- Met primary and Hepatic Encephalopathy (HE) endpoints in
Phase 2 study
- Increase in Skeletal Muscle Index (SMI) observed at Week 24 was
maintained through 52 weeks
- Participants on placebo increased SMI when switched to
LPCN 1148
- Fewer Overt Hepatic Encephalopathy (OHE) events and time
to first recurrent OHE event was longer while on LPCN 1148
therapy
- LPCN 1148 was well-tolerated, with AE rates and severities
similar to placebo.
- Participants on LPCN 1148 were hospitalized for fewer
days
SALT
LAKE CITY, March 28, 2024 /PRNewswire/ -- Lipocine
Inc. (NASDAQ: LPCN), a biopharmaceutical company today announced
positive topline results from a Phase 2 clinical study of LPCN
1148. LPCN 1148 is an oral candidate under development for the
clinical management of cirrhosis, specifically prevention of OHE
recurrence and treatment of sarcopenia. LPCN 1148 is targeted
to be a "First in Class" product candidate with a novel mechanism
of action (MOA). Lipocine plans to meet with the FDA to discuss a
development path to NDA filing.
"We are encouraged with the positive results from our Phase 2
study. These results demonstrate that LPCN 1148 treatment
benefits patients with cirrhosis who are sarcopenic and have
experienced other serious decompensation events such as OHE," said
Dr. Mahesh Patel, President and CEO of Lipocine Inc.
"Cirrhosis management is a significant unmet medical need with a
strong pharmaco-economic rationale. We believe LPCN 1148
both ameliorates sarcopenia and decreases the recurrence of OHE. If
approved, this treatment is a compelling opportunity with the
potential to be the standard of care as a mono or adjunct therapy
in managing advanced cirrhosis."
This Phase 2 proof of concept study was a randomized
placebo-controlled study in sarcopenic male patients with cirrhosis
on the liver transplant waitlist. In Stage 1, 29 patients were
randomized 1:1 to receive either LPCN 1148 or matching placebo
for 24 weeks. At Week 24, the open-label extension Stage 2 of the
study commenced. During Stage 2, 8 participants who were on placebo
in Stage 1 converted to LPCN 1148, and 11 participants who
started the study on LPCN 1148 continued treatment with LPCN
1148.
The study's primary endpoint was a change in L3-SMI at week 24.
L3-SMI estimates whole body skeletal muscle mass. SMI was analyzed
at baseline, and Weeks 12, 24, 36, and 52. Key secondary endpoints
included rates of hepatic encephalopathy and the
safety/tolerability of LPCN 1148.
Results
All LPCN 1148-treated participants completed Week 24 (n=15), and
10 of 14 placebo participants completed Week 24. During the initial
24 weeks, all LPCN 1148-treated participants had at least one
evaluable post-baseline CT scan and are therefore part of the
modified intent to treat (mITT) analysis; 10 placebo-treated
participants had an evaluable post-baseline CT.
As prespecified, L3-SMI analysis was performed on the mITT
population (n=25), with the last evaluable post-baseline
observation carried forward (LOCF). Of those participants on
placebo in Stage 1, 6 out of 8 who went on to receive LPCN
1148 starting at Week 24 had evaluable CT scans in Stage 2.
Primary endpoint
Participants who received LPCN 1148 during Stage 1 had a
significant (p<0.01) increase in L3-SMI of 4.1
cm2/m2 (8.8%) at Week 24, the primary
analysis timepoint, and this increase was maintained through the
additional 28 weeks of the study (Week 52, 4.1
cm2/m2, 8.7%). Placebo participants who began
receiving LPCN 1148 saw a marked increase in SMI as early as
12 weeks after therapy initiation (Week 36, 7.4
cm2/m2, 15.1%), and this increase was
maintained through Week 52 (8.1 cm2/m2,
16.7%).
Table 1: Change in L3-SMI at Week 24 and Week 52
Timepoint
|
LPCN
1148
|
Placebo
|
LPCN
1148
|
N=15
|
N=10
|
(Placebo
converted)
|
|
|
N=6
|
Baseline
(cm2/m2)
|
47.8 (1.8)
|
45.8 (2.3)
|
50.1
(2.7)#
|
Week 24 CFB
(cm2/m2)‡
|
4.1 (0.9)
*†
|
- 0.6 (1.2)
|
|
Week 52 CFB
(cm2/m2)
|
4.1 (1.1) *
|
-
|
8.1 (1.7) *
|
Data are least squares mean (standard error),
LOCF.
# For Placebo participants converted to LPCN 1148, baseline is
considered Week 24 data.
ANCOVA model with treatment and overall baseline L3-SMI as
covariates.
* p<0.01 vs baseline.
† p<0.01 LPCN 1148 vs placebo at Week 24.
‡ Change from baseline in SMI at Week 24 was the study's
primary endpoint.
Hepatic Encephalopathy
Recurrent OHE is defined as an event of OHE in a participant
with a medical history of HE. Most (22/29, 76%) study participants
had experienced HE prior to this study, and there were similar
numbers of these participants in each study arm in both Stage 1 and
Stage 2. Nearly all (21/22, 95%) participants with a history of HE
were on therapy for HE at baseline and during the study (lactulose
and/or rifaximin). During Stage 1, LPCN 1148 treatment resulted in
significantly (p<0.05) fewer cases of recurrent OHE (1 vs 6), a
potential FDA-approvable endpoint. During the open-label Stage 2,
there were two cases of OHE, one in a participant who was receiving
LPCN 1148 since Day 1, and one who began receiving LPCN 1148 at
Week 24. The average time to first OHE recurrence was longer
with LPCN 1148 treatment, at 183 days compared to 35 days for
placebo.
Initial
Randomization
Group
|
LPCN
1148
|
Placebo
|
|
Stage
1
(Through Week
24)
N=15
|
Stage
2
(Week 24 to
EOS)
N=11
|
Stage
1
(Placebo)
(Through Week
24)
N=14
|
Stage 2 – LPCN
1148
(Placebo
Converted)
(Week 24 to
EOS)
N=8
|
History of HE
prior to
randomization
(n)
|
11
|
7
|
11
|
6
|
OHE
(events)
|
2
|
1
|
6
|
1
|
Recurrent OHE
(events)
|
1
|
1
|
6
|
1
|
Average time to
first
recurrent OHE event
(days)
|
114
|
294
|
35
|
140
|
Safety set; includes all participants who received study
drug in a given stage. Overt HE (OHE) is defined as an event of HE
with CTCAE severity ≥ grade 2.
Safety
In this 52-week study, LPCN 1148 was well-tolerated with AE
rates and severities similar to those observed in Stage 1 with
placebo. Participants experienced fewer serious or severe adverse
events when switched from placebo to LPCN 1148. Participants
on LPCN 1148 were hospitalized for fewer total days with
shorter hospital stays.
There were two deaths reported in placebo-treated participants
and one in LPCN 1148-treated participants during the study.
The company plans to share additional results pertaining to
other secondary endpoints at upcoming scientific conferences.
Dr. Arun J. Sanyal, MD, Director,
Stravitz-Sanyal Institute for Liver Disease & Metabolic Health,
Virginia Commonwealth University,
commented, "I am delighted to see the durability of the results
noted in this important trial to improve sarcopenia in a very sick
population of patients with decompensated cirrhosis. The stability
of improvement in sarcopenia and encephalopathy provide proof
of concept that sarcopenia correction with LPCN 1148 may provide
benefit to patients with decompensated cirrhosis and reduce the
risk of breakthrough encephalopathy. These provide a strong
rationale for further studies on the overall benefits and risks
of LPCN 1148 in this population where there is a major unmet
need to improve sarcopenia."
Dr. Jennifer Lai, MD, MBA, UCSF
Professor of Medicine, transplant hepatologist, and study principal
investigator, added, "The rapid and sustained increases in
muscle mass seen in this study with LPCN 1148 are very
exciting, especially as there are currently no FDA-approved
pharmacotherapeutics for sarcopenia in cirrhosis. The observed
trends towards improved clinical outcomes including hepatic
encephalopathy support what we know about the importance of
increasing and maintaining muscle mass in patients with
cirrhosis."
About Cirrhosis
Cirrhosis is an end stage liver disease of varying etiologies
such as alcoholic liver disease, chronic viral hepatitis,
nonalcoholic fatty liver disease and primary cholangitis.
Complications of cirrhosis include decompensation events such as
hepatic encephalopathy due to systemic ammonia buildup,
variceal bleeding, and ascites, which require frequent
hospitalizations. In addition, many patients
exhibit sarcopenia (low muscle mass).
Over 382,000 patients have been diagnosed with decompensated
liver cirrhosis in the US, with few options for managing their
disease other than liver transplant. Poor quality of life is common
while waiting for a liver transplant. Although there is a limited
supply of donor livers, transplant is the only cure for end-stage
cirrhosis.
About HE
HE is a frequent complication and one of the most debilitating
manifestations of liver disease, severely affecting the lives of
patients and their caregivers. For patients with decompensated
liver cirrhosis and sarcopenia, clinical outcomes tend to be worse
- both sarcopenia and myosteatosis are associated with an increased
risk of HE.
OHE is an episodic neurological disorder with a high recurrence
rate. Up to 50% of patients with cirrhosis will experience
an OHE episode in their lifetime. Patients can exhibit global
neurological, psychiatric, and musculoskeletal deficits. HE
has a complex pathophysiology that includes impairment of
ammonia clearance and increased inflammatory cytokine and HE
recurrence is common, despite use of standard-of-care therapies.
Options for prevention/treatment are limited, resulting in
significant enduring unmet medical need as the 1-year survival for
patients with OHE is ~50%. Furthermore, cognitive impairment
associated with cirrhosis results in utilization of more health
care resources.
About LPCN 1148
LPCN 1148 comprises testosterone dodecanoate, a unique androgen
receptor agonist. It is targeted as a differentiated intervention
option with a novel multimodal MOA to elicit potential benefits in
management of cirrhosis and associated comorbidities of
cirrhosis.
About the Phase 2 study
This multi-center study enrolled and dosed a total of 29
patients across 8 centers in the United
States. The primary objective was to evaluate the efficacy
of 24 weeks of LPCN 1148 treatment in men with cirrhosis and
sarcopenia. The secondary objective was to evaluate the safety and
tolerability of LPCN 1148. Following Week 24, the open-label
stage of the study began (Stage 2), wherein all participants
received LPCN 1148 (no placebo in Stage 2).
Baseline characteristics, including age, disease etiology
baseline L3-SMI, and other comorbidities were generally
well-balanced between groups. Overall, the average baseline Model
for End-Stage Liver Disease (MELD) score was 16.8, and 97% of
patients had previously experienced at least one clinical
decompensation event. Sarcopenia, or low muscle mass, was
assessed by computed tomography (CT) scan; total skeletal muscle
area at the third lumbar vertebra was measured by CT scan and
normalized by participant height (L3-SMI, L3-skeletal muscle
index). Patients had study visits every four weeks, with CTs
performed at Weeks 12, 24, 36, and 52. Patients with a variety of
cirrhosis etiologies were eligible. During the study there were no
restrictions on standard of care medications, procedures, or other
interventions. Further details on the study design, including
inclusion and exclusion criteria, can be found
on Clinicaltrials.gov (NCT04874350).
About Lipocine
Lipocine is a biopharmaceutical company leveraging its
proprietary technology platform to augment therapeutics through
effective oral delivery to develop products for CNS disorders.
Lipocine has drug candidates in development as well as drug
candidates for which we are exploring partnering. Our drug
candidates represent enablement of differentiated, patient
friendly oral delivery options for favorable benefit to risk
profile which target large addressable markets with significant
unmet medical needs.
Lipocine's clinical development candidates include: LPCN 1154,
oral brexanolone, for the potential treatment of postpartum
depression, LPCN 2101 for the potential treatment of epilepsy and
LPCN 1148, an oral prodrug of bioidentical testosterone targeted
for the management of symptoms associated with liver cirrhosis.
Lipocine is exploring partnering opportunities for LPCN 1107, our
candidate for prevention of preterm birth, LPCN 1148, for the
management of decompensated cirrhosis, and LPCN 1144, our candidate
for treatment of non-cirrhotic NASH. TLANDO, a novel oral prodrug
of testosterone containing testosterone undecanoate developed by
Lipocine, is approved by the FDA for conditions associated with a
deficiency of endogenous testosterone, also known as hypogonadism,
in adult males. For more information, please visit
www.lipocine.com.
Forward-Looking Statements
This release contains "forward-looking statements" that are made
pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995 and include statements that are not
historical facts regarding our product development efforts, our
product candidates and related clinical trials, our strategic plans
for developing products to treat CNS disorders, our ability to
monetize non-core product candidates, including through entering
into partnering arrangements, the application of our proprietary
platform in developing new treatments for CNS disorders, the timing
and completion of regulatory reviews, outcomes of clinical trials
of our product candidates, the potential uses and benefits of our
product candidates, the potential uses and benefits of LPCN 1148,
and the timing of and our ability to make any NDA filing relating
to LPCN 1148. Investors are cautioned that all such forward-looking
statements involve risks and uncertainties, including, without
limitation, the risks that we may not be successful in developing
product candidates to treat CNS disorders, we may not be able
to enter into partnerships or other strategic relationships to
monetize our non-core assets, the FDA will not approve any of our
products, risks related to our products, expected product benefits
not being realized, clinical and regulatory expectations and plans
not being realized, new regulatory developments and requirements,
risks related to the FDA approval process including the receipt of
regulatory approvals and our ability to utilize a streamlined
approval pathway for LPCN 1154, the results and timing of
clinical trials, patient acceptance of Lipocine's products, the
manufacturing and commercialization of Lipocine's products, and
other risks detailed in Lipocine's filings with the SEC, including,
without limitation, its Form 10-K and other reports on Forms 8-K
and 10-Q, all of which can be obtained on the SEC website
at www.sec.gov. Lipocine assumes no obligation to update
or revise publicly any forward-looking statements contained in this
release, except as required by law.
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