Alnylam Slams Dicerna with Trade Secret Complaint

How times have changed.  Four years ago, Alnylam found itself on the receiving end of a trade secret lawsuit regarding the delivery technology du jour, SNALP LNP then, in which it ended up paying near-bankrupt Tekmira ~$70M to settle the allegations.  As I opined back then, Alnylam seemingly used almost any means to get access to the know-how to make SNALP LNP delivery work in primates in an effort to rid itself of the reliance on Tekmira, the inventors.

At that time, all Alnylam's CEO had to say on the topic of honoring trade secrets: 'you pay for it, you own it'.

Tonight, Alnylam claims to be the victim of similar trade secret misappropriations surrounding RNAi delivery technology.  In this case, Alnylam alleges (see Complaint) that Dicerna had hired ex-Merck RNAi scientists to gain access to critical GalNAc trade secrets invented at Merck after Merck sold their RNAi assets to Alnylam and laid off related employees.

An interesting aside of this is that it appears, contrary to representations by Alnylam, that the GalNAc-ESC technology were invented at Merck, not in-house at Alnylam.

The Complaint makes it clear that Alnylam feels threatened by the technologically very direct competition.  In a way, Dicerna’s new strategy was to become Alnylam's clone.  What could be worse, given the differences in the RNAi trigger lengths (~19bp Tuschl-type siRNAs by Alnylam; 25/27 and longer Dicer-substrate versions by Dicerna) and the apparent importance of stability/degradation in GalNAc technology, there is the distinct possibility that Dicerna’s version, everything else being equal, would outperform (or underperform) Alnylam’s.

In light of recent apparently rapid progress at Dicerna on GalNAc technology and the timing of events, the idea that Dicerna may have benefited from the GalNAc know-how of ex-Merck scientists does not seem far-fetched.  

It is unclear to me, however, whether you can expect expert oligonucleotide chemists to suddenly forget everything about their former job. 

Alnylam obviously takes care of that problem by enforcing harsh non-compete and pay-for-silence practices against their former employees, meaning that if you are an RNAi scientist that job at Alnylam will be your last RNAi job in the industry, period. 

Looking forward, I predict that the outcome of the case will hinge less on the physical documents that were alleged to have been ‘misappropriated’, but on whether or not the ex-Merck scientists could have re-invented GalNAc-ESC based on their skills and publicly available information (including from Alnylam) at the time.  If so, then Alnylam only has Merck to blame that it does not force their employees to leave their profession when they lay them off.

Regardless, the GalNAc-ESC genie is out of the bottle.

Alnylam’s Second-Generation GalNAc Data Impress

Earlier this week at the American Society of Hematology meeting in San Francisco, Alnylam presented first multi-dose knockdown data in humans for its second-generation GalNAc-siRNA conjugate technology (ESC-GalNAc).  Accordingly, an almost 60% knockdown was seen in the first (and so far only) patient dosed at 0.045 mg microgram per kilogram ESC-GalNAc siRNA with the knockdown yet having to reach its nadir.  Moreover, further knockdown benefits are likely to accrue with dosing beyond 3 times weekly as was the case in this study.

At these low doses, no remarkable adverse events were reported, including injection site reactions or increases in liver enzymes which were seen with first-generation GalNAc-siRNAs in humans at much higher doses.

Though the data from this phase I study of ALN-AT3 in hemophilia patients is still early and there will be gene target-dependent differences in knockdown potency, they do support Alnylam’s claim that second generation GalNAc is indeed considerably, as much as 50x more potent than first-generation GalNAcs.  Only last week I had speculated that it may be more appropriate to estimate 2^nd gen GalNAc to be ‘only' 5x more potent than 1^st gen GalNAcs.

I was wrong.

In non-human primates, ALN-AT3 had an ED90 of 0.5mg/kg with weekly dosing.  Based on the phase I data thus far, I expect the corresponding ED90 dose in humans to be a ~ weekly 0.075mcg/kg 0.075mg/kg for a ~7-fold improvement in potency in humans versus non-human primates, a relative potency improvement that is not seen for first-generation GalNAcs.  Add to this the inherent 5x improved intra-species potency of second- versus first-gen GalNAc (Nair et al 2014), it is indeed possible that ESC-GalNAc enjoy an up to 50x improved potency advantage.

In other words, it should be possible to now achieve highly potent knockdown with a once-monthly dosing regime and sub-1 ml subcutaneous injection volumes. 

The value of this for the ALN-AT3 program, which harnesses a unique mechanism in an otherwise crowded hemophilia field which in general is moving towards less frequent dosing/infusion regimens and less immunogenic molecules, remains to be seen.  The slow enrolment pace of the phase I trial, ~5 hemophilia patients enrolled in 6 months, gives cause for commercial concern.     

The competition

While the improved potency is great for Alnylam, the gene knockdown competition is unlikely to yield the liver to Alnylam.  Highly potent knockdowns are possible with other platforms by Arrowhead, ISIS, Tekmira, and possibly Dicerna, too. Beyond route of administration [subQ for Alnylam GalNAc, ISIS (GalNAc-) ASOs, Arrowhead’s single molecule DPCs, and Dicerna GalNAc versus intravenous for Arrowhead’s 2-molecule DPCs and Tekmira’s SNALP LNPs], differentiation will come from safety/tolerability and dosing frequencies.

The next datapoints in this regard will come from the R&D Day by Dicerna early next week (Dicer-substrate GalNAcs) and the 4mg/kg phase I data from the immensely exciting anti-miR122 program by Regulus Therapeutics (employing GalNAc-antisense chemistry) in January 2015.