Yesterday, Ionis Pharmaceuticals disclosed that severe reductions in platelets had been observed
in phase III clinical trials of both IONS-TTRRx for the treatment of TTR
amyloidosis and IONS-ApoCIIIRx for conditions related to highly elevated
triglycerides. Severe platelet reductions are dangerous since it can lead to occult, uncontrolled bleeding and poor blood clotting following injury.
Since the conference call was a PR disaster as the CEO of Ionis has major issues with speaking his scientific mind, and since competitor Alnylam has seemingly become the original source and interpreter of the Ionis thrombocytopenia issues (one wonders how they come into possession of these Ionis trade secrets...), I thought it may be useful to briefly come out of blogging hibernation and lay
out my thoughts about what these events mean for the technology and the
company.
Thrombocytopenia likely limited to systemically administered, unconjugated
PS-oligos >200mg per injection
As a hematological abnormality that has historically been
observed with phosphorothioate (a ‘sticky’ chemistry) oligonucleotides when
given at high doses (>200mg/injection)
I’ve always considered it likely that such thrombocytopenia will be associated with measures
of plasma exposure of the oligonucleotides.
Notable examples for thrombocytopenia with phosphorothioate oligos include
the DMD exon skipper drisapersen by
Biomarin/Prosensa (6mg per kg per week, i.e. around 300mg/week for 50kg boy) and
telomerase inhibitor imetelstat by
Geron (~10mg per kg per week, i.e. around 700mg/week for average adult). Actually, isn’t it ironic, or maybe even
curious that imetelstat is being developed for conditions where elevated
thrombocytes is the problem (see related blog entry)???
Consistent with this notion, there was a study by Flierl et al. in 2015 that looked at the mechanism of platelet activation which may lead to platelet consumption and explain lowered thrombocyte counts. Without going into the details of the
mechanistic aspects of the study, the authors find a strong correlation with peak
plasma exposure (c max) of the oligonucleotides and platelet activation.
So why hasn’t Ionis seen severe cases of thrombocytopenia in
the past (excluding use of PS-oligos in cancer patients which frequently suffer
from potentially confounding bone marrow suppressions from other drugs)? The most probable explanation is a) these
events are quite rare events and b) that their experience with PS-ASOs at
300mg/week and above has been limited. At 300mg and especially 400mg per
week, safety has always looked a bit dicey such that the 300mg per week dose
e.g. for TTRRx was only adopted after 200mg per week was not competitive with the
knockdown results produced by ALN-TTR02 from Alnylam.
Similarly, the initial studies with ApoCIIIRx did not
include the 300mg per week dose and was adopted in favor of the very impressive triglyceride reductions seen at doses higher than 200mg. Usually
the dose escalation of the prototypical Ionis phase I studies involved 50, 100, 200, then 400mg per week
with 400mg per week never being chosen for the phase II and/or pivotal studies.
What I find highly interesting is that the pharmacokinetics
data from the healthy volunteer study of ApoCIIIRx reported by Graham and colleagues in 2013 (see only Table IV) reported a non-linear, 4.5x increase in cmax when doubling
the dose from 200mg to 400mg per week.
This could mean that at doses of 200mg per week and higher, the risk of
severe thrombocytopenia is dramatically elevated by going past the threshold
where platelets become critically activated (à
clotting cascade).
If the cmax theory holds true, then the following should be the impact
of the new findings on the Ionis platform.
The summary takes into account the clinical observations by Ionis that
the platelet reductions are reversible upon stopping dosing and can be
prevented and also treated by steroid use (just as ALN-TTR02 involves steroid
use):
1)
Unconjugated, systemically administered antisense at
300mg per week and above (incl. phase
III assets TTRRx and ApoCIIIRx): need for tight platelet monitoring. May involve temporary halt of studies to
amend protocols. Commercially, need
for tight platelet monitoring could be a problem for less severe diseases due
to convenience and competitive issues.
Note that for all the liver-targeted
programs, backup GalNAc-conjugated versions are in development which should not suffer
from thrombocytopenia (see below).
However, systemic programs targeting other tissues such as DMPKRx for
myotonic dystrophy will have to be under continued scrutiny depending on the
dose.
2) Unconjugated,
systemically administered antisense at 200mg and below per week and below: little impact. Start collecting data more systematically to
learn more about platelet interactions, otherwise no big impact.
3) GalNAc-conjugated
antisense: no impact. Essentially
all the Ionis pipeline, including ApoCIIIRx, has been re-engineered for some
time now to be GalNAc-conjugates. This
is because of their 10-100 fold increased potency over the unconjugated
versions thus decreasing the doses to well below those expected to cause severe
thrombocytopenia. Even at the same
doses, plasma exposures will be much reduced due to the rapid clearance into
the hepatic compartment as demonstrated by Shemesh et al in one of the most
recent publications by Ionis. No thrombocytopenia events to my knowledge were seen with RG-101 (for HCV) by Ionis' 'satellite company' Regulus Therapeutics, where a up to 8 mg/kg of GalNAc-conjugated phosphorothioate oligonucleotide has been administered.
4) CNS programs: no impact. Peak plasma exposures are insignificant
for intathecally administered oligonucleotides as used in Ionis’ CNS franchise,
a franchise which includes exciting drug candidates such as phase III asset
nusinersen for the treatment of spinal muscular atrophy (SMA) and candidates
for other severe neurodegenerative diseases.
In summary, the only programs which could be significantly impacted by the thrombocytopenia findings are the programs that target tissues outside the liver and which involve systemic administration. The liver franchise remains intact especially with the new GalNAc versions although there could be some minor delays and increased competitive impact in those diseases that Alnylam is free to go after according to the Ionis-Alnylam IP agreements. The important CNS franchise remains fully intact.
Disclosure: long Ionis and doubled down yesterday.