By Doug Macron
With a second generation of its core asymmetric siRNA technology in the works, Korean drug developer BioMolecular Therapeutics announced last month that it has forged an RNAi research collaboration with Korea's Samyang.
Meanwhile, BMT is advancing its own programs in scar prevention and dry age-related macular degeneration, and aims to have its first investigational new drug application filed with Korean regulators sometime next year.
Under the deal with Samyang, BMT will conduct validation studies to examine the use of its RNAi technology against targets specified by its partner. Additional terms were not disclosed.
The deal follows Samyang's signing of a mid-2011 RNAi partnership with Takeda Pharmaceutical (GSN 4/14/2011).
BMT's original technology, dubbed asiRNA, involves duplex RNAs between 15 and 16 base pairs long — shorter than the typical 19-mer siRNAs — with 3' overhangs on the antisense strand only. In a paper published in 2009, the company and collaborators at Beth Israel Deaconess Medical Center and Boston Biomedical reported that asiRNAs were capable of triggering gene silencing with reduced off-target effects.
One of the developers of the asiRNAs, Chiang Li, founded a company in 2008 called AiRNA Pharmaceuticals to develop similar RNAi molecules, raising intellectual property concerns (GSN 12/11/2008).
According to BMT founder Dong-ki Lee, both companies, which had filed patent applications for their respective technologies around the same time, recognized the potential problem and discussed a cross-licensing arrangement.
However, before any deal could be struck, BMT developed a promising second-generation version of the asRNAs that “improved gene-silencing activity while maintaining the features of asiRNA structure, such as reduced off-target effects,” he wrote in an e-mail.
Additionally, the new molecules, called lasiRNAs, have been chemically modified so that they can be internalized into cells without the need for a delivery vehicle.
The exact nature of lasiRNAs, including the meaning of the “lasi-” prefix, is not being disclosed right now, Lee said. However, BMT is comfortable that they do not infringe on any other party's IP, and therefore the company no longer requires a license to AiRNA's technology.
Lee noted that details about the lasiRNAs will be made public in an upcoming peer-reviewed publication.
Aiming to take advantage of lasiRNAs' apparent advantages over conventional RNAi agents, BMT has begun developing a topically delivered anti-fibrotic compound for use in surgical scar prevention, with an eye to filing an IND in 2013, Lee said.
BMT's drug is designed to inhibit connective tissue growth factor, a target that has long been associated with fibrosis and which Lee said has been validated through the work of Excaliard Pharmaceuticals.
Last year, Excaliard announced that its antisense-based CTGF inhibitor EXC 001 showed efficacy in reducing scarring associated with elective surgery in three phase II trials, an achievement largely responsible for its recent acquisition by Pfizer.
Given the significant market for cosmetic surgery in Korea, BMT will initially run human trials of its anti-scarring agent in its native country and is currently in discussions with potential industry collaborators with expertise running clinical studies in Korea.
Should these prove successful, Lee said it plans to later tap the US market, although this would likely require the help of a large pharmaceutical partner.
With its second pipeline program in dry AMD, however, BMT hopes to target the US right from the start.
Dry AMD is characterized by the deterioration of the retinal pigmented epithelium, compared with the leakage of blood vessels in the eye that is the hallmark of wet AMD.
Given the relative ease with which drugs can be administered into the eye, wet AMD has been a disease of interest for a variety of RNAi drug firms including Alnylam Pharmaceuticals, Quark Pharmaceuticals, and Sirnaomics.
However, an approved and effective treatment for wet AMD already exists in Genentech's monoclonal antibody agent Lucentis, which raises the regulatory bar for any company aiming to develop its own wet AMD therapy.
There is no treatment for dry AMD and the disease itself has been poorly characterized, Lee noted.
Late last year, however, BMT scientific adviser and University of Kentucky researcher Jayakrishna Ambati published a report showing that siRNAs trigger a kind of retinal degeneration that closely mirrors dry AMD through the activation of immune receptors.
That same year, his lab published data showing that Dicer1 deficiency can trigger Alu toxicity and subsequent retinal pigmented epithelium degradation, suggesting new targets for AMD.
Based on this work, BMT is collaborating with Ambati's lab on an undisclosed dry AMD target using the lasiRNA technology, Lee said.
He offered no timeline on when an AMD candidate might be ready for the clinic, but noted that human trials would require either significant enough investment to allow BMT to hire a contract research organization or a partnership with a bigger pharmaceutical firm.
Until then, BMT has been making do with “some limited funding” and the support of technology-development loans from the Korean government, he said.
Discussions are also underway with other Korean companies that, like Samyang, might be interested in applying BMT's technology to their own programs.
At the same time, BMT is considering dipping its toes in the research market by developing lasiRNA libraries for functional genomic screens.
The company has decided against pursuing the reagent market as it channels its limited resources toward its core area of interest of therapeutics.
“With the current standard siRNA-based genomic screening, there are lots of false positives and false negatives,” Lee said. “Because the asymmetric siRNAs have the advantage of reduced off-target effects, perhaps developing next-generation siRNA libraries for screening purposes may be a reasonable approach for BMT.”
The company would also consider out-licensing the rights to its lasiRNAs for research applications to an interested reagent firm, he added.
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