GTx, Inc. GTXI announced today that new data from two Phase II
studies on the effects of Capesaris^® (GTx-758), a selective estrogen receptor
alpha agonist, for the treatment of advanced prostate cancer, will be detailed
in presentations given by lead author, Evan Yu, MD, Associate Professor of
Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington on
February 14 and 15, at the 2013 American Society of Clinical Oncology (ASCO)
Genitourinary (GU) Cancer Symposium in Orlando, Florida.
"These presentations highlight the significant and novel mechanistic findings
of Capesaris," said Mitchell S. Steiner, MD, Chief Executive Officer of GTx.
"The attributes demonstrated in these Phase II studies underscore the drug
candidate's potential to not only treat advanced prostate cancer by lowering
testosterone in the microenvironment of prostate cancer cells, but also with
fewer estrogen deficiency side effects relative to the standard of care for
the treatment of advanced prostate cancer."
GTx-758 Significantly Reduced Free Testosterone and PSA Levels in Phase II
Studies (Abstract #104)
In two Phase II clinical studies in men with advanced prostate cancer,
patients receiving either 1000 mg or 2000 mg daily doses of GTx-758
demonstrated significant reductions in their serum free (unbound) testosterone
(T) levels, with related reductions in their levels of serum prostatic
specific antigen (PSA). One of the trials (705) compared the effects of 1000
mg and 2000 mg doses of GTx-758 in newly diagnosed advanced prostate cancer
patients with a cohort of patients receiving leuprolide, an established
androgen deprivation treatment (ADT). The primary endpoint of the trial was
the proportion of men who achieved castration (i.e., a serum total T level
less than 50 ng/dL) by Day 60. In hormone naïve advanced prostate cancer
patients, 28 days of 1000 mg or 2000 mg daily GTx-758 or leuprolide therapy
achieved castration in 49%, 56% and 94%, respectively. Although lesser
reductions in serum total T were observed in men receiving either GTx-758
dose, larger decreases in serum free T were observed in these same men, as
compared to leuprolide. Observed reductions in serum PSA at 28 days appear to
be more strongly associated with the observed changes in free T, rather than
total T, with PSA reductions of 84%, 73% and 56% from baseline for the 1000 mg
and 2000 mg doses of GTx-758 and leuprolide, respectively. In men treated with
GTx-758, sex hormone binding globulin (SHBG) levels increased approximately
400% and were associated with the decreases in serum free T and serum PSA.
Although ADT has been utilized for decades, it has become apparent that, in
many men, the levels of serum total T do not reach the levels which some
currently consider to be castrate (20 ng/dL vs 50 ng/dL) and that residual
levels of serum free T, the biologically active, unbound form of the hormone,
remain present at significant levels, potentially promoting clinical
progression of their prostate cancer. The literature suggests the concept that
a maximal suppression of serum free T would benefit men with advanced prostate
cancer. In GTx's Phase II clinical studies, the reductions in free T that were
observed with GTx-758 were greater than those observed with leuprolide. Men
treated with GTx-758 were shown to have increased levels of SHBG and rapidly
lowered free T (within 7 days), as well as decreased PSA values, suggesting
that serum levels of free T may be critical to measure as an indicator of
therapeutic efficacy in men with advanced prostate cancer. In the studies
being presented, GTx-758 lowered free T in both primary and secondary ADT of
advanced prostate cancer. These Phase II studies were stopped early due to an
undesired rate of venous thromboembolic events (VTEs). Based upon evaluations
observed in Phase I and II clinical studies, GTx believes significant
increases in SHBG can result from lower doses of GTx-758 to provide a more
maximal castration by lowering levels of free T.
GTx-758 Ameliorates Hot Flashes Observed in Men on ADT (Abstract #129)
The effects of GTx-758 and leuprolide on hot flashes, a common side effect in
men on ADT, were assessed in 99 evaluable patients (of a total of 159 newly
diagnosed patients with advanced prostate cancer) who reached 90 days of
treatment. While baseline data showed no significant differences in the number
of men reporting hot flashes in any of the treatment groups, the percentage of
men experiencing a hot flash while receiving leuprolide increased
significantly to 60.4% by day 28, and further increased to 80.9% by day 90.
Reports from subjects experiencing hot flashes while receiving GTx-758 were
significantly lower, with 18.8% and 5.6% of the men receiving the 1000 mg and
2000 mg doses of GTx-758, respectively, experiencing hot flashes by 90 days.
Therefore GTx-758 appears to have a low rate of hot flashes in GTx-758 treated
men compared with almost all men on leuprolide experiencing this side effect.
GTx-758 Has a Positive Effect on Biomarkers of Bone Turnover (Abstract #222)
As a result of advanced prostate cancer patients being treated for longer
periods of time with ADT, estrogen deficiency side effects, including a loss
of bone and a higher incidence of fractures, has become a serious side effect
of ADT. The effects of GTx-758 and leuprolide on markers of bone turnover,
C-terminal telopeptides (CTX) and bone specific alkaline phosphatase, were
evaluated in men with advanced prostate cancer in a Phase II study. In men
receiving GTx-758 1000 mg or 2000 mg daily dose treatment compared with the
standard leuprolide ADT, the 1000 mg and 2000 mg doses of GTx-758 had
reductions of greater than 50% for CTX levels, as compared to an almost 50%
increase in the men receiving leuprolide. Similarly, bone specific alkaline
phosphate levels were lower by approximately 20% in men treated with GTx-758,
compared with an increase of 8% in the leuprolide treated group. These
findings indicate that not only was bone maintained in the men treated with
GTx-758, but improved during their course of treatment, as opposed to those
treated with leuprolide, in which most of whom, despite the relatively short
course of treatment, appear to have significant bone turnover and therefore
bone loss.
"Since changes in bone mineral density are a significant side effect that can
negatively affect the health of men on ADT, improvements in bone turnover
observed in men treated with GTx-758 could be significant," said Dr. Steiner.
GTx-758 Decreases Serum IGF-1 levels in Men with Advanced Prostate Cancer
(Abstract #171)
Serum insulin-like growth factor-1 (IGF-1) has been implicated in the
development of prostate cancer as serum IGF-1 levels have been associated with
advanced disease, and IGF-1 is an indirect measure of metabolic syndrome.
IGF-1 levels were measured and compared among patients receiving the 1000 and
2000 mg doses of GTx-758 and leuprolide (n=159), in a Phase II study of men
with advanced prostate cancer. Through day 90, men receiving the 1000 mg and
2000 mg doses of GTx-758 showed IGF-1 levels decreased from baseline by more
than 70 ng/ml (greater than 50%), while levels stayed constant or increased in
men being treated with leuprolide.
New GTx-758 Phase II Study Underway
GTx is currently conducting a Phase II clinical trial (G200712) to evaluate
the safety and effectiveness of lower doses of GTx-758 to treat men with
metastatic castration resistant prostate cancer. Seventy-five men with
metastatic castration resistant prostate cancer will be randomized into one of
three cohorts to receive a 125 mg, 250 mg or 500 mg daily dose of GTx-758.
Each arm will have 25 subjects, and the enrollment will be conducted
sequentially, with the 125 mg cohort currently being enrolled. The enrollment
into the next higher dose of GTx-758 will commence if an acceptable incidence
of VTEs is observed among randomized patients for 30 days following enrollment
of the last patient in the previous cohort. The primary endpoint will be to
lower serum PSA by ≥ 50% by day 90. Other key endpoints include free T levels,
SHBG levels, serum PSA progression as well as time to tumor progression and
progression free survival, in these study subjects. In addition, the study
will evaluate the ability of GTx-758 to treat certain estrogen deficiency side
effects associated with medical castration such as hot flashes, bone loss, and
insulin resistance.
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