For some time now, a
GalNAc IP war has been brewing given that GalNAc
conjugation has been used by both Alnylam and ISIS Pharmaceuticals to enable
tremendous advances in targeting genes in the liver in an ever more potent and
apparently safe and convenient manner.
This has suddenly opened the floodgate to numerous therapeutic targets (ApoCIII,
Factor XI, HBV, TTR etc) and indications with gene knockdown likely to dominate
drug innovation for cardiovascular, metabolic, plus a number of viral and rare
genetic diseases in the years to come.
However, instead of escalating tensions, a
partial armistice was declared this week when the companies announced that they will not
get into each other’s hair for at least 4 gene targets in the liver. According to the Agreement, Alnylam can use
the two companies’ combined IP to support RNAi Therapeutics against the rare
genetic disease targets antithrombin (
for
hemophilias) and ALAS-1 (
for hepatic
porphyrias) while ISIS can leverage the same for antisense therapeutics against
factor XI (
for anti-clotting) and Apo
(a) (
for cardiovascular disease).
Interestingly, the press release talks about a reciprocal IP
cross-licensing that extends to ‘RNA-targeting mechanism’ leaving open the
possibility that Alnylam may use ISIS’ RNaseH antisense chemistry and ISIS in
turn Alnylam’s siRNAs for these targets. This would allow
the companies to maximize the life-cycle opportunities for these targets by
making available multiple routes of administrations (subQ, inhaled, oral) and pharmacodynamics (slow/rapid onset; different effects of gene/protein half-lives on
required dosing frequencies). Moreover,
since some genes are easier targets for a given mechanism than others, chances
are high that you can find a highly potent molecule with either RNAi or RNaseH
ASO.
By thus avoiding duplication of efforts and competition in
the marketplace, the economic value of these targets is likely maximized. I do not expect, however,
that the truce will extend to all targets in the liver given the advanced stage and
importance of for example the TTR amyloidosis programs of the two companies. Moreover, there might be partner (e.g.
Genzyme, GSK) pressures to go after certain targets no matter what. For these targets, it will be interesting to
see whether the companies will resort to patent litigation or whether they
agree to merely compete in the marketplace.
While the economic rationale is obvious, there is a
scientific risk to the non-compete. This
is because you might end up with a late-stage failure, e.g. due to an
unanticipated side effect related to sequence-specific off-targeting that is
only seen in larger patient populations.
This, of course, would be welcome news to 3rd
party competitors such as Tekmira, Arrowhead, and espcially GalNAc wannabe Dicerna who could then be the last
man standing. On the other hand, the
concentration and coordinated use of the IP estates of the two juggernauts in
the RNA Therapeutics space will make circumventing it more
difficult to the competition.
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