Alnylam Chooses Lipidoids over Cationic Liposomes for their First Systemic RNAi Clinical Studies

[Important update at end of this entry]

In an interesting twist, Alnylam announced at the Beyond Genome conference held last week in San Francisco the use of MIT’s lipidoid technology for their first systemic RNAi programs. These formulations will be used for knocking down PCSK9 for the treatment of hypercholesterolemia and the dual siRNA cocktail ALN-VSP01 for liver cancer. This was somewhat surprising, following a proof-of-concept Nature study last year that demonstrated efficient systemic RNAi delivery in primates using cationic liposomes. These were developed by Protiva/Tekmira, and Alnylam consequently established a broad alliance with Inex Pharmaceuticals, now Tekmira, that comprised an exclusive license to Alnylam to Tekmira’s liposomal delivery IP estate. It was therefore largely expected that Alnylam would use Tekmira’s cationic liposome SNALP technology in their systemic RNAi programs which are scheduled to enter the clinic by the end of this year.

As I pointed out in some of my earlier blogs, I was concerned that Alnylam’s plans to move into systemic clinical trials so quickly were too aggressive. This concern was largely based on the considerable, albeit transient elevation in liver enzymes, a measure of liver toxicity, at the 2.5mg/kg dose range reported in last year’s Nature study. Moreover, combined with the non-linear dose response for cationic liposomal siRNA delivery that Alnylam reported at the Keystone RNAi meeting earlier this year, this made choosing the right dose range for human studies less than certain.

Interestingly, at the same Keystone meeting, Dan Anderson together with Rob Langer, a world authority on drug delivery and scientific advisor for Alnylam, presented impressive systemic delivery data using so called “lipidoids”. “Lipidoids” were discovered as part of a library approach as an apparently new class of lipid-like molecules that were very effective in delivering siRNAs systemically to the liver and were structurally sufficiently distinct to conventional lipids and cationic polymers to give it a new name. Only a few months after that, Alnylam and the same groups at MIT announced a broad systemic RNAi delivery initiative in which Alnylam would fund 10 post-doctoral researchers for 5 years in return for exclusive rights to the lipidoid technology and an exclusive option for any new RNAi delivery technologies resulting from the sponsored fellowships.

Importantly, the tiny lipidoid formulations were reported to have a favourable safety profile and showed dose-dependent gene suppression without compromising RNAi knockdown efficacy.

In hindsight, it is very reassuring to see that Alnylam did not go out on a limb by promising an aggressive systemic RNAi timeline and gamble an early program on a potentially unsafe delivery technology. It speaks to the quality of the management and Alnylam’s reputation as the leader in RNAi Therapeutics that it always had valid options outside cationic liposomes.

Where does this leave the Tekmira-Alnylam alliance? Although “lipidoids” appear to be somewhat distinct to cationic liposomes, it is certainly a good insurance to be covered by Tekmira’s important IP estate in the field of liposomal drug delivery. Moreover, as part of the alliance Alnylam invested in Tekmira’s manufacturing capabilities, and it appears this investment will pay off as Tekmira is manufacturing the lipidoid-siRNA formulations for the PCSK9-hypercholsterolemia and liver cancer trials. According to David Bumcrot of Alnylam, IND-enabling studies for these programs are well underway.

PS: In another interesting twist, David Bumcrot noted that part of Alnylam’s decision to target PCSK9 in their hypercholesterolemia program is due to a fatty liver problem seen in targeting the former front-runner ApoB100. This appears to be a target-specific phenotype as this phenomenon has been seen with a number of siRNAs targeting ApoB100. Interestingly, ISIS Pharmaceuticals which has an ApoB100 antisense compound in late phase II trials, but has not reported on that problem has followed Alnylam’s lead in targeting PCSK9 in a new hypercholesterolemia program (see May 9, 2007 post). Once again, Alnylam has demonstrated a characteristically circumspect development approach that includes bringing together the best scientists in a given disease area to carefully characterise RNAi knockdown phenotypes.

[Update May 1, 2008: According to a report by RNAiNews , an Alnylam spokesperson indicated that the company had not given guidance on the specific liposome formulations to be used for their hypercholesterolemia and liver cancer clinical programs. This is in contrast to an earlier report by RNAiNews from last year’s Beyond Genome conference in San Francisco which indicated that Alnylam had chosen “choose lipidoids over SNALPs” for these indications (also discussed in a blog entry here). It therefore seems that Protiva/Tekmira's 0.1mg/kg IC50 liposomal nanoparticle formulations may be the current frontrunners in entering the clinic (see also a recent PR).

The sometimes imprecise use of the terms SNALPs and lipidoids may be partly to blame for the confusion. SNALP refers to a liposomal formulation technique, while lipidoids are a new class of lipids generated by combinatorial chemistry which can now be evaluated for liposomal drug delivery. As such, lipidoids could be used within the context of SNALPs, and both of these approaches are therefore complementary to each other.]