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

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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)

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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