Big De-Risking of ALN-TTR02 and SNALP Delivery Platform

Today, Alnylam reported (PR here, presentation here) first data from its phase II open-label extension study of ALN-TTR02.  ALN-TTR02 is developed for the treatment of TTR amyloidosis (FAP form) and with a phase III study underway is the industry’s lead blockbuster candidate.  There is no doubt that its results will have a big impact on the perception of the technology.   Importantly, the new data revealed at the International Symposium on Amyloidosis show that ALN-TT02 not only maintains consistent knockdown potency following multiple (>2) administrations, but even more importantly, indicate that the biggest risk, long-term safety, will not be a problem.    

Phase II promising, but with efficacy and safety questions

The new data follow on from a 2-dose phase II study (somewhat euphemistically labeled 'repeat administration) showing that ALN-TTR02 can achieve ~80% TTR knockdown levels not only following a first dose, but also following a second dose.  This was good to see because there was theoretical concern that SNALP LNPs could provoke generation of neutralizing antibodies to the PEG component which might compromise efficacy following repeat dosing.  Indeed, TTR levels seemed to return back to normal more quickly following the second compared to the first dose and was responsible for Alnylam switching from a 3-week to a 4-week dosing interval.

On the safety side, infusion-related hypersensitivity reactions are the major concern with SNALP LNP as with most other infused therapeutics, nucleic acids, protein, or small molecules alike.  While the steroid pre-treatment may have ensured that no major immune reaction was seen in the phase II study, infusion reactions had been recorded in 3 of 20 infusions at the key 0.3mg/kg dose.  Intriguingly, when a micro-dosing pre-treatment strategy was employed (increasing the length of infusion from 60 to 70 minutes) no such reactions were seen in the 18 infusions thus administered.  This is probably related to the fact that infusion reactions in general are essentially restricted to the first dose and are dose-related.

Phase II open-label extension data provide highly positive answers

In thinking about a headline for today’s blog entry ‘spectacular’ was on my mind a lot.  However, I refrained from using this term as the scientific results show very comforting consistency. 'Spectacular consistency' may be too oxymoronic.   In stock market terms, however, this consistency may very well be called ‘spectacular’ both for the much increased likelihood that ALN-TTR02 will make it across the finish line and for the safety demonstration of Tekmira’s SNALP delivery platform in general for which the major concern has always been safety, not efficacy.

Importantly, the results revealed today show that the ~80% knockdown potency is maintained following an aggregate of 119 doses of 0.3mg/kg ALN-TTR02 compared to an aggregate 38 doses before.  In the patient who has been on therapy the longest, this was the case following 9 doses over half a year.  The integrated knockdown level over time may have indeed been slightly higher than 80% since TTR levels were measured at their nadir, just before the next dose.  One can therefore conclude that the enhanced recovery from gene knockdown following the second dose did not intensify over time and that sustained and consistent knockdowns can be achieved over the long-term.

Regarding safety, just 3 instances of mild-moderate adverse events were reported in the extension phase that were deemed possibly treatment-related.  Probably only the 2 instances infusion reactions in a single subject call for attention.  Even so, none of them were deemed severe enough that the infusion rate had to be slowed as it is normally done.  The other mild-to-moderate AEs were an ‘increase of diarrhea’ and an 'impairment of taste'.  Maybe not all that bad in a disease like FAP.

Further indicative of the tolerability of ALN-TTR02, Alnylam projects 27 out of the initial 30 patients to participate in the open-label extension study.  First functional results from this OLE are expected to be reported by the end of 2014.

Disclosure: I could not resist but buy back some TKMR today based on the recognition that today’s data represent a great de-risking of the SNALP LNP delivery platform the company depends on.