Akero Therapeutics, Inc. operates as a clinical-stage company dedicated to developing transformational treatments for patients with serious metabolic diseases marked by high unmet medical need, including metabolic dysfunction-associated steatohepatitis, or MASH.
The company’s lead product candidate, efruxifermin, or EFX, is an analog of fibroblast growth factor 21, or FGF21, which is an endogenously expressed hormone that protects against cellular stress and regulates the metabolism of lipids,...
Akero Therapeutics, Inc. operates as a clinical-stage company dedicated to developing transformational treatments for patients with serious metabolic diseases marked by high unmet medical need, including metabolic dysfunction-associated steatohepatitis, or MASH.
The company’s lead product candidate, efruxifermin, or EFX, is an analog of fibroblast growth factor 21, or FGF21, which is an endogenously expressed hormone that protects against cellular stress and regulates the metabolism of lipids, carbohydrates, and proteins throughout the body. The company has initiated a Phase 3 program called SYNCHRONY, which consists of three ongoing clinical trials (Outcomes, Histology, and Real-World) designed to support applications for marketing approval for patients with compensated cirrhosis (F4) due to MASH, and pre-cirrhotic MASH (F2-F3). The SYNCHRONY program builds on two biopsy-based Phase 2b trials in corresponding patient populations, with a combined total of over 300 patients treated for up to 96 weeks. Based on the statistically significant reversal of cirrhosis and fibrosis regression among patients with either biopsy-confirmed compensated cirrhosis (F4) due to MASH, or pre-cirrhotic MASH (F2-F3) observed in the company’s Phase 2b clinical trials, EFX has the potential to be an important medicine for treating MASH.
Results from five randomized, double-blind, placebo-controlled clinical trials evaluating EFX have been reported, and across all trials reported to date, a total of 385 adult patients with either MASH and/or type 2 diabetes have been treated with EFX and evaluated for up to 96 weeks. An additional 66 healthy volunteers or patients with severe hepatic impairment were evaluated in open label, single-dose clinical pharmacology studies.
In January 2025, the company reported preliminary topline week 96 results from SYMMETRY, a Phase 2b trial evaluating the efficacy and safety of EFX in patients with biopsy-confirmed compensated cirrhosis (F4), Child-Pugh Class A, due to MASH. The trial previously showed a numerical trend but not statistical significance on the primary endpoint of =1 stage improvement in fibrosis with no worsening of MASH after 36 weeks of treatment, with 24% and 22% for the 50mg and 28mg EFX dose groups, compared to 14% for the placebo arm. At week 96, among patients with baseline and week 96 biopsies (N=134), 39% of patients treated with 50mg EFX (n=46) (p=0.009) experienced reversal of cirrhosis with no worsening of MASH, compared to 15% for placebo (n=47). By intent to treat, or ITT, analysis (N=181), with all missing week 96 biopsies treated as failures, 29% of the 50mg EFX patients (n=63) (p=0.031) experienced reversal of cirrhosis with no worsening of steatohepatitis, compared to approximately 12% for placebo (n=61). Statistically significant results were also observed for MASH resolution by both completer and ITT analyses. In a subgroup of patients with baseline and week 96 biopsies who were not taking a GLP-1 receptor agonist (GLP-1) at baseline (N=97), 45% (p=0.009) in the 50mg EFX group (n=29) experienced reversal of cirrhosis with no worsening of MASH compared to 17% for placebo (n=36), suggesting that the observed reversal of cirrhosis was not attributable to GLP-1 therapy. Results for the 28mg EFX group on these measures were numerically higher than placebo but not statistically significant. Only the 50mg EFX group is being evaluated in the Phase 3 SYNCHRONY Outcomes study in patients with compensated cirrhosis (F4) due to MASH.
In March 2024, the company reported preliminary topline week 96 results from HARMONY, a Phase 2b trial evaluating the efficacy and safety of EFX in patients with pre-cirrhotic MASH, fibrosis stage 2 or 3 (F2-F3). The trial previously met its primary endpoint of =1 stage improvement in fibrosis with no worsening of MASH after 24 weeks of treatment for both the 50mg EFX (41%, p<0.001) and 28mg EFX (39%, p<0.001) dose groups, compared to 20% for the placebo arm. At week 96, the response rates on this endpoint increased to 75% (p<0.001) for 50mg EFX and 46% for 28mg EFX, compared to 24% for placebo. EFX was also observed to achieve statistical significance on additional histology endpoints at week 96. Notably, 36% (p=0.002) and 31% (p<0.001) of patients treated with 50mg EFX and 28mg EFX experienced a 2-stage improvement in fibrosis without worsening of MASH—which is more than 10-fold the placebo rate of 3%. In addition, among a subgroup of patients with F3 fibrosis at baseline (N=56), 68% (p<0.001) of patients in the 50mg EFX group were observed to achieve at least a 1-stage improvement in fibrosis without worsening of MASH, compared to 14% for placebo. Both the 28mg and 50mg EFX dose groups are being evaluated in the Phase 3 SYNCHRONY Histology study in patients with pre-cirrhotic (F2-F3) MASH.
EFX has been reported to be generally well-tolerated across completed clinical trials of EFX to date. Most adverse events, or AEs, were mild or moderate. Diarrhea, nausea, and vomiting, as well as injection site reactions, were generally the most common AEs. Treatment-emergent AEs leading to discontinuation through each study's primary analysis period have been low, ranging from less than 5% in patients with F1-F3 MASH to less than 10% in subjects with compensated cirrhosis due to MASH (F4).
Enrollment for a multi-trial, global Phase 3 program called SYNCHRONY began in the fourth quarter of 2023. The Phase 3 SYNCHRONY program consists of three trials, SYNCHRONY Outcomes, SYNCHRONY Histology, and SYNCHRONY Real-World. SYNCHRONY Outcomes is a two-cohort trial evaluating EFX for the treatment of patients with compensated cirrhosis (F4), Child-Pugh Class A, due to MASH. Patients are receiving weekly injections of either EFX 50mg or placebo. The primary histology endpoint, for Cohort 1 only, is the proportion of patients experiencing = 1-stage improvement in fibrosis and no worsening of steatohepatitis after 96 weeks of treatment. The primary outcomes endpoint for all patients enrolled across Cohort 1 and Cohort 2 is the time from randomization to the first occurrence of any protocol-specified clinical event. SYNCHRONY Histology is a two-cohort trial evaluating EFX for the treatment of patients with pre-cirrhotic MASH, fibrosis stage 2 or 3 (F2-F3). Patients are receiving weekly injections of 28mg EFX, 50mg EFX, or placebo. The primary histology endpoint, for Cohort 1 only, to support an application for accelerated approval, is the proportion of patients experiencing = 1-stage fibrosis improvement and resolution of MASH after 52 weeks of treatment. All patients in Cohort 1 and Cohort 2 will be evaluated for long-term clinical outcomes for up to 240 weeks of treatment. Results for the 52-week primary histology endpoint from the SYNCHRONY Histology trial are expected in the first half of 2027. SYNCHRONY Real-World is evaluating EFX for the treatment of patients with MASH, fibrosis stages 1 through 4, compensated (F1-F4, compensated). The primary endpoint of safety and tolerability will be assessed after 52 weeks of treatment. In January 2025, the company announced the completion of enrollment of the double-blind portion of SYNCHRONY Real-World. Results from the SYNCHRONY Real-World trial are expected in the first half of 2026.
In five separate clinical trials in patients with MASH and/or type 2 diabetes, EFX has been observed to reverse cirrhosis, reverse moderate to advanced fibrosis, resolve steatohepatitis, and help restore healthy metabolism to the whole body.
In June 2018, the company acquired exclusive global development and commercialization rights to EFX from Amgen Inc., or Amgen, which leveraged its deep protein engineering expertise to design and develop EFX. As of February 14, 2024, the company’s patent portfolio relating to EFX and other peptides included 209 issued patents and 17 pending patent applications worldwide, with expected patent exclusivity up to 2034 in the United States, including potential patent term extension. Recently filed patent applications, if granted, may extend patent exclusivity to 2045. Since EFX is a biologic, marketing approval would also provide twelve years of market exclusivity from the approval date of a Biologics License Application, or BLA, in the United States.
Strategy
The key components of the company’s strategy are to advance EFX through clinical development for both compensated cirrhosis (F4) due to MASH and pre-cirrhotic (F2-F3) MASH; scale the company’s capabilities to support development and commercialization of EFX; leverage its knowledge of FGF21 biology to bring EFX to additional patients with metabolic diseases; and enhance its position as a leading metabolic disease company by developing, acquiring, or in-licensing additional investigational product candidates.
Pipeline
The company’s pipeline is anchored by EFX, a potential treatment for MASH. The company has one EFX program focused on patients with pre-cirrhotic MASH (F2-F3) and a second EFX program focused on patients with compensated cirrhosis due to MASH (F4).
Phase 3 Evaluation of EFX
Enrollment for a multi-trial, global Phase 3 program called SYNCHRONY began in the fourth quarter of 2023. The Phase 3 SYNCHRONY program consists of three randomized, placebo-controlled trials: SYNCHRONY Outcomes, SYNCHRONY Histology, and SYNCHRONY Real-World. The comprehensive SYNCHRONY program (N ~3,500) builds on two biopsy-based Phase 2b studies (N ~300) in corresponding patient populations.
SYNCHRONY Outcomes is a two-cohort trial evaluating treatment with EFX in approximately 1,150 patients with compensated cirrhosis (F4), Child-Pugh Class A, due to MASH. Patients are receiving weekly injections of either EFX 50mg or placebo. The primary histology endpoint, for Cohort 1 only, is the proportion of patients experiencing = 1-stage improvement in fibrosis and no worsening of steatohepatitis after 96 weeks of treatment. The primary outcomes endpoint for all patients enrolled across Cohort 1 and Cohort 2 is the time from randomization to the first occurrence of any protocol-specified clinical event.
SYNCHRONY Histology is a two-cohort trial evaluating EFX in the treatment of approximately 1,650 patients with pre-cirrhotic MASH, fibrosis stage 2 or 3 (F2-F3). Patients are receiving weekly injections of 28mg EFX, 50mg EFX, or placebo. The primary histology endpoint, for Cohort 1 only, to support an application for accelerated approval, is the proportion of patients experiencing = 1-stage fibrosis improvement and resolution of MASH after 52 weeks of treatment. All patients in Cohort 1 and Cohort 2 will be evaluated for long-term clinical outcomes for up to 240 weeks of treatment. Results for the 52-week primary histology endpoint from the SYNCHRONY Histology trial are expected in the first half of 2027.
SYNCHRONY Real-World is evaluating EFX in the treatment of approximately 700 patients with fibrosis stages 1 through 4, compensated (F1-F4, compensated), including up to 100 patients in an open-label rollover of placebo patients from the Phase 2b HARMONY and SYMMETRY studies who are being treated with 50mg EFX. The primary endpoint of safety and tolerability is being assessed after 52 weeks of treatment. Enrollment of the double-blind portion of SYNCHRONY Real-World (N=601) was completed in January 2025. Results from the SYNCHRONY Real-World trial are expected in the first half of 2026.
In all EFX Phase 3 studies, patients are self-administering EFX using the LyoJect 3S dual chamber syringe, a pre-filled device intended for commercial use in the event EFX is approved for marketing. This optimized formulation delivers blood levels of EFX comparable to those of the liquid formulation used in prior clinical studies.
Phase 2b Evaluation of EFX
The company’s Phase 3 SYNCHRONY program evaluating EFX for the treatment of pre-cirrhotic and cirrhotic MASH builds on the results of two separate 96-week Phase 2b studies, the SYMMETRY study in patients with compensated cirrhosis (F4) due to MASH, and the HARMONY study in patients with pre-cirrhotic MASH (F2-F3).
Biopsy Analysis in Phase 2b HARMONY and SYMMETRY Studies
Consistent with FDA recommendations, the HARMONY and SYMMETRY studies evaluate all biopsies using consensus readers. Two independent and cross-trained pathologists score each biopsy for NAS score and fibrosis stage. If there are any differences on any component of pathology scoring, the two pathologists determine if consensus can be reached. In the absence of consensus, a third pathologist would adjudicate between the first two pathologists’ scores. Adjudication by a third pathologist was not required because the two principal pathologists achieved consensus on the interpretation of all weeks 24 and week 96 HARMONY and SYMMETRY biopsy samples.
Per applicable FDA guidance regarding endpoints recommended for use in Phase 3 clinical trials, the HARMONY and SYMMETRY studies’ primary and key secondary histology endpoints were defined as:
Proportion of subjects who achieve improvement in liver fibrosis greater than or equal to one stage (MASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis)
Proportion of subjects who achieve resolution of steatohepatitis (defined as a NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis) and no worsening of liver fibrosis on MASH CRN fibrosis score.
Proportion of subjects who achieve improvement in liver fibrosis greater than or equal to one stage and no worsening of steatohepatitis.
EFX for the Treatment of Compensated Cirrhosis Due to MASH (F4)
Compensated cirrhosis due to MASH (F4) represents a high unmet medical need. Approximately 50 percent of patients with cirrhosis die within 5 years of diagnosis, absent a liver transplant. The risk of liver-related clinical events, such as hospitalization for acute or chronic liver failure, or hepatocellular carcinoma, as well as cardiovascular events, is substantially higher for patients with cirrhosis. The FDA has issued draft guidance specific to the development of investigational therapies for patients with cirrhosis due to MASH, who are projected to number more than 3 million patients in the United States by 2030. According to the FDA, the treatment goal for cirrhotic patients is to halt disease progression, thereby preventing clinical decompensation, reducing the incidence of liver transplantation, and improving survival. Published FDA guidance states that long-term clinical outcomes data obtained in Phase 3 trials is required for marketing approval of investigational drugs indicated for the treatment of compensated cirrhosis (F4) due to MASH.
Phase 2b clinical trial of EFX in patients with compensated cirrhosis (F4) due to MASH
The Phase 2b SYMMETRY study was a 96-week multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial in biopsy-confirmed adult patients with compensated cirrhosis (F4) due to MASH. One hundred eighty-two patients were randomized to receive once-weekly subcutaneous dosing of 28mg or 50mg EFX, or placebo. The study incorporated two timepoints for histological evaluation, at weeks 36 and 96. The primary efficacy endpoint for the study was the proportion of subjects who achieved at least a one-stage improvement in fibrosis without worsening of MASH at week 36. Key secondary endpoints included fibrosis improvement without worsening of MASH and MASH resolution without worsening of fibrosis at week 96, and change from baseline in noninvasive markers of liver fibrosis and liver injury, insulin sensitivity, and lipoproteins at 36 and 96 weeks, as well as measures of safety and tolerability.
Treatment with EFX significantly improved two important noninvasive markers of liver fibrosis: ELF and liver stiffness.
Phase 2b HARMONY Study in Patients with Pre-Cirrhotic MASH (F2-F3)
The Phase 2b HARMONY study was a 96-week multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial in biopsy-confirmed adult patients with pre-cirrhotic MASH (F2-F3). The study enrolled a total of 128 patients, randomized to receive once-weekly subcutaneous dosing of 28mg or 50mg EFX or placebo. The primary efficacy endpoint for the study was the proportion of subjects who achieved at least a one-stage improvement in fibrosis without worsening of MASH at week 24. Key secondary histology endpoints included MASH resolution without worsening of fibrosis and a composite endpoint of both MASH resolution and fibrosis improvement at weeks 24 and 96, as well as fibrosis improvement without worsening of MASH at week 96. Additional secondary measures included change from baseline in liver fat, markers of liver injury, noninvasive markers of liver fibrosis, glycemic control, lipoproteins, and body weight at 24 and 96 weeks, as well as safety and tolerability measures.
Evaluation of EFX in combination with GLP-1 therapy in patients with pre-cirrhotic MASH
The Phase 2b SYMMETRY study included an expansion cohort, known as Cohort D, evaluating the administration of EFX to patients with type 2 diabetes who are already being treated with GLP-1 receptor agonist, or GLP-1, therapy. Approximately two-thirds of patients with F2 or F3 MASH, and roughly three-quarters of patients with compensated cirrhosis due to MASH, also have type 2 diabetes. Given the increasing use of GLP-1 for the treatment of patients, the company expects that many patients who could be eligible for treatment with EFX, if approved, may receive GLP-1 therapy. Cohort D was designed to assess whether EFX could be added in patients with MASH who are already being treated with GLP-1 for type 2 diabetes.
Cohort D enrolled a total of 32 patients with type 2 diabetes and F1-F3 liver fibrosis due to MASH. 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.
In addition, on key non-invasive measures of liver injury and fibrosis, EFX combined with GLP-1 therapy was more effective than GLP-1 alone, in most cases with statistical significance despite the modest study size. Likewise, glycemic control and lipid profiles were improved more by the combination of EFX with GLP-1 than GLP-1 alone.
Exclusive license agreement with Amgen Inc.
In June 2018, the company entered into an exclusive license agreement with Amgen Inc., or Amgen, pursuant to which it has been granted an exclusive, royalty-bearing license to certain intellectual property rights owned or controlled by Amgen, to commercially develop, manufacture, use, distribute, and sell therapeutic products, or Products. In particular, the company has been granted licenses under patents filed in both the United States and foreign jurisdictions that are owned or controlled by Amgen, including an exclusive license under certain patents claiming polypeptides consisting of an FGF21 portion with certain point mutations, a linker, and an Fc domain. The company’s exclusively licensed patents include, but are not limited to, the composition of EFX and methods of using the same. In connection with the license, Amgen also licensed and transferred to the company certain know-how related to the manufacture of EFX, as well as certain quantities of EFX drug substance manufactured to Good Manufacturing Practices, or GMP, for clinical use, master cell bank, not-for-human use EFX drug product suitable for nonclinical studies, and critical reagents.
Intellectual property
As of February 14, 2024, the company had licensed from Amgen Inc. approximately 209 issued patents and 14 pending patent applications worldwide.
As of February 14, 2024, the company’s patent portfolio relating to EFX includes 14 issued U.S. patents, one pending U.S. patent application, and issued and pending foreign counterpart patents in Europe, Asia, Canada, Australia, and Mexico. Nine issued U.S. patents include claims directed to the EFX product, the FGF21 polypeptide component of the EFX product, nucleic acids encoding the product and related polypeptides, polypeptide multimers, related compositions, and methods of using EFX to, e.g., treat diabetes, lower blood glucose in patients suffering from a metabolic disorder, improve glucose tolerance, lower body weight, or reduce triglyceride levels in patients. These issued U.S. patents are expected to expire in 2029. The pending U.S. patent application and related foreign counterparts are directed to a method of treating a patient with MASH; if issued, the resulting U.S. patent is expected to expire in 2029. The company currently anticipates that a composition of matter patent will be eligible for patent term extension to 2034 in the U.S. The portfolio further includes five issued U.S. patents that are directed to related polypeptides and methods of use. International patent applications are pending relating to EFX formulations and FGF21 variant multimers. There is a pending U.S. provisional application directed to methods of using EFX to treat liver and lung injury, and a pending U.S. provisional patent application directed to a drug delivery device. A design patent application also has been filed relating to the device.
Manufacturing and supply
The company has an agreement with Boehringer Ingelheim Biopharmaceuticals GmbH, or Boehringer Ingelheim, to manufacture DS for clinical development and plans in the future to enter into an agreement for commercial supply. Whereas the company’s Phase 2a BALANCED study was supplied by DS acquired by Amgen, the company’s ongoing Phase 3 SYNCHRONY studies are being supplied by DS manufactured by Boehringer Ingelheim. Analysis of the Boehringer Ingelheim GMP DS confirmed it met the same release specification as previously used for Amgen GMP DS and was comparable to Amgen GMP DS across a number of protein characterization studies. Validation of the commercial scale Boehringer Ingelheim DS manufacturing process has been successfully completed.
The company has an agreement with Vetter Pharma International GmbH, or Vetter, to manufacture EFX drug product, or DP, for clinical development and plans in the future to enter into an agreement for commercial supply. The GMP DP used for the company’s completed Phase 2b HARMONY and SYMMETRY studies, which was stored as a frozen liquid until immediately before administration to trial subjects, was similar to that for the Phase 2a BALANCED study, which was made from Amgen GMP DS. Analysis of the Vetter Phase 2b GMP DP confirmed that it met the same release specification as previously used for the Phase 2a DP manufactured from Amgen GMP DS.
The company is using a lyophilized DP formulation for Phase 3 SYNCHRONY studies and plans to use this formulation as the initial commercial presentation, if EFX is approved. This drug-device combination product, employing Vetter’s Lyo-Ject 3S dual-chamber syringe, was selected for convenient subcutaneous self-administration by patients. Manufacturing of the product-device combination by Vetter for Phase 3 clinical trials has been conducted under GMP conditions. Analysis of the Vetter Phase 3 lyophilized GMP DP confirmed that it met the same release specification as previously used for the Phase 2b frozen DP. A Phase 1 biocomparison study, performed before Phase 3 clinical studies commenced, confirmed that plasma levels of the lyophilized Phase 3 DP were comparable to those of the frozen Phase 2b formulation, following a single subcutaneous dose.
Sales and marketing
Successful marketing of a new drug for the treatment of MASH will require a targeted commercial infrastructure, which the company has begun making plans for commercialization in parallel with its ongoing Phase 3 SYNCHRONY program. The company intends to develop the commercial infrastructure required for bringing EFX to patients in the United States, if approved. The company also plans to evaluate options for delivering EFX, if approved, to patients in other key markets, such as Europe, Japan, and China, which may include strategic collaborations.
Government Regulation
Prior to beginning the first clinical trial with a product candidate, the company must submit an IND to the FDA.
In the United States, the company’s current and future operations are subject to regulation by various federal, state, and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services, or HHS (such as the Office of Inspector General, Office for Civil Rights, and the Health Resources and Service Administration), the U.S. Department of Justice, or DOJ, and individual U.S. Attorney offices within the DOJ, as well as state and local governments.
In addition to the foregoing, local, state, and federal laws regarding such matters as safe working conditions, manufacturing practices, environmental protection, fire hazard control, and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act, and the Toxic Substances Control Act, affect its business.
Research and Development
The company’s research and development expenses were $247.5 million for the year ended December 31, 2024.
Trademarks
Akero Therapeutics, Inc. is the owner of the AKERO trademark, as well as certain other trademarks, including design versions of some of these trademarks.
History
The company was founded in 2017. It was incorporated under the laws of the state of Delaware in 2017. The company was formerly known as Pippin Pharmaceuticals, Inc. and changed its name to Akero Therapeutics, Inc. in 2018.
