Two High Dose Patients Show Increasing Levels of
Factor VIII Above 50%
BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) announced today
preliminary data from an ongoing Phase 1/2 clinical trial with BMN
270, an investigational gene therapy treatment for hemophilia
A. A total of eight patients with severe hemophilia A
received a single dose of BMN 270, six of whom have been treated at
the highest dose of 6 x 1013 vg/kg, and to date, post-treatment
follow-up ranges from five to 16 weeks. At last observation,
patients at the highest dose experienced increasing Factor VIII
activity levels ranging between 4% and 60% (as a percentage
calculated based on the numbers of International Units (IU) per
milliliter of whole blood), with five of six patients treated at
the high dose now over 5% and two of six at over 50%. (See Table 1)
All high dose patients improved from severe to either moderate,
mild or normal range in terms of factor levels based on World
Federation of Hemophilia criteria. (See Table 2)
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 UK regulatory authorities prior to dosing the
remaining patients.
“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 Hank Fuchs, M.D., Chief
Medical Officer at BioMarin.
“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 John Pasi, Ph.D. F.R.C.P,
Professor of Haemostasis and Thrombosis at Barts and the London
School of Medicine and Dentistry and primary investigator for the
BMN 270 Phase 1/2 clinical trial. “I am looking forward to
further assessing the data over the 16 weeks and beyond in this
ongoing study.”
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 European
Commission and U.S. Food and Drug Administration. Phase 3
design preparation and high volume manufacturing plans are
underway.
Table 1: Summary of 8 Patients Factor VIII Levels
at Most Recent Evaluations
Patient # |
Dose* |
Most Recent Week of Observation |
Percentage Factor VIII activity |
Severity of Hemophilia at Latest
Measurement** |
1 |
Low |
20 |
<1 |
Severe |
2 |
Medium |
16 |
2 |
Moderate |
3 |
High |
16 |
57 |
Normal |
4 |
High |
8 |
60 |
Normal |
5 |
High |
7 |
8 |
Mild |
6 |
High |
7 |
4 |
Moderate |
7 |
High |
6 |
21 |
Mild |
8 |
High |
5 |
10 |
Mild |
* Low = (6 x 1012 vg/kg), Medium = (2 x 1013 vg/kg), High = (6 x
1013 vg/kg)** Information sourced from World Federation of
Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current
as of April 20, 2016)
Table 2: Severity of Hemophilia*
Level |
Percentage of normal factor activity in
blood** |
Description of Severity*** |
Normal range |
50-150% |
|
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 World Federation of Hemophilia,
http://www.wfh.org/en/page.aspx?pid=643 (link current as of April
20, 2016)**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.
Study Design
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 University College London (UCL) in the
treatment of Hemophilia B. At UCL, this technology has shown
evidence to be both safe and effective, correcting bleeding for
greater than four years in a continuing clinical trial.
About BioMarin
BioMarin is a global biotechnology company that develops and
commercializes innovative therapies for people with serious and
life-threatening rare disorders. The company's portfolio consists
of five commercialized products and multiple clinical and
pre-clinical product candidates.
For additional information, please visit www.BMRN.com.
Information on BioMarin's website is not incorporated by reference
into this press release.
Forward-Looking Statement
This press release contains forward-looking
statements about the business prospects of BioMarin Pharmaceutical
Inc., including, without limitation, statements about the
development of BioMarin's BMN 270 program generally and the timing
and results of the clinical trial of BMN 270. These forward-looking
statements are predictions and involve risks and uncertainties such
that actual results may differ materially from these statements.
These risks and uncertainties include, among others: results and
timing of current and planned preclinical studies and clinical
trials of BMN 270, including final analysis of the above interim
data; outcome of the safety analysis following Patient 1’s elevated
ALT levels; the content and timing of decisions by the U.S. Food
and Drug Administration, the European Commission and other
regulatory authorities; our ability to successfully manufacture the
product candidate for the preclinical and clinical trials; and
those factors detailed in BioMarin's filings with the Securities
and Exchange Commission, including, without limitation, the factors
contained under the caption "Risk Factors" in BioMarin's 2015
Annual Report on Form 10-K, and the factors contained in BioMarin's
reports on Form 10-Q. Stockholders are urged not to place undue
reliance on forward-looking statements, which speak only as of the
date hereof. BioMarin is under no obligation, and expressly
disclaims any obligation to update or alter any forward-looking
statement, whether as a result of new information, future events or
otherwise.
BioMarin® is a registered trademark of BioMarin
Pharmaceutical Inc.
1 Source: National Hemophilia
Foundationhttp://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A
2 Source:
CDChttp://www.cdc.gov/ncbddd/hemophilia/data.html
3 Source: World Federation of
Hemophiliahttp://www.wfh.org/en/resources/annual-global-surveyhttp://www.wfh.org/en/abd/prophylaxis/prophylaxis-administration-and-dosing-schedules
Contact:
Investors:
Traci McCarty
BioMarin Pharmaceutical Inc.
(415) 455-7558
Media:
Debra Charlesworth
BioMarin Pharmaceutical Inc.
(415) 455-7451
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