Confidence in SNALP Safety Building

Alnylam Pharmaceuticals disclosed in their Q1 2011 results that it will expand the dose escalation of the phase I study of ALN-TTR01 in TTR amyloidosis, increasing the target dose in that study from 0.4mg/kg to now 1mg/kg. This puts the company in a good position to demonstrate, unambiguously, that systemically administered SNALPs can knock down genes in the human liver. This dose expansion is an important indication that, as we learn more about the clinical performance of SNALP delivery, confidence in its safety is growing.

Given yesterday's news, the phase I study being conducted in Europe should have almost fully enrolled its first 24 patients up to 0.4mg/kg. Regulatory applications for this study were filed in late 2009/early 2010, yet it took over half a year for the first patient to be dosed in July 2010. At that time, Alnylam revealed the 0.4mg/kg target dose. This was somewhat confusing and made me even speculate that TTR01 may involve a ‘generation 1.5’ formulation as it had been Alnylam’s stated goal to demonstrate proof-of-concept of gene knockdown with this study. 0.4mg/kg, depending on the gene, is about where you’d expect to start seeing efficacy with the initial SNALP formulations, so stopping at 0.4mg/kg would have been slicing it quite thinly. Indeed, the ED50 (dose of 50% drug efficacy) for ALN-TTR01 in non-human primates is around 0.4mg/kg.

In retrospect, the original conservative dose escalation schedule might have been due to safety concerns surrounding SNALP delivery. Around the time of the regulatory submissions, Alnylam knew of one death in their liver cancer trial with ALN-VSP02 (also using SNALP delivery) which occurred some time after a patient with extensive liver mets from pancreatic neuroendocrine cancer received a second infusion of 0.7mg/kg SNALP. Dose-limiting toxicities were not observed in that trial until then up to 0.4mg/kg. Although patients in that trial are quite fragile and autopsy revealed that the patient may have in fact died as a result of too much drug efficacy (extensive necrosis of the liver mets), it was a potentially drug-related severe adverse event nevertheless. ALN-VSP02 was subsequently escalated to the robust dose of 1.5mg/kg, with 1.25mg/kg being my predicted maximally-tolerated dose.

Shortly thereafter, in January 2010, Tekmira stopped early their phase I hypercholesterolemia trial for TKM-ApoB after one trial participant at the 0.6mg/kg dose level became hypotensive and suffered from general flu-like symptoms after receiving a SNALP formulation. Because the necessary safety/tolerability profile for a hypercholesterolemia drug differs from that of a cancer drug, Tekmira did the right thing and stopped the trial and take advantage of the technology progress in the SNALP delivery field with the aim of re-entering clinical development with a formulation with presumably improved potency and robust long-term safety. Just as for ALN-VSP02, 0.4mg/kg was the dose level up to which no significant adverse event was observed with TKM-ApoB.

Since no good deed goes unpunished in the competitive area of siRNA delivery, these events were quickly made out to prove that ‘SNALP delivery is toxic’ adding to the SNALP confusion caused by Alnylam's lipidoid line of work. Regulators may not be as emotional, but it is understandable that they and Alnylam took a cautious approach in selecting their initial doses. They were, however, clever enough to design an adaptive trial that would allow for further dose escalation depending on the safety findings up to the 0.4mg/kg level.

The enrollment of the anticipated additional 8 patients should therefore be a very good sign that the safety profile so far has been highly satisfactory, setting the scene for convincingly demonstrating TTR knockdown in the liver as measured by plasma protein levels. Alnylam plans to present top-line data from the completed study in the third quarter, hopefully building on good ASCO data on SNALP-based ALN-VSP02.

There has been some debate around whether the clinical development of SNALP technology was started pre-maturely. Yes, you can try and aim for perfection (that may be what Merck and Roche are waiting for), but by taking the necessary clinical precautions, Alnylam and Tekmira were able, in a timely manner, to gather much clinical data on the SNALP delivery platform that is really starting to pay off now as their synergistic value becomes obvious. Important months for RNAi Therapeutics are ahead of us.