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Key RNAi-Based Drugs in the Clinic: April 2010


Alnylam Pharmaceuticals

ALN-RSV01, an siRNA-based treatment for respiratory syncytial virus, entered phase I testing in late 2005. The drug, which targets the nucleocapsid N gene of the RSV genome, moved into phase II testing in mid-2007 in healthy adults experimentally infected with the virus. A second phase II trial — this time in adult lung-transplant patients naturally infected with the virus — began in early 2008.

Alnylam said that ALN-RSV01 met the primary endpoints of safety and tolerability in that second study, and began a follow-on phase IIb trial in a larger population of RSV-infected lung-transplant patients earlier this year. A next-generation molecule, ALN-RSV02, is slated to enter a phase I trial in a pediatric population sometime this year. That drug has been licensed to Cubist Pharmaceuticals.

ALN-VSP is a cocktail of two siRNAs, one targeting vascular endothelial growth factor and the other targeting kinesin spindle protein, being developed as a liver cancer therapy. The drug entered phase I testing in patients with advanced liver cancers about a year ago.

Calando Pharmaceuticals

CALAA-01 is an siRNA-based cancer therapy targeting the M2 subunit of ribonucleotide reductase. In June 2008, it entered phase I testing in patients with solid tumors, becoming the first formulated RNAi drug to be tested in humans.

Earlier this year, the company published data from that ongoing trial showing that the drug could knock down its intended target mRNA and protein inside a tumor through an RNA interference mechanism when delivered intravenously.


The company began last year a phase I trial of an unnamed cancer therapy that combines its bi-functional shRNA technology with an immune system stimulator.

The bi-functional technology involves an shRNA capable of triggering both cleavage-dependent and cleavage-independent RISC-mediated inhibition of target mRNA. The therapy comprises anautologous vaccine that expresses the immunostimulator recombinant human granulocyte-macrophage colony-stimulating factor and a bi-functional shRNA against furin, an enzyme responsible for lysing the components of the protein TGF-beta, which is involved in cellular proliferation and differentiation.

The study is expected to conclude in December.


PF-4523655, formerly RTP801i-14, is an siRNA drug targeting RTP-801, a gene found to play a role in angiogenesis, vascular permeability, and retinal neuron death. Originally developed by Quark Pharmaceuticals, Pfizer licensed the drug and target in 2006.

The drug entered phase I development in early 2007 for wet age-related macular degeneration, and is currently in phase II testing for both AMD and diabetic macular edema.

Quark Pharmaceuticals

QPI 1002, formerly AKIi-5, is an siRNA being developed as a treatment for acute renal failure. It is designed to temporarily inhibit expression of the pro-apoptotic gene p53.

The drug moved into phase I testing in patients undergoing major cardiovascular surgery in late 2007, while a second phase I trial is ongoing. The drug also entered phase I/II development last year for the prevention of delayed graft function in patients undergoing deceased donor kidney transplantation.

QPI 1007 is an ocular neuroprotectant that recently entered phase I testing for non-arteritic anterior ischemic optic neuropathy. It is ultimately expected to be developed as a glaucoma treatment.

Silence Therapeutics

Atu-027 is a blunt-ended siRNA targeting the protein kinase PKN-3. Originally developed by Atugen, which was later acquired by Silence, the cancer drug entered a phase I study in patients with solid tumors this summer. According to Silence, the trial is scheduled to wrap up around the end of 2010.


SYL040012 is an siRNA designed to inhibit adrenergic receptor beta-2. Sylentis’ first RNAi drug candidate, the glaucoma therapy finished the first portion of a phase I/II trial earlier this year. The second half of the study is slated to begin this summer.

Tekmira Pharmaceuticals

ApoB SNALP is an siRNA-based hypercholesterolemia drug targeting apolipoprotein B that last summer entered a phase I study of patients with elevated low-density lipoprotein cholesterol. In January, the company halted the trial after a patient suffered side effects associated with the drug's payload.

Tekmira expects to begin a phase I/II study with an improved siRNA in the second half of 2010.


TD101 is an investigational treatment for the rare skin disorder pachyonychia congenita caused by a mutation in any one of the dozens of genes encoding keratins. The drug, which targets a particular mutation in one of these genes, entered a single-patient phase I study in early 2008.

In that study, the drug was administered via intradermal injections. A planned follow-on study is expected to use a more patient-friendly delivery approach, but the expected start date of the trial is unknown.


Excellair is an siRNA targeting the intracellular kinase Syk. Delivered directly to the lung, the drug entered phase I testing in late 2008. Phase II testing began late last year.

Source: The companies

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