ALN-VSP02 Was a Good Start, but Directs Focus Towards Improved Formulations

Alnylam recently published detailed phase I results from its RNAi Therapeutic candidate to treat liver cancer, ALN-VSP02.   Although results from this study had already been reported, the new paper by Tabernero and colleagues provides an insightful warts-and-all view of Tekmira's SNALP generation 1.0 (short-circulating DLinDMA particles) in a solid cancer.  The results show that while ALN-VSP02 did achieve a number of important goals, including evidence of tumor response and RNAi activity, it will be necessary to turn to the newer SNALP formulations for more robust efficacy and improved safety.

New Insights on ALN-VSP02 Activity

Previously, Alnylam provided clear evidence of RNAi activity using the 5' RACE assay.  It is now clear, however, that this was only based on 3 positive biopsies out of 15 investigated in this regard, and only for the VEGF, but not the KSP target gene.  Consistent with this less than robust RNAi activity, there was no convincing evidence of target gene knockdown and no spindle abnormalities as would have been expected from KSP knockdown.

New Insights on ALN-VSP02 Safety  

The present paper also provides valuable insights into the safety of a SNALP 1.0.  As was reported before, infusion reactions were seen in a minority of patients and this was readily addressed in practical terms by slowing the rate of infusion.  Interestingly, the infusion reactions appear to be related to complement activation, not cytokine activation.

Some cytokines were also upregulated (rarely TNF-alpha, however), especially above 0.4mg/kg, despite the use of modified siRNAs.  The evidence thus increasingly points towards the DLinDMA lipid itself to be the culprit.

Finally, ALN-VSP02 caused considerable spleen toxicity, especially with prolonged dosing.  In the one complete responder in the study, 90% of the spleen was reduced after receiving 50 doses of ALN-VSP02.  This is consistent with the preclinical monkey data.  Somewhat reassuringly for SNALP 1.0, this effect might be due to on-target efficacy, as the same lipid formulation with a luciferase siRNA did not have this effect in monkeys (note: the spleen is not an essential organ in humans, and I’d much rather have my spleen removed than cancer).

SNALP-based Cancer RNAi Therapeutics in the Future

Based on the above limitations, it is important that future SNALP-based cancer RNAi Therapeutics include the following improvements, essentially all of which have been achieved over the last 6-7 years since ALN-VSP02 had been selected as a development candidate: firstly, a more potent and less immunogenic lipid is required (there should be multiple to choose from now); secondly, the SNALP particles should be less than the 80-100nm with ALN-VSP02 and include more stable PEG-lipids for improved, i.e. prolonged circulation times to better take advantage of the EPR effect of solid tumors (TKM-PLK1 includes such stable PEG-lipids); and finally, as spleen safety might also be affected by lipid accumulation along the endosomal-lysosomal pathway, enhanced lipid biodegradability may be desirable.

ALN-VSP02 has been put on hold by Alnylam for development in the Western markets.  Last year, however, Alnylam licensed development and commercialization rights to Ascletis for the Greater China market where liver cancer (hepatocellular carcinoma, HCC) is prevalent.  The next clinical study by Ascletis is expected to involve more HCC patients who, unfortunately, have been almost entirely missing in the phase I study of ALN-VSP02.  Despite the challenges that ALN-VSP02 will face in HCC, innovative RNAi Therapeutics have an important role to play in the future treatment of HCC, a disease that is proving again and again hard to manage by more conventional approaches as Celsion’s disappointing results (radiofrequency ablation with liposomal doxorubicin) today showed.