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Key RNAi Drugs in the Clinic


Having had over a decade to mature, the RNAi drugs industry has more therapeutic candidates in clinical development than ever, testing in humans agents that incorporate a variety of designs, modifications, and delivery strategies.

Below is a list of the key RNAi-based therapies currently under active development, broken down by their developer.

Alnylam Pharmaceuticals

Patisiran — Formerly known as ALN-TTR02, patisiran is designed to treat TTR-mediated amyloidosis, a condition characterized by the accumulation of amyloid deposits in tissues such as peripheral nerves and the heart. The drug silences the mutant form of the TTR gene, which causes the disease, as well as the wild-type form. The drug is delivered systemically using a lipid nanoparticle technology licensed from Tekmira Pharmaceuticals.

Last year, Alnylam presented data showing that its drug could suppress levels of its target by as much as 93 percent in patients. These data not only led to the initiation of a phase III trial in ATTR patients with a manifestation of the disease called familial amyloid polyneuropathy, but also helped the company secure a $700 million genetic diseases alliance with Genzyme last month.

ALN-TTRsc — This drug is essentially a version of patisiran that replaces Tekmira's lipid nanoparticles with Alnylam's proprietary GalNAc conjugates, which enable subcutaneous delivery to hepatocytes.

In December, Alnylam launched a phase II trial of the drug in patients with a form of ATTR called familial amyloidotic cardiomyopathy, following the release of phase I data that showed the agent could silence its target by about 90 percent.

ALN-AT3 — The newest drug to enter Alnylam's clinical pipeline, ALN-AT3 is a GalNAc-enabled siRNA-based treatment for hemophilia and other bleeding disorders that is designed to silence antithrombin.

Last month, Alnylam began a phase I study of the drug that will first enroll healthy volunteers and then move onto patients with moderate to severe hemophilia A or B.

Arrowhead Research

ARC-520 — The hepatitis B treatment ARC-520 uses novel conjugates called dynamic polyconjugates, — which originated at Mirus Bio and was advanced by Roche (which acquired Mirus in 2008), but ended up in the hands of Arrowhead when Roche sold off its RNA drug assets in late 2011 — to deliver two distinct siRNAs that target highly conserved HBV genomic regions.

In a recently completed phase I study, ARC-520 was found to be safe and well tolerated at all dose levels tested, leading Arrowhead to seek clearance to start a phase IIa trial of the drug in combination with the antiviral agent entecavir.

Benitec Biopharma

TT-034 — TT-034 is a DNA construct that expresses shRNAs targeting three portions of the HCV genome.

Amid financial difficulties, Benitec licensed the drug to Tacere Therapeutics, which later partnered it with Pfizer. However, Pfizer later withdrew from the arrangement and, after improving its position with a series of successful cash raises, Benitec acquired Tacere, along with TT-034, in 2012.

Last month, Benitec began enrollment in a phase I/IIa study of TT-034 that will test the agent's safety and efficacy in HCV-infected individuals.


Cal-1 — A novel approach for treating HIV, Cal-1 involves isolating a patients T cells from peripheral blood and then treated with the HIV-1 fusion inhibitor C46, as well as a self-inactivating lentiviral vector encoding shRNAs against the chemokine receptor CCR5. The cells are then re-infused.

The drug is in phase I/II testing.


FANG — FANG is a personalized cancer vaccine that expresses the immunostimulator recombinant human granulocyte-macrophage colony-stimulating factor, along with bi-functional shRNAs against furin, an enzyme responsible for lysing the components of the protein TGF-beta that are involved in cellular proliferation and differentiation.

Currently, the treatment is being tested in a variety of clinical studies for various indications including phase II trials for colorectal cancer with liver metastases, advanced melanoma, ovarian cancer, and Ewing's sarcoma.

pbi-shRNA STMN1 — This purely RNAi drug comprises bi-functional shRNAs against stathmin-1, which is associated with abnormal cellular proliferation, that are encapsulated in a proprietary fusogenic DOTAP-cholesterol cationic liposome delivery vehicle.

The drug is in phase I testing for advanced and/or metastatic solid tumors.

Nitto Denko

ND-L02-s0201 — The result of a collaboration between Nitto Denko and Quark Pharmaceuticals, ND-L02-s0201 uses vitamin A-coupled lipid nanoparticles to deliver siRNAs targeting heat shock protein 47, a collagen-specific chaperone required for the biosynthesis and secretion of collagen, to treat fibrotic disease.

In mid-2013, the company began testing the drug in a phase I trial of healthy volunteers.

Quark Pharmaceuticals
QPI-1007 — This drug comprises siRNAs that inhibit the pro-apoptotic gene caspase 2 and is being developed to treat NAION, a rare disorder characterized by the death of retinal ganglion cells.

After completing a phase IIa study of the intravitreally injected drug for NAION, the company began a phase II trial in acute primary angle-closure glaucoma, a condition characterized by the sudden and rapid rise of intraocular pressure.

RXi Pharmaceuticals

RXI-109 — RXi's first clinical candidate, the anti-scarring compound RXI-109 is made up of siRNAs designed to inhibit connective tissue growth factor, or CTGF, a protein linked to wound healing and other fibrotic processes. It also incorporates a proprietary self-delivering technology that enables cellular uptake of the RNAi molecules without the need for a delivery vehicle.

After releasing phase I data showing RXI-109 to be safe and well tolerated, RXi moved the drug into phase II testing in patients with hypertrophic scars who are eligible for scar-revision surgery.

Senesco Technologies

SNS01-T — Stemming from Senesco's early work in plant biology, SNS01-T is designed to selectively kill B cell cancers by expressing a pro-apoptotic form of the gene eIF5A, along with siRNAs that silence a wild-type form that expresses a protein that protects cells from apoptosis.

Delivered in a polyethylenimine-based nanoparticle, the drug is currently in a phase Ib/IIa trial for multiple myeloma and non-Hodgkin's B cell lymphoma.

Silence Therapeutics

Atu027 — Incorporating blunt-ended siRNAs and delivered in proprietary lipid-based carriers, Atu027 silences the protein kinase PKN-3, which is associated with cellular morphology and locomotion in endothelial and cancer cells.

The drug is currently in the phase IIa portion of a phase Ib/IIa trial, being tested in combination with the chemotherapeutic gemcitabine in patients with locally advanced or metastatic pancreatic cancer.


LODER — Short for Local Delivery of RNAi, the cancer therapy LODER is essentially a miniature biodegradable polymeric matrix containing siRNAs that is implanted into a tumor. It is designed to protect its therapeutic payload from degradation while slowly and steadily releasing it over a period of several months.

Using siRNAs against the oncogene KRAS, Silenseed is nearing the completion of a phase I trial of its system in patients with operable adenocarcinoma of the pancreas. A phase II/III study is planned for this year.


SYL040012 — This drug is an unmodified 21-mer designed to silence adrenergic receptor beta-2 as a way to treat the ocular hypertension and elevated intraocular pressure associated with open-angle glaucoma.

Administered as eye drops, the drug has been tested in three clinical trials thus far, including a recently completed phase II trial. A phase IIb study is planned for this year.

SYL1001 — Like Sylentis' other drug, SYL1001 is an unmodified siRNA that is delivered topically to the eye. It targets transient receptor potential cation channel subfamily V member 1, which plays a role in pain sensitivity, for ocular pain.

The agent is currently under phase I/II testing for dry eye syndrome.

Tekmira Pharmaceuticals

TKM-Ebola — Being developed under a contract with the US Department of Defense, the Ebola infection treatment TKM-Ebola combines Tekmira's lipid nanoparticles with siRNAs against three targets in the Zaire strain of the virus.

Although the drug had previously been in phase I testing, Tekmira ended that trial early in order to reformulate the drug with next-generation lipid delivery vehicles. A phase I trial with the new drug was initiated last month.

TKM-PLK1 — Also using Tekmira's lipid nanoparticles for delivery is the cancer drug TKM-PLK1, which is designed to stop expression of the proliferation-associated protein polo-like kinase 1.

Last year, the drug moved into a phase I/II trial in patients with gastrointestinal neuroendocrine tumors or adrenocortical carcinoma.