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Dicerna Shows Interest in Rare Diseases, Highlights Lack of Exclusivity with Core Tech

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In breaking out its pipeline in detail for the first time as it looks to go public, Dicerna Pharmaceuticals revealed that it is following along with others in the RNAi therapeutics field, namely Alnylam Pharmaceuticals, by expanding its focus to include rare, genetically defined diseases rather than indications currently addressed by other therapeutic modalities.

Meanwhile, in a filing with the US Securities and Exchange Commission submitted at the end of 2013, Dicerna also warned about its lack of exclusivity for its core RNAi technology, potentially limiting the interest of would-be investors and partners alike.

Dicerna was founded in 2007 to make drugs out of novel RNAi molecules, called Dicer-substrates, created at City of Hope. The oligos are asymmetric, with 27-mer guide strands and 25-mer passenger strands, and are cleaved by Dicer into active siRNAs.

Under its original leadership, the company had set its sights on a handful of high-value diseases including hepatitis C, cancer, type II diabetes, and hyperlipidemia, but later narrowed its focus to oncology as it sought a big pharma partner.

In 2010, it found such an ally in Japan's Kyowa Hakko Kirin, which is working with Dicerna in oncology. That same year, Dicerna replaced its founding CEO with Oxford Bioscience Partners' Douglas Fambrough, who had spearheaded the venture capital firm's investments in both Dicerna and, before that, Sirna Therapeutics.

Dicerna and KHK recently expanded their arrangement to include a second drug candidate after reporting the achievement of in vivo activity with their first — and on its own Dicerna continues to expect its in-house Myc-targeting hepatocellular carcinoma treatment DCR-M1711 will reach human testing this year. But despite these advances in its cancer programs, by 2012 Dicerna had already identified a sea change underway in the RNAi drugs industry led by Alnylam.

As Fambrough noted to Gene Silencing News about a year ago, Alnylam's strategy of going after genetically defined conditions with unmet need represents "a great way to build a company … that wants to bring a drug to market on [its] own."

And based on disclosures in its initial public offering filing with the SEC, Dicerna is employing this approach itself.

DCR-M1711 remains the company's flagship candidate, with a phase I trial planned for the first half of the year to determine its maximum tolerated dose in healthy volunteers when administered in a cycle of three weekly infusions followed by a no-treatment week. A second phase I is planned for the second half of 2014 in order to confirm the drug's safety and tolerability in late-stage liver cancer patients. The drug is delivered using Dicerna's proprietary EnCore lipid nanoparticle technology.

Following close behind is DCR-PH1 for primary hyperoxaluria 1, a rare, inherited autosomal-recessive condition characterized by the liver's inability to metabolize a precursor of oxalate. As a result, calcium oxalate builds up in renal tubules causing kidney stones and fibrosis. The only treatment available is dual transplants of the liver and kidney.

To Dicerna, the condition is ideal for RNAi intervention given that the primary enzyme disrupted in PH1 — alanine-glyoxylate aminotransferase 1 (AGT1) — is mutated in patients. "Under normal circumstances, AGT1 metabolizes oxalate precursors into the harmless amino acid glycine, which is then used by the body or excreted," it said in the SEC filing. "But when AGT1 is mutated, oxalate begins to build up, resulting in progressive loss of kidney function and, ultimately, kidney failure." In mouse studies, silencing the gene responsible for glycolate oxidase, the enzyme upstream of AGT1, prevents the formation of the oxalate precursor and stops oxalate accumulation in urine.

Dicerna expects DCR-PH1, which also employs the EnCore system, to enter the clinic in 2015.

At the same time, the firm is exploring a variety of other rare diseases of the liver including maple syrup urine disease; familial amyloid polyneuropathy/cardiomyopathy; alpha-1 anti-trypsin hepatocyte inclusions; paroxysmal nocturnal hemoglobinuria; and severe hemophilia A and B.

"In each case, we are seeking to target a clear unmet medical need, a readily-identified patient population, favorable market dynamics, potential orphan drug designation, and the possibility to use RNAi-based therapeutics to achieve an optimal combination of high efficacy and low toxicity," the company said in its regulatory filing. Notably, all of these indications except for maple syrup urine disease are already in the pipeline of Alnylam.

Dicerna said that it expects to soon select one of these early-stage programs for formal development, with clinical testing kicking off in 2015.

Despite the work Dicerna has conducted thus far to develop its Dicer-substrate drugs, there remains the potential for direct competition by another RNAi player: Arrowhead Research.

In November 2006, City of Hope had already licensed its Dicer-substrate intellectual property to now-defunct Nastech Pharmaceuticals for use exclusively against five undisclosed targets and non-exclusively against all mammalian targets in all indications except infectious disease. Shortly thereafter, Dicerna acquired exclusive rights to the IP — except as they relate to Nastech.

Nastech eventually structured itself into a pure-play RNAi drug developer called MDRNA (and later became Marina Biotech), which in 2009 sublicensed its non-exclusive Dicer-substrate rights to Roche. As part of its decision to end its internal RNAi drug development efforts, Roche sold off its RNA therapeutics assets, including the Dicer-substrate license, to Arrowhead in late 2011.

In its SEC filing, Dicerna noted that it "cannot rely on [its] patent rights to prevent Arrowhead or third parties working with Arrowhead from developing, marketing, and selling products that compete directly with our product candidates."

Additionally, Arrowhead has "substantially similar access to the same patent rights related to DsiRNA granted to us under our license" from City of Hope, Dicerna stated. "If Arrowhead or another party develops, manufactures, markets, and sells any product covered by the same patent rights and technologies that compete with ours, it could significantly undercut the value of any of our product candidates, which would materially adversely affect our revenue, financial condition and results of operations."

Dicerna officials were unavailable to discuss on the patent situation as the company remains under an SEC-mandated quiet period pending its IPO.

Arrowhead CEO Chistopher Anzalone confirmed in an email to Gene Silencing News that his company maintains its rights to the Dicer-substrate IP, and noted that City of Hope has expressed its willingness to expand that license to include infectious diseases.

He also stated that there have been no discussions between Arrowhead and Dicerna about the situation, and that Arrowhead would not consider giving up its access to the Dicer-substrate technology. He added that Arrowhead is also free to sublicense its rights to other companies if it chooses.

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