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RNAi Drugs Field Sees Candidate Failures as More Drugs Enter the Clinic

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By Doug Macron

Though an increasing number of RNAi drugs continue to move into human testing toward commercialization, the field has seen many of its earliest clinical candidates suffer setbacks, often due to a lack of efficacy.

Currently, there are more than 10 drugs based on the gene-silencing technology in clinical testing. Among them are Alnylam Pharmaceuticals' phase II respiratory syncytial virus therapy ALN-RSV01, Tekmira Pharmaceuticals' phase I cancer treatment TKM-PLK1, Sylentis' phase I glaucoma agent SYL040012, and Quark Pharmaceuticals' phase II acute kidney injury drug QPI 1002.

Initial reports on these and other molecules have thus far been promising. For instance, Silence Therapeutics this summer unveiled phase I data showing its siRNA-based solid tumor drug Atu027 was well tolerated and that a number of patients receiving treatment achieved stable disease (GSN 6/9/2011).

And in March, Gene Silencing News reported that the City of Hope was aiming to start a second clinical study to evaluate an expressed RNAi-based HIV/AIDS treatment after it showed signs of efficacy, albeit statistically insignificant ones, in a small initial trial (GSN 3/17/2011).

But early clinical successes do not guarantee similar outcomes in later-stage development.

Perhaps the most notable to disappoint in the clinic is Opko Health's wet age-related macular degeneration therapy bevasiranib, which holds the distinction of being the first and only RNAi agent to enter phase III testing.

Originally developed by Acuity Pharmaceuticals, which was later acquired by a firm that became Opko, the drug was an unmodified siRNA designed to silence vascular endothelial growth factor. It appeared safe and, in phase II testing, showed the ability to trigger dose-dependent decreases in the ocular lesions that characterize AMD (GSN 9/14/2006).

Questions arose about the drug's mechanism of action, however, culminating in a 2008 paper showing that bevasiranib's anti-angiogenic effect was the result of unintended immune stimulation, not an RNAi effect (GSN 3/27/2008).

Yet Opko pushed forward with the drug, eventually advancing it into a phase III study. However, the company halted that trial in early 2009, a move attributed to a review of the trial's initial data that suggested it was “unlikely” to meet its primary endpoint (GSN 3/12/2009).

Opko has stated that it is evaluating alternatives for continuing to develop bevasiranib, but has not offered any specific details.

Another RNAi-based AMD agent, Allergan's AGN-745, suffered a similar fate.

Originally developed by Sirna Therapeutics, the drug targeted vascular endothelial growth factor receptor-1. Like Opko's bevasiranib, AGN-745 appeared promising in initial human testing, suggesting dose-dependent improvement in visual acuity in treated patients (GSN 5/6/2005). On these data, Sirna licensed the drug to Allergan for $5 million upfront and as much as $245 million in clinical milestones (GSN 10/7/2005).

However, AGN-745 failed to perform as well in Allegan's hands, failing to meet a key efficacy endpoint in a phase II study, prompting the company to hand it back to Merck, which had since acquired Sirna (GSN 5/28/2009).

A Merck spokesperson later confirmed that the firm had no future plans for the AMD drug.

Facing a questionable future is another AMD drug, PF-04523655. Originally developed by Quark Pharmaceuticals and later licensed to Pfizer for use as both an AMD and diabetic macular edema treatment, the agent targets the proprietary human gene RTP-801.

In phase I/II testing, the drug appeared safe and well tolerated in AMD patients, leading Pfizer in 2008 to move it into a phase II trial for DME on its own. However, earlier this year Quark announced that that study was terminated early when it did not yield positive results.

The problem was that the drug, at the dose levels tested, was deemed unlikely to produce a therapeutic benefit superior to the current standard of care. As a result, Pfizer amended its deal for PF-04523655, putting the responsibility for a phase IIb study and leaving itself the option to back out of the arrangement altogether if data from the next trial aren't sufficiently compelling (GSN 3/24/2011).

Data from a Pfizer-run phase II study of the drug in AMD patients are expected by year end.

Setbacks have also beset Alnylam, which earlier this year shelved a second-generation version of its RSV treatment called ALN-RSV02.

ALN-RSV01 was originally licensed to Cubist Pharmaceuticals, but in late 2009 the company decided to pull out of that arrangement shortly after Alnylam reported phase II data for the drug in adult lung-transplant patients. Instead, Cubist opted for access to ALN-RSV02, which was being designed to treat RSV in children (GSN 11/9/2009).

Earlier this year, Alnylam announced that it and Cubist had decided to shelve ALN-RSV02 indefinitely, only stating that the move was a “portfolio decision” made jointly by the companies. Cubist maintains opt-in rights for ALN-RSV01, which Alnylam is currently testing in a phase IIb trial.

Meantime, Tekmira continues to sit on its hypercholesterolemia drug TKM-ApoB after it halted a phase I study of the drug due to apparent siRNA-related immune responses (GSN 1/14/2010). The drug, which is designed to silence apolipoprotein B, remains under review at the company, but Tekmira has yet to provide any specific guidance on its fate as it focuses on other drug candidates.

RNAi research and development hiccups aren't limited to siRNA drugs, however.

Now-defunct Nucleonics made headlines in 2008 as the first company to advance an expressed RNAi drug into human testing with the hepatitis B treatment NucB 1000.

Though Nucleonics began a phase I trial of the drug, it never completed it because the company began to collapse due to its failure to secure needed capital. However, a lawsuit between the company and its co-founders revealed that NucB 1000 may have been rushed into the clinic.

In the suit, Nucleonics accused the co-founders of falsifying preclinical data on the drug in order to speed its advance into human trials (GSN 7/3/2008). The case, which included counterclaims of wrongful termination, was eventually settled out of court, but not before Nucleonics had shut its doors. Alnylam eventually acquired the company's intellectual property assets.


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