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As
biotech firms push the first wave of RNA interference
(RNAi)-based therapeutics through animal models and
into early-phase clinical trials, Big Pharma is taking
note — and negotiating a foothold in the platform.
Already this year, four large deals between major
pharmaceutical companies and RNAi biotech firms have
been announced. In July alone, Abbott Laboratories
unveiled a deal with Dharmacon to develop anti-cancer
agents, while Merck and Alnylam announced a
significant expansion of their collaboration to turn
small interfering RNAs (siRNAs) into therapeutics. The
latter are not revealing information about their
targets.
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“Using
RNAi, we can work to treat disease in a
fundamentally different way than prior
approaches. We have the power to target genes
involved in disease that small molecules and
antibodies cannot."
Barry
Greene, ALNYLAM |
Following
several major advances in the RNAi field, including
the first clinical data and evidence from animal
studies that systemic delivery is possible, large
companies don’t want to miss the opportunity to get
into the potentially profitable field early. “Quite
frankly, most of Big Pharma missed monoclonal
antibodies as a platform to build and now are buying
companies to have that platform — but for billions
of dollars,” says Barry Greene, Alnylam’s COO.
Companies aren’t being so timid about the new
technology.
“Using
RNAi, we can work to treat disease in a fundamentally
different way than prior approaches. We have the power
to target genes involved in disease that small
molecules and antibodies cannot. Merck understood that
breakthrough early on and felt that RNAi was the next
major platform,” says Greene. In the new deal, Merck
will pay Alnylam $120 million for research and
development of nine new targets, which have not yet
been identified. The new program is in addition to the
companies’ existing joint effort to develop a RNAi
therapeutic for spinal cord regeneration by targeting
the NOGO pathway.
With
just a few early-phase clinical trials completed, the
safety data for RNAi therapeutics look encouraging.
The drug farthest along the development pipeline is
Acuity’s bevasiranib (previously Cand5), which
showed positive results in a multicenter randomized
Phase II trial for the treatment of wet age-related
macular degeneration (AMD). The company has plans to
launch a pivotal Phase III trial in the middle of next
year but isn’t saying when they expect to apply for
FDA approval.
Given
the relative ease of delivering an RNAi drug to the
eye, Acuity isn’t the only one going after the AMD
market, which is projected to reach $1 billion. Sirna
Therapeutics’ lead compound, Sirna-027, also looks
good in Phase I trials in AMD. With its partner
Allergan, the company will launch a Phase II
head-to-head trial testing Sirna-027 against
Genentech’s antibody therapy, Lucentis, which was
recently approved for AMD.
Balancing
Acts
The
other RNAi-based therapeutic in clinical trials is
Alnylam’s drug for respiratory syncytial virus
(ALN-RSV01). In a Phase I trial in healthy adults,
ALN-RSV01 showed no unexpected safety signals. The
company plans to initiate challenge trials in healthy
adults later this year and aims to test the drug in
naturally infected individuals by the middle of next
year. “We are balancing the moving fast and
developing this drug in a very high-quality way
because we are developing a whole new class of
drugs,” says Greene.
The
market value for an inhaled therapy for RSV could
exceed $1 billion according to some analysts, and with
that value Alnylam can expect company. Earlier this
year, GlaxoSmithKline (GSK) and Sirna announced a $700
million deal to go after numerous respiratory
ailments, including asthma, RSV, COPD (chronic
obstructive pulmonary disease), and allergic rhinitis.
In a recent report on Sirna, CIBC World Markets noted
that the total market for asthma drugs was $11.8
billion in 2003, and that GSK led in worldwide sales
of such drugs. Thus, the combination of Sirna’s RNAi
know-how and GSK’s familiarity with respiratory
could prove lucrative.
It is
no accident that the first wave of RNAi therapies can
be delivered directly to the site of action. Systemic
delivery of RNAi therapeutics is the major challenge
ahead. “Everyone recognizes that the big technical
hurdle in this is delivery of siRNAs into diseased
cells,” says Bill Kohlbrenner, director of cancer
research discovery at Abbott Laboratories. “There is
a focus on delivery technologies industrywide, and
there are things appearing on the horizon that appear
promising.”
Alnylam
published results in Nature in May showing that
intravenous injection of an siRNA against
apolipoprotein B could effectively silence the gene in
the liver and lowered serum cholesterol and LDL for up
to 11 days after therapy. This is the first published
report of systemic delivery of siRNA in a non-rodent
species, and experts, including Kohlbrenner, agree
that it is an important proof of principle, but that
it is also likely only the start of things to come.
A
quick survey of the field shows he’s likely to be
right. Not only has Alnylam partnered with Inex
Pharmaceuticals for the development of liposomes for
systemic targeting of siRNAs, but the company is also
working on the problem with Isis Pharmaceuticals,
which until now was better known for its antisense
work. Calando Pharmaceuticals has developed a
cyclodextrin-based nanoparticle for siRNA delivery
that can be decorated with specific proteins to
enhance targeting to the cells of interest. And
Sirna’s CEO Howard Robin says they are using a
nanoparticle system that they developed more than two
years ago for delivery of their hepatitis C siRNA. The
nanoparticles, says Robin, mask the RNAi until it
reaches the low pH of the endosome, at which point the
RNA is released into the cytoplasm. And, of course,
there is the more traditional option of delivering
nucleic acids using viral vectors.
It
was with this sort of viral-based delivery system that
Mark Kay’s group at Stanford University uncovered
what is likely to be RNAi’s first — but not only
— hitch. The team found that high-level expression
of a short hairpin RNA (shRNA) against the hepatitis B
virus saturated the native microRNA cellular pathway
in the livers of treated mice and killed the animals.
By titrating the expression of the shRNA the team was
able to obtain suppression of the viral sequence
without causing liver toxicity, but the risk of damage
is clearly significant. Evidence of liver toxicity has
shown up in some other preclinical RNAi tests, though
they haven’t been so dramatic, but that might point
to a more consistent problem than has been considered
so far.
“I
still think RNAi has a lot of chance of working,”
says Kay, who is director of the program in human gene
therapy at Stanford and president of the American
Society of Gene Therapy. “I have worked for many
years in the field of gene therapy and we’ve
developed things that I’ve thought had lots of
technical problems, as well as toxicology problems
that would really limit it from being used clinically.
I’ve always abandoned those approaches because I
don’t see any way around it. Here, I am nowhere near
that stage yet. I really think that this can work.
Off
Target
Another
hurdle in the effort to bring RNAi to the clinic is
dealing with potential off-target events. Dharmacon
recently showed that many of the off-target hits by
siRNAs result from homology between the seed region of
the siRNA guide strand (bases 2 to 7 or 8) and
microRNA target sequences in 3' UTRs. Although the
researchers found that it is difficult to limit such
effects with sequence changes, addition of a
2'-O-methyl group to the ribosyl ring reduced both the
number and magnitude of the off-target hits by
altering RNA interactions with the RISC complex.
That’s
the kind of work that attracted Abbott to Dharmacon
for partnering, says Kohlbrenner. “Dharmacon has a
tremendous background in siRNA technologies, but what
really attracted us to Dharmacon is their research
team. They have real strengths in areas like
bioinformatics, RNA chemistry, cell and molecular
biology. We think those assets combined with what
Abbott knows in the cancer area are really going to
help us advance therapeutics.”
Sirna
Therapeutics meanwhile has removed the ribose
altogether from their siRNAs and have started working
almost exclusively with siNAs, says Robin. siNAs
don’t trigger the unwanted interferon response that
can be a problem with some siRNAs, and siNAs are not
degraded by nucleases, according to Robin. (The only
siRNA-based therapeutic the company is currently
pursuing is Sirna-027.)
Significantly,
siNAs also fall outside of the Tuschl patents, which
are seen as key intellectual property in the RNAi
field. Sirna shares rights to Tuschl I with Alnylam,
but Alnylam is expected to gain exclusive rights to
Tuschl II. By using siNAs, Sirna avoids IP problems,
asserts Robin, which could be an asset given the
complexity and yet-to-be-resolved nature of the
intellectual property landscape in RNAi.
However,
perhaps a more pressing question for individual
investors and companies interested in jumping into the
fray is, “Why should this work any better than
antisense RNA?” Antisense commonly refers to
cleavage of double-strand RNA by RNase H, an enzyme
that resides in the nucleus of cells and functions in
DNA replication. RNase H cleavage is a stoichiometric
process and thus requires a large quantity of
antisense oligonucleotides to get into the cell before
it can significantly reduce the amount of target mRNA.
By contrast, RNAi is a catalytic process and will
require less siRNA to get into target cells for the
same degree of silencing.
“RNAi
is a natural pathway for regulating gene
expression,” says Frank Bennett, senior vice
president of research at Isis Pharmaceuticals.
Currently, with second-generation oligonucleotides
available for antisense and the delivery into cells
worked out, antisense may have a temporary advantage,
he says. However, that isn’t likely to remain so.
“When we do comparisons, we can identify that siRNA
has the potential of being an inherently more potent
mechanism.” And like Big Pharma, Isis
Pharmaceuticals isn’t about to miss the boat. They
already have a substantial division devoted to siRNA
chemistry and formulation.
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