Thursday, July 11, 2013

Alnylam Indicates that 80% Subcutaneous TTR Knockdown Achievable with Magic 2.5mg/kg Dose

This morning, Alnylam announced a milestone in the development of subcutaneously administered, systemically acting RNAi Therapeutics.  A ‘more than 80%’ knockdown was achieved in a phase I trial of ALN-TTRsc, the GalNAc-siRNA conjugate for the treatment of TTR amyloidosis.  It is the first time that a meaningful knockdown in Man was reported using the subcutaneous route of administration.

The key question as to the clinical attractiveness of the liver-specific GalNAc delivery platform versus intravenous alternatives such as SNALP (compare to just reported ALN-TTR02 clinical results) relates to injection volume and frequency of administration.  The hurdle to overcome here would seem a once weekly regimen with dosages of 2.5mg/kg or less.  2.5mg/kg is widely considered to be a threshold as this amount of drug can be accommodated in a 1ml syringe.  Higher injection volumes would likely be quite painful and possibly increase the risk of injection site reactions.  Higher dosing frequencies in order to stay within the 2.5mg/kg limitations would reduce the convenience factor.

Unfortunately, these data points were left undisclosed in today’s announcement.  Instead, we were given a riddle.  The company first stated that the results were in-line with observations in non-human primates.  At another point, they say that 80% knockdown with ALN-TTRsc were achieved in non-human primates with the magic 2.5mg/kg dose.  Logically, Alnylam stated that in humans 80%’ knockdowns were seen with the 2.5mg/kg dose. 

Curiously, the company also stated that dose escalation was continuing.  It makes, of course, sense to push the degree of knockdown.  The difference between an 70% knockdown (e.g. ISIS-TTRRx), an 80% knockdown (current ALN-TTRsc results), and 90% knockdowns (e.g. ALN-TTR02) is that compared to a 90% knockdown, the amount of remaining insulting protein (here: mutated TTR) is twice (80%) and 3x (70%) as high which could result in dramatic differences in the clinical outcome, or even whether a knockdown approach would even work for a disease like TTR amyloidosis.

Maybe we will get more clarity on dose and dose frequency at today’s R&D day.  If not, more detailed results are to be presented at the Annual Scientific Meeting of the Heart Failure Society of America (HFSA), September 22-25.


Henry Stebbins said...

Was that 1 person who acheived an 80% knockdown ( like in their TTR02 results they said 93% but it was 1 patient) or is that the average? or will they specify that in September presentation?
Henry stebbins

Anonymous said...

"The new data show a very impressive 96% knockdown of transthyretin (TTR) with a single subQ administration of 1.0mg/kg SNALP in rodents. This compares to a much more modest ~55% knockdown with ALN-TTRsc at 1.0mg/kg given on 5 consecutive days, the subQ GalNAc-siRNA candidate by Alnylam which just entered clinical development for the FAC form of transthyretin amyloidosis."

Was the 55% knokdown by sub q gal in rodents ? then jumped to 80% pre clin in chimps

Anonymous said...

This press release leaves much to be desired. Compare it to the July 16, 2012 press release on ALN-TTR02 Phase I results which is very detailed regarding knockdown and states there were no SAEs. Overall, while galnac is promising, probably inferior to TTR02 and the ISIS product for the TTR indication. Good day for TKMR and ISIS.

Anonymous said...

"Higher dosing frequencies in order to stay within the 2.5mg/kg limitations would reduce the convenience factor."

Dirk, the oft-invoked notion that injectable therapeutics are incovenient or result in poor patient compliance is a straw man of sorts. Chronic diseases like type I diabetes or the various hemophilias require parenteral administration, respectively, of sc insulin or the appropriate clotting factor iv. If I were afflicted with FAP (I am not)and, a safe and demonstrably efficacious therapeutic became avialable to treat my disease, I would spend little time fretting over the frequency of its SC adminstration.

Having taken injectable insulin for over 40 years, I assure it was an easy choice to reach.

In the RNA therapeutic delivery space, it remains to be be seen who will develop the most "convenient" delivery vehicle.
That assessment is contextual.

My intent, Dirk,is not to target you specifically with this criticism. I read this blog regularly and enjoy your comments.

It's long been my observation that people who make comments about the inconvenience of certain therapeutic adminstrations for the most part don't have their lives depend on them.

Many people whine about injections until their imminent survival depends on them.

Dirk Haussecker said...

Convenience matters when there are therapeutically equivalent alternatives. For severe diseases, I would prefer the more efficacious treatment if accessible to me (in this context: an i.v. SNALP over a subQ GalNAc-siRNA). There are many moving parts though.

Henry..yes, it's probably the same as in the ALN-TTR02 PR: putting best foot forward with deepest knockdown observed in a single person at one time point.

Anonymous said...

Wouldn't it make sense to keep dose escalating regardless of whether 2.5mg/kg does the trick? It's a Phase I, after all, and safety is the primary endpoint. One of the potential advantages of GalNAc over SNALP is a better tolerated profile. If 2.5mg/kg is sufficient, but they can dose all the way up to 10mg/kg with no adverse events, that would be highly promising for the GalNAc platform going forward.

Anonymous said...

It seems at 10mg/kg the volume would be around 4ml. What is the maximum volume that can be safely injected under the skin?

Dirk Haussecker said...

Alnylam reported today that Amgen's subcutaneous PCSK9 drug was a 6ml injection. Not sure though whether these types of volumes can be self-injected.

Terry said...


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