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Dicerna Provides Pipeline Update, Weighs Potential of Delivery Tech for mRNA Drugs


Officials from newly public Dicerna Pharmaceuticals last week provided an update on the company's two pipeline programs, offering some details on the planned Phase I program for its lead cancer therapeutic, as well as timing on when a new drug candidate will be named.

Speaking during a conference call held to discuss the company's fourth quarter financial results — Dicerna's first since its $90 million initial public offering in January — the executives also touched on the possibility that a new delivery technology may be used with the soon-to-be-named compound and that the firm has been considering applications for its core lipid delivery nanoparticles outside of RNAi.

When it filed to go public, Dicerna disclosed that a significant portion of the offering's proceeds would be used to advance its pipeline of Dicer-substrate siRNAs (DsiRNAs), which has long included the Myc-targeting hepatocellular carcinoma (HCC) treatment DCR-M1711.

As previously disclosed, the company aims to begin human trials of the drug this year. However, Dicerna CSO Bob Brown noted during last week's conference call that the company has changed its plan for the Phase I program slightly.

While it had originally expected to begin with a study in healthy volunteers followed by a trial in HCC patients, Brown said that DCR-M1711's clinical development will now begin with a Phase I study in cancer patients with non-HCC tumors followed by a study in patients with advanced HCC.

The decision to begin the Phase I program in non-HCC cancer patients versus healthy volunteers, he noted, in part reflects the therapeutic potential of knocking down Myc in cancers outside of the liver.

"Myc is a gene that is highly associated with many … non-HCC tumors where there is an abundance of frequency of amplifications and other alterations like translocations," he said. "We'll initiate the study in all comers … because the drug has the potential in many patient populations."

Dicerna CEO Douglas Fambrough added during the call that Myc amplification status will not, however, be used as a criteria for patient enrollment.

"It's important to recognize that amplification of the Myc gene in the genome is one of several ways in which Myc can be upregulated," he said. "Other ways include stabilization of the Myc protein and stabilization of the Myc transcript."

As such, it is not clear that only patients with amplified Myc would respond to DCR-M1711, Fambrough said. "We may see Myc-sensitive tumors that don't have genomic amplification. At this stage, we will be assessing … the amplification, but not using it for enrollment. We'll see what kind of correlation comes out in the data."

Each of the Phase I trials will be run as two-part open-label studies, according to Brown. "The first part will be a standard dose escalation to determine the maximum tolerated dose in select patient populations. The second part will then consist of an expansion cohort treated at the maximum tolerated dose."

Brown said that the primary objectives of each of the Phase I studies will be to determine the safety and tolerability of DCR-M1711, with secondary endpoints centering around "various molecular marker assessments."

The first Phase I study in non-HCC patients will kick off in the first half of this year, he said, with data available in 2015.

Dicerna's second drug program, which reflects the company's publicly disclosed interest in rare diseases, focuses on 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.

The primary enzyme disrupted in PH1 — alanine-glyoxylate aminotransferase 1 (AGT1) — normally metabolizes oxalate precursors into the harmless amino acid glycine, which is then used by the body or excreted, according to Dicerna. When AGT1 is mutated, however, oxalate builds up in urine, resulting in progressive loss of kidney function and kidney failure.

Based on mouse studies showing that 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 has been developing a therapy called DCR-PH1.

Brown said that Dicer-substrates against the target gene have been generated and that they are currently being optimized. Thus far in preclinical testing, "we've observed up to 97 percent reduction in glycolate oxidase transcript levels in the liver after a single IV dose of DsiRNAs," he added.

"We intend to complete optimization of DCR-PH1 and nominate a clinical candidate this year," Brown said, with a Phase I trial beginning in 2015. Biomarker proof of concept data from this program is expected to be available before the end of that year.

As it pushed ahead with its two in-house programs — which are unrelated to cancer programs being run under a long-standing collaboration with Japan's Kyowa Hakko Kirin — Dicerna is also continuing to conduct discovery work in a number of other rare diseases including maple syrup urine disease; familial amyloid polyneuropathy/cardiomyopathy; alpha-1 anti-trypsin hepatocyte inclusions; paroxysmal nocturnal hemoglobinuria; and severe hemophilia A and B.

Notably, Fambrough indicated that the company's next program might not use the lipid nanoparticle technology, dubbed EnCore, that is the foundation for both DCR-M1711 and DCR-PH1.

EnCore nanoparticles are composed of lipid/Dicer-substrate cores surrounded by a variety of other lipids that mediate cellular accumulation, internalization, and release into the cytoplasm. But Dicerna is also working on what it calls direct targeted DsiRNAs, which involves the conjugation of delivery agents to the ends of the molecules. Once in the cytoplasm, the conjugated end of the DsiRNA is cleaved off so it does not interfere with the RNAi process.

In a filing with the US Securities and Exchange Commission, Dicerna noted that this delivery approach could enable subcutaneous delivery with "broad biodistribution, similar to monoclonal antibodies."

"There are quite a few targets we are working with internally, any one of which may make for a good program," Fambrough said. "It is conceivable that it could [use] either delivery technology depending on which one of these discovery programs we end up selecting."

Fambrough also noted during last week's call that Dicerna has been weighing the possibility that its EnCore technology may be effective with messenger RNA-based therapeutics, although this is something that would be pursued through collaborations or licensing deals.

Recently, the interest in mRNA therapeutics has been growing, as evidenced by the $240 million deal between Moderna Therapeutics and AstraZeneca last year. And companies with delivery technologies that could enable these kinds of drugs, including Tekmira Pharmaceuticals, have said they are interested in playing in the space.

Fambrough said that the mRNA drugs field is "really interesting," and that lipid nanoparticles appear to be a "particularly appropriate approach" for delivering them.

"It is something that we've had some conversations about … [and] it's something we think a lot about," he added, without providing additional comment.

Q4 swings to loss

For the three-month period ended Dec. 31, 2013, Dicerna's net loss was $6.7 million, compared with a net income of $1.5 million in the year-ago period.

Its research and development spending in the quarter climbed to $4.2 million from $3.3 million, while its general and administrative expenses rose to $2.2 million from $1.2 million.

The company generated no revenues in 2013.

At the end of 2013, Dicerna had cash and cash equivalents totaling $46.6 million, which includes the impact of $59.8 million raised in a Series C round in the third quarter but does not reflect the proceeds of its IPO.