One Pitfall to Look Out for in RNAi Therapeutics

RNAi Therapeutics have turned the corner to being a generally accepted drug modality.  Following years of ridicule and benign neglect, the industry just celebrated the FDA approval of a 2nd drug, Givlaari for the treatment of acute hepatic porphyria. This was followed in short order by the $9.7B acquisition of The Medicines Company by Novartis for its cholesterol-lowering RNAi drug candidate, Inclisiran, a harbinger for how RNAi medicines will change the game in cardiovascular risk management.

Amid all the understandable investor excitement, it is probably a good time to reflect on the potential pitfalls as we move into a world where RNAi Therapeutics dominate liver-related diseases and advance into new big areas such as the CNS and ocular disease.  Remember, investor, it takes one safety event for the most highly valued programs like HBV RNAi candidate AB-729 by Arbutus Biopharma, Arrowhead Pharmaceutical’s ARO-AAT, or the Lpa program by Silence Therapeutics to decimate your investment by half or more.

Off-targeting safety, off-targeting safety, off-targeting safety

When the discovery of RNAi was rewarded with the Nobel Prize in 2006, the Andy Fire and Craig Mello hammered home a message that would resonate for the years to come: to make RNAi Therapeutics, it’s all about the delivery!

Delivery, delivery, delivery

But as the liver has been conquered and the industry is chewing on a number of liver-related therapeutic opportunities and opening up opportunities in new areas, we still have to fully understand the odds of seeing program failures due to the difficult to predict consequences of off-targeting.

Off-targeting is the moderate knockdown of sometimes dozens of genes sharing sequence homology to the target gene.  This was shown over a decade ago and soon thereafter shown to be addressed by using simple modification strategies.

This, however, was at a time when the delivery mantra was practiced and nobody wanted to risk reducing knockdown efficacy by simultaneously considering off-targeting in their RNAi trigger designs.  I was therefore upset, as it turned out rightfully so, that Alnylam let Nastech essentially go bankrupt a decade ago when it should have acquired rights to Nastech's then industry-leading off-target-mitigation technology.

Alpha-1 Antitrypsin as testbed

Alnylam would have to pay dearly for its pride in never treating a smaller competitor well, even if it served its own interest, with off-targeting manifesting itself in markers of liver toxicity in first-generation clinical programs like chronic HBV and alpha-1 antitrypsin-related liver disease.

These two indications, unlike the now approved AHP indication for Givlaari which addresses symptoms outside of the liver, represent the most exacting off-targeting challenge as they affect liver health directly and any further exacerbation of liver stress should be avoided.  

As a result, Alnylam dug out the old off-targeting literature and in their incarnation added a GNA modification at position 7 of the guide strand while, for experimental purposes, leaving the rest of the first-generation molecule unchanged. Translational science at its best (!) and the industry can be thankful for it.

Indeed, for both the ESC+ chemistry ALN-AAT02 and ALN-HBV02 no liver enzyme elevations (above 3x ULN) were observed in 49 subjects tested, whereas 3 of 33 had such elevations with the ESC-only versions.

In Arrowhead’s case, there also were no ALT elevations >3x ULN.  However, 3 treatment-emergent grade 1 ALT elevations not exceeding 2x ULN were reported in the 28 normal healthy volunteers receiving ARO-AAT.  I am curious to see the individual time curves and the doses at which they occurred.  It is certainly an area to watch for that program as it only now moves into patients. 

Add to this considerable uncertainty about patient selection, dose and duration required to have an impact on AAT liver disease, increasingly analysts topping their price targets by the day may have to re-think how they value this program (see disclosure below).

Further behind, we have to see how Silence Therapeutics and Arbutus have addressed off-targeting with first data expected in 2020.  While Silence has avoided indications directly affecting liver health (iron overload, cardiovascular disease), Arbutus with its HBV indication will have a steeper hill to climb, although the pay-off for investors in this $80 market cap company should be considerable should it climb it come Q1 2020.

Personally, my guesstimate for non-optimized GalNAc designs would be a 50% chance of off-targeting success, also depending on preclinical vetting (after all, the very clean $9.7B Inclisiran is such a design); a 85% off-targeting success for optimized designs. 

Disclosures: long Silence Therapeutics, Arbutus Biopharma; short Arrowhead Pharmaceuticals; no position in Alnylam.