WHITEFISH, MT / April 8, 2014 / There has been a disease steadily filling market headlines recently, and no; it’s not cancer. It’s fatty liver disease, particularly Non-alcoholic Fatty Liver Disease, or NAFLD, regarded by many as the most common non-communicable liver disease worldwide. The disease is a silent killer that often goes undetected until late stages, for which there are no FDA-approved treatments. Biotechs focusing on innovative therapies for varying stages of NAFLD are receiving plenty of deserved media coverage. Hepatology leaders in recent headlines include Intercept Pharmaceuticals, (NASDAQ: ICPT), Cempra, Inc. (NASDAQ: CEMP), MediciNova, Inc. (NASDAQ: MNOV), Galectin Therapeutics (NASDAQ: GALT) and Lumena Pharmaceuticals, a company preparing to go public.
A Quick Overview
Some fat in the liver is typically not a big deal, but accumulation of
fat leads to inflammation, called Non-Alcoholic Steatohepatitis (NASH),
which affects between 2 and 5 percent of the U.S. population. NASH
subsequently can progress into scarring of the liver, called fibrosis,
and then severe scarring, called cirrhosis, and eventually to liver
failure and death. There are many points in this progression at which
new therapeutics can target treatment of NAFLD. Aside from Galectin,
most companies are focused on early stages of the disease. This can
present a bit of a problem because there is not a direct correlation in
NAFLD and clinical outcomes. Not all NASH patients will progress to
develop late and more severe stages of the disease, nor is it possible
to discern which patients will progress.
Intercept dominated the news in January with shares ballooning from
around $75 to near $500 in two days after reporting positive results
from a phase 2 trial of the company's experimental therapy obeticholic
acid (OCA) for NASH. MediciNova announced positive pre-clinical test
results from a mouse study showing anti-fibrotic properties of MN-001,
sending shares initially jumping from about $2.15 to as high as $5.25
before cooling back to starting levels. MediciNova is preparing to
initiate a phase 2 trial of MN-001. Also in very early stages, Cempra’s
Solithromycin (CEM-101), a drug candidate in two phase 3 clinical
trials for community-acquired bacterial pneumonia, popped on the scene
this month with a mouse-model discovery that it has potential as a NASH
therapy.
Lumena just finished a $45-million raise and is aiming to add $75
million more as it plans a Nasdaq debut under the ticker “LIVR.” The
San Diego-based company is looking to stockpile cash to continue
advancements of liver disease drugs LUM001 and LUM002. Lumena has
licensed LUM002 from Sanofi (SNY) and expects to report results from a
phase 1 trial from NASH in the first half of 2014 and initiate a phase 2
trial in the latter part of the year. Investors will likely be looking
for a broad move upward in industry players if the results are
positive.
Galectin Therapeutics is developing GR-MD-02 for NASH and taking a
unique approach compared to competitors by targeting NASH patients with
biopsy-proven advanced fibrosis. Pre-clinical research suggested that
the drug has the potential to not only stop the progression of NASH, but
to actually reverse some of the fibrotic damage. Additionally,
Galectin is initially not using the invasive biopsy process as a
biomarker. It is using serum biomarkers, which is supportive of the
industry as a whole in defining more accurate diagnostics with less
invasive technologies to diagnosis disease progression. Last Monday,
Galectin released information from the first cohort in a phase 1
clinical trial, presenting a substantial compilation of clinical data
that deserves a closer look.
The Key Takeaways of the Data
First and foremost, GR-MD-02 was shown to be safe and well tolerated
with no drug-related serious adverse events reported, the primary
endpoint of any phase 1 trial. The initial dose for the first cohort
was 2 mg/kg (80 mg/m2), which will be doubled in the second cohort. 8
patients (6 in the treatment arm, 2 in placebo arm) were enrolled in the
first cohort, seven of which had stage 3 fibrosis and one with stage 4
fibrosis, and all the patients completed the full protocol.
The trial looked at certain hallmarks of any clinical trial, such as
safety and pharmacokinetics, as well as dialing-in the effect of
GR-MD-02 by examining a broad spectrum of serum biomarkers of NASH,
including composite biomarkers of fibrosis, inflammatory cytokines and
ALT levels as a proxy of apoptosis. Galectin’s approach covered the
gamut of pathological processes of NAFLD by studying biomarkers
pertaining specifically to NASH as well as biomarkers specific to
fibrosis and cirrhosis. This analysis provides a wider breadth of
knowledge about GR-MD-02, as these stages of liver disease don’t always
have congruous details. This is an important aspect of the trial,
providing wide-ranging data on the effects in the current study and
helping to delineate future research.
Results from the FibroTest, an indirect biomarker of fibrosis, showed a
significant reduction in scores, which suggests fibrosis regression in
patients treated with GR-MD-02. The ELF (Enhanced Liver Fibrosis) test,
considered a direct biomarker of fibrosis that has been shown to be
predictive of mortality, showed that scores tended to decrease in
patients in the treatment arm, but did not produce a “statistically
significant” change because of the small sample size of the study. To
that point, the researchers will be looking for additional validation of
the trend as enrollment grows throughout the trial.
The study also looked at Hyaluronic Acid (HA) levels, which are known to
be elevated in liver fibrosis. In 3 of the 6 patients treated with
GR-MD-02, HA levels decreased, essentially consistent with pre-clinical
data.
Regarding inflammation, levels of key cytokines associated with the
advancement of NASH were evaluated. Elevated levels of these cytokines
in NAFLD patients are indicative of lipid accumulation and inflammation
of the liver. Patients treated with GR-MD-02 showed about a 25%
reduction in levels of interleukin-8 from day 1 to day 56. Levels of
interleukin-6 and TNF-alpha levels were also significantly reduced in
patients treated with Galectin’s drug, as compared to the placebo group.
A measure of cellular injury looked at ALT and AST, two common enzymes
released by the liver cells, as part of the safety profile. It is
notable that these serum transaminases are relatively poor as a NASH
diagnostic because patients with normal levels of ALT and AST can still
have NASH. What is interesting in the data, though, is that two of the
treated patients with ALT levels above 100 units/liter showed reductions
in ALT levels of 39 U/L and 67 U/L, respectively. Data from these
patients were looked at more closely in combination with the impact of
GR-MD-02 on cell death biomarker cytokeratin 18, a protein that is known
to be predictive of NASH severity.
The two patients that demonstrated a sharp drop in ALT levels also
showed a marked decrease in CK-18 levels by the end of the treatment
period. Taking things a step further, those two patients also showed
significant reduction in FibroTest scores and in levels of the protein
lumican, a matrix protein in the liver involved with fibrogenesis. By
comparison, treated patients with low ALT levels showed improvement in
fibrosis biomarkers, but not in CK-18 levels.
So What Does This All Mean?
The data suggests that Galectin was pretty much right on target with the
assessment of GR-MD-02 before the clinical trial began. There appears
to be data supporting the drug candidate to slow and potentially reverse
tissue damage in patients with NASH with advanced fibrosis, but the
trials are still very early and with a limited number of patients. In
short, efficacy is never a spoken primary goal of early clinical trials,
but the data lends additional confidence of a biological effect of
GR-MD-02 even at low doses, while holding a strong safety profile. As
Dr. Peter Traber, CEO and President of Galactin, said in a conference call discussing the clinical data,
the company is pleased to see “consistent changes in fibrosis markers
and inflammatory markers after four infusions of [GR-MD-02].” Secondly,
by looking at a wide swath of data, Galectin seems to have gleaned some
key information that may better delineate future patient populations
with high ALT levels with respect to cellular injury.
Eight clinical sites are now active to begin enrollment of eight more
patients for the second cohort, to be treated with a substantially
higher dose of GR-MD-02 (4 mg/kg). Galectin said it believes the
optimal dose equivalency from mouse studies would be approximately 8
mg/kg in humans, so the increased dose in cohort two should deliver
valuable info on that matter. Further, FibroScan(TM), an ultrasonic
medical device that measures liver tissue elasticity, has been added to
the protocol to assess the effect of the drug. The results from this
cohort are expected in July or August.
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SOURCE: TDM Financial