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 preliminary topline week 96 results from HARMONY, a Phase
2b study evaluating the efficacy and safety of its lead product
candidate efruxifermin (EFX) in patients with pre-cirrhotic
metabolic dysfunction-associated steatohepatitis (MASH), fibrosis
stage 2 or 3 (F2-F3). The study 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%) and 28mg EFX
(39%) 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% (p=0.07) for 28mg EFX, compared to 24% for
placebo.
The study also met additional histology endpoints at week
96—notably 36% (p<0.01) and 31% (p<0.01) 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%. Results for all of the histological endpoints
are summarized in the table below, based on either the primary
analysis (patients with baseline and week 96 biopsies) or
intent-to-treat (ITT) analysis (all randomized and dosed patients,
with missing data imputed as non-response).
Summary of Week 96 Biopsy Endpoints
|
Primary Analysis1 |
ITT Analysis2 |
Histology Endpoint3
(Proportion of Patients) |
Placebo(N=34) |
28mg(N=26) |
50mg(N=28) |
Placebo(N=43) |
28mg(N=40) |
50mg(N=43) |
≥1 stage fibrosis improvement without worsening MASH (%) |
24 |
46 |
75*** |
19 |
30 |
49** |
≥2 stage fibrosis improvement without worsening MASH (%) |
3 |
31** |
36*** |
2 |
20** |
23** |
Resolution of MASH without worsening of fibrosis (%) |
24 |
62** |
57** |
19 |
40* |
37* |
MASH resolution AND ≥1 stage fibrosis improvement (%) |
9 |
42** |
54*** |
7 |
28** |
35** |
1 All patients with baseline and week 96 biopsies2 All
randomized and dosed patients, with missing data imputed as
non-response3 Biopsy scored independently by two pathologists;
third available to adjudicate (which was not required)* p<0.05,
** p<0.01, *** p<0.001, versus placebo
(Cochran-Mantel-Haenszel test [CMH])
“Notwithstanding inherent limitations in making cross-trial
comparisons, the statistically significant results for ≥1- and
2-stage fibrosis improvement and no worsening of MASH observed for
50mg EFX at week 96 are the largest response rates reported
publicly to date for these endpoints in any MASH population,” said
Stephen Harrison, M.D., medical director of Pinnacle Clinical
Research and the HARMONY study’s principal investigator. “I believe
the magnitude and general consistency of results observed across
the Phase 2a BALANCED and Phase 2b HARMONY studies in patients with
pre-cirrhotic MASH are reasons to be optimistic about results of
the ongoing Phase 3 SYNCHRONY Histology study and the potential for
EFX to be an important MASH medicine, if approved.”
The placebo-adjusted effect size on fibrosis improvement without
worsening of MASH (EFX response rate minus placebo response rate)
more than doubled between week 24 and week 96 for the 50mg EFX
group, with a slight increase observed for the 28mg EFX group.
Specifically, the placebo-adjusted effect sizes for fibrosis
improvement without worsening of MASH grew from 21% to 52% between
week 24 and week 96 for 50mg EFX and from 20% to 22% for 28mg EFX.
Highly statistically significant results for 50mg EFX at week 96
are notable because (1) the study was not fully powered at week 96
and (2) the placebo rate increased rather than decreased. An
increase in treatment rate for placebo means that the increases in
effect size are attributable to higher EFX treatment responses
rather than a decline in placebo rate.
Analysis of the evolution of responses between weeks 24 and 96
indicated not only broader fibrosis improvement without worsening
of MASH but also sustained response, particularly at 50mg EFX.
Among those patients with available week 96 biopsies whose fibrosis
improved at week 24, 92% and 83% of the 50mg and 28mg EFX groups
remained responders, respectively, compared to 40% for placebo.
Analysis of a subset of patients with baseline F3 fibrosis who
had week 96 biopsies showed EFX’s potential to treat patients with
more advanced fibrosis, who are generally considered to be at
higher risk of progression to cirrhosis. For this advanced F3
patient population, 68% (p<0.001) and 40% (p=0.053) of the 50mg
EFX and 28mg EFX groups, respectively, experienced at least a
one-stage improvement in fibrosis without worsening of MASH,
compared to 14% for placebo.
“We believe the statistically significant 2-stage improvement in
fibrosis without worsening of MASH observed in approximately one in
three EFX-treated patients sets EFX apart,” said Andrew Cheng,
M.D., Ph.D., president and chief executive officer of Akero.
“Today’s results show that longer exposure to EFX has the potential
to yield sustained fibrosis improvement as well as widening
anti-fibrotic treatment responses across the treated patient
populations. We look forward to continuing our evaluation of EFX in
patients with pre-cirrhotic MASH and cirrhosis due to MASH in our
ongoing Phase 3 SYNCHRONY program, in which two out of three
studies are actively enrolling.”
Summary of Changes in Effect Size from Week 24 to Week
96 for ≥1 Stage Fibrosis Improvement Without Worsening of MASH
(%)1
|
Placebo |
28mg EFX |
50mg EFX |
Measure (Mean) |
Week 24(N=41) |
Week 96(N=34) |
Week 24 (N=38) |
Week 96(N=26) |
Week 24(N=34) |
Week 96(N=28) |
≥1 stage fibrosis improvement without worsening of MASH, n (%) |
8 (20) |
8 (24) |
115 (39)* |
12 (46) |
14 (41)* |
21 (75)*** |
Placebo-adjusted effect size (%) |
NA |
NA |
20 |
22 |
21 |
52 |
1 All patients with baseline and week 96 biopsies* p<0.05,
*** p<0.001, versus placebo (CMH)
Summary of Breadth and Durability of Treatment Response
for ≥1 Stage Fibrosis Improvement Without Worsening of
MASH
Sustained1 vs.
New2 Response Among Week 96
Responders |
Placebo(N=34) |
28mg(N=26) |
50mg (N=28) |
All week 96 responders, n (%) |
8 (24%) |
12 (46%) |
21 (75%***) |
Sustained response at week 96, n (%)3 |
2 (6%) |
10 (38%) |
11 (39%) |
New response at week 96, n (%)3 |
6 (18%) |
2 (8%) |
10 (36%) |
Proportion of week 24 responders with sustained response, n
(%)3 |
2 of 5 (40%) |
10 of 12 (83%) |
11 of 12 (92%) |
Proportion of week 24 non-responders with new response, n (%)3 |
6 of 29 (21%) |
2 of 14 (14%) |
10 of 16 (63%) |
*** p<0.001, versus placebo (CMH)1 Sustained response refers
to patients who were responders at week 24 and remained responders
at week 96.2 New response refers to patients who were
non-responders at week 24 but became first-time responders at week
96.3 Not analyzed for statistical significance.
Fibrosis Improvement Among Patients with Advanced
Fibrosis (F3)
Patients with F3 Baseline Fibrosis and Week 96
Biopsies |
Placebo(N=22) |
28mg(N=15) |
50mg (N=19) |
≥1 stage fibrosis improvement without worsening MASH (%) |
3 (14%) |
6 (40%) |
13 (68%***) |
*** p<0.001, versus placebo (CMH)
Summary of Week 96 Changes in Key Noninvasive Measures
of Liver Fibrosis and Injury
Measure (LS Mean Change From Baseline to
Week 96) |
Placebo(n=33-35) |
28mg(n=27) |
50mg (n=25-28) |
Pro-C3 (µg/L) (GEN2 ELISA) |
†-17† |
†††-40††† |
**-51** |
ELF Score |
-0.1 |
**-0.7** |
**-0.8** |
Liver Stiffness (kPa) (FibroScan) |
-0.6 |
*-4.0* |
***-7.2*** |
ALT (%) |
-10 |
***-44*** |
**-37** |
AST (%) |
-4 |
*-30* |
**-38** |
* p<0.05, ** p<0.01, *** p<0.001, versus placebo
(MMRM)††† p<0.001, versus baseline (MMRM)
Summary of Week 96 Changes in Key Cardio-Metabolic
Biomarkers
Measure (LS Mean Change From Baseline to
Week 96) |
Placebo(n=34-35) |
28mg(n=25-28) |
50mg (n=26-27) |
Triglycerides (%) |
+8 |
***-15*** |
***-20*** |
HDL Cholesterol (%) |
+5 |
*+18* |
**+27*** |
Non-HDL Cholesterol (%) |
+3 |
**-2 |
**-2 |
LDL Cholesterol (%) |
+4 |
+3 |
+5 |
C-peptide (%) |
+8 |
-2 |
**-20** |
HOMA-IR (%) |
+7 |
-11 |
**-33** |
Adiponectin (%) |
+17 |
†+28† |
**+63** |
Body Weight (kg) |
-1.5 |
-0.3 |
†-3.5† |
* p<0.05, ** p<0.01, *** p<0.001, versus placebo
(MMRM)† p<0.05, versus baseline (MMRM)
EFX was reported to be generally well-tolerated. There were no
deaths. Fifteen serious adverse events were reported, which were
generally balanced across dose groups. Across both EFX groups, the
most frequent adverse events (AEs) were grade 1 or 2
gastrointestinal events (diarrhea, nausea, and increased appetite),
which were transient in nature. A total of three patients treated
with EFX were discontinued due to AEs between week 24 and week 96
(two in the 28mg group and one in the 50mg group), compared with
none for placebo.
In October of 2023, Akero reported week 36 results for the
SYMMETRY study, a Phase 2b trial in patients with compensated
cirrhosis (F4) due to MASH, Child-Pugh class A. The SYMMETRY study
was designed to include a second biopsy after 96 weeks of
treatment, for which the results remain on track to be reported in
the first quarter of 2025.
Conference Call / Webcast DetailsAkero 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 Akero’s website, with the recording and
presentation available immediately following the event.
About MASHMASH (metabolic-associated
steatohepatitis) is a serious form of MASLD (metabolic-associated
steatotic liver disease) that is estimated to affect more than 17
million Americans. MASH 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 MASH is the
fastest growing cause of liver transplants and liver cancer in the
United States and Europe.
About the HARMONY Study The Phase 2b HARMONY
study is a multicenter, randomized, double-blind,
placebo-controlled, dose-ranging trial in biopsy-confirmed adult
MASH patients with fibrosis stage 2 or 3. The study enrolled a
total of 128 patients, randomized to receive once-weekly
subcutaneous dosing of 28mg or 50mg EFX, or placebo for 24-weeks,
126 of whom received at least one study dose. The primary efficacy
endpoint for the study was the proportion of subjects who achieve
at least one-stage fibrosis improvement without worsening of MASH
at week 24. Week 96 secondary measures included ≥1 stage fibrosis
improvement and no worsening of MASH, 2-stage fibrosis improvement
without worsening of MASH, at least one-stage fibrosis improvement
and MASH resolution, change from baseline in liver enzymes,
noninvasive markers of liver fibrosis, glycemic control,
lipoproteins, and body weight as well as safety and tolerability
measures.
About EFXEfruxifermin (EFX), is Akero’s lead
product candidate for MASH, currently being evaluated in the
ongoing Phase 2b SYMMETRY, Phase 3 SYNCHRONY Histology, and Phase 3
SYNCHRONY Real-World studies. EFX has been observed to reduce liver
fat and inflammation, reverse fibrosis, increase insulin
sensitivity and improve lipoproteins in multiple clinical trials.
This holistic profile offers the potential to address the complex,
multi-system disease state of MASH, including improvements in
lipoprotein risk factors linked to cardiovascular disease – the
leading cause of death in MASH 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 TherapeuticsAkero Therapeutics
is a clinical-stage company developing transformational treatments
for patients with serious metabolic diseases marked by high unmet
medical need, including metabolic dysfunction-associated
steatohepatitis (MASH), a disease without any approved therapies.
Akero's lead product candidate, EFX, is currently being evaluated
in two ongoing Phase 3 clinical trials: the SYNCHRONY Histology
study in patients with pre-cirrhotic MASH (F2-F3 fibrosis) and the
SYNCHRONY Real-World study in patients with MASH or MASLD. A third
clinical trial, the SYNCHRONY Outcomes study in patients with
cirrhosis due to MASH, is expected to be initiated in the first
half of 2024. The Phase 3 SYNCHRONY program builds on the results
of two Phase 2b clinical trials, the HARMONY study in patients with
pre-cirrhotic MASH and the SYMMETRY study in patients with
cirrhosis due to MASH. Akero is headquartered in South San
Francisco. Visit us at akerotx.com and follow us on LinkedIn and
Twitter for more information.
Forward Looking StatementsStatements 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; the timing and enrollment of Akero’s Phase 3 SYNCHRONY program
and upcoming milestones, including the results, and expected timing
to report the long-term follow-up 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 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
Tartaglia212.362.1200IR@akerotx.com
Media Contact:Sarah
O’Connell732.456.0092soconnell@vergescientific.com
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