Most advanced siRNA therapy fails first Phase 3 test
OPKO Health has reported that bevasiranib, the most advanced siRNA in clinical trials, has failed its first (and probably only) Phase 3 test, as adjunctive therapy to Lucentis in the treatment of wet AMD, after an independent DMC recommended stopping the study due to futility.
Whether this failure marks a setback for siRNA therapies in general or is specific to this particular therapy remains to be seen, but there is no doubt that the trial will raise the level of debate. Various experts have questioned the specificity of first-generation intraocular siRNA therapy, providing experimental evidence that the effects seen in earlier clinical trials could be attributed to nonspecific antiangiogenesis via stimulation of TLR3 and TLR-7-mediated inflammatory responses.
Looking for some firsthand insight into the issues, I contacted someone with inside knowledge of bevasiranib development, who wishes to remain anononymous and who acknowledges not having seen the Phase 3 data:
It is hard to compete against Lucentis when treated per label … as one must do in a standard trial as it is the standard of care … that being said physicians are trying to go increasingly to treating as needed as assessed by OCT [Optical Coherence Tomography]– perhaps every four weeks is too often for many and every eight weeks is too long for some … what’s worse is that each patient may change during the course of a year. It seems to me that some additional form of therapy to assist patients and physicians keep ahead of wet AMD will eventually be found … if we can get the standard defined to stretch to some combination therapies to every three months that would be ideal—it’s just hard to get a trial (IRB/end-point/regulatory) that can get there. Can one have “fewer required injections” as an end-point? siRNA will eventually have a role to play. Perhaps it is via isoform specific inhibition or by combination therapy.
Clearly, this expert believes that trial design and related regulatory demands played a role in the outcome.
Maybe the treatment hurdle was just too high, or maybe the therapy was just too nonspecific. In either case, it seems that bevasiranib is not going to be the pioneering RNAi therapy many had hoped for. Bring on the second-generation siRNAs.
