Liver function tests have been monitored closely during the course of the trial. The first three patients were not administered prophylactic corticosteroids. Two of these patients experienced elevated alanine aminotransferase (ALT) levels. Patient 3, the first patient treated at the highest dose level, experienced a mild ALT elevation at week 4, which prompted administration of a course of corticosteroids. ALT levels in this patient continued to rise modestly during the corticosteroid therapy, which was completed at week 14. Two weeks later a new corticosteroid regimen was initiated when ALT levels became minimally abnormal for the first time. The expression of Factor VIII continued to increase during this elevation of ALT and is currently at 57%. In addition, 28 weeks after dosing, Patient 1 treated at the lowest dose experienced a rise in ALT level to 128 IU/L, although this patient had never documented Factor VIII expression above 1%. After the third patient, all patients were to be started on prophylactic corticosteroid therapy and to date no further patients have experienced abnormal ALT levels. BioMarin plans to discuss these findings with
"We are encouraged by this early data on BMN 270 and the trend we are seeing in increasing Factor VIII levels over time. BMN 270 could have the potential to reduce and possibly eliminate the need for infusions of Factor VIII," said
"If BMN 270 allows hemophilia A patients to maintain around 5% of normal levels of Factor VIII, it could have a real and meaningful clinical benefit by reducing the need for Factor VIII infusions and spontaneous bleeds," said
Patients with hemophilia A are not able to produce enough functional Factor VIII to prevent bleeding and are currently treated with prophylactic or on-demand infusions of plasma-derived or recombinant Factor VIII. BMN 270 is designed to address the underlying genetic defect that prevents the expression of functional Factor VIII by using an adeno-associated virus (AAV) vector to deliver a functional copy of the factor VIII gene to a patients' own cells with the aim of a single infusion of BMN 270 providing a long-lasting increase in Factor VIII levels.
BMN 270 has received orphan drug designation from the
Table 1: Summary of 8 Patients Factor VIII Levels at Most Recent Evaluations
|Patient #||Dose*||Most Recent
* Low = (6 x 1012 vg/kg), Medium = (2 x 1013 vg/kg), High = (6 x 1013 vg/kg)
** Information sourced from
Table 2: Severity of Hemophilia*
activity in blood**
|Description of Severity***|
|Mild hemophilia||5-40%||People with mild hemophilia usually bleed only as a result of surgery or major injury. They do not bleed often and, in fact, may never have a bleeding problem.|
|Moderate hemophilia||1-5%||People with moderate hemophilia bleed less frequently, about once a month. They may bleed for a long time after surgery, a bad injury, or dental work. A person with moderate hemophilia will rarely experience spontaneous bleeding.|
|Severe hemophilia||Less than 1%||People with severe hemophilia usually bleed frequently into their muscles or joints. They may bleed one to two times per week. Bleeding is often spontaneous, which means it happens for no obvious reason.|
*Information sourced from
**Percentage calculated based on the number of international units (IU) per milliliter (ml) of whole blood.
***Severity describes how serious a problem is. The level of severity depends on the amount of clotting factor that is missing from a person's blood.
The current Phase 1/2 study is evaluating the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe hemophilia A. The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV vector coding for human-coagulation factor VIII and to determine the change from baseline of factor VIII expression level at 16 weeks after infusion. The kinetics, duration and magnitude of AAV-mediated factor VIII activity in individuals with hemophilia A will be determined and correlated to an appropriate BMN 270 dose.
This is a dose escalation study with the goal of observing an increase in factor VIII levels. Secondary endpoints include assessing the impact of BMN 270 on the frequency of factor VIII replacement therapy, the number of bleeding episodes requiring treatment and any potential immune responses. Patients will be monitored for safety and durability of effect for five years.
About Hemophilia A
Hemophilia A, also called factor VIII (FVIII) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a new mutation that was not inherited.1 As an X-linked disorder, hemophila A mostly affects males, occurring in approximately 1 in 5,000 male births.2 People living with the disease are not able to form blood clots efficiently and are at risk for excessive bleeding from modest injuries, potentially endangering their life. People with severe hemophilia often bleed spontaneously into their muscles or joints. The standard of care for the 43 percent of hemophilia A patients who are severely affected, is a prophylactic regimen of factor VIII infusions three times per week.3 Even with prophylactic regimens, many patients still experience microbleeds and spontaneous bleeding events that result in progressive joint damage.
About Gene Therapy
Gene therapy is a treatment designed to fix a genetic problem by adding a corrected copy of the defective gene. The functional gene is inserted into a vector - containing a small DNA sequence - that acts as a delivery mechanism, providing the ability to deliver the functional gene to cells. The cells can then use the information to build the functional proteins that the body needs, potentially reducing or eliminating the cause of the disease. Currently, gene therapy for the treatment of hemophilia A is available only as part of a clinical trial. The AAV approach to gene therapy has been advanced at the
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Traci McCarty BioMarin Pharmaceutical Inc.(415) 455-7558 Media: Debra Charlesworth BioMarin Pharmaceutical Inc.(415) 455-7451
Source: BioMarin Pharmaceutical Inc.