Friday, November 3, 2017

RNAi Drug Trounces Antisense Rival in Paris ATTR Showdown

The audience gasped when Alnylam finally revealed the full dataset from the APOLLO trial in ATTR amyloidosis.  For the first time, patients and docs will have access to a drug that not only delays or just barely halts, but starts to actually reverse disease manifestation in a majority of patients afflicted by this debilitating, multi-systemic disease. 

Efficacy: reversal versus slow progression

A few minutes before the Patisiran RNAi data presentation, Dr. Benson, the lead investigator from the corresponding NEURO-TTR with rival antisense drug Inotersen was not met with nearly as much awe.  Yes, Inotersen did delay disease progression and was quite a bit better than the placebo control.  However, unlike Patisiran (-6 at 18 months), the mean change from baseline in the critical mNIS+7 score was well in positive territory (+5 at 15 months) indicating disease progression.
As such, Inotersen does not appear to be much better than TTR tetramer stabilizer diflusinal (given off-label in the US) which registered a +9.2 score in a trial over 24 months compared to +29.6 in the control.

Patisiran similarly came out ahead in the quality of life (QoL) assessment (improvement versus in this case a halt for Inotersen), although this was not a primary endpoint in the APOLLO trial. 
The NEURO-TTR trial could score some brownie points here as it not only made QoL a co-primary endpoint, it also scored positively in another patient-reported health score, SF-36.  Although investigators seem to prefer ‘hard’ outcomes measures such as the mNIS+7 and biomarkers, regulators and payors seem to prefer QoL endpoints according to comments at the meeting.

That the efficacy was better for Patisiran should probably not have surprised too much given that its knockdown was slightly better (82% mean median in APOLLO) than that of Inotersen (according to Benson: 75-79%, although I am a bit skeptical here as I do not understand what this range means).
As a side note and although everybody likes to see Patisiran versus Inotersen as an either-or issue, if you combined them both, you would easily exceed the 90% amyloid source protein reductions that amyloid researchers believe is necessary to allow tissue clearance exceed fresh amyloid deposition.

Safety: Patisiran once again exceeds, Inotersen disappoints expectations
If you still had difficulty deciding whether to take a drug that likely makes you better or a drug on which you will likely progress, the relative safety profiles should remove any remaining doubt.  Contrary to suggestions by the ‘counter-detailers’ at Ionis, Alnylam could not find any evidence that the steroid treatments to prevent untoward reactions around the time of infusion had any measurable adverse impact on patient health. 

Maybe this should not come as a surprise either given that immune suppression is given only transiently, every 3 weeks.  To make it clear, none of the many cardiologists in the audience voiced any concerns throughout the two days of the conference (where Patisiran was the star) about steroids in patients with cardiac disease manifestations.
If anything, the Patisiran group suffered from less adverse events compared to the placebo group, probably the result of addressing the disease.

The same, namely exceeding expectations, could unfortunately not be said for Inotersen: in addition to the previously disclosed renal and platelet SAEs, there was a 5:0 death imbalance against the drug candidate.  While the drug-related thrombocytopenia case had already been known and the 4 other deaths were attributed to disease progression, one cannot but notice that strangely, when it comes to safety, all the disease-related, random events always end up going against the Ionis drugs. What a coincidence!  And given that Ionis partner GSK had abandoned Inotersen even before the APOLLO trial were announced, I am wondering what other safety findings (in addition to thrombocytopenia, renal AEs, pyrexia, chills, and nausea) will come to light with the FDA briefing documents next year.

Alnylam and the RNAi field could not have hoped for better outcomes from the high-profile APOLLO trial.  If anything, the full results presented at this first European combined patient-doc ATTR conference are more impressive than first indicated by the topline data a month ago.

And regarding the competitive profile compared to the antisense rival, it makes me wonder about the magic of feeding into a biological mechanism that has evolved to do just that: gene silencing.
There are still some questions around the label that these data will support.  Importantly, how much credit will be given to the positive cardiac outcomes since these were not the primary focus of the studies?  But since this is a multi-systemic disease and given the totality of the data, a number of doc presenters made it clear that they will be looking hard for polyneuropathy manifestations in ATTR patients to justify (to payors) treating them with the new agents.

Disclosure: I am short ALNY since the stock may be gasping for air up here, at least in the short-term; long IONS since this public humiliation by the fiercest rival may make them realize that in the orphan drug age, commercialization is a must.


Anonymous said...

Since Alnylam is very focused in the hATTR-polyneuropathy (hATTR-PN) therapeutic space, my expectation is they would be interested in pursuing additional lines of evidence that could demonstrate halting/clearance of amyloid deposition (e.g., via imaging methods) & potential for continued improvement in mNIS+7 change from baseline, beyond 18 months of treatment.

Therefore, I have submitted two questions related to these topics in the hopes of gathering your feedback.

Specifically, I figured it worth inquiring in the event either question was addressed by Alnylam in their Paris ATTR meeting oral presentation (e.g., in a “Future Directions” slide), or in response to a question from the audience in the Q&A session.

Background Information and Question #1

The last sentence of the article abstract from Ezawa et al. (see link to article published in Sept. 2017) could be interpreted as a call to investigate the 11C-PiB PET imaging method, w/ the aim of generating evidence to support Patisiran treatment could either halt amyloid deposition, or promote amyloid plaque clearance, in hATTR-PN patients.

QUESTION #1 – Did Alnylam, or investigators in the audience reference imaging methods, like the one used in Ezawa et al., as it relates to investigating whether they have the sensitivity & robustness to demonstrate halting of amyloid deposition, or amyloid clearance, pre- and post- Patisiran treatment?”

From Ezawa et al abstract..

* "In conclusion, 11C-PiB PET imaging can be used clinically for systemic evaluation of amyloid distribution in AL and ATTRm amyloidosis patients. Quantitative analysis of 11C- PiB PET may be useful in therapy evaluation and will reveal whether amyloid clearance is correlated with clinical response."

Background Information & Question #2

Alnylam noted in slide 10 & 11 of their July 4, 2016 slide presentation “Relationship Between TTR Knockdown and Change in mNIS+7”….

• “Loss of significant correlation between 18 and 24 months suggests that lesser degrees of TTR KD (<70%) may impact neuropathy progression if maintained over longer period of time”

QUESTION #2 – With respect to demonstrating potential for continued improvements in mNIS+7 change from baseline, beyond 18 months of treatment, for a minority of Patisiran-treated hATTR-PN patients achieving < 70% TTR KD, did Alnylam provide any indication they would once again present data (similar to slide 11) for those in the APOLLO phase 3 treatment group that rolled into the open-label extension (OLE) study?

Of course, w/ a small n of 5, the Patisiran phase 2 OLE observation reported by Alnylam in the bullet-point above, is a preliminary observation of continued improvement in mNIS+7 change from baseline, once reaching 24 months of treatment at < 70% TTR KD….

• However, it would seem worthwhile for Alnylam to determine if a similar observation is made in the much larger phase 3 OLE dataset, as this would add additional, more robust evidence of long-term clinical benefit (i.e., even for the minority of Patisiran-treated hATTR-PN patients achieving < 70% TTR KD, “lesser degrees of TTR KD (<70%) may [positively] impact neuropathy progression IF MAINTAINED OVER A LONGER PERIOD OF TIME”)

Anonymous said...

Two comments:
(1) it would make sense in your commentary to at least make one perfunctory comment regarding comparing results across two different clinical trials. Any good scientist recognizes cross-trial comparisons are problematic at best.
(2) this was home court advantage for ALNY. I wouldn’t read too much into the crowd’s reactions.

That said, I enjoy your blog. Please blog more.

Dirk Haussecker said...

Reply to question 1:
While Alnylam hasn’t reported on looking at amyloid deposition from the APOLLO study, they had done so based on skin biopsies in the phase II OLE study. Based on that, I came away with the impression that there was some reduction in deposited amyloid, but that more robust TTR knockdown was need for a more forceful reduction. Amyloid folks seem to believe you need 90% reduction of the insulting protein to achieve that. Patisiran achieves an ~82% time-averaged knockdown.
BTW, Patisiran in combination with Inotersen should easily clear the 90% bar.

Reply to question 2:
Yes, Patisiran does seem to continue to improve disease scores with time. Very impressive. It will also be interesting to learn whether the early indication of a correlation between TTR knockdown and disease improvement in the early Patisiran clinical experience continues to hold true in the APOLLO data. Maybe the Briefing docs will show the corresponding analysis.

PetraD said...


I've not had time to look at the trial results in detail, but one point stuck with me: ALNY APOLLO study population was sicker than the IONS one; do you think this could at least partially explain the different results? I also seem to remember that IONS saw more effect in the sicker sub-population... I'm not sure a small difference in Kd between siRNA and antisense (if even there and not an artifact of conditions and measurement) could explain it.

Also, in my understanding, production of siRNA is more costly than production of antisense oligo, although I haven't managed to get clear answers on how much exactly it currently is. What is your take on this?

It was nice meeting you at OTS!


Anonymous said...


interesting LR doc survey re TTR (n=64) $ALNY $IONS - based on overall profile, 25% prefer patisiran, 23% inotersen, 52% are agnostic

5:05 AM - 5 Jan 2018

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