Tekmira’s partner and licensee Alnylam Pharmaceuticals announced today the submission of files to a European regulatory agency in anticipation of a phase I study with a candidate targeting PCSK9 for the treatment of Severe Hypercholesterolemia. The primary aim of this early-stage study is naturally the safety and tolerability of ALN-PCS. An important secondary aim, not just for Alnylam but also for the entire field of RNAi Therapeutics, will be assessing drug activity as measured by target protein levels in serum. Initial data are expected by year end.
ALN-PCS represents Alnylam’s 4th clinical candidate, three of which are based on Tekmira’s SNALP technology (VSP, TTR, PCS). It also represents the 2nd candidate under its 5x15(TM)program which aims to advance five RNAi Therapeutics candidates into late-stage clinical development by 2015. All disclosed candidates under that program (TTR, PCS, HPN) are based on SNALP technology.
Despite the success of statin in lowering cholesterol, many patients are still considered to be in need of additional treatment options. PCSK9 has emerged as a very attractive target for such uses based on human genetics which suggest PCSK9 knockdown to reduce ‘bad’ LDL cholesterol in addition to being well tolerated. While ALN-PCS is the first RNAi Therapeutics candidate to target PCSK9, other companies have already started clinical development of PCSK9-targeting hypercholesterolemia candidates.
These competitive efforts are based on monoclonal antibodies and antisense approaches and include a recently initiated program by Santaris (LNA antisense) and monoclonal antibody programs by Amgen, Pfizer, and Regeneron amongst others (mostly phase I and II). ISIS with partner BMS together are also developing a PCSK9 antisense candidate. This candidate, however, still appears to be in late preclinical studies following some delays.
The pre-clinical data show that RNAi, antisense, and monoclonal antibodies can all potently down-regulate or bind and inhibit PCSK9. It seems, however, that one advantage of ALN-PCS could turn out to be that it does not simultaneously down-regulate ‘good’ HDL cholesterol as was observed e.g. in a rodent study by
Obviously, it is still early days to speculate on the eventual competitive profile of the various candidates. With regard to safety and tolerability it is notable, however, that the anticipated highest dose with ALN-PCS in the study is 0.25mg/kg. This means that an average Caucasian may receive only about 10-20mg siRNA per week (assuming bi-weekly or monthly administration). While there is still some more uncertainty about the safety profile of non-DLinDMA SNALPs such as ALN-PCS (this candidate uses MC3 while all other SNALP candidates so far made use of DLinDMA), such low doses make me optimistic that the safety profile should be quite competitive.
Adding Tekmira’s efforts, this program is the 5th SNALP candidate in 3 years to enter clinical development. At least two more are anticipated this year. ALN-PCS therefore further illustrates one of the advantages of RNAi Therapeutics development, namely that once there is a suitable delivery technology for a given target organ, in this case SNALP for liver delivery, the indications can be rapidly expanded to multiple drug targets. This also means that the inventor behind and manufacturer of ALN-PCS, Tekmira, should receive a milestone from its partner and licensee upon initiation of dosing, adding to an increasing royalty stream.