Hemophilia B Gene Therapy Receives Orphan Status in United States

Ricki Lewis, PhD

January 05, 2012

January 5, 2012 — A promising gene therapy for hemophilia B that received orphan designation in the European Union in November 2011 received the same status from the US Food and Drug Administration on January 4, 2012, as reported in a press release by Amsterdam Molecular Therapeutics (AMT), a leader in the field of human gene therapy.

Orphan disease status applies to conditions that affect fewer than 200,000 individuals in the United States. The Orphan Drug Act of 1983 provides up to 7 years of market exclusivity after regulatory approval.

"US orphan designation provides additional support for our hemophilia B gene therapy program and supplements the designation in the EU received in November," states Jörn Aldag, CEO of AMT. "The early clinical success seen with the program to date by our partners is very encouraging. We will build on this success in the coming months."

Researchers from St. Jude's Children's Research Hospital, Memphis, Tennessee, and University College London, United Kingdom, previously reported early results of a phase 1/2 clinical study for gene therapy for hemophilia B in the December 10 issue of the New England Journal of Medicine . Amsterdam Molecular Therapeutics is sponsoring the trial. The company, which targets single-gene disorders with an adeno-associated virus (AAV) platform, also has programs for acute intermittent porphyria, a form of Parkinson's disease, and Sanfilippo syndrome B.

Deficiency of factor IX coagulation factor (FIX) causes hemophilia B (Christmas disease), which is X-linked recessive. Since the late 1960s, treatment of hemophilia B has been intravenous injection of FIX 2 to 3 times a week, which is not curative, is very costly, and can lead to production of inhibitors.

Gene therapy delivers the FIX gene in an AAV8 vector into hepatocytes via peripheral vein infusion. A liver-specific promoter helps to target the vector, which has a natural affinity for the liver, and a codon-optimized factor IX construct increases transgene expression.

As reported previously, the investigators delivered a single low, intermediate, or high dose of the gene-carrying vector into the peripheral veins of 6 men with severe hemophilia B, and then measured the patients' FIX levels for from 6 to 16 months. In all participants, FIX levels increased to between 2% and 11% of normal in a roughly dose-dependent manner. Studies had shown that elevating FIX levels just slightly above 1% of normal could restore clotting ability.

The improved FIX production after gene therapy enabled 4 patients to discontinue prophylactic FIX without spontaneous hemorrhaging, and the other 2 patients to require injections less frequently.

These early findings are the first to demonstrate long-term expression of a blood protein associated with clinical improvement. The effect, both clinically and financially, could be substantial if further results validate the gene therapy.

The lifetime cost of intravenous factor IX can exceed $20 million per patient, whereas the cost of the vector per patient is $30,000. Successful gene therapy has the potential to dampen what is otherwise a severe bleeding disorder into a considerably milder form, or even to ameliorate the phenotype entirely.


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