By Doug Macron
Marina Biotech announced this week that it has enrolled the first patient in a phase I study of its familial adenomatous polyposis treatment CEQ508, marking the company's foray into the ranks of clinical-stage drug developers.
At the same time, the program represents Marina's first steps toward becoming a therapeutics marketer, a new but growing trend in the RNAi field as partnerships with bigger players become increasingly harder to secure.
CEQ508 is based on Cequent Pharmaceuticals' 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 inhibit the formation of the colorectal polyps that characterize FAP, and potentially slow the progression to malignancy of existing ones. Marina acquired the program when it bought Cequent last year (GSN 4/1/2010).
In the newly initiated study, an expected 12 patients will receive a single, daily dose of CEQ508 at one of four dose levels for 28 consecutive days. After this, additional patients will be enrolled to receive the highest safe dose, according to Marina.
The primary endpoint of the trial is safety and tolerability, but it will also evaluate changes in beta-catenin levels by comparing biopsies of small and large intestines taken before and after treatment.
Marina President and CEO Michael French said in a statement that the start of patient enrollment is “a first step in what we hope will be a rapid regulatory and clinical timeline to the commercialization of CEQ508.” Notably, the company expects to handle that commercialization itself, a move first disclosed about one year ago.
During a conference call last April, French said Marina could handle selling the drug in the US on its own using a small specialty sales force because CEQ508 had received an orphan drug designation from the US Food and Drug Administration, which provides a product with an expedited regulatory review, among other things. In addition, another treatment for FAP had been approved after a pivotal phase II study, fueling the company's confidence that FDA would approve CEQ508 quickly (GSN 4/8/2010). The other FAP drug, a COX-2 inhibitor, was later pulled from the market for safety reasons.
“With an expedited clinical and regulatory path, we believe that it might be possible to launch an RNAi-based therapeutic for FAP in the 2014 timeframe,” French said at the time.
In doing so, Marina stands to not only receive all of the financial gain from its drug, but also push its technology to the market — a key proof of concept, especially for a technology that has yet to be approved for use in man — without having to first woo a partner.
In general, bigger drug firms tend to avoid orphan designations because the markets for such products are too small, despite their expedited reviews and smaller development fees. FAP, for instance, is estimated to affect one in 8,000 individuals, according to the Stanford Cancer Center in California.
At the same time, big biopharmaceutical firms have recently taken a more cautious approach to RNAi. Perhaps the biggest illustration of this came late last year from Roche. In 2007 it was flying high with RNAi, paying Alnylam Pharmaceuticals $274 million to access its technology and shelling out $15 million to buy its German unit (GSN 7/12/2007). It spent $125 million to acquire Mirus Bio the following year (GSN 7/24/2008).
But last November, it announced it was cutting all of its internal RNAi programs (GSN 11/18/2010).
A Roche spokesperson told Gene Silencing News this week that the company is currently preparing to divest those assets, with the goal of completing a transaction by year end.
Just months later, as first reported by Gene Silencing News, Pfizer decided to shutter its oligonucleotide therapeutics unit, which handled the company's in-house nucleic acid drug-development efforts (GSN 2/3/2011).
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Even before these disclosures, it appeared that the partnering landscape for RNAi was becoming increasingly difficult to navigate, with a number of companies — including Calando Pharmaceuticals, Alnylam, and RXi Pharmaceuticals — missing partnership goals in recent years. Even Marina, which found an ally for its preclinical bladder cancer program in Switzerland's Debiopharm last month (GSN 2/3/2011), failed to meet its 2010 guidance of two industry partnerships.
As a result, Marina appears to have decided that what makes the most sense is moving ahead with CEQ508 rather than searching for a partner as Cequent had been planning to do before it was acquired.
And it's not alone in this regard. Alnylam recently unveiled its so-called Alnylam 5x15 plan under which it promises to have five programs in “advanced” clinical development by 2015 (GSN 1/6/2011). Notably, as part of the pipeline overhaul, the company has shifted its focus onto product candidates against "genetically defined target and disease … [with the] potential to have a major impact in a high unmet need population,” and which it expects to market on its own domestically.
Key programs under this initiative include Alnylam's transthyretin-mediated amyloidosis effort, which is already in phase I trials and is expected to yield a second-generation molecule ready for an investigational new drug application by the end of 2011; the preclinical hypercholesterolemia drug ALN-PCS, which is slated to enter the clinic this year; and a new candidate that inhibits hepcidin, a gene related to iron homeostasis, which is being developed as a treatment for refractory anemia.
Two other programs are to be unveiled later this year, Alnylam said.
Similar to FAP, Alnylam said that the diseases it will focus on under the 5x15 effort offer “clinically relevant endpoints for the filing of a new drug application with a focused patient database and possible accelerated paths for commercialization."
Alnylam's new initiative also follows a decision by Cubist Pharmaceuticals to pass on its license to the first-generation version of the RNAi shop's respiratory syncytial virus drug ALN-RSV01 in favor of a newer version called ALN-RSV02 (GSN 11/12/2009). Both Alnylam and Cubist recently decided to shelve that candidate altogether.
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