RNAi Therapeutics Become Real

It’s been a long ride.

The lives of quite a few of us has been consumed now for close to two decades dreaming about a world in which RNAi Therapeutics have real-world clinical impact.  Yesterday, that dream has officially materialized.

TTR knockdown improves disease state

With the conclusion of the most comprehensive clinical study conducted to date in the severe orphan disease ATTR amyloidosis, Alnylam and investigators have found that prolonged knockdown of the causative transthyretin (TTR) gene improved both objective (mNIS+7) and subjective (quality of life) measures of the main manifestation of the disease, peripheral neuropathy.

There is no doubt that this was the result of on-target TTR gene knockdown since this was a strictly controlled study in which the only difference to the placebo group was the administration of the RNAi formulation.  Furthermore, results from a similar study for this indication (NEURO-TTR) by Ionis earlier this year in which related RNaseH antisense oligonucleotide technology was utilized for TTR knockdown also demonstrated disease benefit, albeit a ‘mere’ halt of neuropathy progression in QoL as opposed to the improvement seen here (note: mNIS+7 was reported only with regard to placebo, not versus baseline).

Importantly, this extra benefit is likely explained by the fact  that the Patisiran RNAi formulation had been shown to be slightly more potent than antisense drug candidate Inotersen in earlier-stage studies (here and here).  While considering a ~80-85% vs ~70-75% knockdown may not seem much at first glance, protein deposition, clearance and in particular misfolding that is at the root of the disease are higher-order concentration-dependent processes (think about crystallization) so a difference of ~17.5% vs ~27.5% (>50% more remaining than with Patisiran) remaining insulting protein may well be highly meaningful. 

Of note, phase II data from Patisiran have demonstrated that the ~80-85% knockdown was able to somewhat tilt the tables in favor of TTR tissue clearance, but also that it was not able to fully do so.

It is therefore of utmost importance to push forward with the development of the even more potent GalNAc-enabled RNAi candidate ALN-TTRsc02.  Preliminary phase I data from that candidate suggest that it should be able to reduce TTR levels to 5% or less with subcutaneous dosing as infrequently as every 3-6 months (Patisiran: intravenous every 3 weeks; Inotersen: weekly).

Why this is such a big deal for RNAi Therapeutics

As I had indicated in last week’s post, the phase III APOLLO results represented a make-or-break moment for RNAi Therapeutics.  If it turned out that RNAi- and delivery-related side effects were to outweigh the benefits of gene knockdown at the conclusion of this decade-long, high-visibility program, the financial markets would have reacted violently and starved the industry of the cash necessary to more fully develop the technology (Alnylam with its cash reserves at least would have mounted a comeback eventually).

If it’s one thing I’ve learned about biotech money matters over the last 15 years of riding the RNAi rollercoaster, it is that the perception of a technology is as important for its continued development as its intrinsic technological validity.

Personally, I am most relieved in that the small, but often pervasive transcriptomic off-target changes introduced by an RNAi trigger (à microRNA-type off-targeting) did not have an apparent detrimental effect on the target organ (here: liver) after prolonged, 18-months treatment.  This should not be entirely surprising based on what we’ve learned about microRNA biology- not all targets of a microRNA are biologically relevant- but is still a great relief to see play out in practice.

To wit, the RNAi industry has been overly focused on potency when selecting RNAi trigger sequences for clinical development and mostly relied on bioinformatics for specificity. Indeed, Alnylam has paid the price for this negligence in that certain RNAi triggers, such as the one for its original alpha-1-antitrypsin program, have caused liver tox most likely due to microRNA-type off-targeting.  It is therefore finally employing chemical strategies such as the incorporation of modified nucleotides in the seed region of the trigger to bias the RNAi apparatus towards RNAi cleavage instead of microRNA-type message destabilization. 

This strategy was first reported by Rosetta Inpharmatics (now Merck) and had then been developed further in the commercial realm by Marina Biotech which then licensed the IP to Roche (then acquired by Arrowhead) and possibly others. 

It will be some time until we have complete certainty that microRNA-type off-targeting won’t rear its ugly head again, but the odds should be getting better and better with the employment of best practices. More generally, Patisiran is only the beginning of a long string of real-world impactful RNAi Therapeutics.