| Renal
cancer, also called hypernephroma or renal cell carcinoma
(RCC), accounts for 3% of all malignancies in humans and
is a histologically diverse disease with an often unpredictable
course. The American Cancer Society predicts there will
be approximately 36,000 new cases of renal cancer in the
US during 2005, resulting in around 26,000 deaths.
The
prognosis of renal cancer is worsened with the onset of
metastasis, and therapies currently available are of limited
success. In addition, over-expression of the multi-drug
resistance (MDR) protein in renal cancer means there is
a low response rate to chemotherapy. The unpredictable nature
of RCC and its difficulty to treat has driven pharmaceutical
companies to fund research into finding alternative treatment
options.
Therapy
options
According
to IMS
LifeCycle R&Dfocus there are more than
80 products being investigated for the potential treatment
of renal cancer. Table 1 details a selection of products
that are in later-stage development for RCC in the US and
Europe.
Table
1: Renal cancer therapies in the pipeline
|
Compound |
Trade name(s) |
Region |
Phase |
Developer |
|
atrasentan |
Xinlay |
US |
II |
Abbott |
|
bevacizumab |
Avastin |
US |
III |
Genentech,
Roche |
|
erlotinib |
Tarceva |
US |
II |
OSI,
Genentech, Roche |
|
MAb,
G250 (MN) antigen |
Rencarex |
US,
Europe |
III |
Wilex,
Esteve |
|
sorafenib |
n/a |
world-wide |
III |
Onyx,
Bayer |
|
sunitinib
malate |
Sutent |
US,
Europe |
III |
Pfizer |
|
temsirolimus |
n/a |
US |
III |
Wyeth |
|
vatalanib
(PTK/ZK) |
n/a
|
US |
III |
Schering
AG, Novartis |
Source:
IMS LifeCycle R&DfocusThe
mechanism of action of compounds being developed for use
in renal cancer includes anti-angiogenic drugs, growth factor
receptor inhibitors, kinase inhibitors and tumour antigen
inhibitors. A number were featured at the 41st annual meeting
of the American Society of Clinical Oncology, held in Orlando
in May 2005.
Angiogenesis,
the process by which tumour vasculature develops, is essential
for the growth and metastasis of cancer cells. Renal cancer
is a highly vascularised tumour type and vascular endothelial
growth factor (VEGF) receptor is over-expressed in the majority
of patients. Binding of VEGF ligand to its receptor leads
to tyrosine kinase phosphorylation and downstream activation
of several signalling pathways that stimulate angiogenesis.
Therefore, molecular inhibition of this pathway is a targeted
therapeutic approach for RCC.
VEGF
inhibitors
Genentech
and majority-owner Roche are developing Avastin (bevacizumab),
a humanised monoclonal antibody against VEGF, for RCC; it
was launched as a therapy for colorectal
cancer in February 2004. At the 41st ASCO meeting, an
update of results was reported from Phase II trials of Avastin
in combination with Tarceva (erlotinib) for renal
cancer; Tarceva is being co-developed by OSI, Genentech
and Roche. Results showed that 15 of 59 evaluable patients
(25%) had objective responses (14 partial responses and
one complete response) and 36 patients (61%) had stable
disease. Median survival in the trial has not been reached;
78% and 60% of patients were alive at 12 and 18 months,
respectively. Grade III adverse events observed included
diarrhoea, rash, nausea/vomiting, hypertension, bleeding,
proteinuria and pruritus; two patients discontinued treatment
because of Grade III skin toxicity. In addition, one Grade
IV toxicity (gastrointestinal bleeding) occurred.
In
February 2005, Roche initiated a Phase III trial in the
US with bevacizumab plus interferon in metastatic RCC.
Sutent
(sunitinib malate), an orally bioavailable inhibitor of
VEGF receptor, platelet-derived growth factor receptor,
and KIT and FLT3 tyrosine kinases, is being developed by
Pfizer for a variety of tumour types. In a US Phase II RCC
trial, conducted during 2004, Sutent induced a partial response,
stable disease and progressive disease in 15 (24%), 29 (46%)
and 19 (30%) patients, respectively. Phase III trials are
under way in renal cancer in the US and Europe.
Kinase
inhibitors
Stimulation
of growth factor receptors leads to activation of a number
of downstream signalling pathways. The Ras/Raf/MEK/ERK and
mammalian target of rapamycin (mTOR) intracellular pathways,
which couple growth receptor signalling to transcription
factor activation, are of particular importance in renal
cancer. mTOR regulates the cell cycle to stimulate cell
cycle progression, angiogenesis, and cell proliferation,
survival and mobility. Inhibition of these intracellular
pathways is another approach to the treatment of RCC.
Bayer
and Onyx are developing sorafenib (BAY 439006), an orally
bioavailable inhibitor of raf kinase and the VEGF-2 and
PDGFR tyrosine kinases. A world-wide, randomised Phase III
trial to evaluate the safety and efficacy of sorafenib in
advanced RCC, which completed enrolment in March 2005, is
ongoing. The trial, the largest ever for RCC, will involve
more than 900 patients with unresectable and/or metastatic
disease who have failed a previous systemic therapy. The
primary endpoint of the trial is improvement in survival;
the study will also examine time-to-disease progression,
overall response rate, safety, pharmacokinetics and quality
of life.
At
the 41st ASCO meeting, preliminary data from this trial
were reported. Sorefenib delayed the progress of advanced
kidney cancer, extending disease progression to 24 weeks
compared with 12 weeks for placebo. Pending regulatory approval,
Bayer and Onyx expect to begin selling the drug in the first
half of 2006. Despite the release of this positive data
at ASCO, however, Onyx's shares fell after some analysts
said they considered Pfizer's earlier-stage data for Sutent
more impressive. On the other hand, Sutent patients must
take a two-week break after each four-week period of treatment
to recover from the fatigue and other side-effects it can
cause.
Wyeth’s
temsirolimus (CCI 779), a sirolimus (Rapamune) analogue
and inhibitor of mTOR, was granted FDA Fast Track designation
as a first-line treatment for poor prognosis RCC in August
2004. In February 2004, Wyeth initiated a randomised, Phase
III trial comparing temsirolimus with alpha-interferon,
a standard current treatment, in 600 patients with metastatic
renal cancer; the trial is ongoing. Wyeth expects to file
for FDA approval of temsirolimus in RCC during the first
quarter of 2007.
Tumour-associated
antigen inhibitors
Tumour
cells express a variety of markers on the cell surface that
allow for the targeting of therapies to cancerous tissue.
G250 is a cell surface antigen that is expressed on the
surface of more than 90% of clear cell adenocarcinomas;
G250 expression in normal tissue is restricted to the larger
bile ducts and mucosa of the upper gastrointestinal tract,
where levels are negligible.
Wilex
is developing Rencarex (WX G250), a chimaeric monoclonal
antibody against G250 (or MN), for the treatment of both
metastasised and non-metastasised renal cancer through a
partnership with Esteve. A US and European Phase III trial,
initiated in June 2004 and designated ARISER, is evaluating
Rencarex versus placebo as an adjuvant therapy for non-metastasised
RCC patients at high risk of recurrence after resection
of the primary tumour.
What
does the future hold?
Renal
cancer is a disease with a complicated etiology that currently
has a high mortality rate. Advances in the understanding
of the molecular mechanisms underlying the disease, however,
have enabled the initiation of clinical investigation into
potential targeted treatment options. Data presented at
the 41st ASCO meeting highlighted the benefit of therapeutics
currently in development both as monotherapies and combination
treatments. According to ClinicalTrials.gov, the clinical trial
database of the US National Institutes of Health, there
are presently 189 studies recruiting RCC patients. These
trials, together with continuing preclinical research into
the mechanism behind renal cancer, will enable progression
towards reducing the mortality rate of this aggressive disease.
This article
was written by Dany Maneely, an editor for R&Dfocus.
Data from the 41st ASCO meeting were reported in IMS LifeCycle
R&Dfocus and in Drug News. Now available
is IMS Biotech Market Analyzer - the most detailed
and comprehensive analysis tool for the global biotech market.
The database publication provides information on biotech sales
performance in both the retail and non-retail sectors world-wide,
by therapy class, corporation and geographic region. For further
information about any of these products, please contact Stephanie
Earle via e-mail or call +44 207 393 5515.
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