By Doug Macron
Although one of its inflammatory bowel disease targets has already garnered the attention of a big pharma, Cequent Pharmaceuticals expects its IBD program will advance into the clinic first with an RNAi molecule against a proprietary target, a company official told RNAi News this week.
Meanwhile, the company remains on track with its more advanced familial adenomatous polyposis drug, CEQ508, and plans to file within the next two weeks an investigational new drug application to begin testing it in humans, according to Cequent President and CEO Peter Parker.
In 2007, as part of an investment deal with the Novartis Option Fund, Cequent gave Novartis an option to acquire its lead IBD candidate (see RNAi News, 7/21/2007). The first point at which Novartis could exercise that option — the selection of a lead target — occurred this summer, although the drugs giant has yet to do so.
The backing of such a big player in the pharmaceutical space, especially one that has already made significant investments in therapeutic RNAi (see RNAi News, 7/23/2009), would be a shot in the arm to any drug-development program. But Parker said that he expects Cequent's in-house IBD efforts to yield a clinical candidate before the work with Novartis, in part because of how focused his company is on the program.
"We think one of our internal candidates would move into the clinic first, just because we're in control of exactly what we have to do," he said. Additionally, the Novartis target, which remains undisclosed, is an unconventional one, according to Parker, making the road to actually formalizing a partnership a little rocky.
In contrast, the IBD targets being explored internally at Cequent are "so well-known that we think we'd have an easier time having people understand [them] … in terms of partnering," Parker explained, adding that the company is intent on forging multiple alliances within the IBD area.
Parker said that the possible targets for Cequent's first in-house IBD program include macrophage targets such tumor necrosis factor-alpha, interleukin-18, and IL-23p19; and epithelial cell targets including IL-7, IL-13Ra1, chemokine (C-C motif) ligand 2, and CCL11.
They are "very different ideas, targeting macrophages or [targeting] epithelial cells," he said. "We're just trying to figure out where we should place our bet. We're re-running some of our animal studies to see which area for us — macrophage targeting or epithelial cell targeting — is more robust."
The company expects to make a decision by the end of the year, he noted.
FAP Program Nears the Clinic
While Cequent's IBD program has more money-making potential given the size of the market, the company's work in familial adenomatous polyposis — largely a proof-of-concept effort for its oral transkingdom RNAi technology, which involves using attenuated Escherichia coli to transcribe therapeutic shRNAs — is poised to move into human trials sooner.
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FAP is an inherited, colorectal cancer syndrome characterized by the growth of colorectal polyps. Though the polyps are initially benign, they become malignant in nearly all cases in the absence of colectomy, according to the company. But by targeting beta-catenin, Cequent hopes that CEQ508, formerly known as CEQ501, will prevent new polyp formation and possibly slow the progression to malignancy of existing ones.
Earlier this year, when the company released primate data showing that it could safely knock down beta-catenin in target tissues of non-human primates using an orally delivered tkRNAi drug, Johannes Fruehauf, Cequent’s vice president of research, said that a phase I trial in FAP was on track to begin before the end of 2009 (see RNAi News, 2/12/2009).
And while this timeline continues to remain a possibility, this week Parker was a little more cautious, stating that although Cequent will be on time with an IND filing, the actual initiation of a phase I study would ultimately depend on the US Food and Drug Administration.
Once an IND is filed, "the agency is completely in control," he said. "It's all up to them."
The proposed design of the phase I study, which will take place at the Fred Hutchinson Cancer Research Center in Seattle, has changed little since Fruehauf made his projection, with the primary difference being the addition of more patients to the study.
The 28-day study is designed to enroll 12 FAP patients, who will be divided into four dosing groups. The first patient in the lowest-dose cohort will be treated for one week, after which two others will begin treatment.
If no adverse events are observed among the patients at the lower dose level, a patient will be treated at the next highest level, and so on until all 12 patients have been dosed. According to Parker, Cequent has now decided to also enroll another six patients at the highest tolerated dosing level, bringing the total number of people in that group to nine.
As typical in a phase I study, the primary endpoint of the CEQ508 trial is safety and tolerability. However, knockdown of mucosal beta-catenin levels will also be evaluated through intestinal biopsies taken from the study participants, giving Cequent an idea of the drug's potential efficacy.
HPV, Metabolic Disease
Though Cequent is mostly focused on its FAP and IBD programs, the company is also exploring the potential of its tkRNAi approach in other indications, including human papillomavirus. And although the company has "selected a sequence … [and] done all the in vitro work, [we] have not worked on [the program] since the summer," Parker said.
For HPV, "you would want to deliver [an RNAi payload] in Lactobacillus or Lactococcus," bacteria highly present in the female genitourinary tract, where E. coli is not present, he said. "We'd have to do a lot of strain development to actually get that ready for delivery in animals … [and it would take] a year to develop that technology to [the point] we're at with, say, the IBD program. We're doing work on it, but not nearly the effort we're putting into IBD."
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At the same time, the company has a "fledgling" effort in metabolic disease, Parker said. "If you can get to targets in the GI tract, [as Cequent has done with its FAP and IBD work], in theory you could look at some of the targets involved in synthesis of cholesterol," for example.
But preferring to "not divert our own equity dollars away from IBD at the moment," Cequent has only done "a little lab work" with metabolic disease, "trying to figure out the right targets, and so forth," he noted.
In the near term, the company would only likely ramp up efforts in this area with the help of a larger partner, he added.