RNAi Therapeutics Now a Commercial Reality

Last Friday, Alnylam received notification from the US Food and Drug Administration (FDA) that ONPATTRO (aka Patisiran) has been approved for the treatment of hATTR-related polyneuropathy.  This marks the culmination of an almost picture-book translation of a brand-new biotechnology into therapeutic reality.  20 years from worms to patients is nothing.

ONPATTRO development path

Much has been made in the press about the great uncertainty, reflected in supposedly unusually long timelines, of whether RNAi can be a therapeutic modality at all.  Of course, the challenges of delivering RNAi triggers in WoMan, staving off unwanted innate immune responses, and the question of how the transcriptional noise stemming from slightly modulating dozens of unrelated targets will affect safety were all daunting at the beginning.

But looking back, with the exception of a 2-3 year delay due to having to change from an insufficiently potent LNP chemistry to the MC3 lipid-based LNP underlying ONPATTRO and having to institute steroid pretreatment to minimize ‘infusion reactions’, all these challenges more or less dissolved in the development path of ONPATTRO.

A special shout-out here to Ian MacLachlan and his team at formerly Tekmira for solving the critical delivery challenge first.

A best-case scenario would therefore have seen an approval in 2015-6.  2018 is therefore not that bad at all.  Here a quick run-down of the milestones leading up to the approval:

1998: discovery of double-strand RNAs (dsRNAs) being the trigger for RNAi in worms

2001: finding that RNAi can be triggered in WoMan by short dsRNAs

2002: first demonstration of RNAi in mice

2005: first therapeutically relevant demonstration of RNAi in monkeys

2009: initiation of first clinical trial of first-generation LNP-RNA (SNALP-ApoB, aka PRO-040201; ALN-VSP02)

2012: start of ONPATTRO clinical development

2012: first solid clinical proof-of-concept for RNAi in WoMan from ONPATTRO phase I study

2012: start of ONPATTRO phase II study

2013: start of ONPATTRO phase III study (APOLLO)

2017: positive data read-out from APOLLO

2018: EU and US marketing approvals for ONPATTRO  

ONPATTRO is just the beginning

Since ONPATTRO had been conceived starting about a decade ago, there has been, of course, considerable progress in RNAi trigger design (safety, efficacy) and (conjugate) delivery technologies.  As a result, a slew of other RNAi drug candidates by Alnylam, including Givosiran for Acute Intermittent Porphyria (likely 2019 approval), Inclisiran for cardiovascular disease (likely 2020 approval), and Lumasiran for primary hyperoxaluria (likely 2020 approval), are about to be approved.  Especially with the adoption of off-target-minimizing chemical modifications, I am confident that the success rate of RNAi drug candidates for tissue types for which delivery is robust will only increase.

After the liver, for which the current crop of marketing candidates is the target organ, the CNS should be the next huge opportunity as Alnylam gears up to bring a first candidate into that organ over the next year.  In addition, Arrowhead Pharmaceuticals and Alnylam have also started to talk about opportunities in the lung and cancer, although here I am still hesitant about whether these are near-term clinical opportunities or something that will have to wait another 3 years or so.

RNAi shatters antisense competition

As the world is abuzz about the first full-blown marketing approval of an RNAi Therapeutic (note: formal marketing authorization in the EU is still pending), I would be remiss not to display a key graph illustrating the power of RNAi gene silencing versus competing approaches such as gene silencing by mass action RNaseH antisense (TEGSEDI by Akcea Therapeutics) and trying to keep bad proteins from acting out with small molecules (generic tetramer stabilizer diflusinal):  

If you were diagnosed with TTR amyloidosis and had an average life-expectancy of 2-5 years, which treatment would you like to be on?

Stock market reaction

When Alnylam opens for trading today, it will likely be down due to disappointment that the FDA label, unlike the anticipated case in the EU, will only specify TTR-related polyneuropathy for which the APOLLO study had been designed, and not cardiomyopathy with none of the exploratory cardiomyopathy data from APOLLO included.  While this is somewhat disappointing in light of biomarker-based accelerated approvals of Eteplirsen in DMD where target modulation and therapeutic hypothesis were enough to win the day, this should only be a minor hiccup in the overall history of RNAi Therapeutic.  In light of the recent Pfizer small molecule Tafamidis cardiomyopathy data, it is very likely that RNAi trials will show a benefit for cardiomyopathy symptoms as well in a dedicated study (à ALN-TTRsc02). 

Until then, it is possible that the cardiomyopathy data are being withheld until Alnylam and the FDA can come up with a way to include those in an amendment, or as part of an accelerated approval submission.  It is also likely that TTR patients will now more readily be referred from cardiologists to neurologist for an intense neuro check-up such that primary cardiomyopathy patients can access ONPATTRO (and get paid for it) at the slightest signs of polyneuropathy.