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Key RNAi Drugs in the Clinic: July 2014


NEW YORK (GenomeWeb) – With more interest from industry and investors than ever before, the RNAi therapeutics field has a record number of drug candidates in human testing for indications ranging from viral disease to cancer to skin disorders.

Below is a breakdown of the top RNAi-based therapies under active clinical development, organized by 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 and is in Phase III testing in patients with a form of ATTR called familial amyloid polyneuropathy that affects the peripheral nervous system.

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.

The drug is in a Phase II trial in patients with a form of ATTR called familial amyloidotic cardiomyopathy that is characterized amyloid deposit accumulation in heart tissue.

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.

The drug is in a two-part Phase I study that will first enroll healthy volunteers and then move onto patients with moderate to severe hemophilia A or B.

Arrowhead Research

ARC-520 — This drug is a treatment for hepatitis B infection that 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.

ARC-520 is currently in a Phase IIa trial, in which it is being evaluated at two dose levels 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.

Benitec had previously licensed the drug to Tacere Therapeutics, which later partnered it with Pfizer. Pfizer later withdrew from the arrangement, after which Benitec acquired Tacere, along with TT-034.

The agent is currently being tested in a Phase I/IIa trial that is beginning with sub-therapeutic doses, after which higher, potentially therapeutic doses will be evaluated.


Cal-1 — A novel approach for treating HIV, Cal-1 involves isolating a patient's T cells from peripheral blood and then treating them 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 therapy is in Phase I/II testing, during which it will first be tested alone then in combination with busulfan, a chemotherapeutic that aids cell engraftment.

Dicerna Pharmaceuticals

DCR-MYC — Formerly known as DCR-M1711, this drug comprises Dicer-substrate molecules designed to silence the oncogene Myc and incorporates a proprietary lipid nanoparticle delivery technology.

DCR-MYC recently entered a Phase I trial in patients with solid tumors, multiple myeloma, or lymphoma who are refractory or unresponsive to other treatments.


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, and ovarian cancer.

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.

Earlier this year, the company completed a Phase I study of the drug in healthy volunteers and said that it is planning a Phase I/II trial in fibrosis patients to examine both safety and efficacy.

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, as well as glaucoma.

A Phase IIa study of the intravitreally injected drug for NAION has been completed, with plans for Phase III testing being made. Meanwhile, Quark recently launched a Phase IIa trial of the drug in patients with unilateral acute primary angle-closure glaucoma, a condition characterized by the sudden and rapid rise of intraocular pressure.

QPI-1002 — QPI-1002 comprises siRNAs designed to silence p53 and recently completed a Phase II trial for the prevention of delayed graft function in kidney transplant patients. Data from the study are slated for release later this summer.

The agent is also in Phase I/IIa testing for preventing ischemia-reperfusion-induced kidney injury in patients removed from a cardiopulmonary bypass pump.

Novartis holds an option to in-license the agent for both indications.

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 — 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.

RXi-109 is currently in two Phase IIa studies — one comparing it against placebo in healthy subjects who undergo an elective surgical revision of a transverse hypertrophic scar on their abdomen and another in healthy subjects who undergo an elective keloid excision.

Senesco Technologies

SNS01-T — This drug 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 first part 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.

Silenseed recently completed a Phase I trial testing the LODER system with siRNAs designed to silence the tissue-signaling gene KRAS in patients with locally advanced pancreatic tumors. Patients also received the chemotherapeutic gemcitabine.

The company is now planning a Phase II trial in patients with unresectable locally advanced pancreatic cancer, who will be treated with LODER and chemotherapy.

Tekmira Pharmaceuticals

TKM-Ebola — Under development through 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 new Phase I study was initiated, but this month US regulators put it on hold until it receives additional safety data from the company.

TKM-PLK1 — This agent is also using Tekmira's lipid nanoparticles for delivery and is designed to stop expression of the proliferation-associated protein polo-like kinase 1.

TKM-PLK1 is in Phase I/II testing in patients with gastrointestinal neuroendocrine tumors or adrenocortical carcinoma.