News this week of Roche licensing antisense technology from Santaris 3 years after having
written down a related $500M+ investment in RNAi Therapeutics, is symptomatic
for the apparent panic and resulting schizophrenic behavior that grips Big Pharma
when it comes to Nucleic Acid Therapeutics (NATs). Can NATs help rekindle their flagging discovery efforts or will NAT companies leave them in the dust as they advance to the top of the Pharma food chain?
Meanwhile,
Big Biotech in the form of BiogenIdec has also recognized that NATs are
critical for their growth in the form of a partnership with Zinc Finger
Nuclease specialist Sangamo Biosciences for the treatment of red blood cell
disorders (sickle cell and beta-thalassemia). This follows significant (~$150-200M) recent investments
in ISIS’ antisense technology for diseases of the CNS and a deal with microRNA Rx company Regulus Therapeutics.
If you sit
back and consider the clinical and preclinical developments in the space (look out for the upcoming RNAi Therapeutics Investment Guide 2014), there
can be no doubt that nucleic acid therapeutics (including oligonucleotide
therapeutics) are about to materialize as the 3rd major chemical
class of drugs following small molecules and recombinant proteins. In fact, their mechanistic versatility (gene
up- and down-regulation, modulation of RNA processing etc) means that in a few
decades, there will be many more NAT-based new molecular entities than small
molecules and recombinant proteins combined, in many cases for genetically
defined patient populations.
Interestingly, in 2013, only 2 monoclonal antibody new molecular entities (NMEs) received marketing authorization by the FDA (see here).
Investors do
not have to take such a very long view as a number of commercially attractive
Oligonucleotide Therapeutics are gearing up to enter the market, including for
TTR amyloidosis, Hepatitis B infection, spinal muscular atrophy, and
hypertriglyceridemia.
For those
interested in the more particular relevance of yesterday’s deals to RNAi
Therapeutics stocks, the Roche-Santaris deal ($10M in upfront plus the usual
biobucks and royalties) represents another blow to ISIS’ claim that it owns the IP in the space, especially in light of the ongoing litigations and patent battles
between the companies and the fact that not long ago, Roche partnered with ISIS
on Huntington’s Disease. This should
provide further comfort to those, including myself, speculating that Marina
Biotech’s CRN chemistry is a valid equivalent, if not superior alternative to
the ISIS and Santaris antisense chemistries.
Regarding the deal between Sangamo and BiogenIdec ($20M upfront plus the
usual biobucks and royalties), it is a validation of the attractiveness of the
hemoglobinopathy market that forms an important part of Alnylam’s pipeline
options.
In additional RNAi Therapeutics developments...
Bad news for Benitec
In a recent paper by Lisowski et al. from Stanford (Kay lab) which appeared in Nature, very strong evidence was presented that the AAV8 serotype is far from ideal when it comes to transducing human hepatocytes. This is in contrast to preclinical results mainly in mice that have shown highly efficient, almost 100% transduction of hepatocytes, the transduction level probably needed to achieve an RNAi cure of HepC.
Based on the preclinical work, the AAV8 serotype was readily embraced by gene therapists and adopted for various liver-related clinical studies. Surprisingly, however, the data so far in hemophilia did not support a significant advantage of AAV8 over the old AAV2 workhorse.
The study by Lisowski et al. shows that this is very likely the result of poor AAV8 transduction of human hepatocytes. Among the multiple striking results, in mice with chimeric human/mouse livers, basically only the murine hepatocytes could be transduced whereas the adjacent human hepatocytes were not.
This is an unfortunate development that Benitec cannot be held responsible for. It could be a double-whammy though for the company as in addition to the commercial concerns about the HepC indication for TT-034, results from the ongoing phase I study may not even support the delivery technology for other liver applications. There is, however, light at the end of the tunnel as there are plenty new AAV serotype that appear to be as good in transducing human hepatocytes as AAV8 is in transducing murine hepatocytes.
