Silence Therapeutics First to Advance Systemic Cancer RNAi Therapeutics into Phase II

Among the first crop of systemic RNAi Therapeutics for cancer (see also CALAA01 by Arrowhead and ALN-VSP02 by Alnylam), Atu027 has become the first to officially enter phase II clinical development.  Following the completion of a bridging phase Ib study testing the safety of Atu027 in combination with chemotherapeutic gemcitabine for a treatment cycle of 28 days, Silence Therapeutics announced this week that safety and efficacy of the RNAi-chemo combo will now be more rigorously tested in an expanded phase II study for the treatment of pancreatic cancer.

The bridging study became necessary since in the initialphase I study, the safety of Atu027 was assessed in isolation only.   The press release by the company now suggests that the bridging study testing 0.253mg/kg of Atu027 along with 1000mg/m2 gemcitabine was uneventful since no expansion of cohorts was deemed necessary.  Such an expansion would have become necessary if a dose-limiting toxicity had been observed.   Accordingly, the results are in line with the phase I studies where a dose limiting toxicity was only observed at the 0.336mg/kg dose of this AtuRNAi-lipoplex formulation.

Given that Atu027 is not thought to have a strong effect in terms of directly killing cancer cells, but instead is expected to inhibit metastatic spread, the company believes that it will be clinically most useful in combination with an antineoplastic agent such as gemcitabine in pancreatic cancer.  The choice of pancreatic cancer was probably driven by the high unmet medical need in this indication and it is possible that additional combinations will be explored for a range of other cancers.  Such an expansion of the Atu027 franchise will have to be balanced by the advancement of other RNAi Therapeutic candidates with more straightforward mechanisms of actions to put the company on a more balanced financial footing.

* In addition to the systemically delivered Atu027, two other RNAi Therapeutics for cancer have entered phase II development.  These are the implanted RNAi trigger-eluting siG12D LODER from Silenseed, also for pancreatic cancer, and ex vivo ddRNAi-GMCSF gene therapy combo bi-shRNAfurin by Gradalis for a variety of cancers.