Four years after Mirus scientists published their seminal paper in polymer-mediated siRNA delivery, and 3 years after the acquisition of the Dynamic Polyconjugate (DPC) technology by Roche, Arrowhead Research, the new owner of the technology, finally lifted the veil on recent progress in bringing DPC technology to the clinic.
The White Paper reveals, for the first time, that DPCs have been successfully delivered to the livers of non-human primates, and moreover that they may also have use for applications outside the liver, one of the theorized attractions of DPCs based on their small size. Reading between the lines, however, it is also possible to identify some of the factors that have delayed clinical translation, and despite the progress and substantial investments by Roche, it remains an open question when the first DPC-based RNAi Therapeutic will enter clinical development.
Short circulation times were one of the deficiencies of 1st generation DPCs. In order to reach tissues besides the liver, it is critical to achieve circulation times that are long enough so that the drug gets a chance to find and accumulate in its target tissues. Although DPCs on paper seemed to incorporate the features necessary for achieving such long circulation times, it came somewhat as a surprise when a DPC imaging paper last year showed DPC circulation times to be quite poor (Mudd et al., 2010). Although the particles were still able to accumulate in the liver, the data also raised questions whether the causes of the unexpected pharmacokinetics could have other consequences besides impacting biodistribution, for example in terms of safety.
It turns out that the short circulation times were the result of the premature exposure of the chemical groups that were supposed to shield the membranolytic functionalities of the DPCs outside their target cells. This would also explain why there seem to have been toxicity issues not just due to the poor biodegradability of the polymers, but also because such premature exposure renders DPCs as troublesome as many of the positively charged first-generation polymer approaches.
The White Paper indicates that the instability (and biodegradability) issue has been remedied to some degree such that the longer-circulating DPCs now show first promise for delivery outside the liver. But DPCs may also be competitive for delivery to the liver considering the following performance in non-human primates (excerpt from the White Paper):
‘Latest generation DPCs are remarkably efficacious in rats and non-human primates with ED80 values of ~0.1 mg/kg siRNA after a single dose. Increasing the dose two-fold in non-human primates results in >99% knockdown with a duration of effect of nearly 7 weeks. This is a 10-fold increase in efficacy compared to first generation DPCs containing PBAVE polymer. Latest generation DPCs are also better tolerated and have therapeutic indices of >10 in non-human primates as calculated from ED80 and NOAEL values.’
A 99% knockdown with 0.2mg/kg for 7 weeks- I’m impressed! It will be important to publish these data so that it is possible to see which model system was used, whether the 99% knockdown was seen for pretty much the 7 weeks, what the tox/tolerability profile was, the route of administration, and finally an explanation why a simple 2-fold increase in dosage had such a dramatic effect on knockdown efficacy.
The White Paper is also a reminder that for RNAi delivery technologies to be viable, there needs to be efficient scale-up. Apparently, manufacturing was, and possibly still is, a major issue with DPCs. At least the initial formulations had to be purified so extensively such that the yield became unacceptable for clinical translation and commercialization. Besides general liposomal expertise, quality manufacturing, of course, is what has always differentiated RNAi delivery company Tekmira from its competition.
My sense is that DPCs still have the potential to become an important delivery alternative. However, it is also clear that the path of DPCs was a tough one and, in the absence of guidance from Arrowhead Research, I expect additional delays (2-3 years?) before we will see the first DPC-based RNAi Therapeutic candidate in the clinic. This view is possibly shared by Alnylam as $10M in upfront and an increase of about $10M in annual operating costs would have been a small price to pay for Alnylam if DPCs were as advanced as Alnylam’s current systemic delivery workhorse, Tekmira’s SNALPs.
Until then, Arrowhead Resesarch needs to hit the ground running on the business development front given the increase in expenses that come with the 40+ research team in Wisconsin. The $15M facility with Lincoln Park Capital at least provides Arrowhead with increased financial flexibility. Ironically, it is positive clinical data from the RNAi Therapeutics candidates that are based on Tekmira’s SNALPs, DPCs most direct competitor that would greatly aid in that goal by re-igniting interest in the RNAi Therapeutics platform.