Widely expected, Alnylam presented over the weekend detailed safety and preliminary efficacy data from its multi-dose, dose-escalation phase I trial of ALN-VSP02 in 41 patients of advanced solid tumors with liver involvement. ALN-VSP02 is a SNALP formulation containing 2 siRNAs, one targeting VEGF (anti-angiogenic mechanism), the other kinesin spindle protein (KSP; anti-proliferative).
The data suggest that ALN-VSP02 has an adequate safety profile for such a cancer application at dosages where gene knockdown can be expected with such formulations in normal liver cells. While not geared towards showing efficacy, there are preliminary signs of efficacy with one case of clear tumor response and a dose-dependent increase in the number of stable patients.
Safety profile bodes well for SNALP delivery platform
Probably as, or even more important than studying the safety of ALN-VSP02, this study was the most rigorous test yet for the SNALP delivery platform. The detailed safety data show that while there were some minor toxicities at the lower dosages, innate immune-related toxicities such as chills and rigor become an issue at doses of 1mg/kg and higher, although none of these events were of high severity (grade 3) where they would be considered dose-limiting. There were also two cases of dose-limiting grade 3 thrombocytopenias at the 1.25mg/kg. Overall, this profile justified a recommended dose of 1mg/kg every 2 weeks for future studies.
Importantly, this study strongly suggests that SNALP delivery is amenable to repeat-administration with no apparent changes in the pharmacology upon re-administration. The ability to repeat-administer had been one of the question marks when SNALP delivery was in its infancy and this was the first such clinical experience.
While this safety profile is adequate for most cancer applications and other applications for severe diseases such as Ebola viral infections, the record suggests that for less severe indications, especially when chronic application is required, improvements in the potency and tolerability of SNALP delivery are necessary. Of course, based on Tekmira’s proprietary insights, considerable improvements in the therapeutic index have been achieved since ALN-VSP02 was locked down. In this light, the 1mg/kg mark determined here is very encouraging. Nevertheless, we still have to await clinical data with the newer formulations, starting with ALN-PCS later this year to fully justify such optimism.
Signs of preliminary efficacy
Although not the primary objective of such a study, Alnylam made significant efforts to study whether ALN-VSP02 works as designed and whether there are any signs of anti-tumor efficacy. In this regard, the highlight of the study is probably a patient with primary endometrial cancer and multiple liver metastases that showed a partial, but very considerable 70% tumor response and that has been on study drug for now more than a year. Moreover, among evaluable patients, only 1 in 13 given a dose up to 0.4mg/kg had stable disease for 2 months compared to 12 in 24 dosed with larger amounts of study drug (caveat: base-line criteria may not be fully comparable as the patient recruitment criteria were slightly adjusted during dose escalation).
In terms of mechanism of action, 5’ RACE RNAi cleavage results and a reduction in tumor blood flow and leakiness as measured by DCE-MRI support an anti-angiogenic mechanism of action due to VEGF knockdown, but overall the mechanism of action data fell slightly short of my expectations, although technical challenges in taking such biopsies and analyzing them may account for that. In particular, no data supporting a knockdown of KSP was reported. 5’ RACE cleavage assays apparently suffered from technical challenges, and the analysis of mitotic spreads was not mentioned at all.
Study validates SNALP siRNA delivery to liver
When I reviewed last year ALN-VSP02, I was a bit confused about Alnylam’s choice of a short-circulating C14-PEG-lipid instead of a longer-circulating C18-PEG-lipid. I even thought that there might be a mistake in Alnylam’s cartoons of the formulations, but my question remained unanswered. Having listened to the recent ThinkEquity presentation by Tekmira’s CEO Mark Murray, it is clear to me that this was not a typo: Tekmira’s solid cancer candidate TKM-PLK1 is a longer-circulating formulation, and as we know, Tekmira is getting more and more interested in competing with ALN-VSP02 in liver cancer.
Why does C14 vs C18 matter? In short, C14-PEG-lipids are most suited for gene knockdown in normal liver cells, not liver cancer cells. Normal hepatocytes largely derive their blood supply from the portal vein, whereas most liver cancers primarily tap into the arterial blood supply. For this reason, even when addressing tumors in the liver, a more stable formulation would have been desirable. This also applies to tumors outside the liver (note: the vast majority of patients in Alnylam’s phase I study had such turmors).
Therefore, when Alnylam reports siRNA concentrations in the liver biopsies that were often well above concentrations associated with potent knockdown of genes expressed in the liver in pre-clinical studies, it is mainly a validation that the DLinDMA C14 formulations successfully deliver siRNAs to the liver.
Why did Alnylam choose C14? This may be more of a rhetorical questions and if you follow the Tekmira litigation you will understand why. In other words, my suspicion is that if Alnylam were to develop another liver cancer candidate, it would indeed choose a longer-circulating formulation.
In conclusion, the ALN-VSP02 phase I study nicely adds to the accumulating evidence that up to 1mg/kg of SNALP-siRNA is readily feasible which predicts a comfortable therapeutic index for the liver-targeted SNALP pipeline. ALN-VSP02 will likely have to be studied in more targeted patient population and together with other therapeutic modalities before its real potential becomes clear. It won’t be an easy stroll, but the data show that there are a few reasons to be optimistic.
PS: Silence Therapeutics also presented today at ASCO an update on Atu027 for advanced solid cancers. The press release can be found here. I am currently traveling and will provide further commentary when I get a chance.