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Cequent Hits Milestone in IBD Program; FAP Effort on Track While HPV Drug a Question

Cequent Pharmaceuticals this week announced that it had received an undisclosed milestone payment from the Novartis Option Fund, which holds an option to the first drug candidate to come out of the RNAi drug shop’s preclinical inflammatory bowel disease drug program.
“When we started the Novartis program, we were evaluating eight targets simultaneously as potential therapeutics for inflammatory bowel disease,” Cequent President and CEO Peter Parker said in a statement. “Our milestone goal, which we accomplished, was to winnow the targets down to three that we will further validate in in vivo animal trials before Cequent selects the single target to be the subject of the option agreement.”
Parker told RNAi News this week that Cequent expects to select that target and present to the Novartis Option Fund relevant mouse model data in about six months, at which point the venture capital group could choose to exercise its option to acquire the orally delivered IBD drug candidate (see RNAi News, 6/21/2007).
Should the option fund decide not to exercise its option then, it still has two other points when it could acquire the compound: after optimization of the drug candidate but prior to IND-enabling studies, or when Cequent receives clearance from the US Food and Drug Administration to begin testing the drug in phase I trials.
While Parker noted that the arrangement with the Novartis Option Fund has been a “great thing” for Cequent, providing it with access to expertise from Novartis’ gastrointestinal group in the UK and the Novartis Institutes for Biomedical Research in Cambridge, Mass., the company isn’t putting all of its eggs in one basket.
Although the Novartis Option Fund could take the exclusive rights to Cequent’s initial IBD candidate, Parker noted that the company knows of about 20 promising targets for the disease and is seriously evaluating about 10 of them for use in other potential programs addressing the disease that could be conducted in collaboration with other partners.
“When we get incoming inquiries … from pharma, most of them are about IBD,” he said, adding that these talks are still preliminary. “Obviously, we’re going to show a number of companies the next target.”
While Novartis will likely be near the top of that list, Parker said that he can’t make assumptions about the biopharmaceutical giant’s interest in RNAi for IBD, “so I’d have to be very interested in working with whoever [is] a good partner” for future targets.
FAP Happy
While Cequent’s IBD program has been its first to grab the attention of big pharma, the company’s most advanced effort is an oral treatment for familial adenomatous polyposis, an inherited colorectal cancer syndrome characterized by the growth of polyps on the colon, which the company initiated to showcase its core transkingdom RNAi technology.

“When we get incoming inquiries … from pharma, most of them are about IBD. Obviously, we’re going to show a number of companies the next target.”

The tkRNAi technology involves using attenuated Escherichia coli to transcribe therapeutic shRNAs. According to Cequent, the bacteria express the protein invasion on their surface, which allows them to enter a host cell. They also express listeriolysin, which permits the shRNA payload to escape after bacterial entry.
In 2006, Cequent co-founder and Beth Israel Deaconess Medical Center researcher Johannes Fruehauf and colleagues published data showing that oral administration of E. coli expressing shRNAs against the oncogene beta-catenin resulted in decreased catenin expression in the intestinal epithelium of a mouse model. Intravenous administration of the transkingdom RNAi drug to mice carrying colon cancer xenograft tumors, meanwhile, resulted in a significant drop in beta-catenin expression and reduced cell proliferation.
As reported by RNAi News earlier this year, Fruehauf, speaking at the RNAi World Congress in Boston, disclosed that the FAP program had hit a roadblock and that Cequent wouldn’t file an IND for its drug, which targets beta-catenin, until 2009 (see RNAi News, 5/8/2008). Previously, the company had been expecting to file the IND this year.
Parker confirmed this week that the company remains on track to submit the IND to US regulations next year, likely by July.
Having completed toxicology work in monkeys, “we’re in pretty good shape,” he said. In response to the FDA’s request for additional mouse studies evaluating drug dosing, which delayed the FAP program, Parker said that the company is “going to do another rodent study just to pin down how much efficacy we’re seeing. But overall, it looks pretty good for next year.”
At the same time, Cequent continues to advance its earlier-stage, locally delivered human papillomavirus treatment, but whether this program will continue apace depends on the company’s success with IBD.
Parker said that while Cequent has identified sequences for its HPV targets, it still needs to modify the tkRNAi technology to make it more in tune with the biology of the target tissue, namely the vagina and the surface of the female genital tract.
“We really want to convert over to Lactobacillus [from E. coli] because [it is primarily] the resident flora in the vagina,” he explained. “That’s not simple [to do, but] we’ve talked with a couple of companies that have [Lactobacillus] IP [and we’d] just license their bacteria and put our plasmid in it.”
From a business perspective, however, the market for IBD is significantly bigger than the one for HPV, Parker noted. And while developing the HPV drug would help Cequent demonstrate that tkRNAi is “really a platform, that we can move outside the gut and … [trigger a therapeutic RNAi effect] with other bacteria, and so forth … I’d much rather have two or three more IBD targets ready to partner next year,” he said.

“If that meant taking some resources from HPV, we would,” he added.

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