By Doug Macron
With its ability to down-regulate almost any gene of interest, RNAi has been touted as a technology with almost limitless therapeutic potential, capable of hitting targets that have eluded traditional modalities such as small molecules.
Despite this promise, companies working in the space have taken a decidedly measured approach in building their internal pipelines, focusing on a relatively small number of drug-development programs.
RNAi drugs kingpin Alnylam Pharmaceuticals, for example, boasts the industry's broadest intellectual property estate and a financial position — $435.3 million in cash, cash equivalents, and marketable securities at the end of 2009 — that rivals other more-established biotechs.
Currently, Alnylam lists five programs in its development pipeline, but just two of those have reached human testing. The most advanced is a candidate for respiratory syncytial virus that entered a phase IIb study in adult lung-transplant patients earlier this year (see RNAi News, 2/25/2010).
While it had been partnered to Cubist Pharmaceuticals (see RNAi News, 1/15/2009), the drugmaker later opted against developing the drug in favor of an earlier-stage, second-generation molecule dubbed ALN-RSV02, which is being developed as a pediatric RSV treatment (see RNAi News, 11/12/2009).
Alnylam's second clinical-stage drug is the liver cancer therapy ALN-VSP, which entered a phase I study about a year ago (see RNAi News, 4/9/2009). This program is currently unpartnered.
Elsewhere in the company's pipeline is ALN-TTR01, a treatment for the rare hereditary disease TTR amyloidosis that is expected to enter human trials in the first half of 2011; the hypercholesterolemia therapy ALN-PCS, slated to enter the clinic next year; and ALN-HTT, a Huntington's disease treatment being developed with Medtronic for which Alnylam has not publicly provided a development timeline.
Alnylam is working on a variety of other programs, all of which are either in the discovery or early-development stages and not included by the company in its formal development pipeline.
Another relatively mature clinical-stage RNAi drug company is Silence Therapeutics, which moved a solid tumor treatment called Atu-027 into phase I testing around the middle of last year (see RNAi News, 7/9/2009).
Aside from Atu-027, which it acquired with its purchase of the drug's original developer, Atugen, in 2005, Silence has three other cancer programs moving through its pipeline, but these all are preclinical and the company has provided no details on when they may enter human trials.
A handful of other companies have RNAi drugs in the clinic, including TransDerm, which is developing a phase I treatment for the skin condition pachyonychia congenital that affects an estimated 600 patients worldwide (see RNAi News, 4/23/2009). While the company expects that it may later begin work on other skin disorders, it is currently focused on PC.
Another firm, Arrowhead Research subsidiary Calando Pharmaceuticals, continues working on its phase I cancer drug CALAA-01, which became the first formulated siRNA-based therapeutic to enter human testing in the middle of 2008 (see RNAi News, 6/5/2008).
Although Calando had expected to advance a second cancer drug, CALAA-02, into the clinic, financial troubles within its parent firm have put all other drug-development programs on hold (see RNAi News, 11/5/2009).
Tekmira Pharmaceuticals also has an RNAi drug in the clinic, the high cholesterol therapy ApoB SNALP, which entered phase I testing in July. However, the company stopped that trial early in January, although it plans to begin testing a second-generation version later this year (see RNAi News, 1/14/2010).
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Tekmira is also working on a siRNA-based cancer drug called PLK1 SNALP, and has said that a phase I study of this agent could begin sometime this year. A third clinical candidate may also be unveiled in 2010.
Bucking the Trend
In addition to those firms that have managed to reach the clinic, there are a number of other earlier-stage players in the RNAi drugs space. But these, too, have kept their focus fairly limited.
MDRNA, for instance, currently has just two programs — one in bladder cancer, which is expected to yield an investigational new drug application in the fourth quarter, and one in liver cancer, which could be filed with US regulators in the first half of next year.
Cequent Pharmaceuticals, which is developing a novel RNAi approach known as transkingdom RNAi, has one program in advanced familial adenomatous polyposis, for which an IND has already been approved, and an earlier-stage effort in inflammatory bowel disease.
Dicerna Pharmaceuticals, meanwhile, has only disclosed an interest in oncology, and stated that its lead program will be in solid tumors (see RNAi News, 1/7/2010). Similarly, RXi Pharmaceuticals continues to define its pipeline, only stating publicly that it is evaluating a number of disease areas (see RNAi News, 11/19/2009).
But one company, Quark Pharmaceuticals, has proven to be somewhat of an anomaly in the RNAi space, moving three agents for five indications into the clinic in the roughly four years it has been working with the gene-silencing technology in earnest, with plans to advance an additional drug into human testing this year.
Quark's most advanced candidate, PF-4523655, formerly RTP-801i, is in two phase II studies: the first in diabetic macular edema and the second in wet age-related macular degeneration. It was acquired by Pfizer in 2006 (see RNAi News, 9/28/2006).
Another Quark drug undergoing two clinical trials is QPI-1002. The first study, a phase I, is evaluating whether the drug can prevent acute kidney injury in patients undergoing cardiovascular surgery, while the second, part A of a phase I/II, is looking to see if it can prevent delayed graft function in patients undergoing kidney transplant surgery.
A phase II study in acute kidney injury and part B of the phase I/II in delayed graft function are both expected to begin this year (see RNAi News, 12/3/2009).
And earlier this month, Quark announced that it had dosed the first patient in a phase I study of QPI-1007, an ocular neuroprotectant being evaluated for non-arteritic anterior ischemic optic neuropathy, but expected to ultimately be developed as a glaucoma treatment (see RNAi News, 3/4/2010).
As for its planned IND, Quark said it expects it will be for a drug in lung injury, although details of that program, including its targets, have not been disclosed.