Thursday, March 10, 2011

Big Pharma Giving RNAi Technology the "Silent Treatment"

Soon after Andrew Fire and Craig Mello reported the mechanism of a biological process able to post-transciptionally silence gene expression (RNA intereference) in 1998, scientists were quick to dream of the possibilities it held to cure diseases such as cancer.  RNAi also took over gene therapy as the hot spot of biotechnology.  Big Pharma companies, biotechs, and hundreds of academic researchers (including myself) went into full gear to develop platforms for siRNA treatments.  To avoid any confusion, the reader should note that simply RNAi is the process through which the macromolecule called siRNA works.

Almost 13 years later, we have yet to meet the expectations of the optimist bunch.  Companies such as Novartis and Roche are beginning to abandon their research in the field.  Novartis ended its collaboration with Alnylam late last year (Alnylam has approximately $300 million in cash reserves and trades for about $10.  The stock price has been decreasing since 2008) and Roche is running away from its program after investing nearly $500 million into it.  It seems as if these companies have become impatient with the progress and forgotten the saying, "good things come to those who wait."   Or could it really be that the two biggest recent discoveries in genetics (sequencing of the human genome and discovery of RNAi) bear no fruit?

The primary challenge hindering successful treatment with siRNA (short interfering RNA) has been finding a suitable carrier to deliver siRNA to target organs or tissues and protect against degradation in the vasculature.  Developing a carrier, either polymers, dendrimers, or lipid nanoparticles, is another task for pharma companies to undertake.  This can significantly increase R&D costs although the company may be able to obtain a separate patent for it and use it for a variety of siRNA therapies. 

Other issues such as off targeting have concerned researchers and clinicians.  RNA interference is a specific therapy.  However, it's aim to block the production of a protein can be performed in any cell expressing that specific protein.  Researchers tend to target proteins that are over-expressed or mainly expressed in the disease cells.    

Unlike monoclonal antibodies, siRNAs are easier to copy and may see generic versions sooner after patent expiration.  This may be a slight deterrent for some companies.

siRNA therapy effectiveness is limited by lifetime of the targeted protein, protein turnover rate, and stability/lifetime of siRNA within the cell and association of RNA induced silencing complex.  To be maximally effective, siRNA must be delivered to cells before necessary proteins are made.  If delivered after protein production, the protein needs to have a high turnover.  siRNA may secure a niche as an adjunct therapy to prevent resistance to chemotherapy.  As a sole therapy for the treatment of cancer, siRNA therapy has been riddled with sup-optimal results and failures.

The cost of siRNA therapy, once it is proven successful, can make or break its future.  A lower cost can help siRNA therapy to be used as adjunctive therapy.  If cost approaches the realms of monoclonal antibodies, siRNA may have no market except in rare diseases and would need to secure Orphan Drug Status.  Effectiveness of current siRNAs would be warrant such status.
Despite the exits of two giants, there is some good news for the future of RNAi therapeutics.  Dicerna signed an agreement with Kyowa Hakko Kirin.  Pfizer and Santaris have reached an agreement  over Santaris' locked nucleic acid (LCA) technology.   There are a few siRNA drugs in clinical trials, primarily in Phase 1.  Alnylam, Kyowa Hakko Kirin, and cubist have collaborated on a siRNA for treatment of RSV and it is in Phase 2B trial.  Pfizer has license to a siRNA drug (from Quark) for the treatment of age related macular degeneration andand diabetic macular edema.  It seems that Pfizer/Quark siRNA has the greatest chance of success because of the local administration to the eye.  However, it needs to compete with Lucentis, a monocloncal antibody.

siRNA therapeutics is beginning to look like the Miami Heat.  Despite early anticipation of greatness, things have started to go south as of late and people are beginning to lose faith.  We're all waiting for the Black Swan that will catapult siRNA therapies into the next level.