Wednesday, October 23, 2013

Regulus Borrows from RNAi Delivery Technologies…5 Years Late

With the gift of birth of having access to all the technology toys from parent companies Alnylam and ISIS, Regulus Therapeutics in 2007 was poised to speed into the clinic a new class of RNA Therapeutics: microRNA Therapeutics.  Today, Regulus has yet to put a single compound into clinical development.  This not only reflects the increased biological complexity of microRNAs as opposed to for example single gene knockdown approaches such as RNAi Therapeutics, it also reflects a fear of breaking with the dogma that for microRNA inhibition ‘naked’ antisense technologies should be used.

It turns out that only now, Regulus finds that in order to optimize the product profile for their lead program, anti-miR122 for the pan-genotypic treatment of HCV infection, they really ought to borrow from RNAi delivery, in this case GalNAc-conjugates from Alnylam.  With this, they will achieve more potent miR-122 inhibition as well as increase the therapeutic window through the targeted delivery.  This is opposed to saturating the target organ along with the rest of the body with ‘naked’ phosphorothioate molecules, a concept I'm struggling to get comfortable with. 

The case for such a facilitated delivery strategy is even stronger for an antiviral anti-miR candidate such as this one because hitting the virus instantly instead of only slowly reaching effective drug concentrations in the target organ reduces the risk of drug resistance.

As a result, Regulus will enter the clinic with RG-101 at a time when the first all-oral HCV therapeutics with high cure rates will have hit the market.  This is a commercial catastrophe for an otherwise scientifically sound target.

One already has to be thankful that a small organization such as Regulus is able to show such flexibility at all (I don't even want to know in which antiquated terms Big Pharma is thinking about microRNA Therapeutics).  This achievement almost makes me afraid to ask why they have not thought it through to the logical end and adopted more structured, and much more potent anti-miR structures along with these delivery technologies?  This armchair CEO would have had a SNALP/structured anti-miR strategy tested in 2008.

However, Regulus Therapeutics has a chance to redeem itself- at least partly.  As it evaluates GalNAcs and LNPs (SNALP?) for an anti-miR program in liver cancer (HCC), it could for example help the RNAi Therapeutics industry understand whether the GalNac-receptor (ASGPR) is suitable for RNAi Therapeutics candidates for the attractive liver cancer indication.  So as Tekmira has followed Arrowhead Research into HBV, maybe Arrowhead Research may want to follow Tekmira (TKM-PLK1) into HCC.

Disclosure: The idea for this blog entry came after I started to look into RGLS ahead of the AASLD meeting (Nov1-5).  I concluded that there would be a good chance that with presenting a promising profile for RG-101 at AASLD and maybe some new data for the Alport Syndrome at the Kidney Week also in early November (Nov5-10), we could see RGLS bounce back into the $9-10 range by mid-November.


tettrazini said...

"It turns out that only now, Regulus finds that in order to optimize the product profile for their lead program, anti-miR122 for the pan-genotypic treatment of HCV infection, they really ought to borrow from RNAi delivery, in this case GalNAc-conjugates from Alnylam."

Presumably they will have to pay to borrow.

Anonymous said...


Probably not. Remember, Alnylam still holds a monster position in Regulus. The question for me is why has Alnylam not pushed harder for the adoption of their delivery technology by Regulus?

tettrazini said...

Alnylam owned 17% of Regulus stock at the end of 2013. That position has been further diluted by a 5+ million share secondary.

Anonymous said...

Regulus addresed this in their last earnings CC: they are free to use GalNAcs with no additional payments due to the agreements signed when the company was created, which allow them to use any of Alnylam or Isis's inventions in their miRNA efforts. I believe the parent companies are due royalties on any future drugs.

Anonymous said...

Regulus was founded by Isis and Alnylam and IP from both companies was assigned to Regulus for microRNA purposes. Oh, and by the way, GalNAc was first used for single strand antisense molecules. Mano, who championed it at Alnylam, used it for ASOs when he was at Isis.

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