Cequent Pharmaceuticals to Enter Clinic with First Oral RNAi Therapeutics

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.

RNAi Therapeutics Universe Expanding and Gaining Visibility

Today, I will pause and take stock of what I think have been remarkable months for the public understanding of RNAi Therapeutics.

Indeed, the climate for RNAi Therapeutics has never been better. Only recently, a number of external factors have come together that should significantly support the progress of developing the basic science of RNAi into a whole new drug class. Following the award of the Nobel Prize for the discovery of RNAi late last year, the political willingness to support RNAi has begun to extend beyond the NIH to initiatives like the one announced last month by the Governor of Massachusetts to provide $1 billion support over the next 10 years for innovative life sciences, particularly therapeutic RNAi.

These developments have consequently reached a stage where the leading political/financial journal The Economist is featuring SMALL RNAs on this week’s title page of the print issue, under the heading of “Biology’s Big Bang- Unravelling the secrets of RNA” (http://www.economist.com/printedition/). All this excitement comes at a time when the pace of Investigational New Drug applications for RNAi Therapeutics has reached one IND filed every month such that eight announced RNAi Therapeutic clinical development programs are now underway in the US and Europe. And there is every sign that this pace will pick up before it slows down.

Appropriately, the second half of this year has the potential to mark another milestone in the validation of RNAi as a human therapeutic. The leading RNAi company Alnylam intends to announce by the end of this month the detailed clinical plan for a phase II experimental infection study of ALN-RSV01, an siRNA for the treatment of RSV infection in infants, the elderly and other immune-compromised adults. In this study, volunteers are inoculated nasally with attenuated RSV and the effect of siRNA on various parameters of infection is measured, most importantly viral titers.

According to the company, the study will involve 90 volunteers in a randomised, double-blind, placebo-controlled trial. If results are as hoped, this trial therefore has the potential to show for the first time statistically significant antiviral, that is therapeutic activity of an RNAi agent in man. This would represent another major de-risking event which should not only benefit Alny’s corporate objectives, but the field as a whole.

Note: Last week Alnylam (ALNY) gained almost 10% to $16.89, possibly in anticipation of these potentially value-creating events. This comes after Alnylam lost 1/3 of its value from its all-time high of $24.46, partly pressured by short sale tactics following the issuance of new shares. It should be noted that little more than 11% is held non-institutionally and if the above events should attract new major investors, prices could easily be propelled higher. Notably, last Friday saw a number a large blocks changing hands on more than twice the average daily volume, sending the stock higher by 6.43% in one day.