Comparison of the Efficacy of Brolucizumab with Natural Disease Progression in Wet AMD Using Clinical Data from the Phase III HAWK and HARRIER Trials and Modelled Placebo Data

ABSTRACT

Aim: To compare the treatment effect of brolucizumab, a novel anti–vascular endothelial growth factor therapeutic, with a putative placebo in patients with wet age-related macular degeneration.

Materials and Methods: Clinical treatment-effect data from patients receiving brolucizumab 6 mg in the HAWK and HARRIER studies were compared with modelled placebo data using a previously developed and validated indirect response, non-linear, mixed effects model describing the natural visual acuity decline in wet age-related macular degeneration. The placebo model incorporated patient-level data from the sham injection arms of the MARINA and PIER studies, corrected for baseline best corrected visual acuity and age difference between these studies and the HAWK and HARRIER studies.

Results: Compared with a modelled placebo, brolucizumab treatment was associated with an overall best corrected visual acuity gain of approximately 22 Early Treatment Diabetic Retinopathy Study letters at Week 48 and 28 letters at Week 96.

Conclusions: As anti–vascular endothelial growth factor therapy is now a standard of care for wet age-related macular degeneration, it is not feasible to conduct placebo-controlled trials for new wet age-related macular degeneration treatments. By allowing comparison with the natural decline in visual acuity without treatment, this analysis conveys the clinical importance of brolucizumab for the treatment of wet age-related macular degeneration.

KEYWORDS:

• Brolucizumab
• wet age-related macular degeneration
• natural disease course
• putative placebo
• indirect response model

Acknowledgments

Medical writing support was provided by Susan Browne, PhD of Novartis Ireland Ltd., in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). The funding for this writing support was provided by Novartis.

Conflicts of interest

Andreas Clemens and Etienne Pigeolet are employed by and hold shares in Novartis Pharma AG. Zufar Mulyukov is an employee of Novartis Pharma AG and Valeria Colafrancesco is an employee of Novartis Farmaceutica SA. David Gaucher is a board member for Novartis and Thea, and has received financial support for congress attendance from Bayer, FCI, and Allergan. Miltiadis Tsilimbaris has received research grants and financial support for congress attendance from Novartis, Bayer, Johnson & Johnson, and Allergan. Pilar Calvo is a board member and has received lecture fees from Novartis, and financial support for congress attendance from Novartis, Thea, Bayer, and Allergan. Novartis has provided travel and study grants to Freiburg University Hospital, where Hansjürgen Agostini and Felicitas Bucher are employed.

Data availability statement

The data described in this article are openly available in the Open Science Framework at DOI:10.17605/OSF.IO/TPA6U.

Additional information

Funding

This work was supported by the Novartis Pharmaceuticals Corporation.