Skip to main content
Premium Trial:

Request an Annual Quote

As it Matures, RNAi Field Sees Failures of Key Clinical Candidates


Despite the promise of RNAi as a therapeutic, the road from the clinic to the marketplace for drugs based on the gene-silencing technology has proven to be a bumpy one with the failure of some of the field's earliest candidates.

Among the most notable is Opko Health's bevasiranib, an siRNA-based treatment for wet age-related macular degeneration that was the first drug of its kind to enter human testing (see RNAi News, 11/12/2004) and the first to reach the final phase of clinical development (see RNAi News, 6/28/2007).

Bevasiranib was originally developed by Acuity Pharmaceuticals. But in early 2007, Acuity was acquired by a publicly traded shell company that was later became the ophthalmics firm Opko (see RNAi News, 3/29/2007).

An unmodified siRNA targeting vascular endothelial growth factor, the drug, formerly known as Cand5, showed potential early on (see RNAi News, 6/8/2006 & 9/14/2006). However, questions about bevasiranib's efficacy began coming to the surface, culminating with the 2008 publication of data in Nature showing that the drug's anti-angiogenic effect was the result of toll-like receptor 3 activation rather than an RNAi effect (see RNAi News, 3/27/2008).

About a year later, Opko announced that it had halted a phase III study of bevasiranib after preliminary data indicated that the drug was "unlikely" to meet its primary endpoint (see RNAi News, 3/12/2009). While the company did not expressly say that it was stopping development of the AMD therapy, it has not made any mention of bevasiranib since and all references to the drug have disappeared from Opko's corporate website.

Suffering a similar fate as bevasiranib is AGN-745, a chemically modified, VEGF receptor-1-targeting siRNA that had been under phase II development for AMD.

Developed by Sirna Therapeutics as Sirna-027, the drug was licensed to Allergan in 2005 while still in phase I testing (see RNAi News, 10/7/2005). Like bevasiranib, it was designed to be injected directly into the eye and inhibit abnormal blood vessel growth.

But in the same 2008 paper than examined bevasiranib's immunostimulatory properties, AGN-745 was also found to trigger TLR3 and not work via RNAi. Allergan later said that AGN-745 failed to meet the primary endpoint of a phase II trial, and handed back the drug's rights to Merck subsidiary Sirna, which has said it has no plans to further its development (see RNAi News, 5/28/2009).

Also proving to be an RNAi has-been is NucB 1000, a plasmid DNA encoding four short hairpin RNA molecules, which was under development by now-defunct Nucleonics as a treatment for hepatitis B.

Nucleonics' efforts to get the drug into the clinic were rocky from the start. After missing a number of publicly disclosed dates for starting NucB 1000's clinical development, the company in late 2006 faced the National Institutes of Health's Recombinant DNA Advisory Committee, which expressed concerns about the design of a proposed phase I study (see RNAi News, 12/21/2006).

Chief among the issues raised by the RAC reviewers are the doses Nucleonics proposes to test in the clinical study, which the committee believes could potentially overwhelm patients’ natural RNAi processes, and the company’s decision to evaluate NucB 1000 only in mouse models in its preclinical research.

[ pagebreak ]

But that committee has no authority beyond making comments and recommendations, and Nucleonics pressed forward toward the clinic. In mid-2007, the company was cleared to begin testing NucB 1000 in humans (see RNAi News, 5/3/2007).

The drug's development, however, was derailed about a year later, however, amid a legal dispute that saw Nucleonics terminate the phase I trial of NucB 1000 and fire its co-founders.

According to court documents, the firm alleged that its co-founders had "falsified and/or grossly misjudged" certain of the preclinical data for NucB 1000 in an attempt to move the drug into phase I testing. The co-founders, meanwhile, sued the company and its president and CEO for alleged wrongful termination and defamation, among other charges (see RNAi News, 7/3/2008).

Although the litigation was eventually settled out of court (see RNAi News, 11/6/2008), the damage had been done. Unable to secure the necessary financing, Nucleonics shut down and sold off its intellectual property assets to Alnylam Pharmaceuticals (see RNAi News, 12/11/2008).

Never Was

In addition to those RNAi drugs that faltered in the clinic, the space has seen a number of therapeutic candidates flame out while still under preclinical development.

In addition to an AMD therapy that was shelved in order to focus on a treatment for respiratory syncytial virus (see RNAi News, 9/23/2005), Alnylam had also been developing an siRNA-based influenza drug in collaboration with Novartis (see RNAi News, 2/23/2006).

Despite initial optimism over tackling flu, Alnylam later put the flu effort on hold, citing difficulty in creating effective, optimized siRNAs against the virus (see RNAi News, 9/16/2007). According to Alnylam, the program remains in the discovery stage.

And Alnylam isn't the only company to find the flu a challenge. MDRNA, in its previous incarnation as Nastech Pharmaceutical, had acquired the RNAi assets of startup Galenea, which primarily consisted of an early-stage flu program (see RNAi News, 2/23/2006). The company has since made little mention of its efforts in flu, and earlier this year announced that it would focus exclusively on liver cancer as it struggles under a cash crunch (see RNAi News, 3/26/2009).

Also this year, an official from Intradigm told RNAi News that the company had decided to end a years-long bid to develop the siRNA-based cancer therapeutic ICS-283 after determining that the drug's target, VEGF, lacked commercial promise (see RNAi News, 1/8/2009).

Under the Gun

A difficult economy, meanwhile, has cast doubt on the future of certain RNAi drug candidates, including Calando Pharmaceuticals' cancer treatment CALAA-01.

Last month, Calando parent firm Arrowhead Research announced that it will have its subsidiary halt clinical development of CALAA-01 after it completes an ongoing phase I trial, and that further development will be contingent on the company partnering or out-licensing the drug (see RNAi News, 5/21/2009).

At the same time, Arrowhead said that Calando would cease all preclinical development efforts until it can secure additional financing.

Also in May, Targeted Genetics said that it would close down its operations, which include the development of an expressed RNAi-based treatment for Huntington's disease, if it can't raise cash during the second quarter (see RNAi News, 5/14/2009).

The company had been developing the drug in collaboration with Sirna. However, Sirna handed off the drug's rights to Targeted Genetics following its acquisition by Merck since the program did not fall within the big pharma's areas of interest (see RNAi News, 4/10/2008).

The Scan

Boosters Chasing Variants

The New York Times reports that an FDA advisory panel is to weigh updated booster vaccines for COVID-19.

Not Yet

The World Health Organization says monkeypox is not yet a global emergency, the Washington Post reports.

More Proposed for Federal Research

Science reports that US House of Representatives panels are seeking to increase federal research funding.

PLOS Papers on Breast Cancer Metastasis, Left-Sided Cardiac Defects, SARS-CoV-2 Monitoring

In PLOS this week: link between breast cancer metastasis and CLIC4, sequencing analysis of left-sided cardiac defects, and more.