Shire submits NDA to FDA for Hemophilia A Gene Therapy Candidate

Shire plc has announced the submission of an investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA) for SHP654, also designated as BAX 888, an investigational factor VIII (FVIII) gene therapy for the treatment of hemophilia A.

SHP654 aims to protect hemophilia A patients against bleeds through the delivery of a long-term, constant level of factor expression. The IND filing for SHP654 represents the latest step forward for Shire’s gene therapy program, which shows promise for both hemophilia A and B populations.

“Shire is leveraging decades of scientific leadership in hemophilia to advance research in gene therapy for this community,” said Paul Monahan, M.D., Senior Medical Director, Gene Therapy, Shire. “Drawing from our rich heritage, Shire is well equipped to sustainably support the development of gene therapies that aim to advance current standards of care and minimize the burden of this disease. SHP654 uses a proprietary technology platform designed to produce sustained levels of factor similar to the natural mechanisms of the body. Our goal with gene therapy for hemophilia is to uphold the highest standards for safety and efficacy.”

Shire’s gene therapy program for hemophilia A uses a recombinant adeno-associated virus serotype 8 (rAAV8) vector, which selectively targets the liver. It involves the delivery of a functional copy of FVIII to the body’s liver to enable its own production of FVIII, rather than relying on a factor-based treatment. SHP654 uses the rAAV8 vector to deliver a codon-optimized, B-domain deleted FVIII (BDD-FVIII) specifically to a patient’s liver, where FVIII would then be produced and used to manage bleeds. The FVIII expression is further controlled in patients by incorporating the liver-specific transthyretin (TTR) promoter/enhancer.

The IND filing for SHP654 was based on the results of pre-clinical and phase 1 studies demonstrating the potential utility of this candidate, inlcuding the following which were presented at the International Society on Thrombosis and Haemostasis (ISTH) 26th Biennial Congress in Berlin, Germany, from July 8 – 13, 2017:

Development of SHP654, a highly efficient AAV8-based BDD-FVIII gene therapy vector for treatment of hemophilia A.
Integration site analysis in mice demonstrates excellent biosafety profile of a recombinant (r) FVIII adeno-associated virus (AAV8) gene therapy product.
Dose response and long-term expression of a human FVIII gene therapy construct in hemophilia A mice.
Nonclinical safety evaluation of a human FVIII gene therapy construct in mice.

An IND is a request for FDA authorization to administer an investigational drug to humans. Following the FDA’s acceptance of the IND for SHP654, Shire will study SHP654 in a global multi-center study evaluating safety and examining the SHP654 doses required to boost factor VIII activity levels and affect hemophilic bleeding and will pursue bringing this innovation to markets worldwide.