- Significant improvement in steatohepatitis with >2 point
improvement in NAS score without worsening fibrosis, the primary
endpoint of the study
- Achieved key secondary endpoint of MASH resolution without
worsening of fibrosis
- More ION224 treated patients had an improvement of >1 stage
fibrosis compared to placebo
- ION224 was safe and well-tolerated in this study with
once-monthly subcutaneous dosing
CARLSBAD, Calif., March 13,
2024 /PRNewswire/ -- Ionis Pharmaceuticals,
Inc. (Nasdaq: IONS) announced positive results from a Phase 2
study of ION224, an investigational DGAT2 antisense inhibitor in
development for the treatment of metabolic dysfunction-associated
steatohepatitis (MASH), previously referred to as nonalcoholic
steatohepatitis (NASH). The study met its primary endpoint at both
doses (120 mg and 90 mg), achieving liver histologic improvement,
and also met the important secondary endpoint of MASH
resolution.
Key highlights from the 160-patient study at 51 weeks
included:
- ION224 achieved statistically significant liver histologic
improvement as measured by at least a 2-point reduction in NAFLD
Activity Score (NAS)* (p<0.001 (120 mg) and p=0.015 (90
mg)).
- Subgroup analysis indicated that significant improvements in
the primary endpoint were observed in patients with both F2 and F3
(advanced) fibrosis.
- ION224 achieved statistically significant MASH resolution
without worsening of fibrosis, as measured by biopsy
(p=0.039).
- 44% of patients treated with 120 mg achieved ≥50% relative
reduction in liver steatosis as measured by MRI-PDFF compared to 3%
for placebo.
- 32% of patients treated with 120 mg achieved a ≥1 stage
improvement in fibrosis without worsening steatohepatitis as
measured by biopsy compared to 12.5% for placebo.
- ION224 was safe and well-tolerated in the study.
"This Phase 2 trial of ION224 is the first to demonstrate
clinical evidence that the reduction of hepatic fat after DGAT2
inhibition correlates with improvements in MASH histological
endpoints," said Rohit Loomba, MD,
MHSc, professor of medicine and chief, division of gastroenterology
and hepatology, University of California San
Diego; founding director, MASLD Research Center,
University of California San Diego. "I
believe ION224 offers a unique precision medicine opportunity with
an approach that is potentially complementary to others in
development for MASH, and I look forward to continued evaluation of
this important investigational medicine."
MASH is the more severe form of metabolic dysfunction-associated
steatotic liver disease (MASLD) and can lead to liver fibrosis,
cirrhosis and liver-related death. ION224 is an investigational
LIgand-Conjugated Antisense (LICA) medicine
designed to reduce the production of diacylglycerol acyltransferase
2 (DGAT2) to treat patients with MASH.
"Reducing the production of DGAT2 enzyme decreases the
overproduction of triglycerides that contribute to excess liver
fat, which can result in liver damage and inflammation. We are
encouraged by these ION224 data, showing that a monthly
subcutaneous medicine targeting DGAT2 has the potential to improve
MASH and prevent its progression to more severe stages, including
advanced liver fibrosis and cirrhosis," said Sanjay Bhanot, MD, PhD, senior vice president
and chief medical officer at Ionis. "The inhibition of DGAT2
represents a novel approach for MASH, a progressive disease in need
of better treatment options. We look forward to sharing the full
results from this study at an upcoming medical conference and
discussing next steps to advance this potentially promising therapy
for patients."
In this study, ION224 was safe and well-tolerated in MASH
participants. Those in the ION224 study arms did not experience any
worsening of hepatic or renal function or gastrointestinal side
effects, and there was a lower rate of early termination compared
to placebo. Additionally, there were no on-study deaths or
treatment-related serious adverse events.
The adaptive Phase 2, two-part, multi-center, randomized,
double-blind, placebo-controlled study was designed to assess the
efficacy, safety and pharmacokinetics of multiple doses of ION224
when administered subcutaneously once-monthly in adults with MASH.
The study enrolled 160 patients to receive ION224 or placebo over a
period of 49 weeks. In Part 1, 93 patients were randomized 1:1:1 to
the three dose cohorts (60, 90, and 120 mg) and within each dose
cohort, randomized 3:1 to receive ION224 or placebo. In Part 2, an
additional 67 patients were randomized 1:1 to two selected dose
cohorts (90 and 120 mg) and then in a 2:1 ratio to receive either
ION224 or placebo within each cohort. The study was powered for the
primary endpoint, which was the percentage of patients who achieved
MASH histologic improvement, defined as achieving at least a
2-point reduction in NAS with at least 1-point improvement in
hepatocellular ballooning or lobular inflammation, and without
worsening of fibrosis at end of the treatment period.
About ION224
ION224 is an investigational
LIgand-Conjugated Antisense (LICA) medicine
designed to reduce the production of diacylglycerol acyltransferase
2 (DGAT2) to treat patients with MASH. DGAT2 is an enzyme that
catalyzes the final step in triglyceride synthesis in the liver.
Reducing the production of DGAT2 should therefore decrease
triglyceride synthesis in the liver. Additionally, there is
evidence of an increase in both fatty acid oxidation and oxidative
gene expression associated with antisense inhibition of DGAT2.
ION224 offers a unique approach, which is potentially complementary
to other therapies currently in clinical development.
About Metabolic dysfunction-associated steatohepatitis
(MASH)
MASH is the more severe form of metabolic
dysfunction-associated fatty liver disease (MASLD). It is related
to the epidemic of obesity, pre-diabetes and diabetes. Unlike liver
disease caused by alcohol consumption, MASH is the result of an
accumulation of fat in the liver, which can lead to inflammation
and cirrhosis, an advanced scarring of the liver that prevents the
liver from functioning normally. About 20% of MASH patients are
reported to develop cirrhosis, which is associated with increased
risk of liver-related and overall mortality.i MASH is
the fastest growing indication for liver transplantation in the
U.S. and Europe.ii
In 2023, several multinational liver societies made the
recommendation to update NAFLD to metabolic dysfunction-associated
steatotic liver disease (MASLD) and to update non-alcoholic
steatohepatitis (NASH) to metabolic dysfunction-associated
steatohepatitis (MASH). Ionis has adopted the use of MASH to
describe this Phase 2 trial. ION224-CS2 is registered on
clinicaltrials.gov as a study in patients with non-alcoholic
steatohepatitis (NASH) and was registered before the recommended
update.
About Ionis Pharmaceuticals, Inc.
For three decades, Ionis has invented medicines that bring better
futures to people with serious diseases. Ionis currently has five
marketed medicines and a leading pipeline in neurology, cardiology,
and other areas of high patient need. As the pioneer in
RNA-targeted medicines, Ionis continues to drive innovation in RNA
therapies in addition to advancing new approaches in gene editing.
A deep understanding of disease biology and industry-leading
technology propels our work, coupled with a passion and urgency to
deliver life-changing advances for patients. To learn more about
Ionis, visit Ionispharma.com and follow us on X (Twitter) and
LinkedIn.
Forward-looking Statements
This press release includes forward-looking statements regarding
Ionis' business and the therapeutic and commercial potential of
ION224, additional medicines and technologies. Any statement
describing Ionis' goals, expectations, financial or other
projections, intentions, or beliefs is a forward-looking statement
and should be considered an at-risk statement. Such statements are
subject to certain risks and uncertainties, including but not
limited to those related to our commercial products and the
medicines in our pipeline, and particularly those inherent in the
process of discovering, developing and commercializing medicines
that are safe and effective for use as human therapeutics, and in
the endeavor of building a business around such medicines. Ionis'
forward-looking statements also involve assumptions that, if they
never materialize or prove correct, could cause its results to
differ materially from those expressed or implied by such
forward-looking statements. Although Ionis' forward-looking
statements reflect the good faith judgment of its management, these
statements are based only on facts and factors currently known by
Ionis. Except as required by law, we undertake no obligation to
update any forward-looking statements for any reason. As a result,
you are cautioned not to rely on these forward-looking statements.
These and other risks concerning Ionis' programs are described in
additional detail in Ionis' annual report on Form 10-K for the year
ended Dec. 31, 2023, which is on file with the SEC. Copies of this
and other documents are available
at www.ionispharma.com.
Ionis Pharmaceuticals® is a registered trademark of Ionis
Pharmaceuticals, Inc.
* Nonalcoholic Fatty Liver Disease Activity Score (NAS)
with at least 1-point improvement in hepatocellular ballooning or
lobular inflammation, and without worsening in fibrosis stage.
iLe MH, et al. Clin Mol Hepatology
2022;28:841–850.
iiEstes C, et al. Hepatology. 2018;67(1):123-133.
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