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.

FDA Cautious on Triglyceride-Lowering Antisense Drug WAYLIVRA

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.