RNA Interference and the Paradigm Shift

from Drug Discovery to Drug Design

Guy A Tremblay, August 2008
R&D Research Scientist / Hybridization Immunochemistry Study Director
Charles River Preclinical Services Montreal

In the last 25 years, the number of new drugs submitted to the FDA has declined
significantly. Paradoxically, over the same period, biomedical research has flourished.
For instance, U.S. Pharma R&D spending increased from $100 to 250 millions per year
between 1993 and 2002. In addition, the investment required to launch a new drug has
greatly increased. And that’s not talking about the expiring patents for a number of drugs
by major pharma 1.

In parallel to the pharmaceutical crisis, RNA interference (RNAi) was discovered

a decade ago, which led to a renewed interest in an old molecule, RNA.

Andrew Z. Fire and Craig C. Mello were awarded the 2006 nobel prize “for their
discovery of RNA interference - gene silencing by double-stranded RNA”. The RNAi
field expanded fast, as academic labs quickly adopted RNAi for the purpose of testing
hypothesis about their favorite gene, by knocking down its expression in cell culture.

RNAi is mediated by small double-stranded RNA molecules of 19 to 25

nucleotides that can specifically block a given mRNA—i.e. the product of gene
expression. RNAi may be considered as an acquired intracellular immunity targeted at
RNA.

RNAi is a natural mechanism that has been observed from plants to animals, and
that seems present in all cell types. RNAi targets double stranded RNA from viruses, and
also plays a role in regulating development and genome maintenance.

The appeal or RNAi in biotechnology derives from the ease, in theory, with which
a drug can be custom-tailored to target a given gene. A researcher can design an RNAi
drug from scratch using solely the gene sequence of a faulty or “diseased” mRNA. The
RNAi drug is synthesized, tested in cell lines and mice, and you’re all set for preclinical
testing. The drug design process with RNAi is in sharp contrast with traditional drug
discovery, where typically thousands of chemical entities are screened in a laborious
endeavor to find the right “hit”.

On the RNAi biotech front, leader of the pack Alnylam Pharmaceuticals owns an
impressive IP portfolio and has three lead candidates. Another big player is Sirna
Therapeutics, now a subsidiary of Merck. Sirna used to be called Ribozyme
Pharmaceuticals Inc. (RPI). I know well of the company because the lab of the late
Robert Cedergren, where I studied at the Université de Montréal, collaborated with RPI.
 RPI had no luck with ribozymes—neither did I—, so the company converted to
RNAi, along with its name. Sirna’s focus turned out to be a very good choice: Merck
acquired Sirna for no less than a shiny $1.1 billion.

Generally speaking, in the arid landscape of biotech financing, RNAi strikes out
as a blossoming oasis. To quote Armstrong 2: “Kalorama Information estimates that the
best case market for RNAi and other nucleic acid therapies is worth $210 billion. Since
2005, […] Alnylam has inked milestone deals ranging from $700 million to more than $1
billion with Novartis, Roche, and Takeda […]” The involvement of major pharma in
RNAi deals is not surprising considering the pharma crisis and the comparatively low
cost of RNAi drug development.

The dream of a drug that can be custom-tailored for each disease and condition is
not new. The so-called antisense approach, as well as ribozymes, were hoped to play that
role. However, RNAi seems to have a better chance at that now, considering the relative
efficacy of RNAi. In fact, antisense proved dicey, whereas ribozymes and other nucleic
acid therapies simply flunked.

Effective as they may be, RNAi drugs will face the same hurdles as its rugged
predecessors. Among the principal challenges: nucleotide chemistries that will increase
plasma half-life and potency, delivery vehicles (liposomes, nanoparticles, etc.), specific
targeting of organs/cell types and routes of administration, since at the moment RNAi
cannot be formulated into a pill.

In July 2008, Roche has set foot in the RNAi arena by acquiring straight-out
Genentech. Tekmira and Protiva, two small biotechs firms from Vancouver focused on
lipid formulations for the delivery of RNAi, have merged in March 2008. There are also
rumors of a merger between Alnylam and ISIS Pharmaceuticals, the flagship company
for the antisense approach.

RNAi technology is at its infancy and we can expect that drug design with
oligonucleotides will bring about more news of wealth and dynamism in biotech.

References

1. See Big pharma faces grim prognosis. Washington Post. December 2007. and
Innovation or Stagnation? Challenge and Opportunity in the Critical Path to New
Medical Products. March 2004. U.S. Department of Health and Human Services. Food
and Drug Administration.

2. Armstrong, W. 2008. RNA Revolutionaries: Could gene silencing be the next great
innovation in drug development? Pharmaceutical Executive, July 1st.

3. Osborne, R. 2007. Companies jostle for lead in RNAi, despite uncertainties. Nature
Biotechnology. 25: 11.