Melanoma (deadliest type of skin

Melanoma is the most dangerous type
of skin cancer. It is the leading cause
of death from skin disease.

It involves cells called melanocytes,
which produce a skin pigment called
melanin. Melanin is responsible for
skin and hair color.
Melanoma is a rare skin cancer, but
accounts for most of the 66,000
annual deaths from skin cancer
worldwide. If caught early, before
cancer cells break off and spread,
surgery can stop melanoma. But most
people, diagnosed after melanoma has
metastasized die within a year.

In November 2011 the FDA approved
the first-of-its-kind device, that makes
detailed, digital images of skin growths
and uses a computer to analyze them
for signs of cancer, offering a sort of
second opinion to doctors. The device
is approved only for dermatologists
and only for use on growths that don't
have obvious signs of cancer but still
have one or two worrisome traits.

The hope is to find more melanomas
sooner. Nearly all patients diagnosed
with early-stage melanoma can be
treated and cured, but 85 percent of
patients with late-stage melanoma die
from it within five years.

In August  2011 the U.S. Food and
Drug Administration  approved
Zelboraf (vemurafenib), a drug to treat
patients with late-stage (metastatic) or
unresectable (cannot be removed by
surgery) melanoma, the most
dangerous type of skin cancer.

Zelboraf is specifically indicated for the
treatment of patients with melanoma
whose tumors express a gene mutation
called BRAF V600E. The drug has not
been studied in patients whose
melanoma tests negative for that
mutation by an FDA approved

Zelboraf is being approved with a first-
of-a-kind test called the cobas 4800
BRAF V600 Mutation Test, a
companion diagnostic that will help
determine if a patient's melanoma cells
have the BRAF V600E mutation.

The BRAF protein is normally involved
in regulating cell growth, but is mutated
in about half of the patients with late-
stage melanomas. Zelboraf is a BRAF
inhibitor that is able to block the
function of the V600E-mutated BRAF

In 2011 Japanese company Daiichi
agreed to pay Plexxicon $805 million
up front plus another $130 million in
milestone payments tied to approvals
for Zelboraf.

The drug's first go-ahead came in
August 2011, when FDA okayed it for
patients with BRAFV600E mutation-
positive inoperable or metastatic
melanoma as detected by an approved
test. FDA also approved a companion
diagnostic, the cobas 4800 BRAF
V600 Mutation Test, making it just one
of two drug-diagnostic combos green-
lighted last year.

Since then, Zelboraf has won
approvals in Switzerland, Israel, Brazil,
New Zealand, Canada, and the EU.
Submissions for Zelboraf are currently
under review by health authorities in
other countries including Australia,
India, and Mexico.

Bristol-Myers Squibb's  Yervoy for late-
stage metastatic melanoma was
approved in March 2011.

Two Phase III studies—one completed
after approval—showed a significant
overall survival benefit. The drug also
won EC approval in July 2011, after
which it was launched in Germany and
some other countries on the continent,
The firm expects Yervoy to be
commercially available and reimbursed
in most of its top eight EU countries by
mid-2012 and in almost all EU
countries by the end of 2012.

In Europe as in the U.S., Yervoy is
indicated for previously-treated
patients whose tumors had spread or
could not be surgically removed.

Yervoy will need to generate sales
overseas, since the U.S. accounted for
$118 million of the total $144 million

Yervoy was evaluated in combination
with chemotherapy while vemurafenib
was compared with chemotherapy.

Yervoy, which stimulates the patient's
immune system to fight cancer cells,
rarely leads to profound tumor
shrinkage but results in prolonged
remissions and perhaps cures in 5-
10% of patients.

Zelboraf (Vemurafenib) on the other
hand, disrupts signaling in cancer cells
and shrinks tumors in the majority of
patients, but durable remissions are
quite rare. One advantage
vemurafenib has is its benign safety
profile compared to Yervoy's
problematic safety profile which could
be fatal in some cases.

Yervoy's biggest advantage is its
intended use for all melanoma
patients. This is in contrast to Zelboraf,
which will be used only in patients with
BRAF mutations (50-60% of melanoma

GlaxoSmithKline Plc  is starting studies
needed for approval of its combination
of two novel drugs, after the cocktail
helped almost all of the patients in its
first human trial.

The study combines Glaxo’s
GSK2118436 drug, which blocks one
mutated protein that spurs melanoma’s
spread, with a treatment that thwarts a
related growth-promoting molecule to
keep cancer from evading treatment.

The study may provide a clue to
whether the approach to control
resistance is viable.

Provectus Pharmaceuticals, Inc. is
focused on the development of cancer
and psoriasis treatments based on the
Rose Bengal compound.
The company’s PV-10 is preparing to
undergo Phase III clinical trials for the
treatment of metastatic melanoma and
has shown promising results in Phase
II clinical studies published last year.

Rose Bengal is a compound that has
been in use for over thirty years by
ophthalmologists to assess damage to
the eye. It has also been used as an
intravenous diagnostic to detect
ailments of the liver. Rose Bengal has
an established safety history, a short
half-life in the bloodstream, and is
excreted via the liver and kidneys.

Provectus has discovered a novel use
for Rose Bengal based on the
observation that it is selectively toxic to
cancer  via a process called
chemoablation whereby cells undergo
a form of cell death that mimics both
features of necrosis and apoptosis.

Delcath's proprietary system for
chemosaturation is designed to
administer high dose chemotherapy
and other therapeutic agents to
diseased organs or regions of the
body, while controlling the systemic
exposure of those agents.

The delivery system  in 2010 trials
helped melanoma patients whose
cancer had spread to their liver live
more than three times as long as
patients treated with best available

"This is the overall survival show-
stopper," said Delcath Chief Executive
Officer Eamonn Hobbs.

Delcath's system is designed to deliver
high doses of the chemotherapy drug
melphalan directly to the liver, through
the hepatic artery. The drug is very
toxic, but not for normal cells in the

The system aims to minimize side
effects by filtering the drug out of the
blood stream as it leaves the liver, but
some of the drug leaks out. The major
side effect seen in the trial was bone
marrow suppression.

The overseas regulatory process has
been a much easier one to traverse.
In 2010, Delcath concluded a Phase III
metastatic melanoma study, and the
Company IN 2011 completed a multi-
arm Phase II trial to treat other liver
cancers. The Company obtained a
European approval CE Mark for the
Hepatic CHEMOSAT delivery system in
April 2011. The Company has not yet
received FDA approval for commercial
sale of its system in the United States.

MelaFind acquires digital images of the
lesion with illumination in different
spectral bands, from visible to near
infrared, and automatically analyzes
these images.

In September 2011 MELA Sciences  
announced that it received CE Mark
approval for MelaFind, allowing the
company to market its MelaFind device
to dermatologists across the European
Union (EU). The company intends to
initially market MelaFind in Germany,
which has the highest incidence of
melanoma in Europe.

The CE (Conformité Européenne, or
"European Conformity") Mark approval
allows the company to market
MelaFind freely across the 27 nations
that comprise the EU. The EU is the
world's largest economic bloc with over
500 million residents and annual
economic output of over $16 trillion.

Melanoma rates in Germany have
doubled over the last decade and the
national mortality rate from the disease
is the highest in Europe. Over 20,000
Germans are expected to be
diagnosed with melanoma by 2016.
Germany is the only country in the
world with a nationwide skin screening
effort in place for men and women age
35 and older.

The studies used to support the CE
Mark application were the 1,383-
patient U.S. pivotal trial and the
companion reader study of 110
dermatologists: the device
demonstrated a 98% sensitivity;
whereas dermatologists had a 72%
sensitivity in the companion reader
study. MELA Sciences worked with the
U.S. Food and Drug Administration
(FDA) to design the pivotal study, the
largest ever conducted in melanoma
detection, and has a Binding Protocol
Agreement with the FDA.

Approximately 11% of all lesions and
melanomas in the MelaFind database
were obtained from European clinical

Melafind is not approved  in the US.

Cancer vaccines for melanoma are
also being explored.

BioVex Inc. created the vaccine
OncoVEX GM-CSF, which contains a
virus that only replicates in the
melanoma tumor and creates proteins
to stimulate the immune response
there, enhancing rejection of the tumor.
OncoVEX also carries biological
agents that boost the immune
response to melanoma.
OncoVEX GM-CSF is currently in
phase III clinical trials for melanoma
with Rush University Medical Center is
a leading center.


A team of UK scientists in 2001 has
made the discovery that drugs that
target a fault in a protein called BRAF
could actually fuel the progression of
cancer in some cases.

The BRAF inhibitors work to stop
spontaneous mutations in a gene
known as BRAF. If a defective gene
encodes a protein, the cancer begins
because it then becomes part of a
pathway to help cells grow and
PLX4032 or Vemurafenib in a  phase 1
clinical trial using a new formulation of
an experimental drug that targets the
BRAF cancer gene, has shown early
promise in treating melanoma in
patients with a mutated form of the
gene and whose skin cancer has
progressed to the metastatic stage.

Many melanomas have a mutation of
BRAF that activates a protein called
serine-threonine kinase (B-RAF or
BRAF) that drives the growth of cancer
cells. The mutation is called V600E.
These mutations of BRAF also occur in
other cancers.

In this phase 1 trial, Dr Flaherty and
colleagues from other research
centers in the US and Australia, found
that a new formulation of PLX4032 (an
earlier formulation had not succeeded
in a previous trial), inhibited the V600E
mutation of BRAF and 26 of the 32
patients they treated with it (81
percent) showed a partial or complete
response that lasted at least 19

The BRAF mutation that the new drug
targets is active in more than half of all
melanomas, and until this discovery
patients and doctors had very few,
reliable therapies.

PLX4032, a BRAF inhibitor is
developed for the treatment of
malignant melanoma by Plexxikon and
Roche/Genentech.  Daiichi Sankyo Co.
bought Plexxikon, Roche is a licensee.

The BRAF gene is faulty in about half
of malignant melanomas and many
other cancers, making it a suitable
drug target.
Drugs that block BRAF function in cells
are already showing positive results in
early clinical trials in melanoma
patients in the US.
About half of the melanomas that do
not have faults in BRAF have errors in
a different protein, called RAS.
Scientists examined the effect of drugs
that block BRAF function on the
melanomas with faulty RAS.
They found that the drugs caused an
unexpected activation of the processes
that drive cancer-cell growth.

This will enable clinicians to select
which patients they administer these
drugs to, allowing them to personalise
treatment for each patient.
This research also provides the
springboard for developing drugs that
will work in patients whose tumours
carry a faulty RAS gene.

The impact of this research will enable
doctors' testing BRAF inhibitors in the
clinic to target the treatments more
precisely to patients who will definitely
benefit and avoid treating those who