When Ionis presented data from the phase III NEURO-TTR study last year in Paris, they
clung to numbers close to ‘zero’ to make the point that its TTR-lowering
antisense drug TEGSEDI (aka inotersen) was 'stabilizing' and ‘halting’ disease progression. According to a newly released document by the European Medicines Agency (EMA), this, however, does not seem to be truthful: TEGSEDI only delayed the
progression of polyneuropathy compared to placebo, but patients on placebo
still got worse over the 15 month study period.
This not
only widens the apparent distance in therapeutic efficacy between TEGSEDI and
RNAi competitor ONPATTRO (which improved on disease parameters), but
even puts it apparently behind generic tetramer stabilizer diflusinal. Diflusinal also happens to be much better
tolerated than TEGSEDI which has been plagued by platelet and renal issues.
EMA
document suggests numbers were inflated
According
to the ‘Summary of Product Characteristics’ document issued by EMA following its approval of antisense drug TEGSEDI for the
treatment of TTR-related polyneuropathy, mNIS+7 after 15 months increased by +11 points vs 25 points for placebo. By contrast, Ionis Pharmaceuticals (which has
now licensed the drug to subsidiary Akcea Therapeutics) claimed a mere +5 point progression. Curiously the placebo values
haven’t changed.
This compares to an increase of +9.2 for
diflusinal over 24 months and -6 for ONPATTRO over 18 months.
Similarly,
on another measure of disease progression, the Norfolk Quality of Life questionnaire
increased by only +0.99 per the Paris presentation last year, but by +4.38 per the EMA
document. Once again, the placebo numbers remained essentially the same.
Finally,
what had been heralded as a TTR knockdown close to that of ONPATTRO, a median
75-79% TTR reduction vs 82% for ONPATTRO, now looks much different when
considering that mean knockdown was only 68-74%, possibly reflecting the poor
tolerability profile of TEGSEDI and missed doses.
I am sure
that Akcea and Ionis will have eloquent explanations for the discrepancies which just so
happens to conveniently and selectively favor their drug when analyzed by them. These new numbers, however, are not just
minor adjustments, but represent substantial changes to the TEGSEDI narrative.
ONPATTRO
heart aches
In the
phase III APOLLO study, patients treated with ONPATTRO were numerically less
likely to die compared to those on placebo (~50% reduction in death rate). Following the Paris meeting, I came away with
the impression that the deaths in the ONPATTRO arm were largely due to cardiac
failure and infection.
According tothe New England Journal of Medicine publication on the study, this seems to be a misunderstanding
as infection was a main cause of death in the placebo arm while all deaths in
the ONPATTRO arm were cardiac. As has
been pointed out by others on Twitter (@ionisdisrupts and @artkrieg), this could
raise questions in the minds of regulatory bodies whether to include TTR
cardiomyopathy applications on the label despite of ONPATTRO improving on related secondary endpoints.
In fact, considering
that the recent study design agreement with the FDA for follow-up drug ALN-TTRsc02
also focuses on polyneuropathy endpoints, it is all but official that the label
for the upcoming approval of ONPATTRO will be targeted at the polyneuropathy
population only and that separate trials will have to address the patients
mainly suffering from cardiomyopathy symptoms.
Disclosure: short AKCA, long ALNY.
