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Allergan Drops Development of siRNA Rx for AMD on Poor Phase II Data

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Allergan has halted development of its siRNA-based wet age-related macular degeneration treatment AGN-745 after the drug failed to meet a key efficacy endpoint in a phase II study, a company spokeswoman confirmed this week.

The trial was comparing the effect of three different monthly doses of AGN-745 with Genentech's antibody drug Lucentis, the standard of care for AMD, in treating the subfoveal choroidal neovascularization associated with the disease. Both drugs are administered via intravitreal injection.

According to the spokeswoman, no safety issues were associated with AGN-745, a chemically modified siRNA targeting vascular endothelial growth factor receptor-1. But since the drug did "not meet its efficacy hurdle" — improvement in visual acuity — Allergan opted to halt its development, she wrote in an e-mail to RNAi News.

Allergan acquired AGN-745, formerly called Sirna-027, from Sirna Therapeutics in late 2005 for $5 million upfront and up to $245 million in clinical milestones, as well as royalties, research funding, and contract manufacturing revenues (see RNAi News, 10/7/2005). The companies also agreed to work together to develop additional RNA-based drugs for other ocular diseases.

The spokeswoman noted that Allergan plans to "consider" other targets for further development under the alliance with Sirna, now part of Merck, but she declined to provide specific details on the status of the partnership.

A Merck spokeswoman confirmed that her company has received the rights to the drug back from Allergan, but said that there are no plans to continue its development.

Although AGN-745 had initially held promise as the second RNAi drug to enter human testing (see RNAi News, 11/26/2004) and early data suggested its efficacy (see RNAi News, 5/6/2005), Allergan's decision to shelve the drug was not entirely unexpected in light of a recent report on immunostimulatory nature of siRNAs.

In early 2008, researchers led by University of Kentucky researcher Jayakrishna Ambati published data showing that siRNAs at least 21 nucleotides in length suppress neovascularization, regardless of their sequences or targets, by triggering the double-stranded RNA immune receptor toll-like receptor 3 (see RNAi News, 3/27/2008).

In that work, the team tested various siRNAs, including AGN-745 and Opko Health's siRNA-based AMD therapy bevasiranib, and found that they all suppressed hemangiogenesis in mouse models of choroidal and dermal neovascularization by activating cell-surface TLR3 on blood endothelial cells, rather than because of an RNAi effect.

Then, about a year later, the same team reported new findings demonstrating that siRNAs at least 21 nucleotides in length suppress both blood and lymphatic vessel growth by activating TLR3 (see RNAi News, 4/9/2009).

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Further calling AGN-745's future into question was Opko's decision earlier this year to stop a phase III study of bevasiranib, which is designed to silence VEGF, after the drug was deemed "unlikely" to meet the trial's primary endpoint of vision-loss prevention (see RNAi News, 3/12/2009).

But even if AGN-745 or bevasiranib had proven effective in the clinic, the drugs were widely expected to face an uphill climb when trying to secure a share of the AMD market given the strong safety and efficacy profile of Lucentis, a sentiment expressed early on by RNAi kingpin Alnylam Pharmaceuticals.

Alnylam had been developing its own VEGF-targeting siRNA drug, dubbed ALN-VEG01, but by mid-2005 the company began hinting that it would drop the program — its most advanced at the time — in light of the growing competition in the space.

During a conference call at the time, Alnylam's CEO John Maraganore specifically cited newly released one-year data from a phase III study of Lucentis, which binds to VEGF-A, that showed the drug could not only prevent vision loss but also improve visual acuity (see RNAi News, 9/12/2005).

A few months later, Alnylam confirmed that it was dropping ALN-VEG01 in order to focus its efforts on respiratory syncytial virus (see RNAi News, 9/23/2005).

Despite the RNAi field's loss of three drug candidates for AMD, it appears that the target, rather than the indication, may be the main issue.

Earlier this year, Intradigm's top official told RNAi News that the company was stopping development of its investigational cancer therapy, an siRNA targeting VEGF, because it had deemed the target not commercially promising enough (see RNAi News, 1/8/2009).

“The real value of siRNA and our delivery technology is to develop drugs that treat diseases whose targets are not accessible through antibodies or small molecules,” Intradigm CEO Phil Haworth said at the time. “VEGF’s value was that it was validated through antibodies and small molecules.”

Therefore, the target “loses the real benefit of a siRNA approach,” he said.

Meanwhile, Quark Pharmaceuticals continues to move forward with its own RNAi-based AMD treatment that is designed to silence the proprietary human gene RTP-801 in collaboration with Pfizer, which exclusively licensed both the target and the drug in 2006 (see RNAi News, 9/28/2006). That drug, called PF-4523655, is currently in two phase II trials, one for AMD and one for diabetic macular edema.

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Importantly, Quark recently released data showing that PF-4523655, a 19 nucleotide-long, 2'-O-methyl-modified siRNA, is able to enter target cells in the eye and inhibit its target gene, but does not activate TLR3 (see RNAi News, 5/14/2009).

These data were generated in collaboration with the University of Kentucky's Ambati, who is also a member of Quark's medical advisory board.

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