Serepta Clarification

I saw a few comments on an investor website concerning my post on RiAN BioSciences and the Disappearing Bees.  It was accurately pointed out that I erroneously labeled Serepta as an RNAi company. I need to clear up my mistake. They are not an RNAi company. Their drug is a non-traditional RNA antisense product. They point out, "Unlike most other RNA-based approaches, such as small interfering RNA (siRNA), Serepta's technology can directly target both messenger RNA (mRNA) and precursor messenger RNA (pre-mRNA) to either down-regulate or up-regulate targeted genes or proteins."

I simply lump all RNA drug companies together because I think targeting RNA is a mistake. I stand by that claim. Serepta, like the others, has some interesting chemistry in its product. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic structures modeled after the natural nucleic acid framework of RNA. They replace the ribose ring with morpholine which is linked through phosphorodiamidate rather than anionic phosphodiester bonds. You can get some of this stuff from a company called GeneTools LLC and start your own RNA company or just do some research with it.

Gene Tools, LLC produces and markets Morpholino oligos for antisense applications and ancillary products for basic research. We are also engaged in research relating to delivery of Morpholino oligos into cells and use of Morpholino oligos as probes and in diagnostic systems.

Morpholino oligos and the subunits used in their assembly were invented and developed at Sarepta Therapeutics (formerly AVI BioPharma Inc. and earlier ANTIVIRALS Inc.), the pioneer antisense company founded by James Summerton in 1980. Gene Tools manufactures and markets research quantities of Morpholino oligos. In Japan, Funakoshi Co. is the distributor of Morpholino oligos and related products. 

Lest people think I am against everything, I want to say that I love this kind of science. It is not unlike the work of one of my heros Gertrude Elion. Here she talks about her work with nucleic acid analogs:

The work became fascinating almost from the very beginning. We were exploring new frontiers, since very little was known about nucleic acid biosynthesis or the enzymes involved with it. I had been assigned quite early to work on the purines and, with the exception of a few deviations into the pteridines and into some other condensed pyrimidine systems, the remainder of my work concentrated almost completely on the purines. Each series of studies was like a mystery story in that we were constantly trying to deduce what the microbiological results meant, with little biochemical information to help us. 

There came a time where Gertrude had to go off the beaten path and deduce what the results meant. She went from chemistry to biology to "what do these results mean?" It is at this same juncture in the research process where GeneTools LLC and  Serepta parted ways. GeneTools LLC represents the science of PMOs versus RNA.  Serepta represents the business of drug approval. Somewhere between the work of GeneTools LLC and Serepta we enter the Cargo Cults.

Why didn't James Summerton make that journey? The powers of his PMOs as a drug, over RNAi molecules, are touted on the Serepta website:

• The ability to target specific gene sequences without non-specific interactions
• Safe at higher doses
• Able to UP and down regulate gene expression 
• Easier to deliver to specific cells
• Resistant to enzymatic degradation

The questions that AVI and Serepta had to answer was "what to do with it?" and "what do these results mean?" Serepta made some pretty astounding claims. Dr. Summertons PMOs have a superiority (as a drug) over the Nobel Prize winning science of RNA interference. 

A PMO is physically a PMO for sure. The mechanism of action is different. It may very well have the superiority over RNAi molecules that Serepta claims. But RNA deep inside a cell is the target. This is where the science gets soft. A Cargo Cult does not concern itself with the complexity of a cell. Gene expression is not within the purview of Serepta management. That is in the job description of a scientist, not a businessman. What management needs from the lab is positive results that can be used to sell their promise of cargo to investors. And they weren't getting it from their people in Oregon and Washington.

Serepta began in Oregon then moved to Washington then to Massachusetts in search of the magical Pixy dust that will turn PMOs into a drug. The inventor of PMOs did not have that Pixy dust nor did anyone in Bothell WA. What was CEO Chris Garabedian looking for when he sacked his Oregon and Washington staff and moved to Cambridge MA? You won't read about it on their website. You will read about PMOs and the work of the common scientists. What about that Pixy dust? What was the knowledge that could only be found in Cambridge MA that puts the 33 year science project on the final leg of it's journey? After 33 years we can now look to the skies and expect the cargo planes to come because some people on the east coast knew what to do with James Summertons PMOs. 

Investors are starting to have their doubts. Sereptas lead candidate is Eteplirsen:

Eteplirsen is a treatment for Duchenne muscular dystrophy, or DMD, patients, a rare genetic muscle-wasting disease caused by the absence of dystrophin, a protein that is necessary for muscle function. The disease affects one in 3,500 boys worldwide and is one of the most common fatal genetic disorders. Currently, there is no approved treatment for DMD.

Eteplirsen works by skipping exon 51, helping resolve a genetic mutation and allowing for the creation of dystrophin. This, in turn, corrects the body's inability to build muscle. Eteplirsen showed promising results in phase 2b studies, which, following a meeting with the FDA in July, led the company to report that the FDA was willing to consider those results as part of an early approval process. As a result, the company indicated its plans to file an application with the FDA in early 2014.

A good deal has changed since the July conversation with the FDA Several things have changed since that announcement. Most important, an announcement came that GlaxoSmithKline's (NYSE: GSK  ) and Prosensa's (NASDAQ: RNA  ) competing exon-skipping drug drisapersen came up short in phase 3 trials. In that trial, drisapersen failed to significantly improve muscle function despite showing considerable promise in earlier trials.

That late-stage failure kicked off a flurry of interest in eteplirsen. Investor hopes for early approval may have jumped the gun, however. Given that Glaxo's drug and eteplirsen similarly produce dystrophin by exon skipping, some are wondering if the FDA will back away from its earlier willingness to solely consider phase 2b data.

What interests the Cargo Cult Scientist the most is the disease. How does it work and are we ready to fix it? Apparently the approach Prosensa took was a little off. What were the details and why then does Serepta have a better shot with the same exon 51 skipping approach? Investors and biotech CEOs are speculators. Scientists find ways of injecting certainty into their predictions of future outcomes. Will morpholinos succeed where RNA failed? We will be watching.