Cequent Pharmaceuticals will not meet its previously announced goal of filing an investigational new drug application this year for its lead RNAi drug candidate, a treatment for familial adenomatous polyposis, a company official disclosed at last week’s RNAi World Congress in Boston.
The IND now is expected to be filed sometime in 2009, Johannes Fruehauf, Cequent’s vice president of research, said at the meeting.
He also unveiled two recent additions to the company’s pipeline — a treatment for human papillomavirus and a modified version of its core delivery technology that is expected to open the door to systemic administration — and gave an update on its inflammatory bowel disease program, to which Novartis holds an option.
The delay in the FAP program is primarily the result of a request by the US Food and Drug Administration for additional mouse studies evaluating drug dosing, which is something “that we didn’t have in our plans,” Fruehauf told RNAi News this week. “We wanted to have this IND filed in 2008, and now we’re not going to make it.”
Once these studies are completed, however, Cequent expects development of the candidate, called CEQ501, to proceed apace, and Fruehauf provided meeting attendees with an overview of the company’s planned phase I trial for the drug.
Cequent was founded in 2006 to develop a novel bacterial-based delivery technology created by Fruehauf and colleagues at Beth Israel Deaconess Medical Center. Called transkingdom RNAi, the approach involves using attenuated Escherichia coli to transcribe therapeutic shRNAs.
According to the company, 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, 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.
Heartened by these data, the company began developing an oral, RNAi-based treatment for FAP, an inherited colorectal cancer syndrome characterized by the growth of polyps on the colon. Though the polyps are initially benign, they become malignant in nearly all cases in the absence of colectomy, according to the company.
Cequent expects that treatment with CEQ501, which targets beta-catenin, will prevent polyp formation and the progression to malignancy of existing ones.
In its planned phase I trial, Cequent will evaluate daily oral administration of CEQ501 at five dosing levels in 30 FAP patients. In order to avoid any potential adverse events, the first patient will be given the lowest dose for two weeks before up to five more patients in this cohort receive treatment.
“Only if this patient tolerates the drug well [would] other patients at the same dosing level” receive the drug, Fruehauf explained. Once the additional patients in the lowest-dose group have been treated for a week without any side effects, then another single patient will receive two weeks of CEQ501 treatment at the next-highest dose.
Should that patient not have any negative reaction to the treatment, additional participants will begin receiving the drug at the next highest dose for one week, and so on through the rest of the dose levels. The size of the doses were not disclosed.
Cequent is also making strides with its IBD drug CEQ600, which Novartis is poised to acquire should preclinical results prove positive.
“The idea is that we can use the live bacteria … to make a … particle that still has the same properties as the entire bacterium but will not have any bacterial chromosome, so it cannot divide … and can never make an infection.”
Last year, Cequent closed a $9 million Series A round of financing, which included cash from a venture capital arm of Novartis (see RNAi News, 6/21/2007). The round was later increased to $13.5 million with additional investments by the company’s existing shareholders.
In conjunction with its investment, Novartis also acquired an option to CEQ600, which gives the biopharmaceutical giant three points at which it can license the drug: following the completion of in vivo mouse model testing, after the optimization of a lead candidate but before IND-enabling toxicology studies start, or when Cequent is cleared by US regulators to begin testing the drug in phase I trials.
Cequent CEO Peter Parker told RNAi News this week that the company is nearing completion of functional validation studies of the tkRNAi approach in cell-based assays, and would likely be in a position to provide Novartis with in vivo data from the mouse studies “in seven or eight months.”
Although Fruehauf indicated during his RNAi World Congress presentation that CEQ600 would be ready for an IND filing next year, Parker said that he doesn’t expect Cequent to “be in control of the fling date for anything in IBD” since Novartis is expected to exercise its option to the program.
HPV and Tweaking tkRNAi
At the RNAi World Congress, Fruehauf also offered a glimpse at two previously undisclosed programs under development at Cequent. The first is a locally administered treatment for HPV that could yield an IND filing as early as next year.
“HPV will be an attractive target for anyone who is doing RNAi, to be frank,” he told RNAi News. “The good thing about these targets … is that we don’t have them in our genome so there will be no worry about over-silencing them.”
But the targets are especially attractive for Cequent because “it’s another disease that is related with the epithelium of what we see as an external surface – the vagina and the surface of the female genital tract,” both of which are exposed to bacteria, including E. coli, in normal situations, he said.
The company’s HPV candidate, called CEQ400, targets two subtypes of HPV, HPV16 and HPV18, that Fruehauf said account for the majority of cervical cancer cases.
These subtypes “have the ability to express two oncoproteins, E6 and E7, [that are] translated off of a single transcript … [and] interfere with the function of certain tumor suppressor genes,” he explained. “When these are deregulated, cells can proliferate more quickly and develop more aggressive cancer phenotypes.”
With its tkRNAi technology, “we would be able to introduce bacteria of the same flora … that would express shRNA against these targets and work in the local epithelium to hopefully suppress the oncogenic transformation of these cells,” he added.
Currently, Cequent is collaborating with researchers from the University of Queensland in Australia, who Parker noted had worked closely with Merck on the development of its recently approved HPV vaccine Gardasil.
“We have a few in vivo experiments done, [but] we’re still working to get better in vivo proof that it is working,” Fruehauf said of the HPV program.
The second program involves tweaking the tkRNAi technology in hopes that it could be used systemically.
Although the technology uses highly attenuated bacteria that are not expected to pose safety issues since drugs incorporating the technology are directed to areas of the body where bacteria are already present in large numbers, it isn’t appropriate for systemic drug administration since the bacteria have the potential to replicate and cause infection.
“The idea is that we can use the live bacteria … to make a … particle that still has the same properties as the entire bacterium but will not have any bacterial chromosome, so it cannot divide … and can never make an infection,” Fruehauf explained.
“We call these bacterial therapeutic particles because [they] share the therapeutic properties of our bacteria — they have the ability to invade cells, they have the ability to rupture the endosome after uptake into the host cell, and they have the ability to deliver hairpin RNA,” he said. ”Presumably, they will be just as able to induce gene silencing as the total bacteria are … [and] we are on the way to prove this is the case” through in vitro experiments.
Cequent is also actively pursing partnerships with academic labs with expertise in animal models of disease, the RNAi and microRNA field, and with bacterial vector systems for therapeutic applications, Fruehauf said during his presentation.
“Being a limited company with 24 employees … we cannot research all the potential uses of tkRNA,” he told RNAi News this week. “If there is a lab that specializes in a disease where they believe that tkRNAi could be of use, we’d be happy to talk to them and maybe co-develop the tkRNAi for their particular indication.”
Cequent is also willing to provide free licenses to the tkRNAi technology to academic partners, he added.
Parker added that the company is on the lookout for additional industry partnerships, including ones in which the tkRNAi technology is used for research applications. The company is currently negotiating with two undisclosed big pharmas who want to use the technology to validate targets in the gastrointestinal tract, Fruehauf noted.
Yet Cequent doesn’t expect to rely on funding from industry alliances to make ends meet. Parker said that the company is planning to initiate a Series B financing round in the early part of next year.
He said that the company hopes to raise about $20 million in the round.