means the risk of liver failure in hepatocellular carcinoma as well as the need for liver transplantation is substantially higher for cirrhotic patients. Slide 6 highlights data presented by Dr. Arun Sanyal at AASLD 2020, showing that reversal cirrhosis was associated with greatly improved clinical outcomes for NASH patients. The charts represent pooled analysis of Gilead studies with selonsertib and simtuzumab in patients with F4 cirrhotic NASH. The incidence of liver-related clinical events for the pool of patients, whether treated or placebo, with cirrhosis shown in the green bars, was compared with that with the pool of patients who remained cirrhotic, shown in the red bars. This analysis illustrates a reduction of greater than 80% in risk of liver-related clinical events associated with reversal of cirrhosis, emphasizing the medical need and benefit to be gained. As illustrated on Slide 7, there have been several attempts to be the first investigational product to show success in cirrhotic NASH patients. Here, we show each of the investigational products that have been evaluated as a single agent in cirrhotic NASH patients for which fibrosis improvement or fibrosis improvement without worsening of NASH have been publicly reported. Unfortunately, none have succeeded, even when dosed for 1 to 2 years. I'll turn the presentation over to our Chief Development Officer, Kitty Yale, to explain why our confidence at EFX's potential for treating chronic cirrhotic patients is high.

Thank you, Andrew, and good afternoon, everyone. I'm pleased to report our end-of-treatment results from Cohort C, the extension to our Phase IIa BALANCED study in patients with compensated cirrhosis fibrosis stage IV. Before sharing the results, I'd like to review the study design for Cohort C, which is shown on Slide 8. The study was a randomized, double-blind, placebo-controlled study. All patients had biopsy-confirmed NASH F4, as read by a local pathologist. The study enrolled 30 patients in a 2:1 randomization, with 20 patients in the EFX 50-milligram arm and 10 patients in placebo. Patients were randomized to receive once-weekly subcutaneous doses of EFX or placebo for 16 weeks. The primary endpoint of the study was to assess safety and tolerability of EFX in NASH patients at the greatest risk of progressing to end-stage liver disease. The study was originally designed to have noninvasive efficacy endpoints, specifically liver stiffness by transient elastography using fibroscan and serum markers of fibrosis, Pro-C3 and ELF. However, the protocol was subsequently amended after requests from patients and investigators to add end of treatment-bought biopsies at week 16. These biopsies were patient-optional as the amendment was implemented after patients had already consented to the study. Today, we report top line data on a combination of efficacy and safety endpoints. On Slide 9, we review the baseline demographic which are consistent with what have been reported in other cirrhotic NASH clinical studies and are generally representative of F4 patients. Half of the patients had diabetes. Mean AST and ALT values are in the low 30s, consistent with Stage IV fibrosis. Health and Pro C levels -- sorry, Pro-C3 levels are higher than seen in the BALANCED main study, again, consistent with higher levels of fibrosis. Liver stiffness values, again, are consistent with the cirrhotic population. Mean triglyceride levels are substantially lower than seen in the F1 to F3 patients in the BALANCED main study, as expected, because of diminished hepatocyte population in livers of patients with cirrhosis. Patient disposition is shown on Slide 10. 30 patients were randomized and dosed. 27 of 30 patient biopsies were confirmed to be F4 by the central reader. The 3 other patients were not included in the histology analysis set. 2 patients discontinued prior to week 16: 1 placebo patient who withdrew consent and 1 EFX patient due to adverse events. 8 patients did not consent to end-of-treatment biopsy. End-of-treatment biopsies were obtained for 17 confirmed F4 patients: 5 on placebo and 11 on EFX. Slide 11 summarizes the percentage of patients with fibrosis improvement of 1 stage without worsening of NASH. Fibrosis improvement without worsening of NASH was achieved in 33% of the EFX arm compared to 0% in the placebo group, an impressive level of response, particularly given the short study duration of just 16 weeks. While not powered to assess the statistical significance of histological endpoints, we are not aware of any other reported results showing this level of fibrosis improvement in patients with compensated cirrhosis. As Andrew described previously, a 1-stage improvement in fibrosis could be expected to translate into a greater-than-80% reduction in the relative risk of liver-related clinical events. On Slide 12, we report multiple noninvasive markers of fibrosis, which provide support for the histological fibrosis improvement seen with EFX. The chart on the left reports change from baseline and liver stiffness, measured by transient elastography. Here, we see absolute reduction of 5.7 kilopascals for EFX compared to a reduction of 1.9 kilopascals for placebo. This is approximately a 26% reduction with EFX, a magnitude that has previously been correlated with the 1-stage improvement in fibrosis. The middle chart reports baseline -- change from baseline for a serum biomarker of new collagen synthesis in the liver, Pro-C3. Here, we see a statistically significant absolute reduction of 9 micrograms per liter for EFX compared to 3.4 for placebo, approximately a 35% reduction with EFX. The absolute reduction observed for EFX is greater than the reported magnitude of Pro-C3 reduction quoted in the literature as correlating with 1-stage improvement in fibrosis. The right chart reports change from baseline and enhanced liver fibrosis or ELF score, a noninvasive test derived from an algorithm based on 3 serum biomarkers of fibrosis. Elevated serum levels of these analytes represent increased turnover of the extracellular matrix and have been shown to correlate with various stages of liver fibrosis and cirrhosis. Here, we see a statistically significant reduction of 0.4 for EFX compared to a 0.3 increase for placebo. The magnitude of improvement of serum biomarkers of fibrosis in this F4 cohort is comparable to what is observed in the F1 to F3 population and the main portion of the BALANCED study and confirms the potential for reproducible and robust effects of EFX on fibrosis. Slide 13 shows our other histological endpoint, NASH resolution, which was achieved in 25% of EFX patients compared to 0% in the placebo group. To note, there was no overlap between patients achieving fibrosis improvement and NASH resolution. So as a result, a total of 7 out of 12 EFX patients in the biopsy analysis set, or 58%, met either fibrosis improvement or NASH resolution. We believe that reducing steatohepatitis, as indicated by NASH resolution should ultimately, in time, lead to reversal of fibrosis. On Slide 14, we report changes to the markers of liver injury, both ALT and AST. As highlighted earlier, patients in Cohort C had lower liver enzymes at baseline, a mean of 32 and 30 for ALT and AST, respectively, consistent with the smaller hepatocyte population in livers of patients with cirrhosis. For reference, baseline ALP range from 51 to 63 and AST ranged from 35 to 45 amongst F1 to F3 patients in the mean portion of the BALANCED study. The left chart reports change from baseline and ALT. And here, we see a statistically significant absolute reduction of 10 units for EFX compared to 1.3 for placebo, approximately a 30% reduction. The right chart reports change from baseline and AST. Here again, we see a statistically significant absolute reduction of 9.6 units for EFX compared to 4.5 for placebo, again, approximately a 30% reduction. Let's shift now to safety and tolerability, beginning with a high-level overview on Slide 15. In terms of discontinuations, 1 placebo patient withdrew consent and 1 patient in the EFX arm discontinued due to adverse events. This patient experienced abdominal distension, constipation, diarrhea and pruritis, discontinuing treatment at week 5. 1 patient in the placebo arm reported a serious adverse event of pulmonary embolism. Slide 16 provides an overview of the most frequently reported drug-related treatment-emergent adverse events. The most frequent events were transient, mild to moderate diarrhea and nausea, which often resolved on study without treatment. All of the injection site reactions were Grade 1. And there were no reports of tremor. I'll now have our Chief Scientific Officer; Timothy Rolph, present our lipoprotein and glycemic control data.

Thank you, Kitty, and good afternoon, everyone. By way of context, for Slide 17, more than 80% of NASH patients are dyslipidemic with elevated levels of triglycerides in LDL-cholesterol and low levels of HDL cholesterol. Dyslipidemia is a major contributor to the high incidence of cardiovascular morbidity and mortality amongst NASH patients. As with the BALANCED main study, clinically meaningful improvements in lipoprotein profile are evident following 16 weeks of treatment with EFX. Starting on the left, levels of triglyceride were reduced 29% by comparison to an increase of 1% for placebo. This reduction in triglyceride is not as large as it was observed in prior EFX trials. However, mean levels at baseline were 135 mgs per deciliter, considerably lower than the corresponding value of approximately 180 mgs per deciliter in the BALANCED main study. Moving to the right, LDL-cholesterol was reduced significantly by 80% compared with a 16% increase for placebo. The next chart shows a substantial increase in HDL of 33% compared with 3% for placebo, in line with prior studies, the effects in NASH and type-2 diabetes patients. The final chart shows change from baseline in non-HDL cholesterol. Because EFX reduces cholesterol primarily by decreasing the LDL with a smaller effect on LDL, the potential of EFX to lower bad cholesterol is best captured by change in non-HDL cholesterol. Like LDL cholesterol, non-HDL cholesterol is a cause of risk factor for cardiovascular disease. Levels of non-HDL cholesterol were reduced significantly by 14% compared with a 12% increase for placebo. To put Slide 18 in context, approximately half of F4 NASH patients have type-2 diabetes. Generally, their diabetes is not well controlled, so improving their glycemic control was highly desirable. As seen here, EFX solicited clinically meaningful improvements in multiple markers of glycemic control, which we believe can be attributed to incident sensitization. Starting from the left, hemoglobin A1c is a clinical diagnostic for long-term control of the [ diabetes ]. Hemoglobin A1c was reduced significantly by 0.4% absolute after 16 weeks treatment compared with an increase of 0.1% for placebo, an improvement consistent with that observed in the BALANCED main study. The next chart shows change in baseline in adiponectin, generally accepted as a biomarker of insulin sensitivity. Here, we see a highly significant mean increase of 95% for efruxifermin-treated patients compared with an increase of 4% for placebo, again, comparable to the BALANCED main study. The next histogram shows change from baseline in C-peptide, the best indicator of insulin secretion. A significant reduction of 20% was observed for treated patients, indicating lower rates of insulin secretion. This contrasts with a smaller decrease of 7% for placebo. Achieving beta glycemic control by improving insulin sensitization is highly desirable because it's rectifying the fundamental driver of type 2 diabetes that is insulin resistance. This means EFX has a potential to achieve a sustained reduction in hemoglobin A1c in contrast to diabetes therapies, which permit insulin secretion, whose efficacy wanes over time. Improved glycemic control and restoration of a healthy lipoprotein profile have now been observed in 3 independent studies with efruxifermin. Amgen's original Phase I study in type 2 diabetes, BALANCED main study in F1, F3 NASH, and now, Cohort C in F4 NASH, underscoring the reproducibility of these beneficial effects. The final chart shows body weight change after 16 weeks treatment. As observed in the BALANCED main study, there was a trend to lose weight, approximately 4 to 5 pounds, while the placebo group trended up by about 2 pounds. This consistent trend toward weight loss contrasts with another class of insulin sensitized, the PPAR-gamma agonists. This class includes established antidiabetic drugs like pioglitazone, whose uses declined substantially because of weight gain and edema. And lanifibranor, for which encouraging efficacy results in NASH nonetheless associated with weight gain of about 5 to 6 pounds and an incidence of 6% to 8% edema. We continue to view the trend toward weight loss observed with EFX as a key element of differentiation, with the potential for weight loss likely to be attractive to NASH patients and clinicians. These very encouraging metabolic data should be viewed holistically rather than in isolation. We believe these results support the potential for EFX to rectify each aspect of the metabolic dysfunction associated with NASH. As seen in the BALANCED main study, it has improved glycemic control by enhancing insulin sensitivity, restore the healthy lipoprotein profile and helped lower body weight. Last summer, we said that these broadly based improvements increased our confidence that the rapid reduction of steatohepatitis and collagen deposition seen in BALANCED would be sustained, in turn, allowing further resolution of fibrosis beyond the highly encouraging improvements evident after just 16 weeks of treatment. The magnitude of the metabolic improvements also points to the potential of EFX to reduce the high incidence of heart attack and stroke among NASH patients. Today's results strengthen our confidence. The breadth of desirable effects elicited by EFX, sets it apart from other candidates in development for NASH, which frequently trade off resolution of liver pathology against undesirable effects on lipoproteins, increased body weight and no improvement in glycemic control. By restoring a healthy metabolic profile to the whole body, EFX appears to reduce the excessive metabolic load on the liver of patients with NASH. The results are consistent with our predictions based on FGF21 biology and efruxifermin's engineering. Nevertheless, these results again exceeded our expectations and support further development for this population. On Slide 19, we show EFX's potential to reverse fibrosis without worsening NASH by comparison with results of prior studies, which Andrew summarized earlier. Acknowledging these are not head-to-head comparisons and employ different studies and designs, albeit with comparable F4 patient populations. The improvement in fibrosis observed in 33% of treated patients after only 16 weeks of treatment with EFX is double the highest response reported for any other single development candidate and twice the highest response for placebo when all of these compounds were dosed for a period of roughly 1 to 2 years. On Slide 20, we offer an interpretation of these exciting results. We know it's possible to reverse fibrosis by reducing or eliminating the underlying pathogenic drivers of steotosis and hepatocyte stress. This allows the hepatocyte population at liver to regenerate. But this takes time, a commodity in short supply for F4 patients. We believe it certainly takes longer than 16 weeks because fibrosis is so extensive in cirrhotic liver. As highlighted earlier, our BALANCED data suggests that EFX reserves both direct and indirect antifibrotic effects. Today's results, we believe, provide further evidence of EFX's direct antifibrotic effects, as suggested by the preclinical literature on FGF21. We believe the critical question in NASH development is whether a compound has the potential to act directly or merely indirectly to reverse fibrosis. And we believe today's results provide the strongest dividends yet of EFX's directly antifibrotic properties. The reversal of fibrosis by 1 stage in 33% of cirrhotic patients and 2-stage improvement of fibrosis in F2/F3 patients, in each case, after only 16 weeks of treatment, likely reflects direct anti-fibrotic activity. There likely isn't enough time for acting only on underlying disease drivers to yield these kinds of results in 16 weeks. Recall that most early NASH studies were 18 months or longer because it was believed it would take that long to see whether there was a discernible impact on fibrosis. When one thinks about the roughly 60% 5-year mortality rate for cirrhotic patients, Andrew presented earlier, it's easy to see how fibrosis reversal is especially advantageous for cirrhotic patients. There remains an important role for indirect anti-fibrotic activity. Addressing underlying NASH disease drivers may indirectly contribute to fibrosis reversal of F1 to F3 patients who have longer time for their liver to regenerate. And most importantly, redress of the underlying NASH disease drivers is necessary to sustain fibrosis reversal across all stages of fibrosis, whether F1 through to F4. That's why we believe EFX has so much potential. From what we have seen in our clinical trials to date, we believe EFX may offer the complete package. It has addressed the underlying disease drivers by reducing liver fat and hepatocyte stress, which can help reverse fibrosis over time and preserve fibrosis reversal. EFX also appears to have the horsepower to reverse fibrosis by acting directly to reduce inflammation and collagen synthesis. I'll now hand the presentation back to Andrew.

Thank you, Tim. Let me conclude with a critical review of where we are in EFX development with Slide 21. On the left-hand side of the table, we provide an overview of our Phase IIa program consisting of the BALANCED main study in F1 to F3 patients and Cohort C in F4 patients. The right-hand side of the table shows what we plan to undertake in 2 Phase IIb studies in parallel in 2 distinct NASH populations, F2 and 3, and F4. Earlier this year, we announced initiation of our Phase IIb HARMONY study in F2/F3 patients. That study is evaluating the 28- and 50-milligram doses for a 24-week treatment period. We expect to report HARMONY results in the second half of 2022. We are still in the process of designing our planned Phase IIb F4 SYMMETRY trial. Subject to review by regulatory authorities, we plan to initiate SYMMETRY in the second half of 2021. Details of the SYMMETRY trial design will be reported later this year. We look forward to working with the FDA and EMA to further our development program, and ultimately, if approved, to making an exciting new treatment available to patients. Finally, let me take a moment to extend a heartfelt thank you to all of the patients, investigators and study site staff who participated in the BALANCED study. So that exciting data will not have been possible were it not for our patients, many of whom completed clinic visits and study procedures despite the ongoing COVID-19 pandemic. And the dedication of our investigators and their teams, all of whom who worked tirelessly to serve their patients despite the challenges of the global pandemic. We are truly grateful for their commitment during these difficult times. I'd now like to turn things over to the operator for questions and answers. Thank you.

[Operator Instructions] First question comes from Eric Joseph with JPMorgan.

Congrats on the data. We have a couple. First, with respect to the data on NASH resolution, can you comment a bit on sort of average NASH scores that were observed at baseline in the 2 arms and how they trended over the treatment period? Secondly, were there any notable baseline patterns among EFX-treated patients who didn't see a 1-stage reversal of that fibrosis? Did perhaps gender play a role? And would you anticipate a greater proportion of subjects achieving that threshold with longer time on drug based on some of the noninvasive analysis and biomarker analysis conducted? And just thirdly, as a market sizing question. Of that 3.5 million projected estimate of cirrhotic patients or cirrhotic NASH subjects, what proportion is reflected by a patient eligibility criteria for C? Would you anticipate a similar risk -- benefit risk profile in subjects with somewhat more advanced disease, perhaps those with portal hypertension or various [ CL lesions ]?

Thank you, Eric. 3 questions are tricky. So let me just start with the last one, if I remember that -- that's easiest for me to remember. So I think in terms of the entry criteria, we developed them pretty broadly with -- so they would be generalizable to patients with Child-Pugh Class A compensated cirrhosis. So for patients with more advanced disease, I think we haven't studied them, so we'll have to wait until we get more data as we look to future studies. And we may expand our entry criteria to address those. And when you think about the 3.5 million in 2030, difficult to see how people will break down in terms of Child-Pugh A, B and C, as one thinks about that overall. In terms of your other first 2 questions, they're pretty specific. I would say that the -- we're at a top line data phase, and we haven't been able to provide -- generate those data that would answer your question at this time.

Okay, great. Well, congrats again.

Our next question is from Matthew Harrison with Morgan Stanley.

Thanks for all the detail. I guess 2 from me. So first one, Andrew, would you expect -- and I know you sort of answered this on the last question. But when we think about F4 patients versus other patients who aren't as severe, would you expect to continue to see a greater benefit over time in these patients? Or is there anything specific to the patient characteristics that you wouldn't expect to see that same trend that you've seen in earlier line patients? And then, I guess, the second question is just really about how you think about -- I guess what I should ask is, what do you think might be the regulatory hurdle here for an F4 population, just given that -- and no one else has tried to pursue that. And I realize it's under review and you're discussing it still, but just broadly what are your thoughts on what the regulatory hurdle might be?

Thank you, Matthew. So let me do the first one, and I'll ask Kitty to do the regulatory one. So overall, I would say that when we think about these patients, we obviously have the 4 patients that had a 1-stage improvement of fibrosis already. But then when we begin to look at the patients that had NASH resolution, those are the types of patients we begin to see that -- where there's both an indirect and direct component playing a role there. And so those who are beginning to resolve their inflammation and ballooning, we feel are on their way towards improvements in fibrosis. So as we begin to think of the 7 of the 12 patients who had 1 form of histologic improvement or the other, it gives us a little bit of a preview for what we could see down the road with longer-term dosing, recognizing that 16 weeks is incredibly short. So we think that what we're seeing here really is the floor of what we can achieve, not the ceiling. So we're looking forward to demonstrating that in future studies. But let me turn it over to Kitty now to think -- to comment on the regulatory pathway.

So I'm sure you're aware that the current regulatory guidelines for compensated cirrhotic patients are looking for endpoints in terms of clinical outcomes versus histologic. And when you read that particular guidance document, the draft guidance, it's very clear that the FDA, perhaps based on the lack of positive data in cirrhotic patients, are really concerned that maybe fibrosis reversal is not possible in this patient population. And so I think with all regulatory guidance, new data will help influence the regulators. And so I think it's really up to us now to share our data and then to really sort of discuss with the regulators the best way for us to move EFX forward. I think we would still look at a combination of histologic and clinical outcomes in any F4 patient study that we would do because based on the data Andrew presented earlier today, there really is clear benefit in terms of clinical outcomes by regressing fibrosis by a stage.

Our next question comes from Maneka Mirchandaney from Evercore.

Great. Congrats on the update. Just had 2 questions from our end. The first is, as you think about histology here, were there any meaningful differences in benefits in the noninvasive metrics between patients who elected to do a post-treatment biopsy and those who didn't? And then I just wanted to follow-up on the previous question. Did you look at the time course of benefit for some of the noninvasive markers of fibrosis, especially as we think about extrapolating benefit to a longer study? And what do you kind of see there?

So let me ask Kitty to answer your question about how consistent the response was in the noninvasive measures, recognizing that we didn't get biopsies in everyone.

Okay. Yes. The results were pretty consistent across the board for patients that had both histology and end-of-treatment biopsies and those that did not. We haven't done a full correlation of each individual patient. But basically, on looking at the data, there's really nothing distinct that I can really see about the patients that had biopsies versus not. And then maybe in regard to your second question, we do have data that will show the response over time. We don't have that data to present currently right now, and that's something we will present at future upcoming scientific conference.

And we have time for just one more question. Question from Ed Arce with H.C. Wainwright.

This is Thomas Yip asking a couple of questions for Ed. I also want to say congratulations on the great results in these patients. So perhaps switching gear to adverse events and that single patient who discontinued the study. Would you say earlier on in the study or later in the study, over 16 weeks? And also, second question. Is there an expansion study for patients who completed treatment in this Cohort C?

Tom, this is Andrew. So I would say for the second question, we do not have an extension goal for this study in patients who completed Cohort C. At the time we designed this, we only had coverage for 16 weeks of tox. So we had to stop the study at that time. And then maybe I'll ask Kitty to talk a little bit about -- at a high level, about when this patient discontinued.

So this patient actually discontinued at week 5. So had 4 previous doses of EFX before they discontinued. So they completed the first month of treatment.

Okay. And also, in general, the adverse events that you mentioned as generally mild. Are they general -- early in the study or later in the study?

Yes. In general, yes, the GI adverse events were mild to moderate, and so transient or intermittent in nature. It is in testing. When I was asking some of the investigators to describe the diarrhea, I mean what I basically heard them really describe it as sort of nonurgent. So it's not like these patients are running to the bathroom, and therefore, really not affecting day-to-day activities, and more so of the frequency of loose stools.

Okay. Understood. Thank you so much for the details and congratulations again.

Thank you, Thomas. I think operator, we're sort of out of time.

We have one more question available from Michael Yee from Jefferies.

Yes, I'm not sure what's going on there. Maybe actually, if I take a step back, you sort of talked about it, but my question was around the idea that you had a number of people who had a fibrosis improvement and a number of people who had a NASH resolution improvement, but neither overlapped. Was your view that actually the NASH resolution people eventually would become a fibrosis improvement if there just is more time. And so the learnings here are that F4 patients is a little bit different than F2, 3, and just with more time, these results could actually get a lot better, is that sort of the thinking? And then tie that together with the learnings overall about this drug. Is your view that this drug ultimately should have similar fibrosis improvements, 40% to 50-plus- percent in both populations?

Mike, it's Andrew. So I would say the first part of the question is yes. I think it's important to recognize that there is some heterogeneity when it comes to the amount of steatosis in some of these F4 patients. Some have more, some have less. And those who -- that have less, it's a little more difficult for one thinks about the indirect pathway where people are getting reductions in steatosis leading to improvements in hepatocyte stress, and then ultimately, improvements of fibrosis. So we think for those patients that have NASH resolution, they are likely to lead to fibrosis improvements. But not all of the patients have enough fat, liver fat remaining because it's been replaced by fibrous tissue to benefit from that pathway. So -- and then in terms of longer-term dosing, we see this compound having the potential to be -- have high levels of histologic improvement or when it comes to 1-stage improvement of fibrosis. So I think we agree with you.

Thank you. And this concludes our conference for today. Thank you for your participation. Ladies and gentlemen, have a good night. You may now disconnect.