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FDA rejects first DARPin

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The FDA has rejected AbbVie, Allergan and Molecular Partners’ VEGF-targeting abicipar pegol for wet age-related macular degeneration (AMD), owing to concerns over intraocular inflammation with the biologic candidate. While AbbVie is considering next steps for the programme, which it gained in its acquisition of Allergan, Molecular Partners is pivoting to other therapeutic opportunities.

DARPins (designed ankyrin repeat proteins) are low-molecular-weight biologics that bind targets with high affinity and specificity, promising advantages over monoclonal antibodies. Molecular Partners, founded in 2004 to advance this modality, prioritized abicipar pegol to validate the clinical potential of these agents. Whereas the VEGF-targeting antibody fragment ranibizumab is dosed monthly for wet AMD, phase III data shows that abicipar provides efficacy with quarterly dosing. But intraocular inflammation with abicipar was over 15% in this trial, compared with less than 1% with ranibizumab.

Molecular Partners’ CEO Patrick Amstutz says the partners have since improved their ability to purify the biologic and that their internal data suggests that should reduce inflammation rates. “The question is how and if AbbVie will show that this new material is of the quality that you can give it on a global scale to many, many patients,” he says.

Despite the disappointment for Molecular Partners, Amstutz still calls the abicipar data “highly validating”. The company is now focusing on other programmes, with an emphasis on multi-specificity opportunities. Its immuno-oncology candidate MP0301, which is partnered with Amgen, binds fibroblast-activating protein (FAP) on cancer cells and 4-1BB on T cells to facilitate T cell clustering at tumour sites. “We're taking biology that has been shown in the clinic to be active — but too active — and seeing if we can find a molecular architecture via multi-specificity to create local activity,” says Amstutz. A phase I dose-finding trial is underway, and combination trials could start next year.

Nature Reviews Drug Discovery 19, 501 (2020)

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