The impact of regulatory strategy on business goals: uniQure’s Phase 3 product optimization for hemophilia B

Regulatory approval of a product and the associated strategic presentation of data are critical to driving business goals; however, strategic regulatory positioning supported by rational scientific principles can create significant opportunities to rapidly advance the development phase leading to approval. uniQure is engaged in ongoing Phase 3 efforts to develop a gene therapy product (AMT-061) for the treatment of hemophilia B (Factor IX deficiency). Congenital hemophilia B is an inherited bleeding disorder characterized by an increased bleeding tendency due to either a partial or complete deficiency of the essential blood coagulation protein, Factor IX (FIX). Hemophilia clinical care is currently based on treatment or prevention of bleeding with clotting factor concentrates. The goal of gene therapy in this setting is to establish the continuous expression of an active Factor IX protein, modifying the disease phenotype from severe or moderately severe to mild, or complete amelioration. AMT-061 is comprised of a recombinant AAV5 vector containing the human Factor IX-Padua (FIX-Padua) gene, codon-optimized for optimal expression in humans [1,2]. AMT-061 is a modified derivative of AMT-060 which contained the wild-type human Factor IX. The Factor IX-Padua protein differs from the wild-type human FIX protein by a single amino acid; where arginine is replaced by leucine at position 338 (R338L) of the mature protein. This modification results in a five- to ten-fold increase in the specific activity of Factor IX [1]. The regulatory strategy pursued during uniQure’s hemophilia B development program enabled the company to rapidly transition from AMT-060, the vector expressing wild-type Factor IX studied in Phase 1/2, to AMT-061, the vector expressing the Padua mutation, in Phase 3. This change played a critical role in uniQure’s ability to execute a public offering securing funds to fuel Phase 3 development in a highly competitive therapeutic space.

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