Friday, October 7, 2011

Santaris Terminates PCSK9 Hypercholesterolemia Trial

Antisense company Santaris seems hardly able to catch its breath these days. After being sued by ISIS Pharmaceuticals for patent infringement, reporting first clinical proof-of-concept for a MicroRNA Therapeutic, it has now been revealed that the company prematurely terminated a phase I trial of its PCSK9 phosphorothioate LNA RNase H antisense inhibitor SPC5001 for the treatment of hypercholesterolemia. This study had been initiated in May of this year with an estimated enrollment of 40 healthy and familial hypercholesterolemia subjects.

Reasons for the trial termination were not revealed. However, since this was a phase I safety trial, it is likely that the trial termination was due to some safety issue. Supporting this is that, coinciding with the PCSK9 trial termination, enrollment has been halted in another phase I hypercholesterolemia trial sponsored by Santaris, this time targeting ApoB (SPC4955).

Consequently, after the premature trial termination last year of BMS/ISIS’ phosphorothioate 2’ MOE RNase H PCSK9 antisense inhibitor (BMS-844421), Alnylam’s SNALP-delivered ALN-PCS has suddenly taken the lead in the race to develop a PCSK9-targeting RNA Therapeutic, pitting it against the monoclonal antibodies by the likes of Regeneron and Amgen.

Without explanations for the trial terminations, it is difficult to pin down the exact cause(s) of the presumed toxicities. What the compounds by Santaris and BMS/ISIS Pharmaceuticals obviously share is that they both use phosphorothioate chemistries and work via an RNaseH mechanism. Phosphorothioates are widely used in antisense development because they bind to proteins in the plasma and various tissues, thereby allowing one to achieve tissue concentrations high enough such that mass action will allow for cell penetration and target gene knockdown. In my opinion, phosphorothioate oligonucleotides are promising for a number of local applications. The problem with systemic applications, however, is that the high concentrations reached in tissues such as liver, spleen, and kidney, ultimately limit their therapeutic window. Some industry experts have referred to this issue as the ‘hazardous waste’ problem of systemic phosphorothioate oligonucleotides.

ISIS supporters will point out that Santaris’ specific LNA chemistry is the most likely culprit, whereas ISIS’ chemistries are relatively safe as supported by ISIS’ comparative studies. Of course, these studies were published to make Santaris look bad, just as the recent lawsuit was aimed at blunting Santaris’ competitive threat. Conspiracy theorists may even suspect that the sudden turmoil around Santaris is no coincidence and was orchestrated to inflict maximum damage at a time that Santaris seemed to be on a roll with a number of trial initiations, positive HCV data, and depriving RNAi Therapeutics of a deal with Pfizer (Pfizer apparently being attracted to ‘naked’ oligonucleotide approaches over RNAi nanoparticle ones). However, if Santaris intended to go public to satisfy its increasing cash needs (maybe less so with the trial terminations), it can probably scratch that now.

RNA Therapeutics is intensely competitive as they compete for pretty much the same investment dollars. Investors, including Big Pharma, are easily influenced by public opinions and fashion trends. 4 years ago it was all about the fear of being left behind in RNAi Therapeutics, with little attention being paid to true enablement and expertise in a noisy field. This made antisense look like the ugly cousin. In the last 2 years, however, antisense has regained favor as the RNAi delivery ‘problem’ became widely publicized which made antisense look deceptively simple. Santaris especially made a living of that by advertising, e.g. at conferences and press releases, the delivery problem of RNAi Therapeutics and getting a few laughs by stating their motto of 'staying naked’ and ‘staying short’.

Needless to say, my favored technology is RNAi Therapeutics: ‘natural’ and ‘potent’ is my motto. The hypercholesterolemia arena will be a particularly good battleground for antisense and RNAi Therapeutics to test their metals: same targets, easy biomarkers, chronic applications. The next chapter will be top-line data from Alnylam’s ALN-PCS phase I trial which are expected by year-end.

5 comments:

Anonymous said...

Dirk, any word on the street as to when or if pfizer will commence P1 trial of the tt-033 compound?

Anonymous said...

As an investor in both antisense and RNAi I have greatly appreciated your insight, particularly with respect to the pros and cons of both approaches.

Any prudent investor should be seeking out the most knowledgeable, unbiased and up-to-date information regarding the cumulative safety database for each approach.

I agree 100% with your last paragraph that now, finally, with both approaches being in the clinic and targeting some of the same indications and biomarkers we can just let the data do the talking (particularly for me the long-term safety database for both approaches).

Based on your last paragraph then, I'd be most grateful if you could provide an update from time to time of the emerging biomarker knockdown and long-term safety data (for clinical trials where antisense and RNAi knock down the same targets in the same patient population). Also, Isis recently reported its total number of treated patients and duration as of April 2011...I look forward to seeing similar treated patient numbers for RNAi as more trials get underway.

Lastly, I would assume you would consider Isis' intrathecal delivery for neurodegenerative diseases as a local application (since oligos do not distribute to peripheral tissues with this approach).

Dirk Haussecker said...

Not sure about the fate of the tt-034 compound. The glacial pace with which this compound seems to move could be a bit worrisome. I don't see Pfizer spearheading DNA-directed RNAi Therapeutics.


"Lastly, I would assume you would consider Isis' intrathecal delivery for neurodegenerative diseases as a local application"

I was thinking about exactly this issue as I was trying to formulate my viewpoint on phosphorothioate oligos. For local applications, it is probably a more differentiated picture. In some applications such as dermatology, phosphorothioate oligos, even at high concentrations, probably won't pose life-threatening tox issues, even if something escapes into the systemic circulation. The CNS, however, is a particularly sensitive organs. Even small changes, e.g. ion imbalances or slightly elevated pressures due to drug infusion, can affect its health. We will have to see how lipophilic agents, including phosporothioate oligos and cholesterol-siRNAs and the likes, will be tolerated in the CNS.

Anonymous said...

Dirk man it would be ausome if your treatment of certain companies would be a little more unbiased.

Jannah Delfin said...

I appreciate all of the information that you have shared. Thank you for the hard work!
rnase inhibitor is an acidic, 52 kDa protein that is a potent non-competitive inhibitor of pancreatic-type ribonucleases such as RNase A, RNase B, and RNase C.

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