SAN RAFAEL, Calif.,
July 11, 2017 /PRNewswire/
--
- BioMarin Provides BMN 270 Data at International Society on
Thrombosis and Haemostasis (ISTH) 2017 Congress
- Initiation of Phase 3 Registrational Study Planned for Q4 2017
with 6e13 vg/kg Dose
- 97% Reduction in Mean Annualized Bleed Rate (ABR) with 6e13
vg/kg Dose Compared to Prophylaxis
- 94% Reduction in Mean Annual Factor VIII Infusions with 6e13
vg/kg Dose Compared to Prophylaxis
- Gene Therapy Facility in U.S. Constructed
- Conference Call and Live Webcast Tuesday, July 11th at 2:30pm CEST/8:30am
ET
BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) announced today an
update to its previously reported interim results of an open-label
Phase 1/2 study of BMN 270, an investigational gene therapy
treatment for severe hemophilia A. The updated results will be
presented by John Pasi, Ph.D.
F.R.C.P, at Barts and the London School of Medicine and Dentistry
and Haemophilia Clinical Director at Barts Health NHS Trust and
primary investigator for the BMN 270 Phase 1/2 clinical trial,
during an oral presentation at the International Society on
Thrombosis and Haemostasis (ISTH) 2017 Congress being held
July 8-13, 2017 in Berlin, Germany. Professor Pasi will
present the data in a late breaking abstract on July 11, 2017, which will be the only clinical
data in gene therapy for hemophilia A to be presented at the
meeting.
In the open-label Phase 1/2 study, a total of 15 patients with
severe hemophilia A1 (defined by the World
Federation of Hemophilia (WFH) as having Factor VIII activity
levels less than 1%, expressed as a percentage of normal factor
activity in blood) received a single dose of BMN 270, seven of whom
were treated at a dose of 6e13 vg/kg and an additional six of whom
were subsequently treated at a lower dose of 4e13 vg/kg. The
other two patients in the study were treated at lower doses as part
of dose escalation in the study and did not achieve therapeutic
efficacy. According to the WFH rankings of severity of
hemophilia A, the normal range of Factor VIII activity levels for
people without disease is between 50% and 150%, expressed as a
percentage of normal factor activity in blood, and the mild
hemophilia A range of Factor VIII activity levels is between 5% and
40%. (See Table 6 for further information on severity
levels)
As of the May 31, 2017 data
cutoff, all patients at the 6e13 vg/kg dose had reached 52 weeks of
post-treatment follow-up. Median and mean Factor VIII levels
from week 20 through 52 for the 6e13 vg/kg dose cohort have been
consistently within the normal levels post treatment as a
percentage calculated based on the numbers of International Units
per deciliter (IU/dL) of plasma. (See Table 1). At one year
after dosing, the median and mean Factor VIII levels of the 6e13
vg/kg cohort continue to be above 50%. (See Table
6)
Table 1: Factor VIII Levels (%) of 6e13 vg/kg Dose
Patients* by Visit (N=7)
Week**
|
20
|
24
|
28
|
32
|
36
|
40
|
44
|
48
|
52
|
6e13 vg/kg
Dose
|
|
|
|
|
|
|
|
|
|
N***
|
7
|
7
|
7
|
6
|
7
|
7
|
7
|
7
|
7
|
Median
Factor VIII Level****
(%)
|
97
|
101
|
122
|
99
|
99
|
111
|
105
|
105
|
89
|
Mean
Factor VIII Level****
(%)
|
118
|
129
|
123
|
122
|
116
|
124
|
122
|
106
|
104
|
Range
(low,
high)
|
(12, 254)
|
(12, 227)
|
(15, 257)
|
(26, 316)
|
(31, 273)
|
(17, 264)
|
(20,242)
|
(23,196)
|
(20, 218)
|
*All patients had severe hemophilia A, defined as less than
1% of Factor VIII activity levels, expressed as a percentage of
normal factor activity in blood.
**Weeks were windowed by +/- 2 weeks
*** For week 32, one patient had no Factor VIII
reading
****Bolded numbers are in the 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 June 30, 2017). Factor VIII levels
are determined by one-stage assay.
The median and mean Factor VIII levels from week 8 to 24 for all
patients observed at the 4e13 vg/kg dose are in the mild
level. Three of these subjects who have been observed for 24
weeks are at the upper end of mild. (See Table 2 for Factor VIII
levels and Table 6 for severity levels)
Table 2: Factor VIII Levels (%) of 4e13 vg/kg Dose
Patients* by Visit (N=6)
Week**
|
4
|
8
|
12
|
16
|
20
|
24
|
4e13 vg/kg
Dose
|
|
|
|
|
|
|
n
|
6
|
6
|
6
|
3
|
3
|
3
|
Median
Factor VIII Level***
(%)
|
4
|
15
|
21
|
35
|
37
|
33
|
Mean
Factor VIII Level***
(%)
|
5
|
13
|
19
|
33
|
38
|
33
|
Range
(low,
high)
|
(2,10)
|
(3,21)
|
(6,32)
|
(28,38)
|
(31,45)
|
(24,41)
|
*All patients had severe hemophilia A, defined as less than
1% of Factor VIII activity levels, expressed as a percentage of
normal factor activity in blood.
**Weeks were windowed by +/- 2 weeks
*** Bolded numbers are in the mild 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 June 30, 2017). Factor VIII levels
are determined by one-stage assay.
Annualized Bleed Rate (ABR) and Factor VIII Infusions
For the six patients who were on pre-study prophylaxis after
receiving a single dose of BMN 270 at 6e13 vg/kg dose and after
reaching a Factor VIII level above 5%, the mean ABR was reduced by
97% from 16.3 to 0.5. The median ABR for those same patients
was reduced from 16.5 to zero. The mean annualized Factor
VIII infusions were reduced by 94% from 136.7 to 8.5. The
median annualized Factor VIII infusions were reduced from 138.5 to
zero. The 7th patient was receiving Factor VIII on
demand treatment before the study and was not included in this
summary. (See Table 3)
Table 3: Summary of Mean Annualized Bleeding Rate (ABR)
and FVIII Infusions of 6e13 vg/kg 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 year per
subject)
|
16.3 (16.5,
15.7)
|
0.5 (0.0,
1.1)
|
Annualized FVIII
Infusions**
(infusions per
year per subject)
|
136.7 (138.5,
22.4)
|
8.5 (0.0,
20.8)
|
*A 7th patient received Factor VIII on demand and
was not included in analysis.
**Post infusion data were based on data after Factor VIII levels
were above 5%
***Obtained from medical records.
****5 of 6 patients had 0 bleeds requiring Factor VIII infusions
and 0 Factor VIII infusions after Factor VIII levels were above
5%.
For the six patients who were on pre-study prophylaxis after
receiving a single dose of BMN 270 at 4e13 vg/kg dose and after
reaching a Factor VIII level above 5%, the mean ABR was reduced
from 12.2 to zero. The median ABR for those same patients was
reduced from 8.0 to zero. The mean annualized Factor VIII
infusions were reduced from 144.2 to zero. The median
annualized Factor VIII infusions were reduced from 155.5 to zero.
(See Table 4)
Table 4: Summary of Mean Annualized Bleeding Rate (ABR)
and FVIII Infusions of 4e13 vg/kg 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 year per
subject)
|
12.2 (8.0,
15.4)
|
0.0 (0.0,
0.0)
|
Annualized FVIII
Infusions*
(infusions per
year per subject)
|
144.2 (155.5,
43.3)
|
0.0 (0.0,
0.0)
|
* Post infusion data were based on data after Factor VIII
levels were above 5%
**Obtained from medical records.
***6 patients had 0 bleeds requiring Factor VIII infusions and 0
Factor VIII infusions after Factor VIII levels were above
5%.
Quality of Life (QoL)
Patients on the 6e13 vg/kg dose demonstrated improvement in
Haemo-QoL-A (HRQOL), a validated health related quality of life
measurement tool for patients with hemophilia, as early as 16 weeks
with maintenance through 52 weeks after receiving a single dose of
BMN 270. By week 16, patients achieved a clinically
meaningful difference from baseline with a mean score change of
13.4 with a standard deviation (SD) of 11.2. The minimal
clinically important difference (MCID) based on prior studies
ranges from 5.2 to 7.9. Patients demonstrated sustained clinically
meaningful HRQOL score changes through to week 52 with a mean score
change from baseline of 9.6 with an SD of 12.7. (See Table
5). The score improvement achieved an MCID, which was
observed across all six domains tested, i.e. Consequences of
Bleeding, Physical Functioning, Role Functioning, Emotional Impact,
Treatment Concern and Worry.
Table 5: Change from Baseline in Total Health-Related
Quality of Life (HRQOL) Score of 6e13 vg/kg Dose Cohort
|
6E13 vg/kg Dose
Cohort (N=7)
|
|
Total HRQOL
Score
|
Change from
Baseline
|
Baseline
|
Mean (SD)
|
71.9
(16.6)
|
(na)
|
|
Median
|
76.2
|
(na)
|
Week
16
|
Mean (SD)
|
85.3
(13.0)
|
13.4
(11.2)
|
|
Median
|
84.7
|
6.0
|
Week
28
|
Mean (SD)
|
84.8
(12.5)
|
12.9
(13.7)
|
|
Median
|
87.5
|
8.0
|
Week
52
|
Mean (SD)
|
81.6
(15.1)
|
9.6 (12.7)
|
|
Median
|
86.7
|
7.0
|
SD = standard deviation; na = not applicable.
"The data continue to build the clinical case for the
potentially groundbreaking impact of BMN 270 gene therapy for
treating patients with hemophilia A. Patients at the two
highest doses have stopped prophylactic treatment and to date,
bleeds have effectively been eliminated," said John Pasi, Ph.D. at Barts and the London School
of Medicine and Dentistry and Haemophilia Clinical Director at
Barts Health NHS Trust and primary investigator for the BMN 270
Phase 1/2 clinical trial. "In addition to the clinical data
showing meaningful improvement in bleeds and Factor VIII levels up
to 52 weeks, the quality of life data from the patients at the
highest dose demonstrate that the potential clinical benefit could
also represent a tangible improvement in a patient's quality of
life."
"With this important clinical data, we are moving into a Phase 3
registrational study for BMN 270 gene therapy at the 6e13 vg/kg
dose. BMN 270 has demonstrated an unprecedented result in
potentially shifting severe hemophilia A patients to the normal
range of Factor VIII expression, which is consistent with someone
who has no disease," said Hank
Fuchs, M.D., President, Worldwide Research and
Development at BioMarin. "We are striving to make a big
difference for patients with severe hemophilia A by developing a
treatment that not only has the potential to eliminate bleeds, but
also has the potential to eliminate the requirement for recombinant
Factor VIII infusions for hemophilia A patients related to trauma,
surgery and day-to-day activities."
Safety
Overall, BMN 270 was well tolerated by patients across all
doses. No patients developed inhibitors to Factor VIII and no
patients withdrew from the study. The most common adverse
events (AEs) across all dose cohorts were alanine aminotransferase
(ALT) elevations (10 patients, 67%), arthralgia (7 patients, 47%)
and back pain, fatigue, headache (5 patients each, 33%). Two
patients reported Serious Adverse Events (SAEs) during the study.
One patient was hospitalized for observation after developing
Grade 2 pyrexia with myalgia and headache within 24 hours of
receiving BMN 270 (4e13 vg/kg dose). The event resolved
within 48 hours following treatment with paracetamol, an
over-the-counter treatment for pain and fever. The event was
assessed as related to BMN 270. The other SAE was assessed as
not related to BMN 270, and was attributed to a planned knee
surgery to treat hemophilic arthropathy, and Grade 1 in
severity. It resolved without any further
complications.
AEs of ALT elevation were reported in 10 of the 15
patients. All events of ALT increases were non-serious and as
of the data cutoff, seven of the 10 patients had durations of ALT
greater than 1.5 times the Upper Limit of Normal (ULN) range from
0.4 to 7 weeks and Grade 1 in severity. All of the seven patients
at the 6e13 vg/kg dose remain off of corticosteroids with no
lasting significant impact on Factor VIII expression and normal ALT
levels. Three of the six patients at the 4e13 vg/kg dose
received corticosteroids for ALT increases, one has successfully
tapered off corticosteroids and two are tapering off of
corticosteroids.
Phase 3 Study and Regulatory Status
BioMarin plans to initiate a Phase 3 registrational study in Q4
2017 for BMN 270. Final determination of the design of the
study in severe hemophilia A patients is underway; the study will
likely include fewer than 100 patients and collect data for not
longer than a year after a single dose of BMN 270 with subsequent
long-term follow-up.
The company is moving the 6e13 vg/kg dose forward based on the
possibility to get most patients safely into the normal Factor VIII
range, which could provide them the opportunity to engage in normal
daily activities without concern for spontaneous bleeds or the need
for additional Factor VIII due to trauma (including sports and
minor injuries) or invasive procedures. However, to evaluate
a dose that may have a different drug profile, we will consider
doing an additional 4e13 vg/kg dose clinical study later.
While we may do further study on a lower dose, by going forward
with the 6e13 vg/kg dose now, we hope to bring this novel therapy
to patients as quickly as possible.
The European Medicines Agency (EMA) has granted access to
its Priority Medicines (PRIME) regulatory initiative for BMN
270. To be accepted for PRIME, an investigational therapy has
to show its potential to benefit patients with unmet medical needs
based on early clinical data. PRIME focuses on medicines that may
offer a major therapeutic advantage over existing treatments, or
benefit patients with no treatment options. These medicines are
considered priority medicines within the European Union (EU).
Gene Therapy Manufacturing
In addition, BioMarin has designed and constructed its first
gene therapy manufacturing facility located in Novato, California. Good Manufacturing
Practices (GMP) production of BMN 270 is anticipated to commence
imminently to support ongoing clinical development activities and
if approved, commercial demand.
"BioMarin has built a manufacturing facility that can produce
BMN 270 at the scale and quantity to support clinical development
and projected commercial demand, if approved," said Robert Baffi, Ph.D., Executive Vice President
Technical Operations. "We drew upon our expertise in
manufacturing complex biologics to efficiently build one of the
largest gene therapy manufacturing facilities in the world, which
will allow us to control scheduling, quality and costs to
facilitate rapid product development."
Conference Call and Live Webcast to be held Tuesday, July
11th at 2:30pm CEST/8:30am ET
Interested parties may access a live webcast of the conference
call via the investor section of the BioMarin
website, www.biomarin.com. The Late Breaker slide presentation
will be available to download in advance of the call. A
replay of the call will be archived on the site for one week
following the call.
U.S. / Canada Dial-in Number: (866) 502-9859
International Dial-in Number: (574) 990-1362
Conference ID: 41581309
Replay Dial-in Number: (855) 859-2056
Replay International Dial-in Number: (404) 537-3406
Conference ID: 41581309
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 Factor VIII
activity levels, expressed as a percentage of normal factor
activity in blood. 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.
The study has completed enrollment.
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.2 As an X-linked disorder, hemophilia A mostly
affects males, occurring in approximately 1 in 5,000 male
births.3 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.4 Even with
prophylactic regimens, many patients still experience microbleeds
and spontaneous bleeding events that result in progressive joint
damage
Table 6: 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 June 31, 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 at BioMarin
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, the data regarding this technology has demonstrated the
ability to correct bleeding and to be generally well tolerated 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 six commercialized products and multiple clinical and
pre-clinical product candidates.
For additional information, please visit www.biomarin.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, the impact of BMRN 270 gene therapy for
treating patients with hemophilia A, the potential for BMN 270 to
bring Factor VIII levels to normal and to reduce or eliminate
bleeds, the planned Phase 3, or other possible future clinical
studies 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 other risks detailed from time to time under the
caption "Risk Factors" and elsewhere in BioMarin's Securities and
Exchange Commission (SEC) filings, including BioMarin's Quarterly
Report on Form 10-Q for the quarter ended March 31, 2017, and future filings and reports by
BioMarin. BioMarin undertakes no duty or obligation to update any
forward-looking statements contained in this press release as a
result of new information, future events or changes in its
expectations.
BioMarin® is a registered trademark of BioMarin
Pharmaceutical Inc.
1 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
2 Source: National Hemophilia Foundation
http://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A
3 Source: CDC
http://www.cdc.gov/ncbddd/hemophilia/data.html
4 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:
|
Media:
|
Traci
McCarty
|
Debra
Charlesworth
|
BioMarin
Pharmaceutical Inc.
|
BioMarin
Pharmaceutical Inc.
|
(415)
455-7558
|
(415)
455-7451
|
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