SAN RAFAEL, Calif.,
Jan. 8, 2017 /PRNewswire/
-- BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) announced today
an update to its positive interim results of an open-label Phase
1/2 study of BMN 270, an investigational gene therapy treatment for
severe hemophilia A, which will be presented as part of a company
overview at the 35th Annual J.P. Morgan Healthcare Conference in
San Francisco, Calif. These
data are an update from previously reported results presented in
July 2016.
A total of nine patients with severe hemophilia A received a
single dose of BMN 270, seven of whom have been treated at the
highest dose of 6 x 1013 vg/kg. As of the
Dec. 9, 2016 data cutoff,
post-treatment follow-up ranges from 34 to 50 weeks. Median
Factor VIII levels for the high dose cohort have been consistently
within the normal range from 20 weeks through 44 weeks of
treatment. (See Table 1) For those seven patients, as of each
patient's most recent reading, six of seven patients continue to
have Factor VIII levels above 50%, as a percentage calculated based
on the numbers of International Units per deciliter (IU/dL) of
plasma, and the seventh continues to be above 15%. (See Table
2)
For the six patients at the high dose and previously on a Factor
VIII prophylactic regimen, the mean annualized bleeding rate
dropped 91% from 16.3 before the BMN 270 infusion to 1.5 two weeks
after being dosed (median annualized bleeding rate dropped from
16.5 to 0). For those same six patients, the mean annualized
Factor VIII infusions fell 98% from 136.7 to 2.9 (median annualized
Factor VIII infusions fell from 138.5 to 0). (See Table 3)
Since the last update, six of the seven patients at the high
dose as of the most recent reading are within the normal alanine
aminotransferase (ALT) range, and one patient is less than 5% above
the upper limit of normal, which is 43 U/L for the central
laboratory in this study. (See Table 4) Patients
successfully tapered off of steroids with no lasting significant
impact on Factor VIII expression or ALT levels. The
requirement for prophylactic corticosteroids has been removed for
all newly enrolled patients in this study.
Study medication was generally well tolerated. No serious
adverse events were observed, and most common adverse events were
mild in severity.
The next steps for the program are to begin a potentially
registration enabling Phase 2b study in 3Q 2017. In addition,
the company is expected to commission its commercial gene therapy
manufacturing facility by mid-2017.
"These data continue to show promising evidence that restoration
of clotting function can be achieved by gene therapy," 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. "The increase in Factor VIII levels
we have seen has the potential to stop patients bleeding and has
changed how we think about treating hemophilia. For the first time
we can truly start considering the opportunity for our patients to
live a more normal life."
"We are proud that we have been successful in establishing a
leadership position in gene therapy for the most common form of
hemophilia, and we are intent on initiating potentially
registration enabling trials to provide patients with a new
treatment option," said Hank Fuchs,
M.D., President, Worldwide Research & Development at
BioMarin. "To see data that shows a 91 percent drop in the
mean annualized bleeding rate and a 98 percent drop in prophylactic
infusions coupled with mean and median Factor VIII expression
levels in the normal range opens up an exciting treatment
possibility for hemophilia A patients."
Table 1: Factor VIII Levels (%) of High Dose Patients*
by Visit (N=7)
Week**
|
20
|
24
|
28
|
32
|
36
|
40
|
44
|
n***
|
7
|
7
|
7
|
6
|
7
|
6
|
2
|
Median
Factor VIII Level****
(%)
|
97
|
101
|
122
|
99
|
99
|
115
|
119
|
Mean
Factor VIII Level****
(%)
|
118
|
130
|
124
|
122
|
115
|
127
|
119
|
Range
(high,
low)
|
(12, 254)
|
(16, 227)
|
(15, 257)
|
(26, 316)
|
(31, 273)
|
(17, 264)
|
(105, 133)
|
*All patients had severe hemophilia A defined as equal to or
less than 1% of blood clotting factor.
**Weeks were windowed by +/- 2 weeks
***For week 32, one patient had no Factor VIII reading, for
week 40, one patient had not reached week 40 and for week 44, only
2 patients reached a week 44 reading
****Bolded numbers are in normal range of Factor VIII as
defined by the World Federation of Hemophilia,
http://www.wfh.org/en/page.aspx?pid=643 (link current as
of Jan. 8, 2017). Factor VIII levels
are determined by one-stage assay.
Table 2: Summary of Factor VIII Level (%) of High Dose
Patients at Most Recent Evaluation (N=7)
High-dose
Subject
#
|
FVIII level (%) at
last update in July 2016
|
Most recent week
of observation
|
FVIII level (%) at
most recent observation
|
1
|
89
|
50
|
121
|
2
|
219
|
42
|
133
|
3
|
271
|
40
|
222
|
4
|
12
|
41
|
16
|
5
|
133
|
40
|
175
|
6
|
69
|
38
|
77
|
7
|
79
|
34
|
62
|
Table 3: Summary of Annualized Bleeding Rate (ABR) and
FVIII Infusions of High Dose Patients Previously on Prophylaxis
(N=6)
|
Before BMN 270
Infusion**
|
After BMN 270
Infusion***
|
|
Mean (median,
SD)
|
Mean (median,
SD)
|
Annualized
Bleeding Rate* (bleeding episodes per subject per
year)
|
16.3 (16.5,
15.7)
|
1.5 (0,
3.8)
|
Annualized FVIII
Infusions*
(infusions per
subject per year)
|
136.7 (138.5,
22.4)
|
2.9 (0,
7.0)
|
* Rates were based on data from week 3 after BMN270 infusion
through last follow-up visit
**Obtained from medical records.
***5 of 6 patients had 0 bleeds requiring Factor VIII
infusions and 0 Factor VIII infusions from Week 3 after BMN 270
infusion.
Table 4: Summary of ALT Levels in High Dose Patients at
Most Recent Evaluation (N=7)
|
ALT
(U/L);
(ULN = 43
(U/L))
|
High-dose
Subject#
|
Peak ALT
level
|
ALT Level at Most
Recent Observations
|
ALT Level
Status
|
1
|
60
|
15
|
Normal
|
2
|
95
|
16
|
Normal
|
3
|
82
|
42
|
Normal
|
4
|
87
|
33
|
Normal
|
5
|
43
|
38
|
Normal
|
6
|
81
|
45
|
<1.1
ULN
|
7
|
66
|
27
|
Normal
|
All patients currently off steroids.
Phase 1/2 Study Design
The current Phase 1/2 study is evaluating the safety and
efficacy of BMN 270 gene therapy in up to 15 patients with severe
hemophilia A defined as less than or equal to 1% of blood clotting
factor. 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, hemophilia 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% 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.
Table 5: Severity of Hemophilia*
Level
|
Factor VIII 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
Jan. 8, 2017)
**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.
About Gene Therapy
Gene therapy is a treatment designed to alter a genetic problem
by adding a corrected copy of the defective gene. The functional
gene is inserted into a vector – containing a DNA sequence coding
for a specific protein – 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 protein
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.
Live Webcast on Monday, Jan. 9
at 8:30 am PT, or 11:30 am ET
On Monday, January 9, 2017 at
8:30 am PT, or 11:30 am ET, in San
Francisco, California, Jean-Jacques Bienaimé, Chairman and
Chief Executive Officer, will present the updated data from an
ongoing Phase 1/2 study of BMN 270 gene therapy in hemophilia A
along with other company updates. To access the live webcast,
please visit the investor section of the BioMarin website. A
replay will also be archived on the site for at least one week
following the event.
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; any
potential adverse events observed in the continuing monitoring of
the patients in the Phase 1/2 trial; the content and timing of
decisions by the U.S. Food and Drug Administration, the European
Commission and other regulatory authorities; the content and timing
of decisions by local and central ethics committees regarding the
clinical trials; 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 Foundation
http://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A
[2] Source: CDC
http://www.cdc.gov/ncbddd/hemophilia/data.html
[3] Source: World Federation of Hemophilia
http://www.wfh.org/en/resources/annual-global-survey
http://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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