Gemcabene demonstrated statistically significant
lowering of triglycerides (TGs) in SHTG
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 that it
achieved the primary endpoint, reduction of TGs by gemcabene, in
its Phase 2b INDIGO-1 trial in SHTG patients with baseline serum
TGs >500 mg/dL.
Key findings:
- Primary endpoint met with median TGs significantly decreased by
47% in gemcabene (600 mg) treated patients compared to 27% for
placebo-treated patients (P=0.0063; ranked ANCOVA).
- The 600 mg gemcabene group attained a significantly lower
median level of serum TGs of 333 mg/dL compared to placebo of 538
mg/dL (P=0.0137) at the end of the study.
- Statistically significant secondary endpoints achieved with 600
mg gemcabene, including placebo-corrected median decreases in LDL-C
(24%), non-HDL-C (16%), VLDL-C (19%), apoB (12%), apoE (14%),
apoCIII (11%), SAA (23%); (p-values <0.05; ranked ANCOVA).
- No severe adverse events (SAEs) were observed with gemcabene
and adverse events (AEs), which were generally mild to moderate,
occurred less frequently with gemcabene than placebo.
“We are pleased to reach this milestone of meeting both primary
and multiple secondary endpoints and look forward to advancing
gemcabene into Phase 3 trials,” said Dr. Steven Gullans, CEO
of Gemphire. “There are approximately 3.5 million SHTG patients in
the United States in need of lowering their TG levels below
500 mg/dL to reduce their risk of developing acute pancreatitis.
Our once daily tablet has demonstrated promising evidence of
safety, efficacy and tolerability in more than 1,100 subjects thus
far. Moreover, in prior studies 600 mg of gemcabene reduced LDL-C,
hsCRP and other biomarkers that are typically elevated in a broad
range of dyslipidemic conditions.”
INDIGO-1 was designed as a dose-ranging, 12 week, multicenter,
double-blind, placebo-controlled, randomized trial in patients with
SHTG (TG ≥500 mg/dL and < 1500 mg/dL) with or without background
statin therapy. All patients enrolled in the study were also
counseled on the importance of maintaining a heart-healthy diet and
limiting alcohol intake. Patients were enrolled into one of three
arms: gemcabene 300 mg (n=30), gemcabene 600 mg (n=30) or placebo
(n=31) once daily. Demographically the 3 groups were comparable:
~40% diabetic, 50% on statin therapy, median Body Mass Index (BMI)
~31-32, and mean age of 54; one group difference was a larger
proportion of females in the placebo group (39%) compared to the
gemcabene groups (300 mg: 3%; 600 mg: 17%). The primary
endpoint was median percent change in TGs from baseline to the end
of study (defined as the average of weeks 10 and 12). Other
endpoints associated with atherogenic burden included percent
changes in LDL‑C, hsCRP, apoB, non-HDL‑C, very-low-density
lipoprotein cholesterol (VLDL-C) and total cholesterol.
People with TG levels above 500 mg/dL are at increased risk for
acute pancreatitis, a very serious and potentially lethal
complication of SHTG, and therefore, this study focused only on
SHTG patients. Starting from a median TG baseline of 637 mg/dL,
patients receiving 600 mg of gemcabene experienced a median 47%
decrease in TGs compared to a median 27% decrease for placebo
patients, who started at a median of 658 mg/dL (P=0.0063; ranked
ANCOVA). Once daily 600 mg of gemcabene decreased median TG
levels more than 300 mg of gemcabene.
Importantly, since the goal of treating SHTG patients is to
reduce TGs below 500 mg/dL, the absolute levels of TGs were
evaluated in the trial. Gemcabene 600 mg treatment reduced median
TG levels from a baseline of 637 mg/dL to 333 mg/dL, compared to
placebo treated patients with a median baseline of 658 mg/dL
reduced to 538 mg/dL (P=0.0137). In addition, 67% of these
600 mg gemcabene treated patients achieved a serum TG level below
500 mg/dL and some patients experienced more than a 70% reduction
from baseline.
Cardiometabolic patients, including those with SHTG, often have
high levels of serum lipid and inflammatory biomarkers. In the 600
mg gemcabene cohort, multiple secondary endpoints were achieved.
In particular statistically significant placebo-corrected
percent decreases were observed for serum LDL-C (24%), non-HDL-C
(16%), VLDL-C (19%), apoB (12%), apoE (14%), apoCIII (11%), and SAA
(23%); (p-values <0.05; ranked ANCOVA). A placebo-corrected 26%
decrease in serum hsCRP was observed but this did not achieve
statistical significance (P<0.08).
With regard to safety, gemcabene appeared safe and
well-tolerated as monotherapy or as add-on to statins. Overall,
gemcabene patients experienced mild to moderate AEs whose frequency
was less than that observed with the placebo group. One placebo
patient had an SAE, while there were no SAEs in gemcabene patients.
There were no withdrawals due to AEs. One patient with an
elevated alanine transaminase (ALT) at baseline experienced a
confirmed, repeat value for ALT > 3 x upper limits of normal on
600 mg of gemcabene, which, importantly, spontaneously resolved
while remaining on active treatment.
Patients with mixed dyslipidemia (defined as LDL-C ≥100 mg/dL
and TGs ≥ 200 mg/dL) are a particularly high risk subset of
patients including many with SHTG. An analysis of this small
subset of patients (n=9 for placebo; n=14 for gemcabene 600mg) in
INDIGO-1 showed directional and/or significant reductions in
placebo-corrected median TGs of 30% (p=0.1289), LDL-C of 28%
(p=0.0012), non-HDL-C of 38% (p=0.0002), VLDL-C of 61% (p=0.0398)
apoB of 28% (p=0.0023), apoE of 43% (p=0.0009), apoCIII of 27%
(p=0.1356), hsCRP of 48% (p=0.1554), and SAA of 37% (p=0.1823); all
p-values from ranked ANCOVA.
"The INDIGO-1 phase 2 study in
severe hypertriglyceridemia clearly shows the 600 mg dose of
gemcabene to be effective and well tolerated in this difficult to
treat population,” stated Dr. Evan Stein, Director Emeritus,
Metabolic & Atherosclerosis Research Center, Cincinnati.
“Importantly the triglyceride reduction is well supported by
significant reductions in LDL-C, apoB, apoE, and apoCIII and these
potentially beneficial reductions were greater in the subgroups
that are even more difficult to treat, those with diabetes and
already on statins."
In keeping with the Company’s ongoing clinical trial plans, the
INDIGO-1 results further support Gemphire’s rationale for pursuing
gemcabene to treat NAFLD/NASH. Patients in the present study
had profiles typical of cardiometabolic patients who often suffer
from diabetes, dyslipidemia and obesity, which puts them at high
risk for NAFLD/NASH. NAFLD may be present in up to 90% of all
obese persons and up to 70% of Type-II diabetic patients.
NAFLD/NASH patients typically present with an atherogenic
dyslipidemic profile, characterized by increased serum levels of
TGs, apoB, VLDL-C, and LDL-C with a proportionally greater content
of small dense LDL-C (sdLDL-C) (Clin Gastroenterol Hepatol
2015;13:1000; Diabetes Metab Syndr 2016;10(2 Suppl 1):S77;
Metabolism 2016;65:1109). NAFLD is also associated with aberrant
nuclear receptor function and systemic inflammation. (Biochim
Biophys Acta. 2016;1859:1083). The promising evidence that
Gemcabene can improve the dyslipidemic and inflammatory profile of
cardiometabolic patients, suggests that it could provide benefit
for NAFLD/NASH.
In prior studies, gemcabene reduced serum levels of TGs, LDL-C,
VLDL-C, apoB and hsCRP in hypercholesterolemic and hyperlipidemic
patients. Additionally, in animal and cell based models, gemcabene
demonstrates a reduction in de-novo lipogenesis, modulation of
inflammation and reduction of the NAFLD activity score (NAS),
particularly related to hepatic ballooning, steatosis, fibrosis,
and collagen accumulation. Accordingly, in 2018 Gemphire
initiated proof-of-concept trials in pediatric NAFLD and adult
familial partial lipodystrophy. The results of the subgroup
analysis in mixed dyslipidemic patients in INDIGO-1 reaffirms
previous clinical data in patients at high risk for having
NAFLD/NASH.
“The ability to reduce TGs in patients with SHTG, who are at
risk of developing pancreatitis, to below 500 mg/dL is an important
goal of therapy in this high risk patient group,” added Dr. Lee
Golden, Chief Medical Officer of Gemphire. “In patients
treated with gemcabene 600 mg, 67% of patients achieved this
goal. Gemcabene continues to demonstrate reductions in the
overall atherogenic particle burden as well as inflammatory
biomarkers. In particular, cardiometabolic patients,
including mixed dyslipidemic patients, who often have NAFLD/NASH as
well, showed greater reductions in lipid and inflammatory
parameters.”
“On a related note, we are pleased to report that both of our
ongoing NAFLD/NASH proof-of-concept trials are dosing patients and
remain on track to report data in late 2018 and early 2019 as
previously guided,” continued Dr. Golden. “In addition, we
are using the information from our INDIGO-1 trial, particularly the
dose finding results, together with the results from our previous
Phase 1 and 2 clinical trials, to finalize our Phase 3 trial
plans. We expect to communicate more information regarding
the structure and timing of our Phase 3 program once we have
completed our End of Phase 2 meeting with the FDA, which we will
request following the completion of the FDA’s review of the 2-year
carcinogenicity study, which is currently in progress.”
Conference Call and Webcast The Company
will host a conference call and webcast today Thursday, June 28, at
4:30 pm Eastern Time. To access the audio conference, please dial
(844) 494-0188 (domestic) or +1 (425) 278-9114 (international) and
reference conference ID 4998205. To view the slides, please see the
News & Events section of the Gemphire website. The live webcast
can be accessed via the following link:
https://edge.media-server.com/m6/p/r8uwpgpi. A webcast replay will
be available on the News & Events section of the Gemphire
website for all interested parties following the call and will be
archived and available for 90 days.
About Severe Hypertriglyceridemia (SHTG)
SHTG is a condition in which patients have TGs present in the
bloodstream at a level of greater than 500 mg/dL. High TG levels
are associated with an increase in both the risk for cardiovascular
disease and acute pancreatitis. As high TG can lead to organ
failure which can be life-threatening, the current first-line
treatments for SHTG, as recommended by the ATP III guidelines,
include dietary modifications to lower the intake of fatty foods
and the use of fibrates, prescription fish oils and/or niacin.
Current therapies, limited by insufficient efficacy, drug-drug
interaction potential or side-effects, may be inadequate to lower
the TG levels below 500 mg/dL, the level at which patients are at
risk for increased pancreatitis.
Pursuing SHTG may enable gemcabene to reach a large population
of patients with TG levels above 500 mg/dL and offer an oral,
once‑daily dosing with no observed food effects that may have the
potential to offer improved efficacy than standard of care, while
being used concomitantly with statins. Based on a 1.1% prevalence
rate of TG ≥ 500mg/dL in the United States, as published by
the American Heart Association, Gemphire estimates there are
approximately 3.5 million patients with SHTG in the United
States and 75 million patients in the rest of the world, at
risk for developing acute pancreatitis.
About Pancreatitis Pancreatitis is an
inflammation of the pancreas. Once the gland becomes inflamed, the
condition can progress to swelling of the gland and surrounding
blood vessels, bleeding, infection, and damage to the gland.
Digestive juices become trapped and start digesting the pancreas
itself. If the damage persists, the gland may not be able to carry
out normal functions. Pancreatitis may be acute (new,
short-term) or chronic (ongoing, long-term). Either type can
be very severe, and lead to serious complications.
Acute pancreatitis usually begins soon after the damage to the
pancreas begins. Attacks are typically very mild. Mild
attacks may last for a short time and usually resolve completely as
the pancreas returns to normal. Some people only have one
attack, whereas other people may have more than one attack.
About 20% of cases, however, are very severe. Chronic
pancreatitis begins as acute pancreatitis. If the pancreas becomes
scarred during the attack of acute pancreatitis, it cannot return
to its normal state. The damage to the gland continues,
worsening over time. There are reports that more than 300,000
patients are admitted per year for pancreatitis in the United
States, and about 20,000 of those patients die from the disease.
Pancreatitis can occur in people of all ages, although it is very
rare in children. Pancreatitis occurs in men and women,
although chronic pancreatitis is more common in men.
High levels of TGs are associated with acute pancreatitis and
considerable morbidity and mortality. In September 2002,
the National Institutes of Health (NIH) published its Third
Report of the National Cholesterol Education Program Expert
Panel on Detection, Evaluation and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). Although
the focus of the report is on LDL-cholesterol and HDL-cholesterol
levels, it also provides guidance for treatment of patients with
high TG levels. The report states that in cases in which a person’s
TGs are very high (≥500mg/dL), the initial aim of therapy is to
prevent acute pancreatitis through triglyceride lowering.
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 TGs with currently
approved therapies, primarily statins. Gemcabene's mechanism
of action (MOA) enhances the clearance of very low-density
lipoproteins (VLDLs) in the plasma and inhibition of the production
of cholesterol and TGs 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
TGs. 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 TG 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 nearly 1,200 subjects across 25 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 Gemphire Gemphire 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. Gemphire’s Phase 2 clinical
program is evaluating the efficacy and safety of gemcabene in
hypercholesterolemia, including FH and ASCVD, SHTG and
NASH/NAFLD. Two trials supporting hypercholesterolemia and
one trial in SHTG have been completed under NCT02722408,
NCT02634151 and NCT02944383, respectively, and the Company has
initiated two proof-of-concept trials for NAFLD/NASH. Please
visit www.gemphire.com for more information.
Forward Looking Statements Any statements
in this press release about Gemphire’s future expectations,
milestones, goals, 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 gemcabene, expectations for the future
competitive environment for gemcabene, expectations regarding
operating expenses and cash used in operations, and other
statements containing the words "believes," "anticipates,"
"estimates," "expects," "intends," "plans," "predicts," "projects,"
“promising,” "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: developments in the capital markets, 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; the actions of Gemphire’s competitors; 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 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:Ashley RobinsonLifeSci Advisors,
LLC(617) 535-7742
Jeff Mathiesen, CFOGemphire Therapeutics Inc.(734) 245-1700
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