Thursday, August 9, 2018

TEGSEDI worse than tetramer stabilizer according to newly released EMA document

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.

It should be noted that it is likely that tetramer stabilizers and TTR-lowering agents will be taken together by many patients.  The relative efficacy and tolerability numbers, however, put TEGSEDI in a very weak position with regard to direct competitor ONPATTRO, also as it comes to reimbursement decisions. 

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.

1 comment:

Unknown said...

“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.”

The + 0.99 in Norfolk Quality of Life increase from baseline in the Inotersen-treated arm of the phase 3 at week 66 (i.e., 15 months), is exactly what is reported at the bottom of Figure 2 in N Engl J Med. 2018 Jul 5;379(1):22-31,

So in Paris, they were just reporting what is reported at the bottom of Figure 2 in one of the world’s leading medical journals.

* So are your saying there was one or more oversights or failings in the NEJM review process, thereby allowing this +0.99 Norfolk QoL change from baseline in the Inotersen group at 15 months to be reported at the bottom of Figure 2 in their journal?

If so, perhaps you could be specific on what you believe those oversights to be?

And most importantly, if you believe there were oversights or failings in the NEJM review process that allowed that same +0.99 change from baseline to be reported for the Inotersen group in Figure 2 of NEJM….

• have you shared this information w/ ALNY to see if they were interested in contacting the NEJM about what you view as a reviewer oversight or failing (since they would of course have a vested interest in contacting NEJM if they also believed there was an oversight by the reviewers as it relates to the presentation of Inotersen Norfolk QoL data)?

Last, in the NEJM, the mean change from baseline difference b/w the two groups (i.e., Inotersen-treated vs placebo) was -19.7 points, which differs from the 14 point difference in the EMA document you cited .

In other words, when looking at Figure 2 in NEJM, Inotersen is viewed as an ~ 5 point increase from baseline in mNIS+7 at 15 months vs. the ~ 25 point increase from baseline for placebo, thus consistent w/ the -19.7 difference noted above.

With respect to Norfolk QoL, in NEJM it is reported that the mean change from baseline difference b/w the two groups was -11.7 points in favor of Inotersen, which again differs from the 11 point difference you cited in the EMA document.

• So again to summarize, in your view, is the discrepancy b/w what is reported for mNIS+7 & Norfolk QoL in Figure 2 and the “Primary efficacy endpoints” section of the NEJM article with what you cited in the EMA documents an oversight or failing of the NEJM review process and if so, how so specifically?

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