Questions
and Answers with:
Patrick L.
Iversen, Senior Vice President, Research and Development, AVI
BioPharma
Dec. 8, 2005--Antisense pioneer
AVI BioPharma is one of many companies developing bird-flu-related
therapeutics. AVI's proprietary NeuGene antisense technology is
relatively old by biotech standards: It has been in development
for several years and has been tested in about a dozen clinical
trials already. The company has a longstanding antiviral program,
having worked on 45 different viruses representing 17 viral
families. In October of this year, AVI announced the expansion its
anti-influenza program to include the H5N1 avian flu. One
of the big advantages of antisense is how quickly candidate drugs
can be developed. The company's goal is to deliver a single
NeuGene drug that will be effective against a variety of influenza
subtypes, including H5N1 as well as older subtypes, such as H3N2,
that caused earlier pandemics. But antisense is also far from a
proven field, and although AVI's technology is unique, the company
still has to bear the stigma associated with an approach that many
believe has simply not delivered. Heading up AVI's research and
development effort, Patrick Iversen has the dual challenge of
proving his product's worth as a powerful antiviral and
distinguishing it from the earlier, failed antisense compounds.
PharmaWeek:
What's the biggest challenge about being in the antisense
field right now?
Patrick L.
Iversen: The entire field is now suspect
because of several high-profile failures. People
promised a lot, and instead, there have been problems. But the
common problems relate to the first-generation compounds, which
can stimulate complement, trigger interferon responses, release
cytokines, and delay blood coagulation. These
effects are so well known that reviewers automatically ask about
it when you submit antisense-based studies to FDA or journals.
Companies are even working on how to harness that response
as a therapeutic effect. But our compounds are third-generation
antisense called morpholinos. One of their key properties is a
synthetic backbone. We haven't seen any of the
problems associated with traditional antisense compounds with our
drug candidates.
PharmaWeek:
So why keep pushing antisense? What are the advantages?
Iversen:
First of all, these drugs are engineered to match the
target. So when you have the gene sequence, it's remarkably easy
to get a good candidate quickly. Also, this is
a new class of drugs with new capabilities. We
think they'll be more powerful and more specific – that means
they should also be safer. As antivirals, our drugs attack the
viral replication machinery. Finally, we've
been working on this for a long time. We have a growing body of
supporting data. There are more than 1,000 scientific papers on
morpholinos, demonstrating their potential.
PharmaWeek:
So what's holding the company back now?
Iversen:
Antisense got such a bad name, it was hard to get any
attention, especially from partners or investors, which little
companies like ours need to have. We have been publishing lots of
proof of concept studies. We have safety studies going as long as
several months in animals, but we still haven't done the two-year
safety trials. But in this field, because of the bad rap, the bar
keeps rising. What was considered proof of a
legitimate approach 6 years ago isn't enough anymore. Now, you
need to be in late-stage clinical trials for many people to
believe you. That doesn't daunt us though. In
restenosis, for example, our drug is going up against treatments
from major companies, and we are still hanging in there.
PharmaWeek:
What are the next steps for your avian flu NeuGene candidate?
Iversen:
I have submitted a grant to fund our avian flu effort.
Even with that taken care of, there will be challenges. Even key
people at NIH face a constriction point in getting good animal
data because it is so hard to get access to the high-security
bio-containment labs, where those studies using the deadly strains
are done. There are big drug companies testing hundreds of
compounds in there, and it could take a while to get to the front
of the line.
PharmaWeek:
Are you afraid the RNAi-drug developers will quickly pass
by you?
Iversen:
Not at all. Antisense is years ahead of RNAi
development-wise, and they are already seeing far worse off-target
effects than were seen even with the older antisense compounds.
A lot of people with tremendous credibility are standing
behind those companies. Once they've spent their credibility
dollars, they're in trouble.
Related
References:
Alonso, M,
et al. "Inhibition of infectious haematopoietic necrosis
virus in cell cultures with peptide-conjugated morpholino
oligomers." J
Fish Dis. 2005 Jul;28(7):399-410.
Holden, KL,
et al. "Inhibition of dengue virus translation and RNA
synthesis by a morpholino oligomer targeted to the top of the
terminal 3' stem-loop structure." Virology.
2005 Oct 5: (in press).
Neuman, BW,
et al. "Inhibition, escape, and attenuated growth of severe
acute respiratory syndrome coronavirus treated with antisense
morpholino oligomers." J. Virol. 2005;
Aug;79(15):9665-9676. http://jvi.asm.org/cgi/content/abstract/79/15/9665
van den
Born, E, et al. "Antiviral activity of morpholino oligomers
designed to block various aspects of Equine arteritis virus
amplification in cell culture." J Gen Virol.
2005;86:3081-3090. http://vir.sgmjournals.org/cgi/content/abstract/86/11/3081
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Healthtech Institute. All Rights Reserved
