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IRS Awards $7M to RNAi, microRNA Firms; Grants Shed Light on Company Pipelines


By Doug Macron

The US government has awarded a group of RNAi and microRNA drug firms more than $7 million in tax-free grants to support their therapeutic development efforts.

The money is being issued through the Qualifying Therapeutic Discovery Project program, which was created earlier this year through the Patient Protection and Affordable Care Act and being funded by the Internal Revenue Service.

And while specific details about the projects being funded by the grants were not provided, the awards do provide some insight into some of the companies' pipelines.


For instance, Tacere Therapeutics received $488,958 in two grants, the first of which supports development of a new treatment for hepatitis C.

The company is already developing an HCV drug called TT-033, which was licensed by Pfizer earlier this year (GSN 2/11/2010). It is an expressed RNAi-based molecule containing shRNAs against three different sites of the hepatitis C virus, and is encapsulated in an adeno-associated virus protein coat. However, the grant supports the development of a new HCV treatment called TT-034, suggesting that Tacere is working on a second-generation version of TT-033.

Since it was founded, Tacere has been tightlipped on any of its pipeline programs beyond TT-033. According to the IRS, however, the firm may have set its sights on eye diseases, as well, because the second grant it received is for an ocular agent called SMK-01/03.

Tacere officials were not available for comment.


Also pulling in grant funding under the Therapeutic Discovery Project program is Aparna Biosciences, which was launched by Intradigm founder and one-time CSO Martin Woodle.

The company has previously received funding from the National Institutes of Health to develop RNAi-based technologies to elucidate the function of cancer-related genes. According to the IRS, the firm has now been awarded $244,479 to advance a program developing siRNA nanoparticles for the treatment of non-small cell lung cancer.


Dicerna Pharmaceuticals also was awarded two grants, together worth a total of $488,958. One of the grants will support the company's continued development of its Dicer-substrate technology, which involves the use of 27-nucleotide-long RNA duplexes to trigger a therapeutic RNAi effect.

The other grant, however, is specifically for the development of a castration-resistant prostate cancer treatment targeting the androgen receptor, providing the first clues as to where the company is directing its oncology research.

Earlier this year, Dicerna CEO Doug Fambrough told Gene Silencing News that the company's lead drug-development program focused on an undisclosed oncology target that is initially druggable by existing treatments but mutates into an undruggable form as the cancer advances (GSN 5/13/2010). He declined to provide additional details at the time.


On the miRNA side, Mirina has been awarded $488,958 by the IRS to develop antagonists of the small, non-coding RNAs as treatments for cancer and fibrotic liver disease.

Mirina was founded to develop miRNA inhibitors using the so-called minor groove binder technology it licensed from Nanogen. MGBs are peptide antibiotics that non-covalently bind to the minor grooves of nucleic acid duplexes, and had originally been developed as cancer therapeutics, according to Nanogen.

Although they did not prove effective for this application, they were later shown to stabilize DNA duplexes and potentially boost the target selectivity and potency of miRNA antagonists.

Since then, however, the company has provided no details publicly as to what indications it plans to pursue.

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One of the more interesting IRS grants is one worth $244,479 awarded to Opko Health for the development of the siRNA-based wet age-related macular degeneration drug bevasiranib.

Bevasiranib has the distinction as being the first RNAi drug to enter phase III testing. However, in early 2009, Opko, which picked up the vascular endothelial growth factor-inhibiting molecule through its acquisition of Acuity Pharmaceuticals, said that the clinical program was being halted early after being deemed "unlikely" to meet its primary endpoint (GSN 3/12/2009).

Opko officials were not available for comment, but on the company's website it states that it is considering "alternate ways to develop bevasiranib … such as new dosing schedules, combining it with marketed products for AMD, and enhancing delivery with novel siRNA delivery vehicles."


RXi Pharmaceuticals also picked up four grants under the Therapeutic Discovery Project program worth a combined $977,917.

The first three are focused on developing the company's so-called self-delivering rxRNA molecules, which are designed to get into target tissues without the need for a delivery vehicle, for fibrotic diseases, age-related macular degeneration, and amyotrophic lateral sclerosis.

Both the fibrosis and AMD programs have been key areas of interest for RXi since its new president and CEO, Noah Beerman, took the company's reins about a year ago. This June, he formally unveiled RXi's therapeutic strategy, naming dermal and ocular disorders as two disease areas the firm will primarily focus on in the near term (GSN 6/17/2010).

The ocular disease initiatives center around wet and dry AMD, as well as diabetic macular edema and diabetic retinopathy, Beerman said at the time.

Fibrotic disorders fall under what the company has dubbed indications of "opportunistic" interest, which "represent attractive opportunities" but have to be de-emphasized until significant data is generated in the core areas of ocular and skin diseases, he noted. These include liver and pulmonary fibrosis.

ALS, meantime, had once been the centerpiece of the RNAi efforts of CytRx, which spun out RXi in 2007, but has fallen by the wayside to make room for nearer-term opportunities.

CytRx was pursuing ALS since 2003, but this effort began to wane as CytRx increasingly focused on small molecules. In 2007, the company spun out RXi to advance its RNAi assets, and ALS remained a key part of the company's pipeline through 2008 (GSN 10/23/2008).

By early 2009, however, the ALS effort had apparently been put on the back burner (GSN 3/26/2009).

When detailing RXi's drug-development strategy this summer, Beerman did not quite resurrect the ALS program, but he did say that the company is maintaining a "strategic interest" in spinal cord injury, which is a project it could carry through preclinical testing on its own and has "the potential for an early proof of concept [with] well-established targets for a number of [other] diseases," namely ALS.

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RXi's fourth grant will provide an infusion of funding for an oral-delivery technology the company had once been pinning its hopes on but has recently been leapfrogged by the sd-rxRNA approach.

That project aims to develop RXi's orally delivered glucan-encapsulated siRNA particles, or GERPs, for rheumatoid arthritis.

In 2009, RXi had gone so far as to name an undisclosed program in inflammatory disease, using the GERP technology, as its lead therapeutic effort. And in April that year, collaborators from the University of Massachusetts Medical School published data showing the GERPs could suppress inflammation-associated gene expression in mouse macrophages in vitro and in vivo (GSN 4/30/2010).

Under its new leadership, however, the company stepped away from this guidance, and inflammatory disease was not even mentioned by Beerman when he broke out the firm's therapeutic strategy.

Other Grants

A number of other RNAi/miRNA companies received funding under the IRS' program, although these grants will support projects the firms have already publicly disclosed.

Marina Biotech was awarded $733,000 to help fund two of the drug programs the company picked up when it acquired Cequent Pharmaceuticals earlier this year, as well as the company's lead bladder cancer program.

The first centers around CEQ508, which is designed to treat familial adenomatous polyposis, an inherited, colorectal cancer syndrome characterized by the growth of colorectal polyps, and is poised to move into phase I testing shortly.

The drug uses Cequent's oral transkingdom RNAi technology, which uses attenuated Escherichia coli to transcribe therapeutic shRNAs. Marina said this year that it is weighing the possibility of marketing the drug itself (GSN 4/8/2010).

Marina's second grant will support the development of CEQ626, which also uses the transkingdom RNAi approach, for inflammatory bowel disease.

Cequent has been working on this indication for some time, and in 2007 the company inked a deal giving Novartis an option, which has yet to be exercised, to acquire an IBD drug candidate against an undisclosed target.

But Cequent has also been developing drugs against proprietary IBD targets not covered by the Novartis option, including CEQ626. In April, Cequent's former President and CEO Peter Parker said that the company was in a position to advance one of these in-house IBD candidates even before the optioned one, and that it could still develop one or more of them even if Novartis acquired the candidate.

Marina's final grant will provide funding for the company to further develop a drug candidate for non-muscle-invasive bladder cancer, which is the firm's lead program and expected to yield an investigational new drug application before the end of the year (GSN 3/25/2010).

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Gradalis secured a grant worth $244,479 to develop a cancer therapy based on its novel bi-functional technology, which involves an shRNA capable of triggering both cleavage-dependent and cleavage-independent RISC-mediated inhibition of target mRNA.

Earlier this year, Gradalis co-founder John Nemunaitis told Gene Silencing News that although it had planned to begin human trials of a drug that combines a bi-functional shRNA against stathmin-1, a protein linked to abnormal cell proliferation when mutated that is over-expressed in about 65 percent of all cancers, it moved an agent against a different target into phase I testing in order to further validate the approach (GSN 3/11/2010).

The IRS grant, however, will fund the stathmin-1-targeting molecule.

TransDerm also received a single $244,479 grant under the program, which will support its work developing siRNA therapeutics for skin disorders, although the nature of the disorders was not specified.

The company has been primarily focused on developing a treatment for the rare skin condition pachyonychia congenital, and even moved a therapy into a one-patient phase I study (GSN 4/23/2010).

A TransDerm official previously stated, however, that the firm is also interested in pursuing other skin indications down the road.

Quark Pharmaceuticals received three grants totaling $733,437, the first two of which will fund the continued development of QPI-1002, an siRNA-based p53 inhibitor in phase II testing as preventative of acute kidney injury in patients undergoing cardiovascular surgery and as a preventative of delayed graft function after deceased donor kidney transplantation.

The third grant is supporting the development of QPI-1007, an ocular neuroprotectant that recently entered phase I testing in patients with non-arteritic anterior ischemic optic neuropathy.

Traversa Therapeutics won two grants worth a combined $488,958, the first of which will fund the continued development of its proprietary siRNA delivery technology, called PTD-DRBD.

The approach involves protein transduction domains linked with a double-stranded RNA-binding domain. An siRNA coated with PTD-DRBD molecules binds to cell-surface proteoglycans, which stimulates macropinocytosis. The drug then enters the cell inside a macropinosome, at which point the pH inside the vesicle drops and the siRNA is released from the PTD-DRBD molecules into the cytoplasm.

The second grant will fund the development of RNAi treatments for brain cancer, a key area of research for Traversa co-founder Steve Dowdy (GSN 5/27/2010).

Arrowhead Research received a $244,479 grant to fund the continued development of the Rondel drug-delivery technology, which is being used by its Calando Pharmaceuticals subsidiary in its phase I siRNA-based cancer drug CALAA-01.

The technology comprises a linear, cyclodextrin-containing polycation capable of binding to the anionic backbone of an siRNA. When mixed together, the polymer and siRNA self-assemble into nanoparticles that are protected from nuclease degradation in blood serum.

Miragen Therapeutics also secured a $244,479 grant, which will fund its development of miRNA-based treatments for cardiovascular disease.

The company has long kept its focus on cardiac and muscle diseases, namely treatments for post-myocardial infarction remodeling and chronic heart failure. This summer, Miragen President and CEO Bill Marshall told Gene Silencing News that the company expects one of those programs to yield an investigational new drug application in 2011 (GSN 7/15/2010).

Another miRNA drug developer to receive grant funding is Regulus Therapeutics, which was awarded two grants worth $488,989 support its ongoing development of microRNA-based drugs for hepatitis C and for fibrosis.

By far, Alnylam Pharmaceuticals was the biggest winner among those receiving QTDP grants, pulling in nearly $2 million in eight awards.

According to the IRS, the grants will fund the company's work on its liver cancer drug ALN-VSP and its transthyrein-mediated amyloidosis drug ALN-TTR, both of which are in phase I development, as well as its phase II respiratory syncytial virus therapy ALN-RSV.

The company also received grants for its preclinical programs in Huntington's disease and hypercholesterolemia.

Alnylam also received grants to fund its development of a single-stranded RNAi technology (GSN 4/30/2009), new delivery approaches, and to advance its biologics manufacturing initiative (GSN 11/19/2009).