Today, the
FDA released review material for the Advisory Committee Meeting on Volanesorsen (trade name WAYLIVRA) this Thursday. WAYLIVRA has been developed for the lowering of serum triglyceride level in patients with a
genetic form of severely elevated triglycerides, familial chylomicronemia
syndrome (FCS). Briefing Docs
provide valuable insights as to the safety of drug candidates which are often
glossed over by sponsor companies leading up to such regulatory events.
Echoes
of KYNAMRO
The last
time we had this opportunity in the phosphorothioate antisense space was in 2012 when the subject was the ApoB-lowering
KYNAMRO. Like KYNAMRO, WAYLIVRA is a second-generation 2’-MOE phosphorothioate-backbone
oligonucleotide that was given at high doses in the registrational trials (200mg
for KYNAMRO, 300mg for WAYLIVRA).
It should therefore not come as a surprise that the safety and tolerability of WAYLIVRA was quite poor. In particular, not only did the
at times drug-induced severe thrombocytopenia cause considerable bleeding concerns, the
sponsor Akcea and parent company Ionis Pharmaceuticals have no idea about how
to mitigate such risk. Dose adjustments
and increased platelet monitoring apparently did not change the
thrombocytopenia risk substantially and apparently are still being made to this date without much rhyme or reason.
In addition,
there were the flu-like symptoms, liver enzyme elevations, renal tox, even a case of
anaphylaxis causing around half of what should be highly motivated
patients with FCS to drop out from the clinical studies.
This
time it’s potent though
Fortunately,
unlike KYNAMRO, WAYLIVRA has robust potency.
For those that managed to stay on the 300mg weekly dose, serum
triglyceride lowering in excess of 70% was seen (reflecting ~90% target ApoCIII-lowering;
cf. ~20% target-gene lowering with KYNAMRO).
Even the FDA had to acknowledge here that this is an unparalleled
achievement.
But the positives end here already, with the FDA noting that in contrast to Akcea’s/Ionis’
claims there is no reliable reduction in measures of actual morbidity of FCS
patients such as pancreatitis attacks, abdominal pain, and general
well-being. In fact, on most measures
there was not even a numerical benefit favoring WAYLIVRA. This, the FDA agrees, is also a
function of the low number of patients available for such ultra-orphan disease
studies.
The FDA admits that lowering of the biomarker serum
triglyceride, even to much lesser extents than WAYLIVRA, has formed the basis for approving other drugs for
hypertriglyceridemia-related disease. In light of this,
I expect WAYLIVRA to receive a favorable panel vote on Thursday on the condition
that access to WAYLIVRA is strictly limited and safety tightly monitored (à REMS). It apparently scares the FDA that while FCS has
an estimated prevalence of 1 to 2 in a million, up to 1 in 600 have very high
triglycerides resembling FCS.
Having said
this, I am not quite clear why there should be different risk/benefit threshold with
regard to the triglyceride-related morbidity for FCS and conditions resembling
FCS as long as these other patients have exhausted options to treat the underlying causes for their particular hypertrigliceridemia. As such, I believe the market potential estimates ought to be dramatically increased for WAYLIVRA.
WAYLIVRA
competition
It is
already clear, however, that WAYLIVRA will have a limited shelf-life. Hot on its heels is a GalNAc-conjugated in-house
competitor (ApoCIII-LRx) which has shown triglyceride lowering approaching that of WAYLIVRA,
but at 5-10x lower dose levels, less frequent dosing and, crucially, with
supposedly none of the worrisome safety issues of WAYLIVRA. A phase III study of that compound is planned
for 2019. By that time, an RNAi GalNAc
compound by Arrowhead should also be well in the clinic setting up
ApoCIII-lowering to become a substantial market for oligonucleotide
therapeutics by expanding the market well beyond the FCS population.
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