A Framework for Progressing RNAi Therapeutics into the Clinic

This week was quite busy for the RNAi Therapeutics space with important corporate developments for CytRx/RXi (succesful spin-out/IPO), Nastech/mdRNA (announcements of patents filings and scientific advisory board), Silence Therapeutics (extension of AstraZeneca collaboration to Atuplex delivery), and Arrowhead Research/Calando (filing of first cancer IND). I hope to provide a wrap-up soon, but as I am contemplating the further developments in delivering RNAi to the liver, I would like to use the clinical development of liposomal RNAi as a case example of how one might think about development timelines for RNAi Therapeutics in general. While this discussion focuses on SNALP/liposomal-siRNAs just because it is an area that I am following more closely than others, it can easily be translated to for example to PEIs and delivery to the lung, or for that matter AAV/lentivirus and delivery to the brain.

RNAi Therapeutics are thought to speed up drug development, because once a target is identified, finding an appropriate siRNA should be a straight-forward process. However, it is clear that right now developing ways to get the RNAi triggers into the cells is the rate-limiting factor, meaning that the benefits of rapid drug development won’t necessarily all be realized for a good fraction of the first crop of RNAi Therapeutics. In order to assure that the next batch may more readily move through development, it will therefore be important to establish a number of predictable delivery technologies for the different target tissues. Once such a delivery system has been identified for a given tissue, virtually any gene of interest could be targeted in a manner that reduces development risk mainly to target risk (should be quite low given the virtually unlimited target space of RNAi) and safety profile of the particular RNAi trigger (particularly due to the less predictable off-targeting effect).

The question for Alnylam now is whether to choose liver cancer or hypercholesterolemia as the indication for their first SNALP/lipidoid-RNAi IND. Assuming that they feel quite confident with the gene targets and that they intend to use the same delivery formulation since the target tissue is fairly similar (normal versus tumour liver tissue), why choose one over the other? As we know, safety and finding a SNALP/lipidoid formulation with a good therapeutic index is as much of a concern as is efficacy. One could argue that starting with liver cancer may be a less risky business decision since the length of dosing and nature of the disease should be more forgiving in terms of the tolerated safety profile. By contrast, to derive a cardiovascular benefit through cholesterol lowering requires long-term chronic treatment which is why tolerability is so important for this indication. On the other hand, the PCSK9 program would provide a host of information as to the efficacy of this novel delivery system. Circulating PCSK9 levels could be readily measured and this information be used to adjust dosing strategies not only for the late-stage development of this particular program, but also all the other programs, including liver cancer, making use of the same delivery system.

I can imagine that the decision won’t be an easy one to make, but with improvements in the therapeutic index of SNALP-RNAi, the PCSK9 program becomes relatively more attractive. If successful, it should be possible to realize the anticipated advantages of RNAi Therapeutics in terms of increased development speed. Although true for drug development in general, from a technology and business development point-of-view it is therefore particularly important for the field of RNAi Therapeutics that its early clinical candidates, using unproven delivery systems, target genes where proof-of-concept can be established at an early stage.