Nexavar (sorafenib toxylate) Benefits and Side Effects

SORAFENIB (BAY 43-9006) SIDE EFFECTS

The Food and Drug Administration (FDA) today approved Nexavar
(sorafenib tosylate), a new anti-cancer medicine used to treat adults
with advanced renal cell carcinoma, the most common type of kidney
cancer.

"The approval of Nexavar to treat advanced kidney cancer brings a much
needed option for this group of cancer patients," said Dr. Steven Galson,
Director of FDA's Center for Drug Evaluation and Research (CDER). "FDA
is working hard to support the development of new and effective
treatments for patients with cancer and other serious illnesses who
have limited alternatives."

In the United States, kidney cancer accounts for approximately 3
percent of all adult cancers. According to the American Cancer Society,
about 32,000 new cases are diagnosed and about 12,000 people die
from the disease annually. Kidney cancer occurs most often in people
between the ages of 50 and 70, affects men almost twice as often as
women and, if detected early enough, may be curable surgically.
However, tumors that are advanced (i.e., cannot be surgically removed
or have spread to other parts of the body) are difficult to treat.

Two studies in patients with advanced kidney cancer have shown that
patients treated with Nexavar had more time before tumor progression
or death. In the larger study, most patients had previously received
treatment with interleukin-2 or interferon. The median time to tumor
progression or death in the Nexavar treated arm was 167 days
compared to 84 days in people not treated with the drug.

Some common temporary side effects reported with Nexavar are rash,
diarrhea, increases in blood pressure, and redness, pain swelling, or
blisters on the palms of the hands or soles of the feet.

Nexavar will be distributed and marketed by Bayer Pharmaceuticals
Corporation of Westhaven, CT.

Development of Nexavar (sorafenib tosylate)
In pre-clinical models, sorafenib targeted members of two classes of
kinases involved in both tumor cell proliferation (tumor growth; An
increase in the number of cells as a result of cell growth and cell
division.) and tumor angiogenesis (tumor blood supply; The formation of
new blood vessels). The kinases included RAF kinase, VEGFR-2, VEGFR-3,
PDGFR-;, KIT, FLT-3 and RET. [1]

Currently, Bayer and Onyx are conducting large, international,
multicenter Phase III clinical studies of sorafenib (BAY 43-9006) in
patients with advanced kidney cancer, advanced primary liver cancer
and metastatic melanoma. Because Sorafenib (BAY 43-9006) is able to
inhibit multiple kinases, this agent is also being evaluated in single-
agent Phase II clinical trials in lung, breast, and other cancers, along
with several Phase I/II clinical trials studying the agent in combination
with a range of standard chemotherapeutics and other anticancer
agents (such as carboplatin/paclitaxel, 5-Fu, docetaxel, capecitabine,
oxaliplatin, irinotecan, Gemcitabine, gefitinib, doxorubicin, DTIC and IFN.
[2]

In May 2005, Bayer and Onyx reported at the annual meeting of the
American Society of Clinical Oncology that sorafenib was well tolerated
and significantly delayed disease progression in an ongoing Phase III
clinical trial in patients with advanced kidney cancer. As assessed by
independent radiologic review, progression-free survival was doubled to
a median value of 24 weeks in patients receiving sorafenib, compared to
12 weeks for patients receiving placebo. [2]

In July 2005, Bayer and Onyx submitted a New Drug Application (NDA)
for possible approval in this indication by the U.S. FDA. Subsequently,
the NDA application had been accepted and granted priority review
status by the FDA. In September 2005, a Marketing Authorization
Application was submitted to the European Medicines Agency for
approval to market sorafenib within the European Union for the same
indication. [2]

SORAFENIB SIDE EFFECTS

In a few studies, Sorafenib (BAY 43-9006) appeared to be safe, well-
tolerated and showed anti-tumor activities. The toxic effects of Sorafenib
(BAY 43-9006) were manageable and included hypertension, edema,
diarrhea, hand and foot syndrome, rash, and hair loss where the rash
involved the scalp. [7]

In a Phase I study, 44 patients with advanced, refractory solid tumors
were administered with 50 to 800 mg b.i.d of Sorafenib (BAY 43-9006)
for repeated cycles of 21 days on/7 days off. The side effects or the
most frequently reported adverse events in this study were
gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain
(64%), or hepatic (61%) related. Sorafenib (BAY 43-9006) was absorbed
rapidly; steady-state conditions were reached within 7 days. [5]

In another study, 69 patients with advanced refractory solid tumors
were administered with 50 to 800 mg b.i.d of Sorafenib (BAY 43-9006).
They found that mild to moderate diarrhea was the most common (55%)
treatment-related side effect. The maximum-tolerated dose was 400 mg
bid continuous. Dose-limiting toxicities were grade 3 diarrhea and
fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. [6]

PARTNERSHIP

According to Oxnyx online publication, Onyx is funding 50 percent of the
development costs for sorafenib. In return, Oxnyx has a 50/50 profit
share in the United States, where they can copromote the product with
Bayer. Everywhere in the world except Japan, Oxynx share is somewhat
less than 50 percent since Bayer has exclusive marketing rights. In
Japan, Bayer funds product development, and Onyx will get a royalty
based on any sales there.

ABOUT RAS AND RAF

Mitogen-activated protein kinase (MAPK) signaling pathway is important
in transmitting proliferative signals generated by cell surface receptors
and cytoplasmic signaling elements to the nucleus. Several important
signaling elements of the MAPK pathway, particularly Ras and Raf, are
encoded by oncogenes, and as such, their structures and functions can
be modified, rendering them constitutively active.

Raf, which is an essential serine/threonine kinase constituent of the
MAPK pathway and a downstream effector of the central signal
transduction mediator Ras, is activated in a wide range of human
malignancies by aberrant signaling upstream of the protein and
activating mutations of the protein itself, both of which confer a
proliferative advantage.

Because the MAPK pathway is dys-regulated in a notable proportion of
human malignancies, many of its aberrant and critical components
represent strategic targets for therapeutic development against cancer.
[3]

ABOUT VEGF AND EGF

Hypoxia-regulated genes such as vascular endothelial growth factor
(VEGF) and epidermal growth factor (EGF) are both important for tumor
progression in renal cell carcinoma (RCC). Results from a Phase III
clinical trial with sorafenib show only a 2% response rate; however, a
statistically significant improvement in progression-free survival was
observed. [4]

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REFERENCE
[1] Bayer and Onyx Announce Access to Sorafenib (BAY 43-9006) for Individuals
with Advanced Renal Cell Carcinoma, Bayer HealthCare Press Release, May 14
2005.
[2] Products in the clinic Â– Sorafenib, Onyx Pharmaceuticals Online Publication,
October 09. 2005.
[3] Beeram M et al, Raf: a strategic target for therapeutic development against
cancer. J Clin Oncol. 2005 Sep 20;23(27):6771-90. [4] Favaro JP and George DJ
Targeted therapy in renal cell carcinoma. Expert Opin Investig Drugs. 2005 Oct;14
(10):1251-8. [5] Awada A et al, Phase I safety and pharmacokinetics of BAY 43-
9006 administered for 21 days on/7 days off in patients with advanced, refractory
solid tumours. Br J Cancer. 2005 May 23;92(10):1855-61. [6] Strumberg D et al,
Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular
endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced
refractory solid tumors. J Clin Oncol. 2005 Feb 10;23(5):965-72. Epub 2004 Dec
21. [7] Ahmad T and Eisen T Kinase inhibition with BAY 43-9006 in renal cell
carcinoma. Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6388S-92S.

FDA approved Nexavar (sorafenib toxylate) to treat adults with advanced renal cell carcinoma, the most
common type of kidney cancer on December 20, 2005. Sorafenib (BAY 43-9006) is an oral multi-kinase
inhibitor targeting serine/threonine and receptor tyrosine kinases in both the tumor cell and tumor vasculature.

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