Wednesday, December 3, 2014

Alnylam Second-Generation GalNAc Chemistry ~5x More Potent

The GalNAc-RNAi trigger strategy pioneered by Alnylam and Arrowhead Research has opened up new opportunities for RNAi Therapeutics, partly due to the fact that they may be administered subcutaneously (note: for Arrowhead that means the single molecule DPC which is not yet in clinical development).  Although the first such product candidate, ALN-TTRsc, looks like it could be a decent drug for a severe disease such as TTR amyloidosis, there is room for improvement both in terms of efficacy (--> injection volumes) and tolerability/safety (liver enzyme elevations, skin reactions).

It is therefore no surprise that Alnylam keeps stressing the fact that it has improved upon ALN-TTRsc, now referring to the original GalNAc chemistry as ‘standard chemistry’ (STC) and the improved version as ‘enhanced stabilization chemistry’ (ESC).  By inter- and extrapolating data from various model systems and for various target genes, the company has come up with the notion that ESC ‘has the potential’ to be around 50x more potent than STC (IR departments know that investors will be blind to qualifiers like ‘has the potential’).

I love it when maths meets biology.

These numbers games, of course, make little pharmacological sense, mostly due to the fact that the same delivery chemistry can result in disparate knockdown efficacies just due to sequence and target gene differences.  In addition, concluding anything about a dose response from a ~25% knockdown in a single-dose, single dose level phase I study (--> ALN-AT3) is impossible.  In RNAi, a 25% knockdown can be achieved with homeopathic drug levels and does not inform at which drug concentrations more robust >50% knockdowns will be observed.

Apparently, Alnylam is seeing it the same way and probably has received the same criticism from other sources.  It has now provided on two recent occasions much more informative datasets on the relative potencies of STC versus ESC.

At the Cantonese Nucleic Acids Forum (CNAF) in Guangzhou, China, in early November, Dr. Manoharan revealed that if you turn the STC of ALN-TTRsc into an ESC, the gain is a 5x in potency.  Consistent with this 5x notion is the Nair et al. paper that published 2 days ago in JACS where the same exercise for an siRNA sequence against the murine transthyretin gene resulted in the same 5x improved potency.

Of importance to the RNAi community, the enhanced metabolic stability was achieved by the use of phosphorothioate bonds at the 5’ ends of both the guide and passenger strands, while the 3’ ends are protected in both generations by phosphorothioates in the overhang (guide strand) and the GalNAc ligand (passenger strand), respectively.  I would not necessarily have predicted that phosphorothioates were tolerated at the guide 5’ end and this could be all the material difference there is between STC and ESC.

All eyes are now on the ALN-AT3 phase I data presentation at the upcoming ASH meeting next Monday (abstract here).  To wit, in part A of that study, Alnylam reported a ~25% mean peak knockdown for the 0.03mg/kg starting dose in healthy volunteers earlier this year (single dose).  Although there was no dose response data and they had failed to reach the maximum allowable AT3 knockdown of 40%, part A was deemed a success with the study proceeding into part B in hemophilia patients for further dose escalation and repeat dosing.  First data from that part is to be revealed.  


Anonymous said...

You have many errors in your blog. ESC TTRsc is 5X more potent than TTRsc in NHP. But ESC TTRsc is 10X more potent in human (not proven yet) than in NHP. So ESC TTRsc is 50X (10X5) more potent than TTRsc in human.

Alnylam also claims AT3 is 50X more potent than TTRsc in humans. TTRsc achieved about 80% KD with a weekly dosing of 5mg/kg. So AT3 should achieve about 80% KD with a weekly dosing of 0.1mg/kg if Alnylam is right. We will have to wait until the middle of next year to verify this.

Dirk Haussecker said...

Your arguments are even more contrived than what Alnylam's had been until recently.

Anonymous said...

ESC TTRsc has not been even tested in humans yet. So how can you claim that ESC TTRsc is 5X more potent than STC TTRsc? This is all based on NHP data and not on human data. There is no doubt that ESC GalNAc is much more potent and durable in humans than in NHP. Expect ESC TTRsc to be substantially more than 5X more potent than STC TTRsc.

While Alnylam's argument is based on mathematics and extensive clinical and preclinical testing, your argument is merely based on speculation. It is distorted, biased and without any merits. You will be proven wrong when more clinical data emerges from several other programs from Alnylam next year.

Anonymous said...

Will it be worthwhile going to their R&D day next Friday?

They might be able to tell us all about RGLS. Or how they're going to close in on BIIB's Alzheimers lead.

Dirk Haussecker said...

I rather rely on relative data from the same organism (NHPs) rather than data from different organisms and target genes. In the end, we only know when comparing TTR-STC and TTR-ESC data in humans. Alnylam is expected to take TTR-ESC into the clinic, but it will take I guess 2-3 years until we see such data.

Anonymous said...

I would like to know what do you use to be always update on the topic...PLEASEEEEEEEEE

Anonymous said...

Widespread correction of central nervous system disease after intracranial gene therapy in a feline model of Sandhoff disease.

Sixteen weeks after four intracranial injections of AAVrh8 vectors, Hex activity was restored to above normal levels throughout the entire CNS and in cerebrospinal fluid, despite a humoral immune response to the vector. In accordance with significant normalization of a secondary lysosomal biomarker, ganglioside storage was substantially improved, but not completely cleared. At the study endpoint, 5-month-old AAV-treated SD cats had preserved neurological function and gait compared with untreated animals (humane endpoint, 4.4±0.6 months) demonstrating clinical benefit from AAV treatment. Translation of widespread biochemical disease correction from the mouse to the feline SD model provides optimism for treatment of the larger human CNS with minimal modification of approach.Gene Therapy advance online publication, 4 December 2014; doi:10.1038/gt.2014.108.

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