Cequent Pharmaceuticals is somewhat of an oddity in the RNAi Therapeutics space. Neither does it use synthetic RNAi triggers, nor does it fit properly into the DNA-directed RNAi paradigm. Instead, it is based on the so called trans-kingdom RNAi (tkRNAi) technology where genetically engineered bacteria are utilized to both generate and deliver the RNAi trigger, particularly to areas where commensal bacteria occur naturally. This includes the epithelia of the gastrointestinal tract, skin, and urogenital areas. This differentiation then allowed it to become the first RNAi Therapeutics company to test an orally administered RNAi Therapeutic in the clinic. The candidate drug, CEQ508, aims to prevent the formation and malignant progression of polyps in Familial Adenomatous Polyposis (FAP).
FAP is a rare ('orphan') inherited disease in which mutation of the tumor suppressor APC gene initiates events that cause the growth of countless polyps that ultimately progress to become malignant by the age of 40-50. CEQ508 contains an shRNA that is targeted against beta-catenin which is the major mediator of APC-regulated signaling, and the knockdown of which should therefore delay polyp proliferation and development of malignancies. In the trial, 18 adult FAP patients will be given capsules containing lyophilized tkRNAi bacteria daily for 28 days. Of course, safety is the primary objective of this phase I trial, but beta-catenin levels will also be measured as an early biomarker for drug efficacy. A cute video from Cequent's website explains the technological approach of this trial much better than I could ever do here:
Let me say a few general words about tkRNAi. When I saw the seminal paper initially, years before my direct interactions with the company (disclosure: I have been consulting for the company), I was somewhat skeptical of the approach. One of the reasons was that bacteria are very complex systems compared to other RNAi delivery systems, which means that there should be an increased likelihood for causing off-target phenotypes. The other concern was that maximal knockdown levels in vitro appeared to be less than typically achieved with siRNAs and shRNAs. Since then, however, I have learned a little bit more about tkRNAi convinced myself that it indeed does knock down genes, and that at this stage a carefully chosen target could allow for clinical success at ~50-60% knockdown levels as observed in the CEQ508 non-human primate studies. As to the off-target effects, the tkRNAi products have been shown to be well tolerated in a number of animal models. In addition, I learned that Cequent was not the first to harness bacteria as therapeutic agents for the transfer of genetic material so that additional safety and mechanistic information is available already.
Because of the awesome powers of bacterial genetics I would expect that the speed and creativity with which specificity (e.g. engineering of targeting ligands; reduction of key components responsible for off-targeting; increase of the ratio of shRNA to bacterial RNA and DNA following release into cytoplasm etc) and potency (e.g. shRNA designs; co-expression of factors affecting shRNA maturation etc) can be increased should be quite considerable. On the other hand, with the recent fund raising, it will be the immediate focus of the company to conduct the phase I trial where it will gain first clinical experience with the system in the gastrointestinal tract, lessons from which should also be also applicable towards follow-up gastrointestinal applications such as the inflammatory bowel disease program it co-develops with Novartis.