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

Welcome to the conference for Akero Therapeutics Reports Biopsy Data and Safety/Tolerability for 16-week Phase IIa BALANCED Study in NASH Patients. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to Bill White, Chief Financial Officer. Please go ahead.

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 main study portion of our ongoing BALANCED Phase IIa clinical study of efruxifermin or EFX, formerly known as AKR-001, for the treatment of NASH. Before we begin, I'd like to remind you that various statements that we may make during this call will include forward-looking statements as defined under applicable securities laws. Forward-looking statements include those regarding implications of this analysis 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 under Press Releases in the Investor Relations section. We also posted a presentation, which we will reference during our remarks. This presentation is also available on our website under Events & 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, I'm extremely proud to announce exciting new data from our Phase IIa BALANCED study in NASH patients. We believe the data, which exceeded our expectations, point to the potential for EFX to be a foundational monotherapy for the treatment of NASH. Roughly half of all treatment responders who at end-of-treatment biopsy had fibrosis improvement of at least one stage without worsening of NAS, and roughly half had NAS resolution without worsening of fibrosis. We believe these results put EFX at the forefront of the NASH field, and that's just after 16 weeks of treatment. On Slide 4, we summarize key results, which include substantial improvements in multiple measures of liver health as assessed through liver biopsy. In addition, 2 individual Phase III histology components, 28% of all biopsied EFX patients at least -- achieved at least a 2-stage improvement in fibrosis, and 28% of all biopsied EFX patients achieved a combination of both fibrosis improvement of at least one stage and NASH resolution. As Kitty will explain, the highest numerical results were observed for the 50-milligram dose. This includes 62% of 50-milligram patients achieving at least a 1-stage improvement of fibrosis without worsening of NAS and 38% achieving at least a 2-stage improvement of fibrosis. In addition, 54% of 50-milligram patients achieved NASH resolution without worsening of fibrosis. EFX was generally reported to be well tolerated. Importantly, there were no discontinuations due to adverse events in the 50-milligram dose group, where we observed the highest response rate. Across EFX groups, the most frequent adverse events were grade 1 or 2 gastrointestinal events, which were transient in nature. There were no discontinuations due to the most common adverse event of diarrhea. There were no treatment-related effects on blood pressure, heart rate or bone mineral density. The BALANCED study results underscore EFX's potential to address multiple important NASH comorbidities. Clinically meaningful improvements in glycemic control were observed, including significant reductions in hemoglobin A1c in both the 50- and 70-milligram dose groups. Mean weight loss was reported in all EFX groups, with significant reductions for the 70-milligram group. And consistent with results from the prior multiple ascending dose study, we observed that EFX improved dyslipidemia, including significant decreases in triglycerides, non-HDL cholesterol and significant increases in HDL cholesterol across all groups. There were no increases in LDL for the EFX dose groups, an important consideration given the recent cardiovascular -- increased cardiovascular risk that NASH patients face. We therefore believe, if approved, EFX has the potential to be a foundational monotherapy for the treatment of NASH and a potentially leading treatment to patients. I'll now have our Chief Development Officer, Kitty Yale, present today's new data.

Thank you, Andrew, and good afternoon, everybody. I'm pleased to report our end-of-treatment results for the BALANCED study. Before diving into the study results, I'd like to review the design of the main BALANCED study, which is shown on Slide 5. The study was a randomized, double-blind, placebo-controlled study. All patients had biopsy-confirmed NASH F1 through F3 and a NAFLD activity score of at least 4, baseline liver fat of at least 10% based on MRI-PDFF. The study enrolled 80 patients, with approximately 20 patients in each treatment group. Patients were randomized to receive once-weekly subcutaneous doses of either 28, 50 or 70 milligrams of EFX or placebo for 16 weeks. At week 12, patients who achieved at least a 30% relative reduction in liver fat were considered responders and became eligible for end-of-treatment biopsies. As previously reported, a total of 50 patients met this responder definition. We were able to collect biopsies for 42 or 84% of these patients despite the ongoing COVID-19 pandemic. Today, we report exploratory efficacy end points, including histology and overall safety and tolerability. On Slide 6, we review the baseline demographics, which are consistent with what has been reported in other NASH clinical studies and generally representative of the NASH population. Mean liver fat content ranged from 18% to 21%, and roughly 62% to 65% of patients were fibrosis F2 or 3. On the bottom of the slide, we define the analysis sets that will be referenced in today's presentation. All of the week 12 primary and secondary end points were reported on using the full analysis set, all 80 patients who were randomized into the study. Today's results are based on 3 additional analysis sets. The safety set includes 79 patients who received at least one dose of study drug. The MRI evaluable set includes 64 patients -- 68 patients, sorry, who have both baseline and week 12 MRI results. Finally, the liver biopsy evaluable set, which includes 42 patients who have baseline and end-of-treatment liver biopsy results. On the left of Slide 7, we recap the results of the primary end point of absolute reduction in liver fat and the secondary end point of relative reduction in liver fat, both of which were met and we previously reported in March. We're not aware of any other reported results of liver fat reduction in a placebo study in NASH patients with greater than 70% relative reduction in liver fat, as was attained for the 50- and 70-milligram EFX group. And what does a 70% reduction mean? It means some patients have very large reductions in liver fat as is illustrated by this patient, whose absolute liver fat content went from 22% to 2% in just 12 weeks and thereby normalizing liver fat. Additional analysis of the results for absolute and relative reductions in liver fat were consistent across several preplanned stratifications. There was no difference in the results based on type 2 diabetes status, amount of baseline liver fat and whether the patient was fibrosis stage F1 versus F2/3, underscoring the consistency of effect on liver fat. On the right, we report the results for a proportion of patients in each dose group who met the responder definition of achieving at least a 30% relative reduction in liver fat at week 12. The response rate here is shown as a prespecified exploratory analysis of response rate based on the MRI-PDFF evaluable analysis set. And this includes only patients who had week 12 MRI results and excludes any discontinuations or missing data. Here, we see that the response rate was 100% for EFX patients compared to 10% for placebo. Consequently, the responder base design did not lead to any enrichment for EFX responders in the biopsy population. As we'll see in a moment, the design did have an enrichment effect for placebo responders. On Slide 8, we provide additional detail regarding reduction in ALT, a validated marker of liver damage. And we extend the analysis to 20 weeks compared to the 12-week cutoff reported in March. On the left, we see that the reductions in ALT were both rapid and sustained, with each of the EFX doses achieving at least a 40% mean reduction by week 8 and maintaining these levels through the remainder of the study. Statistically significant dose-related improvements were also observed for 3 additional markers of liver injury: AST, GGT and alkaline phosphatase. On the right, we report change from baseline for the serum biomarker of new collagen synthesis, Pro-C3. Pro-C3 is an important marker because similar to MRI-PDFF, it provides a view of what's happening throughout the entire liver. And here, we see statistically significant reductions of 27% to 34% across the EFX groups compared with a 4% increase in Pro-C3 for placebo. A clear signal emerges from the totality of the noninvasive data, whether we look at liver fat reduction as measured by MRI-PDFF, markers of liver injury or Pro-C3. We see consistent robust effects across all EFX dose groups relative to placebo, demonstrating the therapeutic potential of all 3 doses evaluated. It appears that each of the EFX doses are performing at or near to the maximum of the dose response curve. Turning now to the histology results on Slide 9. We present our secondary histology end point: NAS reduction of greater than or equal to 2 points with no worsening of fibrosis, the FDA-recommended histology end point for shorter treatment duration Phase II studies. On the left, we see impressive response rates of 2-point NAS reduction across all EFX arms. But first, let's focus on the placebo response rate. As a reminder, any patient with at least a 30% reduction in liver fat were designated responders and eligible for an end-of-treatment liver biopsy. As such, only 2 placebo patients met this definition, while the remaining 19 were nonresponders. We believe this enriched the biopsy -- sorry, this enriched the placebo biopsy analysis set, allowing a single patient to achieve a 50% response rate. Notably, this one patient had an 11% or 25-pound reduction in body weight over 16 weeks. With this in mind, a 2-point reduction in NAS without worsening of fibrosis was observed for a combined 31 patients in the all-EFX group, representing a 78% response rate. And we see a very consistent dose effect with 77% to 79% response rate across all doses. On the right, we report mean change from baseline and NAFLD activity score. Here again, we see substantial reductions for all EFX arms, with 2.9- to 3.6-point reduction for the EFX groups compared with an enriched 2.5-point reduction for placebo. Again, very consistent improvements in NAS across all 3 EFX doses. Slide 10 shows the percentage of patients with NASH resolution with no worsening of fibrosis. This is the first of 2 histology end points defined by both the FDA and EMA for use in Phase III registrational trials. We see high levels of NASH resolution across all arms. NASH resolution without worsening of fibrosis was observed for a combined 19 patients in the all-EFX group, representing a 48% response rate, with consistent responses of 43% to 54% in the dose groups. Again, a single placebo patient achieved the end point to yield a 50% placebo response rate. As shown on the right, we followed best practices for biopsy analysis to minimize reader variability. Slide 11 on the left summarizes the percent of patients with fibrosis improvement of greater than or equal to 1 without worsening of NAS, which is the second defined NASH histology end point for use in Phase III registrational trials, again using the biopsy analysis set. Fibrosis improvement without worsening of NAS was 48% for the all-EFX group compared to 0% in the placebo group, an impressive level of response, particularly given the short study treatment duration of just 16 weeks. Looking at the group separately, 46% improved at 28 milligrams, 62% at 50 and 36% at 70. As shown on the right, an impressive 28% of patients or 11 out of 40 had at least a 2-stage improvement in fibrosis. Slide 12 shows the percentage of patients with a combination of both NAS, NASH resolution and fibrosis improvement. Here again, we see encouraging numbers of responders with 28% in the all-EFX group, 31% at 28 milligrams, 39% at 50 and 14% at 70 milligrams compared to 0% in the placebo group. As Andrew mentioned, these results exceeded our expectations for these exploratory end points. When we combine our histologic outcomes with the highly consistent reductions in liver fat, markers of liver injury and Pro-C3 across all doses, it is clear that EFX delivered rapid and meaningful clinical activity. We believe that larger and longer-term studies should continue to yield impressive histological outcomes. Let's shift now to safety and tolerability, beginning with a high-level overview on Slide 13. There were no deaths in this study. In terms of patients who had treatment-emergent adverse events that led to discontinuation, one patient discontinued in the placebo arm, 2 at 28 milligrams, 0 at 50 and 4 at 70. One of the discontinuations in the 70-milligram group was not drug-related. Nausea and vomiting were the only event that led to discontinuation in more than one patient. One patient in the 28-milligram arm discontinued for panic attack and anxiety-linked tremor. This patient had an extensive and complex past medical and psychiatric history, including recurrent panic attacks, persistent anxiety, fibromyalgia and restless leg syndrome in addition to NASH. Concomitant medications included both Cymbalta and Neurontin, both of which have been associated with tremor. Looking at SAEs. One patient in the 28-milligram arm reported a post-liver biopsy complication prior to study drug initiation. And one patient in the 70-milligram arm experienced acute pancreatitis with subsequent diabetic ketoacidosis, which led to study drug discontinuation. This patient entered the study with morbid obesity, severe insulin resistance and hyperinsulinemia. The incidence rate of pancreatitis amongst obese patients is around 1%. It's also worth noting that the preclinical data suggests that FGF21 alleviates stress on the pancreas and therefore would not be expected to cause pancreatitis. Slide 14 provides an overview of the most commonly reported study drug-related, treatment-emergent adverse events. The most frequent were transient, mild-to-moderate gastrointestinal events. The majority of the GI events were grade 1 that result from study drug. These events were often single episodes that occurred in the first month of treatment. And overall, frequency decreased over the 16-week treatment period. There were no discontinuations for diarrhea, the most commonly reported adverse event. There was also no discontinuations due to injection site reactions, which were few in number and the majority of which were grade 1 and infrequent. There was also no discontinuations due to any adverse event for the 50-milligram group, which, as reviewed earlier, had the highest numerical histological responses amongst EFX dose groups. As outlined on the right, there was no treatment-related effects on either systolic or diastolic blood pressure, heart rate or bone mineral density. And even though increased appetite was reported as an adverse event, mean body weight reduction was observed across all EFX dose groups. I'll now turn the presentation over to our Chief Scientific Officer, Tim Rolph, who'll present the totality of our biomarker data.

Thank you, Kitty, and good afternoon, everyone. To put Slide 15 in context, approximately 40% of F2/F3 NASH patients have type 2 diabetes. Generally, their diabetes is not well controlled, so improving their glycemic control is highly desirable. As seen here, EFX elicited clinically meaningful improvements in multiple markers of glycemic control, which we believe can be attributed to insulin sensitization. Starting from the left. Hemoglobin A1c is the clinical diagnostic for long-term control of blood glucose. We observed reductions in hemoglobin A1c of 0.1%, 0.4% and 0.5% for the 28-, 50- and 70-milligram doses compared with an increase of 0.1% for placebo. These reductions are statistically significant for both 50- and 70-milligram doses. These results exceeded our expectations because EFX was dosed on top of antidiabetic medications for approximately 50% of the patients in the study with type 2 diabetes. Moving across the slide. The next histogram shows change from baseline in homeostatic model of insulin resistance or HOMA-IR. There is a clear trend towards insulin sensitization as evidenced by lower values for HOMA-IR, with reductions of 17%, 26% and 49% for 28, 50 and 70 milligrams, and the 70-milligram dose attained significance. By comparison, HOMA-IR increased almost 150% for placebo. Moving further to the right. The next histogram shows change from baseline in C-peptide, the best indicator of insulin secretion. We observed significant reductions of 24%, 26% and 33% for 28, 50 and 70 milligrams, indicating lower rates of insulin secretion. This contrasts with an increase of 23% for placebo. Finally, the chart at right shows change from baseline in adiponectin, generally accepted as a biomarker of insulin sensitivity. Here we see significant increases of 69%, 88% and 120% for 28, 50 and 70 milligrams compared with a decrease of 4% for placebo. The overall improvement in glycemic control is consistent with observations previously reported by Amgen after treating type 2 diabetic subjects for 4 weeks, underscoring the reproducibility of this effect. Achieving better glycemic control by improving insulin sensitization is highly desirable because it's rectifying the fundamental driver of type 2 diabetes, which is insulin resistance. This means EFX has the potential to achieve a sustained reduction in hemoglobin A1c in contrast to diabetes therapies, which promote insulin secretion and whose efficacy wanes over time. The next slide reinforces this point, as the improvement in glycemic control at 50 and 70 milligram is accompanied by mean reductions in body weight of 2.3 and 3.7 kilos after 16 weeks, corresponding to a mean decrease of 5 and 8 pounds. Weight loss is known to enhance insulin sensitization. It should also be noted that the trend toward weight loss observed with EFX contrasts with another class of insulin sensitizer, the PPAR gamma agonists. This class includes established antidiabetic drugs like pioglitazone, whose use has declined substantially because of weight gain and edema; and lanifibranor, for which encouraging efficacy results in NASH were released recently. It was again associated with weight gain of about 2.4, 2.7 kilos and 6% to 8% edema. The weight loss observed with EFX also contrasts with the weight gain observed with another FGF21 analog targeting only the FGFR1c receptor. From the viewpoint of differentiation, this is the first reported reduction in body weight following longer-term treatment with an FGF21 analog. The potential for weight loss will be attractive to clinicians and NASH patients. By way of context for Slide 17, more than 80% of NASH subjects are dyslipidemic, with elevated levels of triglycerides and LDL cholesterol and low levels of HDL cholesterol. Dyslipidemia is a major contributor to the high incidence of cardiovascular mortality and morbidity amongst NASH patients. Slide 17 illustrates impressive improvements in lipoprotein profile, following 16 weeks of treatment across all doses. Starting on the left with triglycerides. There are substantial reductions of 37% to 45% across treatment groups in contrast to an increase of 8% of placebo. Moving to the right. We observed substantial increases in HDL of 32% to 40% across the treatment groups, while placebo didn't change. The next chart shows change from baseline in non-HDL cholesterol. Because EFX acts to reduce total cholesterol primarily by decreasing the LDL, which carries triglyceride rather than LDL, the potential for EFX to lower bad cholesterol was best captured as change in non-HDL cholesterol, which like LDL cholesterol is a causal risk factor for cardiovascular disease. We observed significant reductions in non-HDL cholesterol of 13% to 20% across the treatment groups compared with no change for placebo. Looking at the final chart. The most important point is that LDL cholesterol did not increase for any of the EFX dose groups. These very encouraging metabolic data should be viewed holistically rather than in isolation. EFX is rectifying each aspect of the metabolic dysfunction associated with NASH. It is improving glycemic control by enhancing insulin sensitivity. It is restoring a healthy lipoprotein profile and lowering body weight. These broadly based improvements increase our confidence that the rapid reduction of steatohepatitis and collagen deposition seen in BALANCED will be sustained, in turn allowing further resolution of fibrosis beyond the highly encouraging improvements evident after just 16 weeks of EFX treatment. The magnitude of metabolic improvements, particularly in lipoproteins associated with risk of cardiovascular disease, also points to the potential of EFX to reduce the high incidence of heart attack and stroke among NASH patients. In conclusion, 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 fibrosis against detrimental effects on lipoproteins, increased body weight and no improvement in glycemic control. With EFX, we see potential to restore a healthy metabolic profile, not only to the liver but also to the whole body. The results are consistent with our predictions based on FGF21 biology and efruxifermin's engineering. Nevertheless, as Andrew said, these results exceeded our expectations. I'll now hand the presentation back to Andrew.

Thank you, Tim. On Slides 18 and 19, we put today's histologic results in the context of the broader NASH development landscape. Of course, these data are derived from different clinical studies after different periods of treatment, albeit with similar patient populations. No head-to-head clinical trials have been conducted. Despite these caveats, the histologic improvements observed following treatment with EFX for only 16 weeks are arguably the most compelling histology results to date, particularly for fibrosis improvement. As shown on Slide 18, EFX 50-milligram achieved a higher rate of NASH resolution without worsening of fibrosis than any other compound except a high daily injectable dose of semaglutide, which was administered for 72 weeks. Now turning to Slide 19. The proportion of subjects who have at least a 1-stage improvement of fibrosis without worsening of NAS, we believe the 62% response for the 50-milligram group is the largest that has been reported to date on this measure. Moreover, the 48% response rate across all 3 EFX groups matches the highest response rates seen for any Phase II or Phase III NASH program to date. Again, these results are particularly compelling considering a 16-week treatment period compared to 24 to 78 weeks for these other 6 product candidates. We expect even stronger results when EFX is evaluated for a longer treatment period. It is also important to note that EFX is the first treatment administered once weekly to report histology results. Given the commercial success of weekly GLP-1 drug products over daily GLP-1 products, we believe weekly administration is an important differentiated benefit for EFX. Slide 20 summarizes why we believe EFX has a unique potential to be a foundational monotherapy. As a complex disease, NASH requires intervening at many stages of its pathogenesis. Based on the remarkable results of the BALANCED study reported today, EFX has the potential to address all of the core aspects of NASH pathogenesis in a single treatment: reducing steatohepatitis, resolving fibrosis and restoring healthy metabolism to the whole body. We are particularly pleased that the data are so compelling for each of the 20- (sic) [ 28- ], 50- and 70-milligram dose, which gives us design options for future studies. The 28- and 50-milligram doses appear to be likely candidates for evaluation in longer-term studies. We look forward to working with the FDA and EMA to design our registrational development program and ultimately, if approved, to making an exciting new treatment available to patients. In closing, let me take a moment to extend our heartfelt thank you to all of the investigators, study site staff and, most importantly, patients who participated in the BALANCED study. Today's exciting data would not have been possible were it not for the dedification (sic) [ dedication ] of investigators and their teams and for our patients, many of whom who completed clinic visits and study procedures despite the emerging COVID-19 outbreak. We are truly grateful for the support you gave us during these difficult times. I'd now like to turn things over to the operator for questions and answers.

[Operator Instructions] And our first question will come from Michael Yee of Jefferies.

Andrew, congrats on the data across the board, particularly during the COVID pandemic, too. So kudos to that. Just wanted to ask 2 questions. One was around your thoughts around the therapeutic window. Great efficacy across the board, but maybe talk about how people should interpret Slide 14 with the, shall I say, tolerability incidence numbers. Maybe just talk to the AEs and the GIs -- GI issues, particularly with onset of action. How fast does it go away? So if you could just help people walk through that and get comfortable with that? And then my other question was on the efficacy side. Remind me, but I think there was actually a long time from last treatment to the actual biopsy, and then you worked also during the COVID period. So do you think there was any lost effect from the period of time from the actual drug to the actual time it took to date of the biopsy and whether that impacted variability at all or could have impacted results could have been better?

Yes. So thank you, Mike. Why don't we touch sort of in reverse order since that helps me to remember. Kitty, do you want to talk about when the biopsy were taken relative to the last dose of week 16 and how that might have impacted the results?

So thanks, Michael. Our off-treatment biopsies were taken really between weeks 20 to 24. But in reality, actually, the mean time to biopsy was week 20 across the treatment groups. So it was a unique situation, where the patient had been off study treatment for 4 weeks approximately at that time. I think what we can say around the results are that we would really expect that perhaps, there was some fat that returned to the liver. And so that, if anything, our biopsy results are -- would only be better if we actually had taken them while the patients were still being treated.

Kitty, do you want to go ahead and comment a little bit about the onset and the overall tolerability, I think, on Slide 14?

Yes, so overarchingly for the GI-adverse events, as Andrew mentioned, they were mild to moderate, mostly grade 1, transient in nature. So they actually resolved on study. And the majority of the events actually kind of were single instances that occurred within the first month. And I think what you can probably tell, Michael, is that these -- although they were maybe annoying, they actually weren't disruptive to the patients and so really didn't cause study discontinuation.

Our next question comes from Eric Joseph of JPMorgan.

Let me add my congrats on these data. Just I guess picking up on Mike's question, I'm curious to know how you're thinking about dosing or dose selection. Which doses you plan to advance to Phase IIb, given the pretty consistent effect that you're seeing in terms of histology and tolerability and also the dose responsiveness on the metabolic parameters? That's my first question. And then a follow-up question on -- around safety. Just drilling a little bit further down into the discontinuation for -- like panic attack and anxiety, you highlighted that patient's extensive pretreatment history. But I just want to get a sense of how confidently you could rule out any aggravating effects [ I E ] effects and whether there were any patients with a similar background or treatment, similar history of treatment background and whether you anticipate needing to do any focused DDI studies with CNS medications?

Eric, it's Andrew. So we're very comfortable with the CNS profile for this compound. I think it's -- this patient, unfortunately, had a very, as we pointed out, extensive psychiatric and medical history. This was not their first panic attack nor was it their first anxiety episode. So I think we're very comfortable that the CNS profile for this compound is very solid. I think one way to look at it is that we have doses that were twice and 2.5x when you think of the 70-milligram dose. So if this were a drug-related event, we are essentially conducting a sort of a stress study as it were. And so we didn't see this in any other patient in any of the higher doses. So we're pretty comfortable with that profile. And given, if you sort of work through the case, it's a complex one but this wasn't an isolated tremor. In fact, this was the only case of new onset tremor in the entire study. So maybe we can talk a little bit about the doses. And I think, as I touched on earlier, we're very comfortable to look at the 28 and 50 milligrams as the likely doses that we'd want to take forward to Phase IIb and III. However, of course, this is always done in consultation with regulatory agencies, and that consultation and discussion is upcoming.

Our next question will come from Edward Nash of Canaccord Genuity.

Congratulations, guys. This is really impressive data, especially a cardiometabolic marker standpoint. It's really impressive. I have a quick question. One of my questions on Slide 17. Just wanted to get your thoughts on or an explanation as to why we see such a dramatic drop in the LDL cholesterol on the lower dose versus the 50-milligram. [ We seem ] the 50-milligram seems to be the better performing in general, but just curious there on that big difference there.

Tim, could I ask you to sort of take this?

Yes. So I think the magnitude of change in lipoproteins in terms of a reduction in triglyceride and the increase in HDL is sort of unprecedented pharmacologically. So our understanding of how lipids are being passed around the different type of lipoproteins is really not there. So the takeaway really is the responses in terms of non-HDL cholesterol, which is the big change here and I think the important change, is it's essentially pretty flat across the doses. The LDL cholesterol, I don't know whether it's real, that reduction at 28 milligrams. But when you look across all of the doses, the net is that LDL cholesterol hasn't changed.

Yes. And then my other -- my next -- well, my last question was just, obviously, with the COVID environment where -- what it is right now and I know Andrew, you said you're going to have discussions, upcoming discussions with the agency clearly. Just wanted to get an idea on what you think that timing could look like, especially with regard to trying to get into enrollment of a new trial.

So Kitty, do you want to comment?

Yes. So we do have regulatory meetings set up with the FDA later on this year. We are -- I think what we've publicly said is that we would start the next study, which would be a Phase IIb/III study in the first half of next year.

Great. And congratulations again. Really impressive data.

Thank you.

Our last question will come from Ed Arce of H.C. Wainwright.

And let me also add my congratulations on very impressive data across the board here on multiple parameters. The first question is, coming out of the 12-week, the MRI-PDFF data that you reported back in March, I believe there were 50 out of the 59 patients that were responders and would then roll over into the 16-week portion. So if I am reading this press release correctly, there were 40 treatment responders who had an end-of-treatment biopsy. And just wondering if you could explain what happened to the difference of those 10 patients in the interim.

Sure. So Kitty, do you want to walk Ed through this?

Yes. So maybe I can explain. So we had 80 patients randomized into this study. 79 actually were dosed. At week 12, 68 patients remained on study and met the definition of a responder. I think what's happened is, and the way we presented the data, it's all really depending on whether we look at the full analysis set or what we presented today in terms of response rate, where we actually showed the MRI evaluable biopsy set, where we had only included the patients that were in -- had both baseline and week 12 MRI assessment.

Okay. That's helpful. And then I did want to also follow up on the dosing question. Clearly, you're seeing pretty robust responses across all 3 doses. But it looks like, at least to me, the 50-milligram dose is kind of the sweet spot in terms of both the efficacy that you've seen as well as the safety. And just wondering if you might share a little bit your thoughts on that.

Ed, we're aligned. I think the 50-milligram dose really looks fantastic in terms of overall tolerability. The -- no discontinuations. The really -- 62% 1-stage improvement in fibrosis, 38% 2-stage improvement of fibrosis in just 16 weeks. So we're very big on the 50-milligram dose.

Great. And one last question, if I may. A further clarification on this question around the LDL response here. I think you had mentioned earlier that EFX actually has a more direct or primary effect on VLDL rather than LDL. If you could expound upon that as well.

I can take that, Andrew.

Please.

Yes. So I think the important thing to understand is that cholesterol is not just transported on low-density lipoproteins. It's transported on high-density lipoproteins and very low-density lipoproteins. Because the triglyceride is reduced so dramatically with this mechanism, placebo adjusted, we're cutting triglyceride levels by a half. And that's a very substantial reduction. And as a consequence, the cholesterol that's carried on the LDL is being reduced. And the best way to capture that is by calculating the non-HDL cholesterol because the majority of the reduction in total cholesterol in the blood is being reflected by the change in non-HDL cholesterol fraction, which is why we specifically call that out. And the importance of that is, that like LDL cholesterol, it is a very well-established causal factor for cardiovascular disease.

Congrats to everyone again for the positive data.

Thanks very much, Ed.

Thank you.

This concludes our question-and-answer session. I would like to turn the conference back over to management for any closing remarks.

It's Andrew Cheng, Chief Executive Officer. I wanted to thank all of the participants on the webcast for your interest in Akero and look forward to sharing more data in the near future. Thank you.

The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.