Andy, The prevention data came form a rat model of breast cancer. Targretin was just as effective as Tamoxifen, but didn't have the udesired side effect of stimulating uterine tissue (which is why the Tamoxifen human prevention trial was halted). Moreover, Targretin actually helped REDUCE this risk when given in combination. I know that combination trials with Tamoxifen and Panretin have already begun (for treatment), and I'm sure that combination trials using Targretin and Tamoxifen are contimplated or have also begun. Here is the press release on the breast cancer prevention data (as well as the combination therapy):
Ligand's Targretin(TM) (LGD1069) Published in `Cancer Research' as Potential
Preventive Therapy for Breast Cancer
RXR-selective compound equally efficacious as tamoxifen in
NMU-induced animal tumor model
SAN DIEGO, Dec. 16 /PRNewswire/ -- According to results reported in this
week's issue of Cancer Research, Targretin (TM)(LGD1069) reduces tumor burden
and performs at least as well as tamoxifen. Ligand Pharmaceuticals Inc.
(Nasdaq: LGND) announced today that Targretin, the Company's lead retinoid-
based therapeutic compound, has demonstrated efficacy as a chemopreventive
agent in a well-studied, pre-clinical animal model of breast cancer -- the
NMU-induced rat mammary carcinoma model. Tamoxifen is an anti-estrogen based
endocrine treatment that has been administered to cohorts of breast cancer
patients for over 10 years. Targretin-treated animals in the study showed a
90% reduction in tumor burden and tumor incidence compared to controls. The
study results also indicated that Targretin, a retinoid X receptor selective
compound, may offer significant reductions in side effects over other breast
cancer chemopreventive agents.
In the study, Ligand researchers evaluated Targretin's ability to alter
induction of NMU-induced breast tumors in Sprague-Dawley rats. Groups of 15
to 20 animals were randomized one week after carcinogen treatment. Animals
were treated five days a week with either vehicle (control), Targretin or
tamoxifen. Dosing ranges for tamoxifen treatment and Targretin treatment were
formulated based on previous studies.
Targretin(TM) Decreases Tumor Incidence
After 12 weeks of treatment, animals were analyzed to determine incidence
of tumor formation. The control group demonstrated 100% incidence. In
contrast, Targretin inhibited the incidence of NMU-induced tumors at both 30
mg/kg and 100 mg/kg. Tamoxifen also inhibited NMU-induced tumor formation,
however, only at 150 ug/kg.
Treatment Tumor Incidence
Control 100%
Targretin (LGD1069) (30 mg/kg, p.o.) 22%*
Targretin (LGD1069) (100 mg/kg, p.o.) 12%*
Tamoxifen (50 ug/kg, s.c.) 88%
Tamoxifen (150 ug/kg, s.c.) 20%*
*p<0.05
Targretin(TM) Decreases Tumor Burden
After 12 weeks of treatment, animals were analyzed to determine mean tumor
burden (i.e., multiplicity, the mean number of tumors occurring per animal).
Control animals demonstrated a mean tumor burden of 3.0 tumors per animal.
Targretin treatment of 30 mg/kg and 100 mg/kg decreased mean tumor burden to
0.33 and 0.18 tumors per animal, respectively. Tamoxifen treatment at 150
ug/kg decreased tumor burden to 0.25 tumors per animal, however, treatment
with 50 ug/kg did not produce a statistically significant reduction in tumor
burden (1.81) of tumor, per animal.
Treatment Mean Tumor Burden
Control 3.0
Targretin (LGD1069) (30 mg/kg, p.o.) 0.33*
Targretin (LGD1069) (100 mg/kg, p.o.) 0.18*
Tamoxifen (50 ug/kg, s.c.) 1.81
Tamoxifen (150 ug/kg, s.c.) 0.25*
*p<0.05
Targretin(TM) Antagonized Tamoxifen-Induced Endometrial Stimulation
One of the major concerns with tamoxifen therapy is the stimulation of
uterine tissue that is believed to lead to an increased incidence of
endometrial carcinomas. Endometrial stimulatory activity was measured by
evaluating uterine wet weight in control and treated animal populations.
Three-day treatment of immature rats with tamoxifen (1 mg/kg) increased
uterine wet weight approximately two-fold, whereas Targretin treatment
(100 mg/kg) administered alone had no effect versus control animals.
Interestingly, Targretin administered in conjunction with tamoxifen reduced
tamoxifen-induced increases to uterine wet-weight by 25% (p<0.001).
"The data from this study are very encouraging because they indicate that
Targretin may represent a novel therapeutic approach for breast cancer
treatment, and may not have some of the side effects usually associated with
tamoxifen therapy," according to Andres Negro-Vilar, M.D., Ph.D., Ligand Chief
Scientific Officer and Senior Vice President, Research. "This data again
confirms that stimulating very defined receptor signaling pathways may permit
the delivery of specific therapeutic benefits and reduce side effects
associated with more broadly active compounds."
Targretin(TM) is a small organic, compound discovered by Ligand scientists
which selectively activates a subclass of retinoid receptors called RXRs,
which play an important role in several cellular activities. One of the most
important of these activities is called programmed cell death, or "apoptosis,"
a natural process by which the body rids itself of unwanted cells. Targretin
is being developed by Ligand in both topical and oral formulations. Topical
Targretin is already in pivotal Phase III clinical trials for the treatment of
cutaneous T-cell lymphoma (CTCL). In addition, Targretin oral formulation is
in pivotal Phase III clinical trials for CTCL, in Phase II/III trials for lung
cancer and in ongoing Phase, II trials for the treatment of head and neck
carcinoma, systemic Kaposi's sarcoma, lung cancer, ovarian cancer, prostate
cancer, and renal cell cancer. If ongoing pivotal trials are successful, the
company expects to file two new drug applications in 1998 for Targretin in
CTCL.
Ligand Pharmaceuticals Incorporated, founded in 1987, is a leader in gene
transcription technology, particularly intracellular receptor (IR) technology
and Signal Transducers and Activators of Transcription (STATs). Ligand has
applied IR and STATs technology to the discovery and development of small
molecule drugs to enhance therapeutic and safety profiles and to address major
unmet patient needs in cancer, women's health, skin and metabolic diseases,
osteoporosis, cardiovascular and inflammatory disease.
This press release contains certain forward looking statements by Ligand
and actual results could differ materially from those described as a result of
factors including, but not limited to, the following: There can be no
assurance (a) that the preclinical results described herein will be observed
in patients; (b) that these or any new products under development by Ligand or
any of its partners will receive approval from the U.S. Food and Drug
Administration or other authorities to market any of these products; (c) that,
if approved, there will be a market for the drugs; or (d) that interim results
will be predictive of any final results.
SOURCE Ligand Pharmaceuticals
CONTACT: Susan E. Atkins, Vice President, Corporate
Communications and Investor Relations of Ligand Pharmaceuticals,
619-550-7687 |
