Phase 2a trial will investigate gemcabene in
Familial Partial Lipodystrophy (FPL) – a rare genetic disease with
characteristic presentation of cardiovascular disease and
NASH
Gemphire Therapeutics Inc. (NASDAQ:GEMP), a clinical-stage
biopharmaceutical company focused on developing and commercializing
therapies for cardiometabolic disorders, including dyslipidemia and
nonalcoholic steatohepatitis (NASH), today announced the
launch of a clinical program to develop gemcabene as a treatment
for NASH/nonalcoholic fatty liver disease (NAFLD). The
company has an open Investigational New Drug (IND) application for
gemcabene in NASH. The program is beginning with a Phase 2a
proof-of-concept (POC) clinical trial in adults with FPL, a rare
genetic disorder and orphan disease characterized by an abnormal
distribution of fatty (adipose) tissue, which can lead to a variety
of metabolic abnormalities including NASH.
“We are very pleased to initiate this clinical trial as the
first step in our plan to develop gemcabene as a highly
differentiated treatment for NASH,” said Dr. Steven Gullans,
Interim CEO of Gemphire. “As the only compound in development
that targets the triple threat of LDL-C, inflammation and
triglycerides (TG) – addressing the full spectrum of dyslipidemia–
we believe gemcabene has potential to be highly effective in this
adult population, which is burdened by multiple cardiometabolic
risk factors. With the strong preclinical data and scientific
rationale for gemcabene in NASH based on its novel mechanism of
action, we believe there may be significant potential for gemcabene
to demonstrate effects on established measures of NASH that are
also present and evaluable in FPL patients. In addition,
Gemphire plans to launch a second Phase 2a POC trial in NASH early
in 2018. Our goal is that together these trials will pave the way
for confirmatory trials in a broader NASH population.”
FPL is an ideal patient population to demonstrate POC in
adult NASH
FPL is a rare genetic disorder and orphan disease
characterized by an abnormal distribution of fatty (adipose)
tissue. As the body is unable to store fat correctly, a
buildup can occur around all vital organs and in the blood
(hypertriglyceridemia). FPL can also cause an abnormal buildup of
fats in the liver (hepatic steatosis), which can result
in an enlarged liver (hepatomegaly) and abnormal liver
function. FPL can lead to loss of metabolic control and a
variety of metabolic abnormalities, including diabetes,
cardiovascular disease, hypertriglyceridemia and NASH.
“Treatment of FPL is typically directed towards the specific
symptoms present in each individual. FPL patients are also a
high-risk orphan population since currently available medications
do not effectively manage their cardiometabolic comorbidities. Many
patients are statin intolerant and use polypharmacy for their
diabetes and lipid abnormalities with inadequate results,”
said Elif Oral, MD, Associate Professor of Medicine,
Department of Internal Medicine, University of Michigan Medical
Center and Primary Investigator of this study.
"Individuals living with FPL face great medical complications
that currently have no FDA approved treatment. Many struggle with
very high triglycerides and traditional therapies are not tolerated
or effective. Lipodystrophy United is encouraged by this potential
treatment and excited to support the research," said Andra
Stratton, President & Co-Founder of Lipodystrophy United, an
organization with the mission to provide an interactive community,
facilitate support and education for anyone affected by this rare
disease (https://www.lipodystrophyunited.org.)
“Gemcabene’s mechanism of action is uniquely suited toward
treatment of NASH given that it has demonstrated both
cardio-protective and liver protective qualities in prior studies,”
said Lee Golden, MD, CMO of Gemphire Therapeutics. “There are
currently no FDA-approved therapies for NASH and we believe that
gemcabene will be a safe and effective treatment to meet the
significant unmet needs in this population. We will study this
compound in this unique group of patients with the hope of learning
more about the drug and also learning more about disease
mechanisms.”
Phase 2a POC clinical trial will measure NASH-related
endpoints in FPL
The primary objective of this phase 2a study is to
assess the efficacy and safety of two dosing regimens of gemcabene
in up to eight FPL patients with elevated TG and NAFLD. At
entry, patients must have a fasting TG value ≥ 250 mg/dL and
quantifiable steatosis (stage 2 or 3) while on a stable, low-fat,
low-cholesterol diet. Patients will be randomized to two
treatment groups, to receive either gemcabene 300 mg once daily for
24 weeks or gemcabene 300 mg once daily for 12 weeks immediately
followed by gemcabene 600 mg once daily for a further 12 weeks.
The trial’s primary endpoint is the reduction in TG
after 12 weeks of treatment. Secondary endpoints will include
measures of liver fat (MRI-PDFF) and NAS (histology) at 24
weeks. Patients who are considered responders (i.e., defined
as TG lowering > 30% at Week 12) will be offered the opportunity
for long-term therapy with gemcabene in a separate open-label
extension study. Gemphire anticipates top line results from
the trial in the second half of 2018.
“We are very excited to initiate our NASH clinical
program and to collaborate with Dr. Oral, who is a leading
physician in the diagnosis and management of patients suffering
from FPL,” said Lee Golden, MD, Chief Medical Officer, Gemphire
Therapeutics. “This is the first part of our program in NASH
and we expect that these results will not only provide important
insights into how gemcabene may benefit patients with FPL and NASH,
but also for the broader patient population with NASH.”
Novel Mechanism of Action in NASH: Gemcabene has both
liver- and cardio-protective properties
Gemphire’s decision to move forward with development of
gemcabene in NASH is based on the strong mechanistic rationale for
the compound to target the pathology of the disease. It has
the potential to add complementary mechanisms that lower both TG
(fat) and inflammation, which are believed to prevent the
progression of liver fibrosis, particularly for diabetic and obese
patients, who represent a large portion of the NASH
population. It has been shown that obesity and diabetes can
reduce a patient’s ability to remove atherogenic lipids, fat
causing particles, from the blood, and NASH patients have been
shown to have a particularly high burden of disease causing fat
particles. Historical preclinical and clinical studies
have shown significant lowering in plasma of atherogenic particles,
TG and CRP (a measure of inflammation) in subjects given oral,
once-daily gemcabene. Additionally in an animal model of
NASH, gemcabene has demonstrated the ability to reduce the extent
of inflammation, hepatocyte (liver cell) ballooning and fibrosis.
Gemcabene has also demonstrated a doubling of mean increase in
glucose disposal rate compared to placebo suggesting potential
effects on insulin sensitivity. The impact that gemcabene has been
shown to have on abnormalities in NASH patients and the efficacy it
has demonstrated in preclinical models support the evaluation of
the potential utility of gemcabene in a disorder characterized by
excess fat accumulation and inflammation of the liver.
Gemcabene’s clean safety profile confers an important
competitive advantage in NASH/NALFD
Gemphire has compiled a comprehensive data set on gemcabene from
more than 950 subjects across 20 completed trials. The drug
has been shown to be well tolerated and has not shown any liver
toxicities at doses between 150 to 900 mg for up to 12 weeks.
Gemcabene has also shown a low likelihood for drug-drug
interactions, particularly with statins that are widely used in
diabetic and dyslipidemic patients, underlying conditions
associated with NASH.
About NAFLD/NASH
NASH is a severe disease of the liver caused by inflammation and
a buildup of fat in the organ. In the United States, NASH
affects up to approximately 2-5% of the adult population. An
additional 10-30% of Americans have fat in their liver, but no
inflammation or liver damage, a condition called NAFLD or “fatty
liver.” The underlying cause of NASH is unclear, but it most
often occurs in persons who are middle-aged and overweight or
obese. Many patients with NASH have elevated serum lipids,
diabetes or pre-diabetes. Progression of NAFLD/NASH can lead
to liver cirrhosis, fibrosis, hepatocellular carcinoma, liver
failure and liver-related death. Liver transplantation is
currently the only treatment for advanced cirrhosis with liver
failure. At this time, there are no approved treatments by
the FDA for NAFLD/NASH.
Gemcabene’s mechanism of action and safety profile are
highly differentiated from other clinical candidates
Gemphire’s product candidate gemcabene is a first-in-class,
once-daily, oral therapy that may be suitable for patients who are
unable to achieve normal levels of LDL-C or triglycerides with
currently approved therapies, primarily statins. Gemcabene's
mechanism of action (MOA) is designed to enhance the clearance of
very low-density lipoproteins (VLDLs) in the plasma and inhibition
of the production of cholesterol and triglycerides in the
liver. The combined effect of these mechanisms has been
clinically observed to result in a reduction of plasma non-HDL-C,
VLDL-C, LDL-C, apolipoprotein B and triglycerides. In
addition, gemcabene has been shown to markedly lower C-reactive
protein in humans and improve insulin sensitization.
Gemcabene’s MOA is liver-directed involving downregulation of
hepatic apolipoprotein C-III (apoC-III) mRNA expression and
decrease of plasma apoC-III levels. Gemcabene has also been
shown to reduce liver sulfatase-2 mRNA levels, known to be elevated
in diabetic and obese patients. Elevated sulfatase-2 is
thought to reduce the effectiveness of the liver VLDL-remnant
receptor (also known as Syndecan-1), that normally plays a role in
removing triglyceride containing particles from the plasma.
Gemcabene also reduces acetyl-CoA carboxylase (ACC1) and CCR2/CCR5
receptor mRNA levels, markers involved in the progression of
NASH/NAFLD. Gemcabene has demonstrated POC efficacy for NASH
in the rodent STAM™ model developed at SMC
Laboratories in Tokyo, Japan. Gemcabene has been
tested as monotherapy and in combination with statins and other
drugs in 956 subjects across 20 Phase 1 and Phase 2 clinical
trials. Given this profile of efficacy across multiple pathological
pathways, as well as evidence of safety and tolerability,
particularly when used as an add-on to many other therapeutic
drugs, gemcabene has attributes that support studies in humans for
NASH.
About GemphireGemphire is a clinical-stage
biopharmaceutical company that is committed to helping patients
with cardiometabolic disorders, including dyslipidemia and
NASH. The Company is focused on providing new treatment
options for cardiometabolic diseases through its complementary,
convenient, cost-effective product candidate gemcabene as add-on to
the standard of care, especially statins, that will benefit
patients, physicians, and payors. Previously Gemphire
successfully completed two Phase 2b clinical trials for homozygous
familial hypercholesterolemia (HoFH) and heterozygous familial
hypercholesterolemia (HeFH)/atherosclerotic cardiovascular disease
(ASCVD), and also initiated a Phase 2b clinical trial for severe
hypertriglyceridemia (SHTG) under NCT02722408, NCT02634151, and
NCT02944383. A fourth planned trial in NASH is expected to
initiate by year end 2017. Please
visit www.gemphire.com for more information.
Forward Looking Statements Any statements
in this press release about Gemphire’s future expectations, plans
and prospects, including statements about Gemphire’s financial
prospects, future operations and sufficiency of funds for future
operations, clinical development of Gemphire’s product candidate,
expectations regarding future clinical trials, regulatory
submissions and meetings and future expectations and plans and
prospects for Gemphire, expectations regarding operating expenses
and cash used in operations, and other statements containing the
words "believes," "anticipates," "estimates," "expects," "intends,"
"plans," "predicts," "projects," "targets," "may," "potential,"
"will," "would," "could," "should," "continue," “scheduled” and
similar expressions, constitute forward-looking statements within
the meaning of The Private Securities Litigation Reform Act of
1995. Actual results may differ materially from those
indicated by such forward-looking statements as a result of various
important factors, including: the success and timing of Gemphire’s
regulatory submissions and pre-clinical and clinical trials;
regulatory requirements or developments; changes to Gemphire’s
clinical trial designs and regulatory pathways; changes in
Gemphire’s capital resource requirements; Gemphire’s ability to
obtain additional financing; Gemphire’s ability to successfully
market and distribute its product candidate, if approved;
Gemphire’s ability to obtain and maintain its intellectual property
protection; and other factors discussed in the "Risk Factors"
section of Gemphire’s Annual Report on Form 10-K for the year
ended December 31, 2016, Gemphire’s Quarterly Report on Form
10-Q for the quarter ended September 30, 2017 and in
other filings Gemphire makes with the SEC from time to
time. In addition, the forward-looking statements included in
this press release represent Gemphire’s views as of the date
hereof. Gemphire anticipates that subsequent events and
developments will cause Gemphire’s views to change. However,
while Gemphire may elect to update these forward-looking statements
at some point in the future, Gemphire specifically disclaims any
obligation to do so. These forward-looking statements should
not be relied upon as representing Gemphire’s views as of any date
subsequent to the date hereof.
Contact:Andrew McDonald, Ph.D.LifeSci Advisors,
LLC(646) 597-6987
Jeff Mathiesen, CFOGemphire Therapeutics Inc.(734)-245-1700
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