Despite Bevasiranib has been discontinued it’s worth mentioning because it was the first therapy based on the Nobel Prize-winning RNA interference (RNAi) technology to advance to phase III clinical trials.

Bevasiranib was a first-in-class small interfering RNA (siRNA) drug designed to silence the genes that produce vascular endothelial growth factor (VEGF).

“The decision to conclude the clinical program follows a review of preliminary trial data by the Independent Data Monitoring Committee, which found that although Bevasiranib showed activity when used in conjunction with Lucentis^® (ranibizumab, Genentech), the trial was unlikely to meet its primary endpoint.”⁽⁸⁾

The trial was COBALT for “Combination of Bevasiranib and Lucentis^® Therapies” for AMD.

It was a phase III, randomized, double-blinded, parallel-assignment study of the RNAi drug administered either every 8 or 12 weeks as a maintenance therapy following three injections of Lucentis^®(9).

It is a siRNA, 19 nucleotides in length, that inhibits the expression of the hypoxia-inductible gene RTP801.

This stress-response gene mediates the mammalian target of rapamycin (mTOR) pathway.

PF-04523655 has been shown to reduce the volume of choroidal neovascularization in a mouse model.

PF-04523655 has been shown to cause regression of CNV in experimental studies of mice and primates.

Intravitreal small-interfering RNA (siRNA) PF-04523655 (Quark; licensed to Pfizer) used to treat choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) seems to be safe and well tolerated in an interim phase I analysis.

“No adverse events were observed up to the 3,000-µg dose”⁽¹⁰⁾.

Allergan has halted development of its siRNA-based wet age-related macular degeneration, Sirna-027 is the first chemically modified short interfering RNA (siRNA) targeting Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1).

VEGFR-1 is found primarily on vascular endothelial cells and is stimulated by both VEGF and placental growth factor (PlGF), resulting in the growth of new blood vessels⁽¹¹⁾.

By targeting VEGFR-1, Sirna-027 is designed to reduce pathologic angiogenesis mediated by both VEGF and PlGF.

Development was halted for AGN-745 after the drug failed to meet a key efficacy endpoint in a phase II study.

The trial compared 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 were administered via intravitreal injection⁽¹²⁾.

Apparently no safety issues were associated with AGN-745, a chemically modified siRNA.

But since the drug did “not meet its efficacy hurdle” — improvement in visual acuity — Allergan opted to halt its development⁽¹³⁾.