In a milestone for antisense oligonucleotide technology,
Kynamro (aka mipomersen)
yesterday received US regulatory approval for the
treatment of homozygous familial hypercholesterolemia (hoFH). It is the first regulatory approval for a systemically
delivered oligonucleotide-based drug addressing a target in the liver,
following two locally applied oligonucleotide drugs (aptamer Macugen and antisense oligo Vitravene) that have been approved for ocular diseases. Considering that next month a TLR oligo-enhanced
HepB vaccine by Dynavax could join the ranks of oligonucleotides
licensed for medical use, oligo drug technology is rapidly shedding its image as an oddball technology and going mainstream.
Commercial Prospects
The hope, of course, is that Kynamro will also be the first
commercially meaningful oligonucleotide considering lackluster sales histories by
Macugen and Vitravene. Favoring such
success is the strong pricing power with drugs for orphan indications such as hoFH which is estimated to affect 3000 patients in the
US
and
Europe each. Small molecule drug Juxtapid by Aegerion for
example received approval for the same indication last month and
will price at $250.000 per annum. With
1000 patients on the drug, this would mean sales of $250M already. And with the
fudgible definition of
symptomatic, instead of strictly genetically defined
homoFH and the aggressive ‘friending’ of orphan drug salesforces with disease
groups, I expect quite a bit of ‘label creep’ (
Aegerion's CEO has indicated that he expects hoFH patients to somewhat respond to PCSK9 inhibitors which I can only explain if the patient population he considers homoFH includes quite a few non-hoFH when defined genetically).
With an expected price for Kynamro of $100k
per annum, I optimistically project around $100M in annual sales assuming marketing partner Genzyme can get 1000
patients on drug in the
US. With a ~35% profit share, a 50% profit margin
and 50% attrition, ISIS Pharmaceuticals would pocket around $10M in annual profit
share from this approval in a few years.
Update 30Jan13: It appears that according to a WSJ article (to which I cannot get access), Kynamro will be priced at $176k per year. This, of course, would significantly improve ISIS profit share assuming same patient numbers treated (possibly 70% profit margin, slightly higher royalty rate in addition to higher sales --> $20-25M p.a.).
RNAi versus Antisense
for gene knockdown in the liver
To maintain such sales numbers, however, the salesforce will
have to fight hard to keep patients on the drug. During the extension of the phase III study in homoFH, over half of patients discontinued due to safety and tolerability issues, injection
site reactions and liver safety (prompting a
Black Box warning) being the main
culprits. Having said that, the
label for Juxtapid does not look any better, in
fact a bit worse with all the intestinal side effects and drug-drug interactions, offset, however, by the increased
potency in LDL-c lowering.
As some of the side effects are not target-specific (e.g. the injection site reactions and flu-like symptoms and also some of the liver
enzyme elevations which are not fully accounted for by the liver fat elevations), the modest
tolerability of and safety concerns with Kynamro (including vasculitis as well
as liver and skin cancers especially when considering the preclinical data)
raises the question whether systemically delivered phosphorothioate-based antisense
technology has much of a future for gene knockdown in the liver also in light of
increasing competition from RNAi delivery technologies. You will not be surprised that I subscribe to the view that among Tekmira’s
SNALP and the subcutaneous alternatives by Arrowhead (DPC) and Alnylam
(GalNAc), RNAi will become the preferred technology for gene knockdown in the liver.
Whether RNAi or antisense, oligonucleotide therapeutics are here to stay.
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