View
217
Download
3
Category
Preview:
Citation preview
Antisense technology; the concept of designing
a drug that binds irreversibly to part of a
messenger RNA (mRNA) molecule, blocking
translation of that mRNA and so preventing
expression of its gene product, first became a
possibility in the early 1980s. Now, just over
20 years later, the first antisense product for
cancer treatment has reached the clinical trial
stage. In May 2000, researchers at the Royal
Marsden Hospital (London, UK) revealed results
from a three-year follow up of a Phase I trial of
G3139, an antisense drug developed by Genta1
(Lexington, MA, USA).
Bcl-2 is one of the proteins produced by can-
cer cells that gives them immortality; overex-
pression of bcl-2 overwhelms the cell’s usual
apoptotic signals and prevents it from follow-
ing the pathways that lead to programmed cell
death. Bcl-2 blocks apoptotic signals generated
during cancer treatment, conferring high levels
of resistance to standard radiotherapy and
chemotherapy treatments. Ray Warrell, CEO of
Genta, comments that when bcl-2 was discov-
ered in the early 1990s, there was a ripple of
excitement, but since then there has been ‘a
growing realization of just how critical this
molecule is in cancer cell biology’.
G3139, the antisense drug involved in the
Marsden trial and also currently in clinical trial
for nine different cancer types (Table 1), is an
oligonucleotide that is complementary to the
first six codons of the bcl-2 open reading
frame. ‘Studies on G3139 have shown that it
can be administered intravenously in humans,
and that it targets the RNA produced by the
gene that encodes bcl-2. Once bound, the drug
prevents translation of the mRNA and intra-
cellular levels of the bcl-2 protein in cells,
including human cancer cells, fall,’ explains
Warrell. He is keen to point out that although
patients have shown good anti-tumour re-
sponses when the drug is given alone, the best
effects are seen when it is given in combination
with standard anti-cancer treatment. ‘G3139
makes the tumour more susceptible to the ef-
fects of chemotherapy; they become particu-
larly sensitive to apoptotic signals and are killed
more easily,’ says Warrell.
G3139 and non-Hodgkin’s lymphomaBcl-2 is overexpressed in the majority of low-
grade non-Hodgkin’s lymphoma (NHL) cases
and in ~50% of high grade NHL cases, so NHL
was an obvious target for G3139 therapy.
Upregulation of the Bcl-2 protein is most com-
monly caused by a translocation between chro-
mosomes 14 and 18 that brings the bcl-2 gene
under the transcriptional control of the im-
munoglobulin heavy chain promoter. Justin
Waters (Department of Medicine, Royal
Marsden Hospital, Sutton, Surrey, UK) recently
led a study of 21 patients with bcl-2 positive
NHL that had failed to respond to previous
standard treatment. All received a 14-day infu-
sion of G3139. No significant toxicity was seen
at doses up to 110.4 mg m22 d21 but, at higher
doses, side effects such as thrombocytopaenia,
hypotension and fever became apparent and
the maximum tolerated dose was found to be
147.2 mg m22 d21.
Although primarily a safety study, there was
also a clear indication of the efficacy of G3139.
One of the patients experienced complete re-
mission, and remained in continuous remission,
as confirmed by a repeat CT scan and bone mar-
row examination at 36 months after treatment.
Two patients improved significantly, nine pa-
tients remained stable and nine cases pro-
gressed. Bcl-2 protein levels were reduced in
seven out of 16 assessable patients. Waters says
that these preliminary results show that bcl-2
PSTT Vol. 3, No. 7 July 2000 update news
1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00274-1 217
Why antisense technologymakes good sense for cancertreatmentKathryn Senior, tel: 144 118 942 1639, e-mail: ksenior@dircon.co.uk
Table 1. Status of G3139 clinical trials
Type of cancer Trial location Status Partner drug
Melanoma University of Vienna, Vienna, Austria Phase II Dacarbazine (DTIC)Prostate Memorial Sloan-Kettering Cancer Center, NY, USA Phase I–II Taxol® (Paclitaxel); Taxotere® (Docetaxel)Prostate University of Texas, San Antonio, TX, USA Phase II Taxotere® (Docetaxel)Lung (small-cell) Ohio State University, OH, USA Phase I–II Taxotere® (Docetaxel) Colorectal University of Texas, San Antonio, TX, USA Phase II Camptosar® (Irinotecan) Breast Georgetown University, Washington, DC, USA Phase I–II Taxotere® (Docetaxel)Acute Leukaemia Ohio State University, OH, USA Phase I–II Fludara® (Fludarabine)
Reproduced, with permission, from Genta (Lexington, MA, USA).
antisense therapy is feasible. ‘We saw clear evi-
dence for anti-tumour activity, albeit in a lim-
ited number of patients; the observation of a
specific downregulation of Bcl-2 after G3139
therapy in patients’ tumour cells confirms that
G3139 is acting in the way predicted, by an anti-
sense mechanism,’ he comments. However, he
cautions that a short course of treatment de-
signed to modulate the expression of only one
gene might not be enough to alter the course
of a cancer, given the extreme genetic complex-
ity of the disease. ‘Potential advances using this
technique could result from its combination
with standard chemotherapy,’ he says. However,
he adds, at this point it is difficult to predict the
long-term potential of G3139 for lymphoma.
‘Only larger Phase III randomized trials will pro-
vide a clear answer to this question’.
G3139 in combination with other anti-cancer therapiesIn a separate Phase I trial of G3139, in combi-
nation with a standard agent used to treat
metastatic melanoma, significant anti-tumour
responses have been observed. A team led by
Burkhard Jansen (University of Vienna, Austria)
administered G3139 in combination with
dacarbazine to a total of 17 patients with ad-
vanced malignant melanoma. Of the 14 fully
evaluated to date, six have shown a significant
anti-tumour response. Serial biopsies showed
that G3139 markedly reduced levels of bcl-2
within tumour cells.
A 15-month Phase III trial has now begun,
but is currently still at the recruiting stage. The
randomized trial will compare standard dacar-
bazine treatment with combination treatment
with G3139 in at least 270 patients drawn from
the USA, Canada, Europe and Australia. ‘We are
cautiously optimistic that an application for
regulatory approval for G3139 for malignant
melanoma can be lodged with the Food and
Drug Administration (FDA) in the fourth quarter
of 2001, and that the drug could be launched in
the first quarter of 2002,’ predicts Warrell.
Results from another Phase I study, carried
out chiefly in patients with genitourinary
cancers by Scher and colleagues at the
Memorial Sloan–Kettering Cancer Center (New
York, USA), was presented at the annual meet-
ing of the American Society of Clinical
Oncology (20–23 May 1999, New Orleans,
USA). Scher and colleagues showed that out of
35 patients treated with a combination of
G3139 and taxol, some experienced grade 3 ad-
verse effects – thrombocytopaenia, fatigue and
rash – but none showed signs of grade 4 ad-
verse reactions. Bcl-2 expression was reduced
within a few days of treatment. One patient
with bladder cancer showed an excellent radio-
graphic and clinical response to treatment and
is now in remission. Another had relief of pain,
and the cancers in three patients with renal cell
carcinoma did not progress2.
Warrell points out that whilst G3139 is show-
ing great promise, it is a second-generation
compound and Genta has already developed
third-generation antisense drug formulations.
These are more stable, have a longer life in the
body and can be taken orally. ‘In the next five
years, research is likely to focus on identifying
further cancer targets for antisense technology
and developing third-generation antisense
products to suppress their production in many
different forms of cancer,’ concludes Warrell.
References1 Waters, J.S. et al. (2000) Phase I clinical and
pharmacokinetic study of bcl-2 antisense
oligonucleotide therapy in patients with non-
Hodgkin’s lymphoma. J. Clin. Oncol. 18,
1812–1823
2 Scher, H.I. et al. (2000) A phase I trial of
G3139 (Genta Inc.), a bcl-2 antisense drug, by
continuous infusion as a single agent and with
weekly taxol, American Society of Clinical
Oncology (May 20–23, New Orleans, USA)
update news PSTT Vol. 3, No. 7 July 2000
1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00277-7218
There are estimated to be over 5000 identified
rare diseases, which together affect tens of mil-
lions of people worldwide, but individually af-
fect relatively few people. Unfortunately, the
high costs associated with drug development
generally make it uneconomical under normal
market conditions for companies to develop
drugs to treat or prevent these diseases. These
diseases or conditions are therefore known as
‘orphan’ and the products that could be used to
treat or prevent them commonly known as
‘orphan drugs’ or, in Europe, ‘orphan medicinal
products’.
BackgroundIn 1983, the Orphan Drug Act was passed in the
USA. Through a system of tax credits, govern-
ment grants and assistance for clinical research,
seven years of marketing exclusivity for orphan
indications of approved products and exemp-
tions from drug registration fees, this Act
encouraged the development of orphan drugs.
By the end of 1997, this resulted in over 150
new orphan drugs being approved, which are
currently used by over seven million patients.
Japan introduced an orphan drug law in
1993 (Ref. 1), and since then countries such as
Australia and Singapore have followed. Until
recently, however, there has been no concerted
European-wide approach, although some regu-
latory authorities have granted fee exemptions
and reductions for orphan products, and some
money has been made available for rare
diseases in European Community (EU) research
programmes.
In April 1999, however, a four-year pro-
gramme of EU action on rare diseases was fi-
nally adopted. This is intended to promote,
throughout Europe, further understanding
of rare diseases, monitoring and support
New European rules on orphan drugsRichard Binns* and Bryan Driscoll, Simmons & Simmons, 21 Wilson Street, London, UK EC2M 2TX, *tel: 144 (0)20 7628 2020, fax: 144 (0)20 7628 2070, e-mail: richard.binns@simmons-simmons.com
Recommended