Abicipar pegol not approved for treatment of wet AMD
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Citing an unfavorable benefit-risk ratio, the FDA has declined to approve abicipar pegol for treatment of neovascular age-related macular degeneration.
A complete response letter to a biologics license application said the decision was due to the rate of intraocular inflammation observed after administration of abicipar pegol 2 mg/0.05 mL, an investigational DARPin therapy, according to a joint press release from Allergan and Molecular Partners.
The FDA advanced the application in September 2019. In 2018, the companies announced positive phase 3 study results, in which the drug met its primary endpoints but saw higher rates of intraocular inflammation in about 15% of patients. The subsequent MAPLE study results reported a lower rate of intraocular inflammation, 8.9%, which was credited to a modified manufacturing process.
“We continue to believe in the need for treatment options that provide patients with reliable vision gains and less frequent dosing for the treatment of [neovascular] AMD,” Michael R. Robinson, MD, vice president, global therapeutic area head, ophthalmology, at AbbVie, Allergan’s parent company, said in the release. “We are committed to working with the FDA to determine the appropriate next steps for abicipar pegol.”
Perspective
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Nancy M. Holekamp, MD
On June 26, the FDA issued a complete response letter to the biologics license application for abicipar pegol. The letter stated that the rate of intraocular inflammation observed following administration of abicipar pegol 2 mg/0.05 mL results in an unfavorable benefit-risk ratio in the treatment of neovascular age-related macular degeneration. AbbVie plans to meet with the FDA to discuss its comments and determine next steps.
In the current neovascular AMD treatment landscape, this is not entirely surprising news. The FDA is signaling that, above all else, anti-VEGF drugs must be safe. The CEDAR and SEQUOIA clinical trials proved both durability of abicipar pegol and non-inferiority to monthly ranibizumab with a bold clinical trial designed to showcase a next generation anti-VEGF platform — the DARPin. Efficacy is necessary but not sufficient for FDA approval. The 15.4% inflammation rate, including a 1.7% rate of severe vision loss, is an unsurmountable safety blemish when compared with the well-established safety records of established anti-VEGF agents: bevacizumab, ranibizumab and aflibercept. And the recent events following the commercial launch of brolucizumab definitely had to influence the FDA’s thinking on abicipar pegol. The brolucizumab HAWK and HARRIER registration clinical trials disclosed an intraocular inflammation rate of 4%, higher than the 1% seen with aflibercept in those same trials. This either escaped the FDA’s scrutiny or was deemed acceptable. However, real-world use of brolucizumab soon became tainted by not only intraocular inflammation but isolated cases of severe and permanent vision loss due to an occlusive retinal vasculitis — a complication not seen over the prior 15 years of anti-VEGF use with bevacizumab, ranibizumab or aflibercept.
In summary, the FDA is clearly stating with this CRL to AbbVie/Allergan that safety comes first. And the lesson we are all learning is that making an anti-VEGF agent pure enough for intraocular injection may have a high bar.
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