By Doug Macron
Marina Biotech this week announced that it will shortly begin enrolling the second cohort of patients in an ongoing phase Ib/IIa trial of its RNAi-based familial adenomatous polyposis treatment CEQ508.
"Three patients completed cohort 1 of the study last year," Alan Dunton, Marina's consulting chief medical officer, said in a statement. "CEQ508 was well tolerated by patients with FAP and ... the principal investigator, co-investigator, and myself unanimously agreed that the study should proceed” to a three-patient second cohort.
Meantime, Marina is continuing to work on securing a big pharma partnership, which the company expects it could achieve by the end of this year, possibly earlier, according to President and CEO Michael French.
“There is a higher bar today than it was five years ago in terms of what pharma is looking for in terms of a nucleic acid-based approach,” he said. Nonetheless, “pharma is interested.”
CEQ508 is based on Marina's so-called transkingdom RNAi technology, which uses orally delivered attenuated Escherichia coli to transcribe therapeutic shRNAs. The drug is designed to inhibit the oncogene beta-catenin as a way to prevent the formation of the colorectal polyps that characterize the disease, and potentially slow the progression of existing ones to malignancy.
Marina acquired the program when it bought Cequent Pharmaceuticals in early 2010 (GSN 4/1/2010).
The phase Ib part of the trial is designed to evaluate escalating dosing of CEQ508 in 12 FAP patients, divided into four dose cohorts of three patients each. The phase IIa arm of the study will test a stable dose of the drug in six patients, who can either be newly enrolled or have participated in the Ib portion.
Previously, Marina had said that the escalating-dose part of the study would wrap up by the second quarter of this year. However, French said that certain issues related to the GMP stability testing of the agent prompted the company to outsource this work to a contract research organization.
“We spent [nearly] the last two quarters transferring all those assays [to the CRO, which] put a little delay in our plans,” French told Gene Silencing News. Now Marina anticipates completing the phase Ib arm around the end of this year, with the stable-dose portion wrapping up in the first quarter of 2013.
Despite the delay, Marina is expecting CEQ508 to hit the market within four years, in part because the company is taking a path to commercialization already blazed by Pfizer with its COX2 inhibitor Celebrex.
Celebrex was originally developed as a treatment for arthritis-associated pain, but also received US Food and Drug Administration approval as an FAP therapy based on the results of a pivotal phase II trial since the disease is considered an orphan indication.
CEQ508 received orphan drug status from the FDA in late 2010.
Pfizer eventually pulled Celebrex off the market for FAP because the dose indicated was “outside the cardiac safe zone,” French explained. Since Celebrex's initial approval, high doses of the drug have been associated with increased risk of heart attacks and stroke.
Nevertheless, Pfizer's success securing approval for the drug for FAP has provided Marina a “development timeline and path, as we're trying to simulate it,” he said.
“We've looked at that development process and regulatory approval … [and] we think we're on that trajectory,” French added. “We think we can complete the pivotal phase II sometime in early 2015 … allowing us to launch at the end of 2015,” assuming there are no unforeseen setbacks.
Marina anticipates a pivotal phase II study to enroll somewhere between 80 to 120 patients.
As previously disclosed, Marina also expects it could handle the drug's full development on its own, noting that the cost of goods for a product such as CEQ508 are “minimal” and that bringing the drug through the regulatory approval process will run “somewhere around $10 million, which is very manageable for us,” French said.
As it works to advance CEQ508, Marina is also on the hunt for a big pharma partnership — a longstanding goal for the firm, which is banking on the breadth of its technology offerings to help woo potential collaborators.
“If pharma comes to us with a target, we have an arsenal of nucleic acid therapeutic approaches to go after that target,” French said. Among these are the transkingdom RNAi technology; and Marina's Smarticle lipid delivery technology, which was recently licensed to Mirna Therapeutics for use with its microRNA mimics (GSN 1/5/2012) and is already in the clinic with ProNai Therapeutics' phase I single-stranded DNA decoy-based cancer drug PNT2258.
When partnered with Marina, “you don't have to be committed to double-stranded RNA in liposomal formulations,” he said. “We can construct everything from double-stranded to single-stranded nucleic acid sequences to microRNA mimics and antagonists because we have both the chemistry and delivery to do all that.”
As for its own pipeline, Marina is taking things slow, French said, noting that the financial landscape for small biotechs is particularly challenging.
He said Marina is exploring miRNA antagonists in-house and is working with an undisclosed academic partner on a single-stranded nucleic acid drug, modified with the company's conformationally restricted nucleotide technology, for myotonic dystrophy.
However, he declined to provide a timeline on when a new drug-development program would be unveiled.
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