UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
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FORM
CURRENT REPORT
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| Item 2.02 | Results of Operation and Financial Condition. |
On June 5, 2023, Akero Therapeutics, Inc. (the “Company”) provided an update regarding the amount of cash, cash equivalents and short-term marketable securities it had on hand as of June 2, 2023. Although the Company has not finalized its financial results for such period, the Company currently anticipates that its cash, cash equivalents and short-term marketable securities were approximately $660 million as of June 2, 2023. This information is unaudited and does not present all information necessary for an understanding of the Company’s financial condition as of June 2, 2023.
| Item 7.01. | Regulation FD Disclosure. |
On June 5, 2023, the Company issued a press release titled “Akero Therapeutics’ Phase 2b SYMMETRY Cohort D Study Met Safety & Tolerability Endpoints and Showed Adding EFX to GLP-1 Therapy Significantly Improved Non-Invasive Markers of NASH-Related Disease.” A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The Company from time to time presents and/or distributes to the investment community slide presentations to provide updates and summaries of its business. A copy of its corporate slide presentation is being furnished herewith as Exhibit 99.2 to this Current Report on Form 8-K. The Company undertakes no obligation to update, supplement or amend the materials attached hereto as Exhibit 99.2.
The information under this Item 7.01, including Exhibit 99.1 and Exhibit 99.2 hereto, is being furnished herewith and shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall such information be deemed incorporated by reference into any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
| Item 8.01. | Other Events. |
On June 5, 2023, the Company released topline data from an expansion cohort (N=31) of the Phase 2b SYMMETRY study known as Cohort D. The primary aim of the 12-week study was to assess safety and tolerability of its lead product candidate, efruxifermin (“EFX”), compared to placebo when added to an existing GLP-1 receptor agonist (“GLP-1”) in patients with Type 2 diabetes (“T2D”) and F1-F3 liver fibrosis due to non-alcoholic steatohepatitis (“NASH”).
EFX was reported to be generally well tolerated in Cohort D with comparable results for the EFX (N=21) and placebo (N=10) groups. The overall tolerability profile was similar to that observed in the Company’s BALANCED and HARMONY studies. The most frequent adverse events for EFX-treated patients were grade 1 or 2 gastrointestinal events (diarrhea, nausea, and increased appetite). One patient treated with EFX discontinued due to nausea and one EFX-treated patient discontinued after withdrawing consent. There were no drug-related serious adverse events. Cohort D also met all key secondary endpoints, including relative reduction of liver fat and proportion of patients whose absolute liver fat level normalized to 5 percent or less.
On June 5, 2023, the Company also announced that it has cash, cash equivalents and short-term marketable securities sufficient to fund its current operating plan into 2026.
Forward-Looking Statements
This Current Report on Form 8-K and certain materials furnished or filed herewith contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding: the Company’s business plans and objectives, including future plans or expectations for EFX, the therapeutic effects and clinical benefits of EFX, as well as the dosing, safety and tolerability of EFX; and expectations regarding its uses of capital, expenses and financial results, including the expected cash runway.
Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: risks related to the impact of public health epidemics affecting countries or regions in which we have operations or do business, such as COVID-19, which has been labelled a pandemic by the World Health Organization, including potential negative impacts on the Company’s employees, manufacturers, supply chain and production as well as on global economies and financial markets; the company’s ability to execute on its strategy; positive results from a clinical study may not necessarily be predictive of the results of future or ongoing clinical studies; regulatory developments in the United States; and risks related to the competitive landscape. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in the Company’s annual report on Form 10-K filed, with the United States Securities and Exchange Commission (SEC) and quarterly reports on Form 10-Q filed with the SEC, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s other filings with the SEC. All forward-looking statements contained in this presentation speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Press Release issued by Akero Therapetuics, Inc. on June 5, 2023. | |
| 99.2 | Corporate slide presentation of Akero Therapeutics, Inc., furnished herewith | |
| 104 | Cover Page Interactive Data File (embedded within Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Date: June 5, 2023 | AKERO THERAPEUTICS, INC. | |||||
| By: | /s/ Andrew Cheng | |||||
| Andrew Cheng, M.D., Ph.D. President and Chief Executive Officer | ||||||
Exhibit 99.1
Akero Therapeutics’ Phase 2b SYMMETRY Cohort D Study Met Safety & Tolerability Endpoints and Showed
Adding EFX to GLP-1 Therapy Significantly Improved Non-Invasive Markers of NASH-Related Disease
Patients treated with EFX for 12 weeks combined with GLP-1 achieved a 65% relative reduction in liver
fat, compared to a 10% relative reduction for GLP-1 alone
88% of patients treated with EFX combined with GLP-1 had normalized liver fat at week 12, compared
with 10% of those treated with GLP-1 alone
EFX-treated patients also experienced statistically significant improvements in liver enzymes and
noninvasive markers of fibrosis, glycemic control, and lipids
Investor webcast at 8:00 am ET today to further discuss data
SOUTH SAN FRANCISCO, Calif., June 5, 2023 — Akero Therapeutics, Inc. (Nasdaq: AKRO), a clinical-stage company developing transformational treatments for patients with serious metabolic disease marked by high unmet medical need, today released topline data from an expansion cohort (N=31) of the Phase 2b SYMMETRY study known as Cohort D. The primary aim of the 12-week study was to assess safety and tolerability of Akero’s lead product candidate, efruxifermin (EFX), compared to placebo when added to an existing GLP-1 receptor agonist (GLP-1) in patients with Type 2 diabetes (T2D) and F1-F3 liver fibrosis due to non-alcoholic steatohepatitis (NASH).
EFX was reported to be generally well tolerated in Cohort D with comparable results for the EFX (N=21) and placebo (N=10) groups. The overall tolerability profile was similar to that observed in Akero’s BALANCED and HARMONY studies. The most frequent adverse events for EFX-treated patients were grade 1 or 2 gastrointestinal events (diarrhea, nausea, and increased appetite). One patient treated with EFX discontinued due to nausea and one EFX-treated patient discontinued after withdrawing consent. There were no drug-related serious adverse events.
Cohort D also met all key secondary endpoints, including relative reduction of liver fat and proportion of patients whose absolute liver fat level normalized to 5 percent or less. We believe these data, together with statistically significant improvements across many other key NASH-related measures, show that EFX could be an important treatment for patients with NASH who are being treated with GLP-1 for T2D or obesity.
“A substantial portion of patients who have NASH are obese and have Type 2 diabetes, with utilization of GLP-1 therapies increasing rapidly to treat these underlying comorbidities”, said Stephen Harrison, M.D., chairman and founder of Pinnacle Clinical Research and principal investigator for the SYMMETRY study. “With this in mind, it is highly encouraging that the Cohort D results not only showed that EFX combined with GLP-1 appeared to be adequately tolerated, but also the combination offered substantial benefit over GLP-1 therapy alone based on multiple key NASH endpoints. Hepatic steatosis was still present in patients on GLP-1 therapy, approximately two-thirds of whom were treated with GLP-1 for over one year, and 88% of patients resolved hepatic steatosis completely when EFX was added.”
“We’re highly encouraged by the strength and consistency of results across our Phase 2 studies to date,” said Kitty Yale, chief development officer of Akero. “With the added support of this newest data set, we believe EFX has the potential to play an important role in treating patients with NASH who are receiving GLP-1 therapy in addition to the potential to be a foundational monotherapy for patients with NASH. We look forward to initiating two Phase 3 SYNCHRONY studies later this year to further our goal of addressing high unmet need across the globe for patients living with NASH.”
Summary of Week 12 Changes in Liver Fat
| Measure |
Placebo (N=10) |
EFX 50mg (N=16) |
||||||
| Hepatic Fat Fraction (MRI-PDFF) (%), LS Mean Relative Change from Baseline |
-10 | -65 | *** | |||||
| Proportion of patients achieving ≥50% Relative Reduction in Liver Fat (%) |
0 | 88 | *** | |||||
| Proportion of patients with Normalized (≤5%) Liver Fat (%) |
10 | 88 | *** | |||||
| *** | p<0.001, versus placebo (ANCOVA) |
Summary of Key Markers of Fibrosis and Liver Injury, LS Mean Absolute Change from Baseline to Week 12
| Measure |
Placebo (N=10) |
EFX 50mg (N=21) |
||||||
| Pro-C3 (µg/L) |
-2.7 | -5.2 | †† | |||||
| ELF Score |
+0.1 | -0.6 | ** | |||||
| Liver Stiffness (kPa) (FibroScan) |
-1.1 | -3.0 | ††† | |||||
| FAST Score |
+0.04 | -0.16 | *** | |||||
| ALT (U/L) |
-1.0 | -10 | * | |||||
| AST (U/L) |
+1.5 | -5.3 | * | |||||
| * | p<0.05, ** p<0.01, *** p<0.001, versus placebo (Mixed Model Repeated Measures [MMRM]) |
| †† | p<0.01, ††† p<0.001, versus baseline (MMRM) |
Summary of Key Cardio-Metabolic Biomarkers, LS Mean Relative Change from Baseline to Week 12
| Measure |
Placebo (N=10) |
EFX 50mg (N=21) |
||||||
| HbA1c (%, absolute) |
-0.2 | -0.5 | ††† | |||||
| Insulin (%) |
-13 | -26 | ||||||
| C-Peptide (%) |
-3.5 | -22 | † | |||||
| Adiponectin (%) |
+16 | +129 | *** | |||||
| Triglycerides (%) |
-4.1 | -42 | *** | |||||
| Non-HDL Cholesterol (%) |
-6.8 | -19 | ††† | |||||
| Apolipoprotein B (%) |
-4.5 | -21 | * | |||||
| LDL Cholesterol (%) |
-6.1 | -8.0 | ||||||
| HDL Cholesterol (%) |
+2.5 | +38 | *** | |||||
| Body Weight (kg) |
-0.8 | -1.2 | ||||||
| ** | p<0.01, *** p<0.001, versus placebo (MMRM) |
| † | p<0.05, ††† p<0.001, versus baseline (MMRM) |
In July of 2021, Akero initiated the SYMMETRY main study, a Phase 2b trial in biopsy-confirmed NASH patients with compensated cirrhosis (F4), Child-Pugh class A. Akero expects to report results from the ongoing study in the fourth quarter of 2023.
Conference Call / Webcast Details
Akero will host a conference call and webcast with slide presentation at 8:00 a.m. ET today. The live webcast will be available on the Events & Presentations page of the Akero website, with the recording and presentation available immediately following the event.
About NASH
NASH is a serious form of NAFLD (non-alcoholic fatty liver disease) that is estimated to affect 17 million Americans. NASH is characterized by an excessive accumulation of fat in the liver that causes stress and injury to liver cells, leading to inflammation and fibrosis, which can progress to cirrhosis, liver failure, cancer and eventually death. There are no approved treatments for the condition and NASH is the fastest growing cause of liver transplants and liver cancer in the US and Europe.
About Efruxifermin
Efruxifermin (EFX), formerly known as AKR-001, is Akero’s lead product candidate for NASH, currently being evaluated in the ongoing Phase 2b HARMONY and SYMMETRY studies. EFX is designed to reduce liver fat and inflammation, reverse fibrosis, increase insulin sensitivity and improve lipids. This holistic approach offers the potential to address the complex, multi-system disease state of NASH, including improvements in lipoprotein risk factors linked to cardiovascular disease – the leading cause of death in NASH patients. Engineered to mimic the biological activity profile of native FGF21, EFX is designed to offer convenient once-weekly dosing and has been generally well-tolerated in clinical trials to date.
About Akero Therapeutics
Akero Therapeutics is a clinical-stage company developing transformational treatments for patients with serious metabolic diseases marked by high unmet medical need, including NASH, a disease without any approved therapies. Akero’s lead product candidate, EFX, is a differentiated Fc-FGF21 fusion protein that has been engineered to mimic the balanced biological activity profile of native FGF21, an endogenous hormone that alleviates cellular stress and regulates metabolism throughout the body. EFX is designed to offer convenient once-weekly subcutaneous dosing. The consistency and magnitude of observed effects position EFX to be a potentially best-in-class medicine, if approved, for treatment of NASH. EFX is currently being evaluated in two Phase 2b clinical trials: the HARMONY study in patients with pre-cirrhotic NASH (F2-F3 fibrosis), and the SYMMETRY study in patients with cirrhotic NASH (F4 fibrosis, compensated). EFX is also being evaluated in an expansion cohort of the SYMMETRY study, comparing the safety and tolerability of EFX to placebo when added to an existing GLP-1 receptor agonist in patients with pre-cirrhotic NASH (F1-F3 fibrosis) and Type 2 diabetes. Akero is headquartered in South San Francisco. Visit us at akerotx.com and follow us on LinkedIn and Twitter for more information.
Forward Looking Statements
Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, statements regarding Akero’s business plans and objectives, including future plans or expectations for EFX, the therapeutic effects of EFX, as well as the dosing, safety and tolerability of EFX, including in combination with GLP-1 therapies; and upcoming milestones, including the results, and expected timing to report such results of Akero’s Phase 2b SYMMETRY study. Any forward-looking statements in this press release are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: the success, cost, and timing of Akero’s product candidate development activities and planned clinical trials; Akero’s ability to execute on its strategy; positive results from a clinical study, including Cohort D, may not necessarily be predictive of the results of future or ongoing clinical studies; regulatory developments in the United States and foreign countries; Akero’s ability to fund operations; as well as those risks and uncertainties set forth more fully under the caption “Risk Factors” in Akero’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q, as filed with the Securities and Exchange Commission (SEC) as well as discussions of potential risks, uncertainties and other important factors in Akero’s other filings and reports with the SEC. All forward-looking statements
contained in this press release speak only as of the date on which they were made. Akero undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
Investor Contact:
Christina Tartaglia
212.362.1200
IR@akerotx.com
Media Contact:
Sarah O’Connell
732.456.0092
soconnell@vergescientific.com
Exhibit 99.2 Restoring Balance. Renewing Life. Corporate Presentation June 2023
Safe Harbor and Legal Disclaimers This presentation may contain “forward-looking statements” of Akero Therapeutics, Inc. (“we,” “us,” “our,” “Akero” or the “Company”) within the meaning of the Private Securities Litigation Reform Act of 1995 relating to our business, operations, and financial conditions, including but not limited to current express or implied beliefs, expectations and assumptions regarding: the future of our business; future plans and strategies, including our expectations around the therapeutic potential and clinical benefits of Efruxifermin (“EFX”), including in combination with GLP-1 receptor agonist therapies; our development plans for EFX, including our belief in the unique potential of EFX as a foundational NASH therapy; our preclinical and clinical results, including our safety/tolerability, laboratory measures and histology data from our Phase 2a BALANCED study, Phase 2b HARMONY study, and the Cohort D expansion of our Phase 2b SYMMETRY study; the potential benefits resulting from the PRIME, Breakthrough Therapy and Fast Track designations of EFX; the Phase 2b SYMMETRY study, including the Cohort D expansion and expected timing to report preliminary results, and other related milestones; the SYNCHRONY Phase 3 program, including the SYNCHRONY Histology and SYNCHRONY Real-World studies and design of trials and expected timing thereof; the availability of a new drug product formulation to support Phase 3 clinical trials; risks related to the competitive landscape; the timing and potential benefits of our regulatory interactions; our use of capital, expenses and other future financial results, including the expected cash runway; and the potential impact of COVID-19 on strategy, our employees, supply chain, future operations and clinical trials. Words such as, but not limited to, “look forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” “would,” “should” and “could,” and similar expressions or words, identify forward-looking statements. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in our most recent annual report on Form 10-K filed with the Securities and Exchange Commission (the “SEC”), as well as discussions of potential risks, uncertainties, and other important factors in our other subsequent filings with the SEC. All information in this presentation is as of the date hereof, and we undertake no duty to update this information unless required by law. Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and the Company’s own internal estimates and research. While the Company believes these third-party sources to be reliable as of the date of this presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while we believe our own internal research is reliable, such research has not been verified by any independent source. ©2023 AKERO THERAPEUTICS. 2
Corporate Highlights 1 2 3 Potential First-in-Class Building Momentum Toward Experienced & Validated Team & Best-in-Class NASH Drug Phase 3 Pivotal Trials with Substantial Resources • Substantial potential market • Two parallel Phase 2b trials underway • Involved in 20+ FDA approvals opportunity • HARMONY (F2-F3) • ~$660M cash, cash equivalents and • SYMMETRY (F4, compensated) • Differentiated mechanism of action short-term marketable securities on • Regulatory designations hand as of June 2, 2023, including • Strongest reported efficacy data • Breakthrough Therapy (US FDA) proceeds in April and May from the among FGF21s, including: • Fast Track (US FDA) ATM and a Registered Direct • Fibrosis improvement • PRIME (European EMA) offering. • NASH Resolution • Improved glycemic control • Commercial product-device for Ph3 Ph3 SYNCHRONY program announced SYMMETRY readout expected 4Q’23 Cash runway into 2026 ©2023 AKERO THERAPEUTICS. 3
Extensive Development and Commercialization Experience Involved in 20+ Medicine Approvals Kitty Yale | Chief Development Officer Andrew Cheng, MD, PhD | President & CEO • 19 years at Gilead • Over 25 years at Gilead, Roche, Pfizer • Chief Medical Officer & HIV Division Head • VP, Gilead Worldwide Clinical Operations • Major role in 11 NDA/MAA approvals • Major role in 8 global approvals NDA, MAA, JNDA and CFDA Patrick Lamy | SVP, Commercial Strategy Tim Rolph, D.Phil | Co-Founder & Chief Scientific Officer • Over 20 years of commercial experience at Gilead, • Over 30 years at Pfizer & Glaxo Iovance and other small biotech • CSO of Pfizer’s cardiovascular and metabolic disease unit • Most Recently, VP Commercial at Iovance • Head of Groton & UK Discovery Research, Pfizer • Five product launches is liver disease including global • Major role in discovery and early clinical evaluation of two launch lead for Gilead’s HCV franchise medicines: Selzentry (HIV) and Steglatro (Diabetes) Jonathan Young, PhD, JD | Co-Founder & COO William White | CFO & Head of Corporate Development • Over 15 years in biotechnology product development, • 18 years in life sciences investment banking at Goldman law and regulatory policy Sachs, Citigroup and Deutsche Bank • General Counsel and VP Policy, Braeburn • Most recently, Head of US Life Sciences Investment Banking at Deutsche Bank • Partner and General Counsel, FoxKiser • Advised on more than $70bn in M&A and $25bn in financing transactions ©2023 AKERO THERAPEUTICS. 4
Providing a Potentially Effective Treatment for NASH Reducing liver fat Achieving >10% weight is critical to remove loss is challenging for disease driver patients who are obese Peripheral fat Insulin resistance and is the largest source of Type 2 Diabetes drives liver fat in patients with liver caloric burden NASH Reversing fibrosis Dyslipidemia drives 30 Million is key to avoiding cardiovascular disease, the #1 US patients with NASH transplant, cancer, death cause of mortality in the US expected by 2030 ©2023 AKERO THERAPEUTICS. 5
EFX Engineering Potentially Optimal for NASH Efficacy, With Convenient Once-weekly Dosing Key attributes Akero proprietary Increases half-life High affinity for Fc-FGF21, from < 2 hours β-Klotho Point mutations to ~3 days Better translation Balanced potency Inactive βKlotho FGFR βKlotho to human at FGFR1c, 2c, 3c at FGFR4 pharmacology Stanislaus, S et al. (2017) Endocrinology 158(5): 1314-27; Lee, S et al. (2018) Nature 553: 501-505; Kharitonenkov, A et al. (2007) Endocrinology 148(2)774-781 ©2023 AKERO THERAPEUTICS. 6
EFX Acts on Two Major Sources of Liver Fat With Potential for Optimal Reduction Sources of Fat Flowing into and Acting on both hepatic and peripheral sources of liver Through Liver for Patients with NASH fat is key to optimizing liver fat reduction Dietary Fat Source of Liver Fat FGF Receptor EFX Activity (10-20%) Adipose Tissue: Lipolysis Lipolysis FGFR1c Liver: ü (40-50%) De Novo FGFR1c Lipogenesis (30-40%) FGFR2c, 3c FGFR2c De Novo Lipogenesis ü FGFR3c ©2023 AKERO THERAPEUTICS. 7
EFX Direct And Indirect Anti-fibrotic Effects Pathogenesis of Fibrosis Hepatocyte Stress & Death Kupffer Cell Activation Myofibroblast Differentiation Fibrogenesis EFX Anti-Fibrotic Activity Bao, L et al. (2018) Br J Pharmacol 175:3379-3393; Fisher, FM et al. (2014) Gastroenterology 147:1073-1083.e6; Jimenez, V et al. (2018) EMBO Mol Med 10:e8791; Lee, JH et al. (2016) *Cited literature available on company website Am J Transl Res 8:4750-4763; Sanyal, A et al. (2018) Lancet 392:2705-2717; Le, CT et al. (2018) PLOS one 13:e0192146; Xu, P et al. (2016) Toxicol Appl Pharmacol 290:43-53; Yu, Y et al. (2016) Int Immunopharmacol 38:144-152 ©2023 AKERO THERAPEUTICS. 8
Key Regulatory Designations Based on EFX Therapeutic Profile Fast Track PRIME Breakthrough Therapy (US FDA - 2021) (EMA - 2020) (US FDA - 2022) • Enables expedited • Enables more frequent • Enables enhanced development regulatory interactions to regulatory support resolve development issues • Signifies potential for • Signifies potential to offer a with potential eligibility for substantial improvement major therapeutic advantage priority review over available therapy on over existing treatments or clinically significant • Signifies potential to fill an benefit patients without endpoints unmet medical need treatment options • Based on Phase 2b • Based on Phase 2a • Based on Phase 2a HARMONY data BALANCED data BALANCED data Efruxifermin was the first investigational NASH drug to receive all three designations FDA, Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics (2014); ©2023 AKERO THERAPEUTICS. 9 European Medicines Agency, Reflection paper on a proposal to enhance early dialogue to facilitate accelerated assessment of priority medicines (PRIME) (Draft 2015)
Evaluating EFX in Patients with F2-F3 Fibrosis STATISTICALLY SIGNIFICANT EFFECTS AFTER 24 WEEKS FIBROSIS IMPROVEMENT FIBROSIS NASH AND IMPROVEMENT RESOLUTION NASH RESOLUTION ©2023 AKERO THERAPEUTICS. 10
HARMONY Trial Design: Pre-Cirrhotic (F2-F3) NASH Key Inclusion Criteria Key Secondary Efficacy Endpoints Phase 2b Primary Endpoint • F2-F3 NASH • ≥ 1-stage fibrosis improvement • NASH Resolution & No • Lipoproteins • MRI-PDFF without worsening of NASH • NAS ≥4 Worsening of Fibrosis • Glycemic Control • Liver Injury Markers • Liver Fat (MRI-PDFF) ≥8% • Fibrosis Markers • Weight Change Long-Term Safety Follow-Up (up to 96 Weeks) 24 Weeks Placebo Placebo EFX 28mg EFX 28mg EFX 50mg EFX 50mg Regulatory Requirements for Phase 3 Trials Liver Biopsy • FDA accepts one of two endpoints for Phase 3 registrational trials: (1) Fibrosis improvement ≥1 stage & no worsening of MRI-PDFF 1 NASH or (2) NASH resolution and no worsening of fibrosis 2 • EMA requires both endpoints to be met for marketing approval 1 2 FDA Draft Guidance, Noncirrhotic Nonalcoholic Steatohepatitis With EMA, Draft Reflection paper on regulatory requirements for the development of medicinal products ©2023 AKERO THERAPEUTICS. 11 Liver Fibrosis: Developing Drugs for Treatment (2018) for chronic non-infectious liver diseases (PBC, PSC, NASH) (2018) Phase 2b Screening Randomization
Week 24 Patient Disposition & Analysis Sets Key Analysis Sets Randomized (N=128) Full Analysis Set – All subjects who were randomized Randomized Not Dosed EFX (N=2) Safety Set – All subjects who received at least one dose of study drug Dosed (N=126) Biomarker Analysis Set – All subjects who have baseline and on-study Discontinued Prior to Week 24 (N=11) biomarker measurement at given timepoint Administrative Due to AEs EFX (N=5) EFX (N=5) Placebo (N=1) Completed Week 24 (N=115) Biopsies Not Collected EFX (N=1); Placebo (N=1) Primary Endpoint Liver Biopsy Analysis Set – All subjects who have Baseline and Week 24 Biopsies Collected (N=113) liver biopsy results Placebo (N=41) 28mg (N=38) 50mg (N=34) ©2023 AKERO THERAPEUTICS. 12
Baseline Demographics Placebo EFX 28mg EFX 50mg Parameter (Mean) (N=43) (N=42) (N=43) Age (Years) 55 57 52 Sex (% Female) 63 69 53 Weight (kg) 108 104 103 Type 2 Diabetes (%) 65 76 70 1 Fibrosis Stage (% F3) 70 64 63 Enhanced Liver Fibrosis (ELF) Score 9.8 9.7 9.8 2 Pro-C3 (μg/L) 16.5 15.3 18.4 3 Liver Stiffness by VCTE (FibroScan) (kPa) 15 14 16 4 Hepatic Fat Fraction by MRI-PDFF (%) 17.1 18.5 17.5 NAFLD Activity Score (NAS) 5.4 5.1 5.6 Alanine Aminotransferase (ALT) (U/L) 62 50 63 Aspartate Aminotransferase (AST) (U/L) 57 42 52 HbA1c (%) 6.8 6.8 6.7 Triglycerides (mg/dL) 170 158 154 LDL-Cholesterol (mg/dL) 94 96 111 1 2 3 4 All patients either fibrosis stage 2 (F2) or stage 3 (F3); Procollagen 3 N-Terminal Propeptide; Vibration-controlled transient elastography; Magnetic Resonance Imaging Proton Density Fat Fraction ©2023 AKERO THERAPEUTICS. 13
Consensus Reading of Biopsies: Rigorous Approach to Histopathology Based on FDA Input to Minimize Variability Consensus Biopsy Analysis Flow Chart Slides Prepared From Tissue Samples Score 1 Score 2 Key Features of EFX Biopsy Analysis Plan • Biopsies independently scored by two pathologists, with a third pathologist available to adjudicate in absence of consensus Same Score Different Scores • Pathologists underwent protocol-specific training to align on NASH-CRN scoring interpretation Consensus Meeting • Pathologists blinded to subject, treatment, and sequence • No paired biopsy reads (i.e., pre- and on-treatment biopsies not read side-by-side) Consensus Score No Consensus Adjudicated Score Final Score QC’d and Reported to Study Portal ©2023 AKERO THERAPEUTICS. 14
Both EFX Doses Achieved Statistical Significance on Primary Endpoint (Fibrosis Improvement) Fibrosis Improvement ≥1 Stage 1 & No Worsening of NASH at Week 24 60% 50% * * 41 41% % * * 39 39% % 40% 30% 20% 20% 1 Per FDA guidance, this endpoint is defined as: “Improvement in liver fibrosis greater than or equal to one stage (NASH CRN 10% fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis)” FDA Draft Guidance, Noncirrhotic Nonalcoholic Steatohepatitis 0% With Liver Fibrosis: Developing Drugs for Treatment (2018), p.7 Placebo EFX 28mg EFX 50mg 1 N=41 N=38 N=34 * p<0.05, versus placebo (Cochran–Mantel–Haenszel test [CMH]) ©2023 AKERO THERAPEUTICS. Source Data: Liver Biopsy Analysis Set 15
EFX Fibrosis Improvement in Context: Pre-Cirrhotic NASH (≥1 Stage Improvement in Fibrosis and No Worsening of NASH) Akero Madrigal Inventiva Madrigal Novo Nordisk Efruxifermin Pegozafermin Lanifibranor Resmetirom Obeticholic Acid Semaglutide Phase 2b (F2-F3) Phase 1b/2a (F2-F3) Phase 2b (F1-F3) Phase 3 (F1-F3) Phase 3 (F2-F3) Phase 2b (F2-F3) 66% F3 65% F3 % F3 Not Reported 62% F3 54% F3 69% F3 1 4 2 3 3 3 24 Wks / Completers 24 Wks / Completers 24 Wks / Completers 52 Wks / ITT 72 Wks / ITT 72 Wks / ITT Consensus Readers Consensus Readers Single Reader Two Readers Consensus Readers Consensus Readers (Combined Statistically) By Reported Effect Size (Treatment Minus Placebo) * 46% 43% * 41% * 39% 17% 10% 33% 32% 32% EFX 29% Effect † 3% 21% 20% *** *** 26% 26% Sizes *** 24% *** *** 22% 22% 20% 12% 10% 19% 14% 14% 12% 15% HARMONY 10% 4% Placebo 7% Rate Placebo 28mg 50mg Placebo 0.8g 1.2g Placebo 80mg 100mg Placebo 10mg 25mg Placebo 0.2mg 0.4mg Placebo 15mg 30mg (N=41) (N=38) (N=34) (N=62) (N=63) (N=69) (N=316)(N=321)(N=318) (N=311)(N=312)(N=308) (N=58) (N=59) (N=56) (N=61) (N=14) (N=66) 1 2 Note: These data are derived from different clinical trials at Baseline and Week 24 biopsies available; End-of- Pegozafermin - 89Bio (2023) March 22 Corporate Presentation; Lanifibranor - Francque et al. different points in time, with differences in trial design and patient study biopsy available with no major protocol deviations; (2021) New Engl J Med 385, 1547–1558; Obeticholic acid - Intercept (2022) July 7 Press Release; 3 populations. As a result, cross-trial comparisons cannot be Missing biopsies were imputed as non-responders; Semaglutide - Newsome et al. (2020) New Engl J Med 384, 1113-24; Resmetirom – Madrigal 4 made, and no head-to-head clinical trials have been conducted. End-of-study biopsy available. (2022) December 19 Press Release. All trademarks are the property of their respective owners. † ©2023 AKERO THERAPEUTICS. 39.47 - 19.51 = 19.96 * p<0.05, *** p<0.001, versus placebo 16
Both EFX Doses Achieved Statistical Significance on Key Secondary Endpoint (NASH Resolution) NASH Resolution 1 & No Worsening of Fibrosis at Week 24 100% *** *** 80% 76 76% % 60% ** ** 47% 47% 40% 1 Per FDA guidance, this endpoint is defined as: “Resolution of steatohepatitis on overall histopathological reading and no worsening of liver fibrosis on NASH CRN fibrosis score. Resolution of steatohepatitis is defined as absent fatty liver 20% 15% disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis” 0% FDA Draft Guidance, Noncirrhotic Nonalcoholic Steatohepatitis Placebo EFX 28mg EFX 50mg With Liver Fibrosis: Developing Drugs for Treatment (2018), p.7 N=41 N=38 N=34 ** *** p<0.01, p<0.001, versus placebo (CMH) ©2023 AKERO THERAPEUTICS. Source Data: Liver Biopsy Analysis Set 17
EFX NASH Resolution in Context: Pre-Cirrhotic NASH (NASH Resolution and No Worsening of Fibrosis) Akero Novo Nordisk Madrigal Inventiva Madrigal Efruxifermin Semaglutide Pegozafermin Lanifibranor Resmetirom Obeticholic Acid Phase 2b (F2-F3) Phase 2b (F2-F3) Phase 1b/2a (F2-F3) Phase 2b (F1-F3) Phase 3 (F1-F3) Phase 3 (F2-F3) 66% F3 69% F3 65% F3 % F3 Not Reported 62% F3 54% F3 1 2 4 3 3 2 24 Wks / Completers 72 Wks / ITT 24 Wks / Completers 24 Wks / Completers 52 Wks / ITT 72 Wks / ITT Consensus Readers Consensus Readers Consensus Readers Single Reader Two Readers Consensus Readers (Combined Statistically) By Reported Effect Size (Treatment Minus Placebo) *** 76% *** 59% ** ** 49% EFX 47% † 62% Effect * 40% *** 37% Sizes 36% 42% *** 26% 30% *** 32% 17% 26% *** 23% 23% 19% 17% 15% a 20% 35% 16% 10% HARMONY 24% 7% 6% 4% Placebo 2% Rate Placebo 28mg 50mg Placebo 0.2mg 0.4mg Placebo 0.8g 1.2g Placebo 80mg 100mg 10mg 25mg Placebo Placebo 15mg 30mg (N=41) (N=38) (N=34) (N=58) (N=59) (N=56) (N=62) (N=63) (N=69) (N=316)(N=321)(N=318) (N=312)(N=308) (N=61) (N=14) (N=66) (N=311) 1 2 Baseline and Week 24 biopsies available; Missing biopsies were Semaglutide - Newsome et al. (2020) New Engl J Med 384, 1113–1124; Pegozafermin - 89Bio Note: These data are derived from different clinical trials at 3 imputed as non-responders; End-of-study biopsy available with no (2023) March 22 Corporate Presentation; Lanifibranor - Francque et al. (2021) New Engl J different points in time, with differences in trial design and patient 4 major protocol deviations; End-of-study biopsy available. Med 385, 1547–1558; Resmetirom – Madrigal (2022) December 19 Press Release; Obeticholic populations. As a result, cross-trial comparisons cannot be a Modified definition of NASH resolution (requiring ≥2 point acid - Intercept (2022) July 7 Press Release. All trademarks are the property of their respective made, and no head-to-head clinical trials have been conducted. reduction in NAS) might lead to lower placebo response rate owners. † ©2023 AKERO THERAPEUTICS. 76.47 - 14.63 = 61.84 * p<0.05, ** p<0.01, *** p<0.001, versus placebo 18
Both EFX Doses Achieved Statistical Significance on Composite Endpoint (Fibrosis Improvement and NASH Resolution) Fibrosis Improvement 1 AND NASH Resolution at Week 24 Patients Achieving Fibrosis Improvement ≥2 Stages 60% and No Worsening of NASH at Week 24 Placebo EFX 28mg EFX 50mg 50% (N=41) (N=38) (N=34) *** *** 41% 41% 40% 5% 16% 15% ** ** 29 29% % 30% 1 Per FDA guidance, this endpoint is defined as: “Both resolution 20% of steatohepatitis and improvement in fibrosis…. Resolution of steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS score of 0– 10% 1 for inflammation, 0 for ballooning, and any value for 5% steatosis…. Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score)” 0% Placebo EFX 28mg EFX 50mg FDA Draft Guidance, Noncirrhotic Nonalcoholic Steatohepatitis N=41 N=38 N=34 With Liver Fibrosis: Developing Drugs for Treatment (2018), p.7-8 ** *** p<0.01, p<0.001, versus placebo (CMH) ©2023 AKERO THERAPEUTICS. Source Data: Liver Biopsy Analysis Set 19
Magnitude of Reduction and Normalization of Liver Fat Comparable 1 to Phase 2a BALANCED Study Proportion of Patients Achieving LS Mean Relative Percent Change From Baseline Fat Reduction Thresholds at Week 24 in Liver Fat at Week 24 0% Placebo EFX 28mg EFX 50mg Endpoint -10% (N=42) (N=38) (N=35) -6% -20% Relative Reduction in Liver Fat -30% -40% *** *** ≥50% 2% 63% 77% -50% *** *** - -52% 52% Normalization of -60% Liver Fat Content *** *** - -52% 64% -70% Placebo EFX 28 mg EFX 50mg *** *** ≤5% 2% 34% 51% N=42 N=38 N=35 *** *** p<0.001, versus placebo (ANCOVA) p<0.001, versus placebo (CMH) 1 The Phase 2a BALANCED study was a 12-week randomized clinical trial in patients with F1-F3 NASH ©2023 AKERO THERAPEUTICS. Source Data: MRI-PDFF Analysis Set (All subjects who have Baseline and Week 24 liver fat measurements) 20
Rapid and Sustained Statistically Significant Improvements in Markers of Liver Injury ALT AST LS Mean [SE] Change from Baseline (U/L) LS Mean [SE] Change from Baseline (U/L) Baseline: 50-63 U/L Baseline: 42-57 U/L 10 10 0 0 -2 U/L -3 U/L -2% -4% ** *** -10 -10 *** *** *** *** *** *** *** *** *** -21 U/L *** -20 -20 -22 U/L *** -39% *** -38% -28 U/L -30 *** -30 -33 U/L *** *** -49% *** *** *** -47% *** *** *** *** -40 -40 BLW1 W4 W8 W12 W16 W20 W24 BLW1 W4 W8 W12 W16 W20 W24 Placebo EFX 28 mg EFX 50 mg Placebo EFX 28 mg EFX 50 mg ** *** 1 *** 1 p<0.01, p<0.001, versus placebo (MMRM ) p<0.001, versus placebo (MMRM ) Statistically significant improvements also observed for GGT & ALP 1 Mixed Model Repeated Measures ©2023 AKERO THERAPEUTICS. Source Data: Full Analysis Set 21
Statistically Significant Reductions in Non-Invasive Markers Reflect Histological Improvement in Fibrosis LS Mean Change From Baseline to Week 24 Pro-C3 (µg/L) ELF Score Liver Stiffness by FibroScan (kPa) 1 0.2 0 +0.1 +0.1 0.1 0 0.0 -1 -0.7 -1 -0.1 -0.2 -2 -2 -0.3 † † -3 - -2.6 2.6 -0.4 -3 -0.5 -4 -0.6 -4 *** *** -5 - -0.6 0.6 -0.7 ** ** *** *** - -4.3 4.3 *** *** - -5.1 5.1 *** *** - -5.2 5.2 - -0.7 0.7 -6 -0.8 -5 1 Placebo EFX 28mg EFX 50mg Placebo EFX 28 mg EFX 50mg Placebo EFX 28 mg EFX 50mg N=40 N=37 N=35 N=42 N=37 N=34 N=42 N=38 N=36 1 1 2 *** p<0.001, versus placebo (MMRM ) *** p<0.001, versus placebo (MMRM ) ** p<0.01, versus placebo (ANCOVA ) † 2 p<0.01, versus baseline (ANCOVA ) 1 2 Mixed Model Repeated Measures; Analysis of Covariance ©2023 AKERO THERAPEUTICS. Source Data: Biomarker Analysis Set (Pro-C3 and ELF); Full Analysis Set (Liver Stiffness) (non-missing values only, no imputation) 22
Treatment-Emergent Adverse Events (TEAE) Placebo EFX 28mg EFX 50mg TEAE Overview (N=43) (N=40) (N=43) TEAE Leading to Death 0 (0%) 0 (0%) 0 (0%) a,b Drug-Related Serious Adverse Event (SAE) 0 (0%) 0 (0%) 1 (2%) c d,e Drug-Related TEAE Leading to Discontinuation 0 (0%) 2 (5%) 2 (5%) Most Frequent (≥15%) Drug-Related TEAEs Placebo EFX 28mg EFX 50mg Diarrhea 6 (14%) 14 (35%) 14 (33%) Nausea 5 (12%) 10 (25%) 14 (33%) Increased Appetite 2 (5%) 7 (18%) 10 (23%) Frequent Bowel Movements 1 (2%) 8 (20%) 0 (0%) Injection Site Erythema 5 (12%) 6 (15%) 7 (16%) Injection Site Bruising 1 (2%) 6 (15%) 3 (7%) a (1) Esophagitis b There were three additional non-drug-related SAEs: (1) Edema; (2) Covid-19; (3) Pancreatitis c (1) Increased appetite & weight gain; (2) diarrhea d (1) Esophagitis & vomiting; (2) Nausea e There was one additional non-drug-related SAE: Lymphadenopathy (not drug-related) ©2023 AKERO THERAPEUTICS. Source Data: Safety Set 23
Clinically Meaningful Improvements Observed in Glycemic Control and Insulin Sensitivity, Particularly in Patients with T2D 2 LS Mean Change From Baseline to Week 24 1 3 HbA1c(%) C-Peptide T2D Subset All T2D Subset All 0.0 0.0 20% 20% +16% 0.0 0.0 15% 15% -0.1 -0.1 +9% 10% 10% -0.2 -0.2 5% 5% 0% 0% -0.3 -0.3 † † -5% -5% - -0 0..3 3 -0.4 -0.4 -10% -10% * * - -0 0..4 4 -15% -15% -0.5 -0.5 ** ** ** ** - -16% 16% * * * * -20% - -17% 17% -20% - -0 0..5 5 - -0 0..5 5 ** ** *** *** -0.6 -0.6 -25% - -22% 22% -25% - -23% 23% 1 1 1 1 Placebo EFX 28mg EFX 50mg Placebo EFX 28mg EFX 50mg Placebo EFX 28mg EFX 50mg Placebo EFX 28mg EFX 50mg N=27 N=28 N=27 N=42 N=37 N=36 N=26 N=28 N=26 N=41 N=37 N=35 * ** *** † p<0.05, versus placebo (MMRM); p<0.05, versus baseline (MMRM) p<0.01, p<0.001, versus placebo (MMRM) 1 2 3 Absolute change from baseline, %; Patients remained on diabetic medications; Relative percent change from baseline ©2023 AKERO THERAPEUTICS. Source Data: Biomarker Analysis Set 24
Substantial Increases Observed in Adiponectin, a Marker of Insulin Sensitizing Action of EFX Adiponectin, LS Mean Change From Baseline at Week 24 (%) 100 *** +91% 90 80 70 60 50 ** +44% 40 30 20 +10% 10 0 Placebo EFX 28mg EFX 50mg N=42 N=36 N=33 ** p<0.01, *** p<0.001, versus placebo (MMRM) Source Data: Full Analysis Set, non-missing values only, no imputation ©2023 AKERO THERAPEUTICS. 25
Statistically Significant Improvements Observed in Lipoprotein Profile LS Mean Change From Baseline to Week 24 (%) Triglycerides LDL Cholesterol Non-HDL Cholesterol HDL Cholesterol +9% 10% 10% 10% 35% +9% +8% *** *** + +30 30% % 8% 30% 6% 5% *** *** + +24 24% % 0% 25% 4% 20% 2% 0% -10% 0% 15% -2% -5% 10% -4% -20% 5% -6% -10% 0% -8% *** *** -25% ** ** ** ** -25% *** *** *** *** - -8 8% % - -8 8% % - -13% 13% - -13% 13% -2% -30% -10% -15% -5% *** *** -29% -29% 1 1 1 Placebo EFX 28mg EFX 50mg Placebo EFX 28mg EFX 50mg Placebo EFX 28mg EFX 50mg Placebo EFX 28mg EFX 50mg N=42 N=35 N=35 N=42 N=35 N=35 N=42 N=35 N=35 N=42 N=35 N=35 *** ** *** *** p<0.01, versus placebo (MMRM) p<0.001, versus placebo (MMRM) p<0.001, versus placebo (MMRM) p<0.001, versus placebo (MMRM) Source Data: Full Analysis Set, non-missing values only, no imputation ©2023 AKERO THERAPEUTICS. 26
Weight Loss Observed for 50mg EFX Dose Group Body Weight, LS Mean Change at Week 24 (kg) 2.0 1.0 0.0 -0.2 -1.0 -0.6 -2.0 -3.0 †† †† - -2. 2.9 9 †† †† (-2.6% ) -4.0 -5.0 1 Placebo EFX 28mg EFX 50mg N=42 N=37 N=36 †† p<0.01, versus baseline (MMRM) Source Data: Full Analysis Set, non-missing values only, no imputation ©2023 AKERO THERAPEUTICS. 27
Cohort D Study Design 12 Weeks Primary Endpoint • Safety & Tolerability Placebo (N=10) Secondary Endpoints Key Inclusion Criteria • MRI-PDFF • Biopsy-confirmed NASH (F1-F3) • Fibrosis Markers a • Stable Dose of GLP-1 • ALT/AST • HbA1c • C-peptide EFX 50mg (N=21) • Lipoproteins • Weight Change Liver Biopsy MRI-PDFF a Approximately two-thirds of randomized patients were on a stable dose of GLP-1 for more than one year; all patients were on a stable dose for at least three months. ©2023 AKERO THERAPEUTICS. 28 Screening
Week 12 Patient Disposition & Key Analysis Sets Randomized (N=32) Randomized Not Dosed Placebo (N=1) Full Analysis Set – All patients who were randomized and received at Dosed (N=31) least one dose of study drug Safety Set - All subjects who received at least one dose of study drug Discontinued Prior to Week 12 (N=2) Withdrawn Nausea Consent EFX (N=1) EFX (N=1) Completed Week 12 (N=29) Placebo EFX 50mg (N=10) (N=19) ©2023 Akero Therapeutics. 29
Baseline Demographics Placebo EFX 50mg Parameter (Mean) (N=10) (N=21) Age (Years) 55 59 Sex (% Female) 90 43 Weight (kg) 96 101 Fibrosis Stage (% F1 / F2 / F3) 40 / 10 / 50 38 / 33 / 29 1 Hepatic Fat Fraction by MRI-PDFF (%) 15 11 2 Pro-C3 (μg/L) 34 33 Enhanced Liver Fibrosis (ELF) Score 9.6 9.2 3 Liver Stiffness by VCTE (FibroScan) (kPa) 12 10 Alanine Aminotransferase (ALT) (U/L) 31 35 Aspartate Aminotransferase (AST) (U/L) 24 26 HbA1c (%) 6.5 7.0 Triglycerides (mg/dL) 171 163 LDL-Cholesterol (mg/dL) 98 73 Statin Use (%) 50 81 1 2 3 Magnetic Resonance Imaging Proton Density Fat Fraction; Procollagen 3 N-Terminal Propeptide; Vibration-controlled transient elastography ©2023 Akero Therapeutics. 30
Concomitant Diabetic Medications at Baseline Placebo EFX 50mg GLP-1s (N=10) (N=21) 60% 43% Semaglutide Dulaglutide 30% 52% Liraglutide 10% 5% 1 Tirzepatide 0% 0% Other Diabetic Medications Placebo EFX 50mg Metformin 70% 76% Insulin 30% 48% SGLT-2 20% 33% Sulfonylureas 20% 24% DPP-IV 0% 10% 1 With one exception, all patients remained on their baseline GLP-1 therapy through Week 12; one patient entered treatment on a stable dose of semaglutide but switched to tirzepatide after the Week 10 visit due to unavailability of semaglutide. ©2023 Akero Therapeutics. Source Data: Safety Analysis Set 31
Primary Endpoint: Comparable Safety and Tolerability Across Both Treatment Groups Treatment-Emergent Adverse Event (TEAE) Placebo EFX 50mg (N=10) (N=21) Overview TEAE Leading to Death 0 (0%) 0 (0%) a Drug-Related Serious Adverse Event (SAE) 0 (0%) 0 (0%) b Drug-Related TEAE Leading to Discontinuation 0 (0%) 1 (5%) Placebo EFX 50mg Most Frequent (≥15%) Drug-Related TEAEs Diarrhea 3 (30%) 4 (19%) Nausea 1 (10%) 7 (33%) Increased Appetite 0 (0%) 5 (24%) Decreased Appetite 2 (20%) 3 (14%) a Two SAEs in the EFX group were not drug related: post-procedural hemorrhage and uterine cancer. b Nausea ©2023 AKERO THERAPEUTICS. Source Data: Safety Analysis Set 32
Significantly Greater Relative Reductions in Liver Fat by MRI-PDFF for EFX Combined with GLP-1 than GLP-1 Alone LS Mean Relative Percent Change From Baseline in Liver Fat at Week 12 0% -10% -10% -20% -30% -40% -50% -60% *** *** -70% -65% Placebo EFX 50mg N=10 N=16 *** 1 p<0.001, versus placebo (ANCOVA ) 1 Analysis of Covariance Source Data: MRI-PDFF Analysis Set (all subjects with baseline and on-study ©2023 AKERO THERAPEUTICS. 33 measurements assessed by MRI-PDFF [N=26]); Topline preliminary data
EFX Liver Fat Reduction in Context: NAFLD & Pre-Cirrhotic NASH Akero Akero Akero Madrigal Inventiva Novo Nordisk Novo Nordisk Madrigal 2 Semaglutide EFX Cohort D EFX BALANCED EFX HARMONY Pegozafermin Pemvidutide Liraglutide Tirzepatide Resmetirom Phase 1/2 Phase 2b Phase 2a Phase 2b Phase 2b Phase 1b Phase 4 Phase 2a Phase 3 QD QW QW QW QW QW QD QW QD NAFLD NASH (F1-F3) NASH (F1-F3) NASH (F2-F3) NASH (F2-F3) NAFLD T2D/NAFLD T2D/NAFLD NAFLD 12 Weeks 12 Weeks 24 Weeks 24 Weeks 24 Weeks 26 Weeks 48 Weeks 52 Weeks 52 Weeks 2 2 Pbo 30mg 4 Pbo 1.2mg Pbo 50mg Pbo 50mg Pbo 50mg Pbo 2.4mg Insulin 15mg Pbo 100mg Pbo 0.4mg (N=48)(N=44) (NA) (N=57) (N=10)(N=16) (N=21)(N=20) (N=42)(N=35) (N=19)(N=14) (N=318)(N=321) (N=50 (N=53) (N=33)(N=34) 1 3 BL LFC 11% 18% 18% >20% 21% 20% 18% 17% 18% 0% NA -6% -8% -10% -11% -11% -14% -14% -40% -33% -48% -52% -58% -64% -65% -71% -76% 1 2 Baseline Liver Note: These data are derived from different clinical trials Reported reductions only for subset of patients Pegozafermin - 89Bio (2023) May 6 Corporate Presentation; Pemvidutide - Altimmune (2023) Fat Content at different points in time, with differences in trial design with liver fat content ≥10% at baseline March Evercore NASH Renaissance Presentation; Liraglutide - Petit et al (2017) J Clin Endocrinol 3 and patient populations. As a result, cross-trial Estimated for subset of patients with LFC ≥10% Metab 102(2):407-15; Tirzepatide - Gastaldelli et al (2022) Lancet Diabetes Endocrinol 10(6):P393- comparisons cannot be made, and no head-to-head at baseline 406; Resmetirom - Madrigal (2023) May Corporate Presentation; Semaglutide - Flint et al. (2021) 4 clinical trials have been conducted. Insulin Degludec Aliment Pharmacol Ther 54(9):1150-61. All trademarks are the property of their respective owners. ©2023 AKERO THERAPEUTICS. 34
More Patients Treated with EFX Combined with GLP-1 Met Higher Thresholds of Liver Fat Reduction and Normalization than GLP-1 Alone Proportion of Patients Achieving Liver Fat Reduction Thresholds at Week 12 ≥ 50% Relative Reduction Normalization of Liver Fat (≤ 5%) ≥ 70% Relative Reduction 100% 100% 100% *** *** 88% 88% 90% 90% 90% 80% 80% 80% 70% 70% 70% ** 56% 60% 60% 60% 50% 50% 50% 40% 40% 40% 30% 30% 30% 20% 20% 20% 10% 10% 10% 10% 0% 0% 0% 0% 0% Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg N=10 N=16 N=10 N=16 N=10 N=16 *** *** 1 ** p<0.001, versus placebo (CMH) p<0.001, versus placebo (CMH ) p<0.01, versus placebo (CMH) In the HARMONY Study, patients whose liver fat was normalized had 3-fold higher odds of achieving NASH Resolution and Fibrosis Improvement 1 Cochran–Mantel–Haenszel test ©2023 Akero Therapeutics. Source Data: MRI-PDFF Analysis Set; Topline preliminary data 35
Greater Reductions in Markers of Fibrosis for EFX Combined with GLP-1 than GLP-1 Alone LS Mean Change From Baseline to Week 12 1 2 Pro-C3 (µg/L) ELF Score Liver Stiffness (kPa) FAST Score 0 0.2 0 0.05 +0.04 +0.1 0.1 0.00 0.0 -1 -0.1 -2 -1.1 -0.05 -0.2 -2 -0.3 -2.7 -0.10 -0.4 -4 -0.5 -3 -0.15 ††† -0.6 -3.0 ** -0.6 *** †† -0.7 -0.16 -5.2 1 -6 -4 -0.20 1 1 1 Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg N=10 N=21 N=10 N=21 N=10 N=21 N=10 N=21 †† 1 ** ††† *** p<0.01, versus baseline (MMRM) p<0.01, versus placebo (MMRM) p<0.001, versus baseline (MMRM) p<0.001, versus placebo (MMRM) 2 Measured by FibroScan 1 Mixed Model Repeated Measures (MMRM) ©2023 AKERO THERAPEUTICS. Source Data: Full Analysis Set; Topline preliminary data 36
Greater Reductions in Markers of Liver Injury for EFX Combined with GLP-1 than GLP-1 Alone ALT AST LS Mean Change from Baseline (U/L) LS Mean Change from Baseline (U/L) Baseline: 31 U/L (Placebo); 35 U/L (EFX) Baseline: 24 U/L (Placebo); 26 U/L (EFX) 2 2 1 0 +1.5 U/L 0 -2 -1 U/L -1 -4 -2 -3 -6 -4 -8 -5.3 U/L * -5 -10 U/L -10 * -6 * * -7 -12 BL WK1 WK4 WK8 WK12 BL WK1 WK4 WK8 WK12 Placebo EFX 50mg Placebo EFX 50mg * * p<0.01, versus placebo (MMRM) p<0.01, versus placebo (MMRM) ©2023 AKERO THERAPEUTICS. Source Data: Full Analysis Set; Topline preliminary data 37
Clinically Meaningful Improvements in HbA1c after Only 12 Weeks 1 HbA1c HbA1c Normalization LS Mean Change in HbA1c Proportion of Patients with 1 From Baseline to Week 12 Normalized HbA1c at Week 12 30% 0.2 0.1 23% 0.0 20% -0.1 -0.2 10% -0.2 -0.3 -0.4 0% ††† ††† -0.5 -0.5 0% 1 1 Placebo EFX 50mg Placebo EFX 50mg 2 2 N=10 N=21 N=4 N=13 ††† 1 p<0.001, versus baseline (MMRM) Normalization of HbA1c defined as an HbA1c of ≥6.5 at baseline and <6.5 at week 12 2 Number of patients with HbA1c ≥6.5 at baseline ©2023 AKERO THERAPEUTICS. Source Data: Full Analysis Set; Topline preliminary data 38
EFX Complements GLP-1 by Increasing Sensitivity to Insulin LS Mean Change From Baseline to Week 12 C-Peptide Insulin Adiponectin 140% 10% 0% ** +1 +129 29% % 120% 0% 100% -10% -3.5% 80% -10% -13% 60% -20% 40% -20% +16% † 20% -22% -26% -30% -30% 0% 1 Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg N=10 N=21 N=10 N=21 N=10 N=21 ** † p<0.01, versus placebo (MMRM) p<0.001, versus baseline (MMRM) ©2023 AKERO THERAPEUTICS. Source Data: Full Analysis Set; Topline preliminary data 39
Much Greater Improvements in Lipids for Patients Treated with EFX in Combination with GLP-1 than GLP-1 Alone LS Mean Percent Change From Baseline to Week 12 Triglycerides Non-HDL Cholesterol Apolipoprotein B LDL Cholesterol HDL Cholesterol *** 0% 0% 0% 0% 40% +38% 35% -4.1% -10% -5% -5% -2% -4.5% 30% -6.8% 25% -20% -10% -10% -4% 20% -30% -15% -15% -6% 15% -6.1% 10% -40% -20% -20% -8% † †† ††† -19% -8.0% 5% +2.5% * *** *** -42% -21% -42% -50% -25% -25% -10% 0% 1 1 1 1 Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg N=10 N=21 N=10 N=21 N=10 N=21 N=10 N=21 N=10 N=21 *** ††† * *** p<0.001, versus placebo p<0.01, versus baseline p<0.05, versus placebo p<0.001, versus placebo (MMRM) (MMRM) (MMRM) (MMRM) ©2023 AKERO THERAPEUTICS. Source Data: Full Analysis Set; Topline preliminary data 40
Weight Loss Maintained for EFX Combined with GLP-1 Body Weight, LS Mean Change at Week 12 (kg) 0.00 -0.25 -0.50 -0.75 -0.8 -1.00 -1.25 -1.2 Placebo EFX 50mg N=10 N=21 ©2023 AKERO THERAPEUTICS. Source Data: Full Analysis Set; Topline preliminary data 41
Cohort D Adds to a Growing Body of Evidence for EFX’s Potential as a Cornerstone NASH Treatment Key Take-Aways Complementing GLP-1 Potential for EFX on Top of GLP-1 to be More Effective than GLP-1 Alone v EFX and GLP-1 have complementary mechanisms of action. v Addition of EFX to GLP-1 in patients with Normalized NASH and type 2 diabetes was well Liver Fat tolerated, without additive GI side effects. Improved Improved v EFX with GLP-1 showed multiple benefits Fibrosis Lipoprotein After over GLP-1 alone: reduced markers of liver Markers Profile 12 Weeks in steatosis, injury and fibrosis with improved Cohort D glycemic control, dyslipidemia and weight loss maintained. Improved Weight v The Cohort D EFX profile was comparable to Glycemic Loss that seen in the previous BALANCED and Maintained Control HARMONY studies with EFX. ©2022 AKERO THERAPEUTICS. 42
Evaluating EFX in Patients with Cirrhosis Due to NASH (F4) Building on Encouraging 16-Week Data in Patients with F4 Fibrosis a FIBROSIS NASH 58% or in Phase 2a IMPROVEMENT RESOLUTION Achieved a 7 of 12 (58%) patients treated with EFX 50mg in a 16-week expansion cohort (Cohort C) of the Phase 2a BALANCED study achieved either a one- stage improvement in fibrosis without worsening of NASH or NASH resolution without worsening of fibrosis, compared to 0% of placebo patients ©2023 AKERO THERAPEUTICS. 43
Value of Preventing Progression to & Reversing From Cirrhosis Survival Free of Liver Transplantation 100% 80% F0 ~50% 60% 5-year mortality 50% F1 without liver transplant 40% F2 for F4 patients F3 20% F4 P<0.001 0% Follow-up (years) Angulo, P et al. (2015) Gastroenterology 149:389-397 ©2023 AKERO THERAPEUTICS. 44 Cumulative Survival (%)
Design of Phase 2a Proof-of-Concept Trial for Cirrhotic NASH (F4) 16 WEEKS Primary Endpoint • Safety & tolerability Placebo (n=10) Key Inclusion Criteria • Compensated cirrhosis (F4), Child-Pugh Class A Key Secondary Endpoints • Histology • Fibrosis markers EFX 50 mg (n=20) • Glycemic control • Lipoproteins * Liver Biopsy * Protocol amended to include voluntary end-of-treatment biopsies FibroScan Fibrosis Biomarkers (ELF, Pro-C3) ©2023 AKERO THERAPEUTICS. 45 Screening Randomization
High Rate of Fibrosis Improvement After Only 16 Weeks Among Patients with Cirrhosis (F4 NASH) Fibrosis Improvement ≥1 Stage Without 1,2 Worsening of NASH 40% 33% 30% 20% 4 10% 0% 0% Overall Placebo EFX 50mg n=5 n=12 1 2 No increase in NAS for ballooning, inflammation, or steatosis; Study not powered to assess statistical significance of changes in histological endpoints ©2023 AKERO THERAPEUTICS. Source Data: Liver Biopsy Analysis Set, F4 46
* EFX Results In Context: Fibrosis Improvement (F4) Fc-FGF21 ASK-1 Peg-FGF21 GAL-3 FXR FGF19 GLP-1 Efruxifermin Selonsertib Pegbelfermin Belapectin Obeticholic acid Aldafermin Semaglutide 16 Wks (Ph2a) 48 Wks (Ph3) 48 Wks (Ph2b) 52 Wks (Ph2b) 78 Wks (Ph3) 48 Wks (Ph2b) 48 Wks (Ph2b) SC Injection Oral SC Injection Oral Oral SC Injection SC Injection 33% Increasing dosing duration 78 Wks 48 Wks 31% 29% 28% 24% 23% 21% 15% 14% 13% 13% 12% 11% 11% 10% 7% 5% 2% 0% Pbo 50mg Pbo 6mg 18mg Pbo 20mg 40mg Pbo 2.4mg Pbo 2mpk 8mpk Pbo 10mg 25mg Pbo 1mg 3mg (n=5) (n=12) (n≈40) (n ≈40) (n=172) (n=351) (n=354) (n=39) (n=37) (n=39) (n=24) (n=47) (n=45) (n=46) (n=41) (n~306) (n~306)(n~306) (n ≈40) * Includes results from publicly reported NASH studies for single agents in F4 patients Aldafermin – NGM Bio (2023) May 4 Press Release; Selonsertib – Harrison, SH et al. (2020) J Note: These data are derived from different clinical reporting either ≥ 1-stage fibrosis improvement (belapectin and simtuzumab) or ≥ 1- Hepatol 73(1):26-39; Pegbelfermin – Abdelmalek, MF et al. (2021) AASLD Poster LP-8; trials at different points in time, with differences in stage fibrosis improvement and no worsening of NASH (EFX, selonsertib, Semaglutide – Loomba, R et al. (2022) EASL Presentation; Belapectin – Chalasani, N et al. trial design and patient populations. No head-to- Pegbelfermin and obeticholic acid); numerical values represent percent responders (2020), Gastro 158:1334–45; Obeticholic acid - Intercept (2022) September 30 Press Release head clinical trials have been conducted. ©2023 AKERO THERAPEUTICS. 47
NASH Resolution Also Observed in Patients with Cirrhosis (F4 NASH) 1,2 NASH Resolution 30% Change in NAS among Subjects Achieving NASH Resolution 25% EFX Subject Baseline NAS Week 16 NAS 20% A 7 1 B 3 1 C 6 1 3 10% Proportion of Subjects with ≥2 Point NAS Reduction Placebo EFX 50mg 0% 0% 1 (20%) 7 (58%) Overall Placebo EFX 50mg n=5 n=12 1 NAS score of 0 or 1 for lobular inflammation and a score of 0 for ballooning 2 Study not powered to assess statistical significance of histological endpoints ©2023 AKERO THERAPEUTICS. Source Data: Liver Biopsy Analysis Set, F4 48
Improvements in Fibrosis Biomarkers in Patients with Cirrhosis Support Histology Results (F4 NASH) LS Mean Change From Baseline to Week 16 1 Pro-C3 (µg/L) ELF Score Liver Stiffness (kPa) 0 0 0.4 +0.3 0.3 -1 -2 0.2 -2 -1.9 0.1 -4 -3.4 -3 0.0 -0.1 -4 -6 -0.2 -5 -0.3 -8 -6 †† -5.7 -0.4 ** * -0.4 -9.0 -10 -0.5 -7 CFB CFB CFB Placebo EFX 50mg Placebo EFX 50mg Placebo EFX 50mg n=10 n=20 n=10 n=20 n=10 n=20 * ** 1 p<0.05, versus placebo (ANCOVA) p<0.01, versus placebo (ANCOVA) Measured by FibroScan †† p<0.01, versus baseline (ANCOVA) Source Data: Biomarker Analysis Set, F4 (all Cohort C subjects with baseline and interpretable on-study measure of ELF or pro-C3, respectively); Liver Stiffness Analysis Set, F4 (all Cohort C subjects with baseline and interpretable on-study measure of Liver Stiffness); Topline preliminary data ©2023 AKERO THERAPEUTICS. 49
Placebo-Corrected Reductions in Cohort C (F4) Fibrosis Markers Consistent with Magnitude Observed for HARMONY (F2-F3) a b LS Mean Placebo-Corrected Change From Baseline to Week 24 or Week 16 1 Pro-C3 (µg/L) ELF Score Liver Stiffness (kPa) EFX 28mg EFX 50mg EFX 50mg EFX 28mg EFX 50mg EFX 50mg EFX 28mg EFX 50mg EFX 50mg 0.0 0 0.0 -0.1 -0.5 -1.0 -0.2 -1.0 -2.0 -0.3 -1.5 -0.4 -3.0 -2.0 -1.9 -0.5 -2.5 -4.0 -0.6 -3.0 -0.7 -5.0 -0.7 -0.7 -3.5 -0.8 -5.2 -5.3 -0.8 -3.6 -6.0 -5.6 -0.9 -4.0 -3.8 a b HARMONY / EFX 28mg HARMONY study (F2-F3); BALANCED Cohort C (F4) HARMONY / EFX 50mg Cohort C / EFX 50mg HARMONY (F2-F3) Source Data: Biomarker Analysis Set (Pro-C3 and ELF); Full Analysis Set (Liver Stiffness) (non-missing values only, no imputation) ©2023 AKERO THERAPEUTICS. CONFIDENTIAL 50 Cohort C (F4) Source Data: Biomarker Analysis Set (Pro-C3 and ELF); Liver Stiffness Analysis Set, F4
SYMMETRY Trial Design: Cirrhosis Due to NASH (F4) Key Inclusion Criteria Key Secondary Efficacy Endpoints Phase 2b Primary Endpoint • F4 NASH • Fibrosis Improvement • NASH Resolution • Glycemic Control (Cirrhosis reversal) • Fibrosis Markers • Weight Change • Lipoproteins • Liver Injury Markers Long-Term Safety Follow-Up 36 Weeks Placebo Placebo * EFX 28mg EFX * EFX 50mg EFX * Pending finalization of Phase 3 protocol Liver Biopsy Enrollment completed in December 2022 Readout expected in Q4’23 ©2023 AKERO THERAPEUTICS. 51 Phase 2b Screening Randomization
Looking Ahead
Looking Ahead to Phase 2b SYMMETRY Readout in Patients with Cirrhosis and Initiation of Phase 3 SYNCHRONY Studies Phase 2b Phase 3 F2-F3 F1-F3 F4 F2-F3 F1-F3 Patient Population: Cohort D SYNCHRONY SYNCHRONY Real- HARMONY (Expansion of Histology World SYMMETRY) Enrollment Complete; Primary Endpoint Initiation Expected Initiation Expected Status Completed Readout expected Completed in 2H’23 in 2H’23 in 4Q’23 Duration 24 Weeks 12 Weeks 36 Weeks TBD TBD EFX Doses 28, 50mg 50mg 28, 50mg 28, 50mg 28, 50mg Placebo-Controlled üüüüü ©2023 AKERO THERAPEUTICS. 53
Introducing the SYNCHRONY Phase 3 Program Three Planned Parallel Randomized, Placebo-Controlled Clinical Trials • Biopsy confirmed F2-F3 NASH • Non-invasively diagnosed NASH/NAFLD Design to be finalized following • Primary endpoint: ≥ 1-stage fibrosis • Primary endpoint: safety & tolerability SYMMETRY Phase 2b results improvement AND resolution of NASH • 28 and 50mg EFX The duration of and total number of subjects to be enrolled in the SYNCHRONY Histology and Real-World trials are subject to confirmation with the FDA ©2023 AKERO THERAPEUTICS. 54
Supplying API and Drug Product/Device for Phase 3 Drug Substance (API) Drug Product/Device Combination Commercial scale Commercially precedented Released for Phase 3 Released for Phase 3 Comparability demonstrated 1 mL SC weekly injection Self-administered, stable at 2-8ºC ©2023 AKERO THERAPEUTICS. 55
Backup Slides
EFX’s Four Attachment Points to Cellular Surface May Contribute to Stronger Receptor Binding and Enhanced Efficacy EFX Single-chain FGF21 Dimer structure may enable cooperative binding Two independent binding events preclude and enhance avidity effects cooperative binding or avidity effects ©2023 AKERO THERAPEUTICS. 57
Supportive Evidence for EFX’s Cooperative Binding to Cell Surface EFX (bivalent Fc-RGE) Monovalent RGE Monovalent Fc-RGE Monovalent 173-PEG20 association dissociation association dissociation association dissociation association dissociation No chase (labeled ligand removed) Single-chain FGF21 has slower association, Addition of Fc or 20 kDa PEG to single-chain Chase with 10x unlabeled excess faster and more complete dissociation FGF21 analog further slows association FGF21 Analog k (1/[M*s]) k (1/s) K (M) a d D >100-fold tighter binding (K ) of EFX vs. all monovalent D 5 -6 -11 EFX 1.8 x 10 3.3 x 10 1.8 x 10 analogs, i.e., RGE, Fc-RGE, or 173-PEG20: 4 -4 -9 Monovalent RGE 4.7 x 10 1.4 x 10 3.0 x 10 • faster rate of association [k ] AND a 4 -4 -9 Monovalent Fc-RGE 2.1 x 10 1.1 x 10 5.4 x 10 • much slower rate of dissociation [k ] d 4 -5 -9 Monovalent 173-PEG20 1.7 x 10 8.3 x 10 4.8 x 10 ©2023 AKERO THERAPEUTICS. 58 FITC-labeled FGF21 analog binding analysis to the surface of FGFR1c/KLB-expressing HEK293
Single FGF21 chain analogs fused to “half-life extenders” are 15- to 30- Fold Less Potent than EFX with two FGF21 chains’ or “unmodified FGF21” Bivalent Monovalent Monovalent Monovalent Fc-RGE RGE Fc-RGE 173-PEG20 (EFX) 20 kDa PEG Half-life extension Fc-fusion minimal Fc-fusion at residue 173 N-terminus N-terminus FGF21-receptor 20 kDa PEG linked none linked hindrance at residue 173 to IgG1 Fc to IgG1 Fc mol. FGF21 / 2 1 1 1 mol. analog K (affinity) D .018 nM 3 nM 5.4 nM 4.8 nM on live cells EC (potency), 50 cell-based 0.24 nM 0.52 nM 7.93 nM 16.2 nM bioassay • Monovalent Fc-RGE is less potent (higher EC ) and a partial agonist (smaller fold induction) than Monovalent RGE 50 • Likely steric hindrance effect due to Fc • Adding a second FGF21(RGE) to monovalent Fc-RGE, forming bivalent Fc-RGE (EFX) restores full agonism and is much more potent (lower EC ) 50 • More than overcomes steric hindrance of Fc • Addition of 20 kDa PEG at residue 173 appears to maintain full agonism but is associated with lower potency (higher EC ) 50 ©2023 AKERO THERAPEUTICS. 59
Potential for Translation from Phase 2 to Phase 3: Fibrosis Improvement Akero Madrigal Madrigal Efruxifermin Resmetirom Resmetirom Phase 2b (F2-F3) Phase 2 (F1-F3) Phase 3 (F1-F3) 66% F3 20% F3 62% F3 1 2 3 24 Wks / Completers 36 Wks / Completers 52 Wks / ITT Consensus Readers Single Reader Two Readers (Combined Statistically) * 41% * 39% EFX 29% Effect † 21% 20% *** 26% Sizes *** 24% 5% 24% 20% 12% 10% 14% HARMONY Placebo Rate Placebo 28mg 50mg Placebo All Placebo 80mg 100mg (N=41) (N=38) (N=34) (N=34) (N=73) (N=316)(N=321)(N=318) 1 2 Baseline and Week 24 biopsies available; Completed 36 weeks of Resmetirom (Phase 2) - Harrison, S et al. (2019) Lancet 394(10213):2012-24; (Resmetirom Note: These data are derived from different clinical trials at 3 treatment and had end-of-study biopsy; Missing biopsies were Phase 3) – Madrigal (2022) December 19 Press Release. All trademarks are the property of different points in time, with differences in trial design and patient imputed as non-responders. their respective owners. populations. As a result, cross-trial comparisons cannot be made, and no head-to-head clinical trials have been conducted. † ©2023 AKERO THERAPEUTICS. 39.47 - 19.51 = 19.96 * p<0.05, *** p<0.001, versus placebo 60
Potential for Translation from Phase 2 to Phase 3: NASH Resolution Akero Madrigal Madrigal Efruxifermin Resmetirom Resmetirom Phase 2b (F2-F3) Phase 2 (F1-F3) Phase 3 (F1-F3) 66% F3 20% F3 62% F3 1 2 3 24 Wks / Completers 36 Wks / Completers 52 Wks / ITT Consensus Readers Single Reader Two Readers (Combined Statistically) *** 76% ** EFX 47% † 62% Effect Sizes *** 30% *** 32% 26% 25% 15% 10% 15% a 20% 16% 10% HARMONY Placebo Rate Placebo 28mg 50mg Placebo All Placebo 80mg 100mg (N=41) (N=38) (N=34) (N=34) (N=73) (N=316)(N=321)(N=318) 1 2 Baseline and Week 24 biopsies available; Completed 36 weeks of Resmetirom (Phase 2) - Harrison, S et al. (2019) Lancet 394(10213):2012-24; (Resmetirom Note: These data are derived from different clinical trials at 3 treatment and had end-of-study biopsy; Missing biopsies were Phase 3) – Madrigal (2022) December 19 Press Release. All trademarks are the property of different points in time, with differences in trial design and patient imputed as non-responders. their respective owners. populations. As a result, cross-trial comparisons cannot be a Modified definition of NASH resolution (requiring ≥2 point made, and no head-to-head clinical trials have been conducted. reduction in NAS) might lead to lower placebo response rate † ©2023 AKERO THERAPEUTICS. 76.47 - 14.63 = 61.84 * p<0.05, ** p<0.01, *** p<0.001, versus placebo 61
From BALANCED to HARMONY Endpoints Placebo EFX 28mg EFX 50mg % Responders, Histology and Liver Fat Normalization HARMONY BALANCED HARMONY BALANCED HARMONY Fibrosis improvement ≥ 1 stage and no worsening of NASH 20 46 39 62 41 NASH resolution and no worsening of fibrosis 15 46 47 54 76 Fibrosis improvement AND resolution of NASH 5 31 29 39 41 Normalization of liver fat to ≤5% 5 21 34 45 51 a b a b BALANCED HARMONY BALANCED HARMONY Non-Invasive Tests Pro-C3 (μg/L) -5.3 -5.2 -3.9 -5.3 ELF Score -0.7 -0.7 -0.8 -0.8 Placebo-Adjusted # # LS Mean Liver Stiffness (kPa) n/a -1.9 -3.8 -3.6 Absolute Change Body Weight (kg) -0.2 0.4 -2.2 -2.3 HbA1c, % (T2D subset) 0.1 -0.5 -0.6 -0.6 C-peptide -44.9 -25.2 -42.9 -31.7 Adiponectin 72.8 33.9 92.2 80.8 Liver Fat Content -63.0 -45.5 -70.6 -57.6 ALT -41.2 -34.1 -50.8 -43.6 Placebo-Adjusted LS Mean AST -40.1 -37.6 -45.5 -47.4 Relative Change (%) Triglycerides -43.0 -34.0 -51.4 -37.2 LDL Cholesterol -15.6 -16.9 -2.1 -16.2 Non-HDL Cholesterol -20.6 -20.2 -13.1 -20.7 HDL Cholesterol 29.8 25.8 34.6 32.1 a b # Change from baseline to week 12 (ELF, Liver Fat) or week 16 (all other endpoints); Change from baseline to Week 24; Change in Liver Stiffness in BALANCED was only assessed in Cohort C in patients with cirrhotic NASH ©2023 AKERO THERAPEUTICS. 62
High Level of Consistency Across Four Clinical Studies of EFX EFX 50mg EFX 50mg EFX 50mg EFX 50mg 1 2 3 4 BALANCED Cohort C HARMONY Cohort D Endpoints Non-Invasive Tests F1-F3 F4 F2-F3 F1-F3 16 Weeks 16 Weeks 24 Weeks 12 Weeks Pro-C3 (μg/L) -4.7 -9.5 -5.2 -5.2 ELF Score -0.7 -0.4 -0.7 -0.6 LS Mean Liver Stiffness (kPa) NT -5.7 -4.3 -3.0 Absolute Change Body Weight (kg) -1.7 -2.2 -2.9 -1.2 HbA1c, % (T2D Patients Only) -0.6 -0.5 -0.5 -0.5 Insulin -16 -48 NT -26 C-peptide -22 -20 -23 -22 Adiponectin +80 +95 +91 +129 Liver Fat Content -71 NT -64 -65 ALT -51 -22 -47 -24 AST -44 -26 -49 -17 LS Mean Relative Change (%) Triglycerides -48 -40 -29 -42 Non-HDL Cholesterol -15 -14 -13 -19 Apolipoprotein B -12 -11 -3.9 -21 LDL Cholesterol -2.3 -8 -8 -8 HDL Cholesterol +39 +33 +30 +38 1 2 3 4 Change from baseline (CFB) to week 12 (ELF, Liver Fat) or week 16 (all other endpoints); CFB to week 16; CFB to Week 24; CFB to Week 12 NT = Not Tested Note: These data are derived from different clinical trials with differences in patient populations, study duration, trial design, baseline demographics, and placebo rates. ©2023 AKERO THERAPEUTICS. 63
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