Nitto Denko Brings RNAi Therapeutics to Clinic as New Star Rises on RNA(i) Therapeutics Firmament

There is more evidence from the San Diego biotech scene that investment is flocking back to RNAi Therapeutics, from all sorts of sources.  Following successful public offerings by the likes of Arrowhead Research and Alnylam and multi-million dollar VC rounds in two smaller RNAi Therapeutics companies earlier this year, the investment this time is coming from a large diversified company and private investors.

Nitto Denko Tackles Fibrosis

With the initiation of clinical development for an RNAi Therapeutics in fibrosis, not Merck, not Novartis or Takeda, but Japanese materials manufacturer Nitto Denko has become the largest company yet to enter an RNAi Therapeutics into the clinic which originated from internal R&D.  The newest addition to the RNAi Therapeutics pipeline is based on research from Prof. Niitsu’s laboratory at Sapporo Medical University and involves a vitamin A-targeted liposome for gene knockdown of a collagen-specific chaperone (Hsp47) in fibrogenic cells.  Subsequent to the seminal Nature Biotech publication on gene knockdown in hepatic stellate cells for not just the stabilization, but even the reversal of liver fibrosis (Sato et al. 2008), a more recent publication applying the same formulation in pancreatic fibrosis indicates that Nitto Denko is considering ND-L02-s0201 for fibroses beyond the liver.  

Of note, the RNAi trigger design came from Quark Pharmaceuticals (Tuschl workarounds with lots of non-canonical modifications) and Nitto Denko itself has become the world’s largest clinical supplier of oligonucleotides following its 2011 acquisition of Avecia.

Fibrosis is becoming a hot area in Oligonucleotide Therapeutics with a number of companies (RXi Pharmaceuticals, Excaliard/Pfizer, Sirnaomics, BMT etc) chasing fibroses in the skin, eye, liver, and beyond.  As fibrosis is a complication, often the most debilitating consequence of  many diseases involving inflammation (think fatal diseases such as idiopathic pulmonary fibrosis), and little progress has been made in reversing it, the expanded target space available to oligonucleotide therapeutics could bring unique opportunities at changing the way we think about the disease.

RNAi Start-up Arcturus Therapeutics Raises $1.3M in Private Investor Round

Coincidental with the Nitto Denko trial initiation, San Diego-based Arcturus Therapeutics announced that it has raised $1.3M in a private investor round.  Arcturus Therapeutics, curiously founded by former Nitto Denko employees, is said to be developing a liver-targeted RNAi Therapeutics for an unnamed rare/orphan disease indication.  It appears that the value of Arcturus is based on a nanoparticle delivery technology.  Although the nature of the formulation is yet to be disclosed, my impression is that it is a liposomal one given the background of the company founders and the liver indication.

It is very good seeing examples like that where the RNAi Therapeutics appetite is reaching down to the grass-roots levels, unfathomable even just 1 ½ years ago.  While I once worried that the RNAi Therapeutics dry spell (2008-2011) could prove disastrous to innovation in the industry, some seeds were able to survive.  I look forward to following the progress of these technologies and companies as they grow.

Tekmira Awarded Ebola Contract, Continues to Build on Momentum

The mystery surrounding the abrupt halt to the trading of Tekmira shares on July 14 was solved when Tekmira announced that it was awarded a significant US government contract for the development of an Ebola drug worth up to US$140M, $35M of which could be earned over the next 3 years. This essentially provides Tekmira with a free shot on goal for early product revenues, and should also prove beneficial for its overall balance sheet because of the typical fee component of such contracts plus expenses generally applicable to SNALP drug development.

This development nicely builds on the impressive SNALP-Ebola study published in the prestigious journal The Lancet less than 2 months ago where Tekmira scientists along with collaborators from Boston University (Geisbert group) showed for the first time the complete protection of non-human primates in a post-infection model.

While this is not the Big Pharma buy-out deal that I had speculated about yesterday, this endorsement of SNALP technology by the US government only makes one more likely now. It is even more impressive given that Tekmira, based in Canada, obtained this contract on a shoe-string budget without the significant government support that competing groups have enjoyed, and in a much shorter period of time.

The initial funds will be used for IND-enabling pre-clinical development and one phase I human safety study. This should involve more extensive safety and efficacy testing in animals, especially non-human primates, and the development of biomarkers predictive of efficacy in humans where efficacy cannot be tested. Ultimately, the big payout in the form of the first RNAi Therapeutics product revenues may come from government stockpiling contracts after further successful clinical safety and non-human primate efficacy testing.

The contract raises once again questions about Tekmira’s relationship with Alnylam. Alnylam actually have earned from 2007-2009 about $30M in hemorrhagic fever virus R&D government funding and may therefore at one point have competed with Tekmira (then Protiva) for such government contracts. Another interesting issue is whether Tekmira would have to exercise a target pick under the Alnylam RNAi trigger license. It is possible, however, that Tekmira will not have to exercise one because it is likely that the US government, the eventual main customer of any Ebola product, has rights to many of Alnylam’s fundamental RNAi trigger patents. It is also curious that Alnylam appears to have given up their pursuit of Ebola therapeutics, and could possibly reflect the influence that Tekmira enjoys in practical terms in who is able to pursue SNALP products and for which targets (‘Tekmira know-how’).

Overall, this was unexpected news to me. I had mainly considered the value of the Ebola program as being a quite visible proof-of-concept for the wider applicability of SNALP delivery, not expecting any significant funding windfalls. Following the wide publicity that The Lancet paper received, the fact that this study now turns out to have actual positive financial implications for the company could mean a significantly shortened trajectory towards profitability and increased investor interest to coincide with the upcoming Nasdaq listing. If that were not enough, the upcoming filing of the IND for SNALP-PLK1 and the $100M Novartis decision means that the momentum is now decidedly in Tekmira’s favor.

In related RNAi Therapeutics deal news

Quark Pharmaceuticals and Japanese Co. Nitto Denko announced a collaboration whereby Quark will contribute its RNAi triggers, with supposedly structural features that provides them with freedom-to-operate, with Nitto Denko’s siRNA delivery technology to develop an RNAi Therapeutic for cirrhosis of the liver. Financial details were not disclosed, except that it said to be in the double-digit million dollar range. While the exact nature of the delivery technology was not disclosed, the press release referred to a 2008 Nature Biotech paper that successfully employed small molecule-targeted cationic liposomes to knock down a cirrhosis-related gene in specialized cells of the liver. Liver cirrhosis is certainly another disease of the liver of high unmet medical need and attractive for liposomal siRNA delivery. Ligand-targeted liposomes should even further expand the utility of SNALP-siRNA delivery and I look forward to learning more about progress in that area, including the detailed structural and functional characterization of such particles.