While 2007 was in many ways a breakout year for established RNAi drug firms, it also proved to be one of the most fruitful periods for startups taking aim at developing their own therapies based on the gene-silencing technology.
The year was chock-a-block with pivotal milestones: Quark administered the first systemic RNAi drug to humans (see RNAi News, 11/22/2007); Opko Health began the first phase III study of an siRNA-based therapy (see RNAi News, 7/12/2007); and Alnylam Pharmaceuticals sold non-exclusive access to its intellectual property estate for up to $1 billion (see RNAi News, 7/12/2007).
With that as a backdrop, at least five new companies made their way onto the RNAi radar.
Among these new firms is Kylin Therapeutics, which is focused on developing a novel delivery technology for siRNA called packaging RNA.
Developed in the lab of Purdue University researcher and Kylin Co-founder Peixuan Guo, pRNA is derived from bacteriophage phi29 and characterized by the company as a “gear in the DNA packaging machinery” that can be modified with therapeutic RNA such as siRNA (see RNAi News, 7/19/2007).
In May 2006, Gou and colleagues published data describing the construction of folate-conjugated pRNA for the delivery of siRNAs to cancer cells.
And earlier this year, Gou reported that pRNA could be used to escort hammerhead ribozymes into cancer cells.
Although the Purdue investigators have also studied the potential of pRNA to deliver hepatitis treatments, Kylin CEO and Co-founder Eric Davis has said the company will initially focus on applying the technology to oncology.
In line with this, Kylin announced in September that it would work with Wyeth division Fort Dodge Animal Health to develop RNAi-based cancer treatments delivered using the pRNA technology (see RNAi News, 9/20/2007).
Under the deal, Fort Dodge will have the exclusive rights to the technology and drugs resulting from the partnership for use in companion animals. Kylin will retain all rights for human applications.
Another newcomer with a novel delivery technology is Cequent Pharmaceuticals. The company’s core technology, termed transkingdom RNAi, involves engineering non-pathogenic bacteria to express shRNAs. It was developed by company Founder and Director Chiang Li at Beth Israel Deaconess Medical Center.
In 2006, Li and colleagues published research in Nature Biotechnology demonstrating how non-pathogenic Escherichia coli could be made to express specific shRNAs. According to the paper, the researchers engineered the bacterium to transcribe shRNAs from a plasmid containing the invasin gene Inv and the listeriolysin O gene HlyA, which encode two bacterial factors needed for successful transfer of the shRNAs into mammalian cells.
“If you have an siRNA cocktail, the particular design of that cocktail — with particular sequences as composition of matter, a particular delivery system as method of use, and a particular therapeutics application showing utility — is going to be stand-alone IP.”
When administered either orally or intravenously, E. coli encoding shRNA against the oncogene CTNNB1 triggered “significant gene silencing” in the intestinal epithelium and in human colon cancer xenografts in mice.
Cequent’s first target is a relatively small one: familial adenomatous polyposis. The condition, which affects an estimated one in 8,000 people, is an inherited colorectal cancer syndrome characterized by the growth of polyps on the colon, which leads to colon cancer in nearly all cases in the absence of colectomy.
Despite the relatively limited market for FAP, Cequent views the disease as a good starting point to showcase the ability of transkingdom RNAi since it is a disease Li and his colleagues at Beth Israel had been researching before the formation of Cequent (see RNAi News, 1/25/2007).
The company expects to file an investigational new drug application for an FAP therapeutic in the third quarter of 2008.
Although Cequent is starting out small, the company is also eyeing a much more lucrative indication — inflammatory bowel disease — with the help of Novartis. An estimated 1 million people live with the chronic disease in the US, according to the Crohn’s and Colitis Foundation of America, an IBD patient-advocacy group.
In June, Novartis Option Fund contributed an additional $3 million to Cequent’s Series A financing round, which closed at $9 million (see RNAi News, 6/21/2007). As part of that investment, Novartis also picked up an option to in-license Cequent’s nascent IBD program for an undisclosed cash payment.
Another new face in RNAi therapeutics boasting a novel delivery approach is Traversa Therapeutics.
The company, which also hopes to extend its reach into the RNAi reagent and screening markets, was founded by University of California, San Diego, researcher Steven Dowdy to commercialize a delivery technology that combines protein transduction domains linked with a double-stranded RNA binding domain (see RNAi News, 5/10/2007).
This technology encapsulates siRNAs, which can then be systemically administered with no apparent cytotoxicity, according to the company.
Traversa intends to use PTD-DRBD with siRNA-based cancer therapeutics developed in-house. However, it sees nearer-term opportunities in selling the technology to big pharma for use in screening experiments, and to secure a reagent partner that can market and distribute the technology in kits for cellular assay experiments.
One RNAi drug startup that isn’t banking on a novel delivery method is Sirnaomics, which is instead trying to distinguish itself through the use of multiple siRNA cocktails.
Founded in the spring of this year, Sirnaomics is preparing to begin its first clinical trial in early 2008 — an ambitious goal the company expects to reach by running the study in China, where there are fewer regulatory hurdles compared with the US.
The company’s first drug candidate is being developed as a locally administered treatment for a variety of ocular diseases including diabetic retinopathy, herpetic stromal keratitis, and wet age-related macular degeneration. It comprises siRNA targeting three genes associated with neovascularization: vascular endothelial growth factor; and MMP-9 and MMP-2, two genes in the matrix metalloproteinase pathway.
By hitting multiple genes, Sirnaomics hopes that it can design a drug that is more effective but just as safe as other RNAi-based ocular disease drugs under development (see RNAi News, 9/20/2007).
Sirnaomics also expects that its cocktail approach will help it steer clear of any IP roadblocks.
“If you have an siRNA cocktail, the particular design of that cocktail — with particular sequences as composition of matter, a particular delivery system as method of use, and a particular therapeutics application showing utility — is going to be stand-alone IP,” Founder and CEO Patrick Lu told RNAi News earlier this year.
The most recent addition to the RNAi drugs world is Dicerna, which is developing a therapeutic pipeline based on Dicer-substrate technology licensed from the City of Hope.
Dicer-substrates are 27-nucleotide long RNA duplexes that have been shown to be up to 100 times more effective at silencing genes than conventional 21 nucleotide-long siRNAs without inducing an interferon response or activating protein kinase R in cells.
Late last year, Nastech Pharmaceutical took a license to the molecules for use with five undisclosed targets (see RNAi News, 11/9/2006). Seeing potential in the technology, Dicerna exclusively acquired all remaining rights to Dicer-substrates for human therapeutics (see RNAi News, 11/8/2007).
Last month, the company closed a $13 million financing round, which Dicerna Co-founder and CEO James Jenson told RNAi News would fund the company for at least two years and through the filing of its first investigational new drug application.
The company has remained tightlipped on the specifics of its pipeline, but Jenson had said that it is conducting a “broad-ranging assessment of target opportunities,” weighing factors such as target feasibility and validation, commercial opportunities, competition, and the potential for successful delivery.
Jenson noted at the time that Dicerna expects to have selected its initial disease targets before the end of the year.