Genasense Faces Identity Crisis
By Malorye A. Branca
Bio-IT World
BOSTON (02/18/04)—The first new drug in 20 years for advanced
melanoma could make its way into doctors' hands this summer.
Combined with chemotherapy, Genta's antisense drug Genasense (G3139)
appreciably extends lives in patients with this almost untreatable
cancer, and shows promise against other tumors as well.
The promise of Genasense enticed Aventis to enter a $480-million
collaboration with Genta in 2002, and forecasters are bullish on its
prospects. "With additional indications, it has blockbuster
potential," says Tracy DeGregorio at Decision Resources.
But new evidence suggests this drug's success owes nothing to its
intended mechanism — blunting the expression of a well-known
cancer
gene BCL2. Lingering confusion about Genasense's precise mechanism
of action raises new questions about the antisense approach in
general, and G3139 in particular.
Surprisingly, the man asking the questions actually helped develop
Genasense. Cy Stein of the Albert Einstein College of Medicine is an
antisense pioneer, sits on Genta's scientific board, and is due
royalties once the drug hits the market. So why is he raising
questions now? "My scientific credibility is at stake," he
replies. "I've spent my career saying these compounds are more
complicated than we thought."
Stein's findings will be published in an upcoming issue of Clinical
Cancer Research. He uncovered this new evidence while testing RNAi
in collaboration with Dharmacon — specifically, two siRNAs that
suppress BCL2 protein and mRNA levels by 85 percent to 90 percent
for up to eight days.
"The best [siRNA] was really spectacular," Stein says, "and the
results were reproducible." But to his surprise, both the siRNA-
treated and untreated tumor cells showed the same degree of changes
after a dose of chemotherapy. It was only when G3139 alone was
administered that more cells stopped growing. Nor did the group see
any "synergistic effect" between G3139 and chemotherapy, suggesting
Genasense works by itself, not in concert with other drugs.
In another study, Stein tested the effects of fragments of G3139,
which proved as effective at stopping cancer growth as the full-
length molecule (Lai, J.C. et al. Molecular Cancer Therapeutics 2,
1031-43; 2003).
Stein suspects Genasense works by inducing an immune response that
weakens cancer cells. Although he admits his work needs validation
—
the RNAi studies were conducted in a prostate cancer cell line,
which may not mimic actual patients — he maintains, "Every study
I
do points to the same thing."
Stop Making Sense
Genta's CEO, Raymond Warrell, disputes Stein's theory. "It's fine to
have all kinds of hypotheses, but they need to be proven," he says
edgily. "You can give interferon exogenously, and you will not see
the kind of effects we see [with Genasense]."
Warrell's reaction isn't surprising. Initial results from the Phase
III trial were less than clear-cut, but there were signs the drug
works better than standard therapy, which helps a meager 7 percent
of patients. Genta expects to learn this month if the drug will
receive priority review by the FDA.
Warrell maintains that BCL2 downregulation is the only mechanism
ever "proven" for this compound, making Genasense a bona fide
antisense inhibitor. But, Stein notes, "It's clearly established
that if you upregulate BCL2, you get cells that are resistant to
chemotherapy; nobody has proven that downregulating BCL2 makes cells
less resistant."
Harvard University's Stanley Korsmeyer, who cloned the BCL2 gene,
agrees with Stein: "It is an open question ... whether once a cancer
is established, BCL2 is required for its maintenance."
Regardless of mechanism, both Stein and Warrell expect the drug to
succeed. Genasense "has doubled response rates, providing a 60-
percent improvement in progression-free survival," Warrell says. "It
improved overall survival by about 25 percent in patients who were
refractory to other treatment."
Some analysts are unconvinced. "We have to wait and see," says Quyn
Pham at Delafield Hambrecht. Needham & Co.'s Mark Monane, however,
thinks Aventis and Genta have already "put together a compelling
argument." He too is wary about the drug's mechanism of action but
believes Genasense holds promise against other cancers, particularly
given the dismal record of prior therapies.
Genasense would become only the second antisense molecule to win FDA
approval, following Isis Pharmaceuticals' Vitravene, for
cytomegalovirus retinitis. That would be a huge victory for the
technology that has seen its share of disappointments. "The field is
labeled as a sector," says Patrick Iversen, AVI BioPharma's senior
vice president of research and development. "Good news, like bad
news, can affect us all."
However, AVI and Isis say they do not see such off-target effects
because they are working on "second generation" compounds,
fundamentally different from Genasense. "We don't have those
effects, and so we can predict the next success," Iversen says.
Antisense therapy has been poised for a breakthrough for several
years. Establishing the mechanism of Genasense is clearly important
to the scientists. But investors may not be as worried. As Monane
says, "If it works, it works."
ANTISENSE ON TRIAL
Company Compound/Indications Phase
Antisense Pharma AP-12009/Cancer Phase IIb
AVI BioPharma
Resten-NG/Restenosis Phase III
(planned)
AVI-4020/West Nile virus Phase II
AVI-4557/Drug metabolism Phase II
AVI-4126/Polycystic kidney disease Phase II
Oncomyc-NG/Cancer Phase I
Genta
Genasense/Melanoma, other cancers Phase III
Hybridon
GEM231/Various cancers Phase I
GEM-92/HIV Phase I
HYB-2055/Cancer Phase I
Isis Pharmaceuticals
Affinitak/Lung and other cancers Phase III
Alicaforsen/Crohn's disease Phase III
Alicaforsen/Ulcerative colitis Phase II
ISIS-14803/Hepatitis C Phase II
ISIS-1048030/Rheumatoid arthritis Phase II
ISIS-1048030/Psoriasis Phase II
ISIS-113715/Diabetes Phase II
ISIS-112989/ Phase I
Lorus Therapeutics
GTI-2040/Cancer, including breast, kidney, and myeloid leukemia
Phase II
GTI-2501/Cancer Phase I
MethylGene
MG-98/ Phase I
NeoPharm
LErafAON/Cancer, including pancreatic Phase I/II |
