SAN RAFAEL, Calif.,
Dec. 11, 2017 /PRNewswire/
-- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced
updates on valoctocogene roxaparvovec (formerly BMN 270), an
investigational gene therapy treatment for severe hemophilia at
ASH.
Efficacy Data with Valoctocogene Roxaparvovec 4e13 vg/kg Dose
and 6e13 vg/kg Dose as Presented at ASH
With the 4e13 vg/kg dose, the three patients with the longest
follow-up (at week 48) have Factor VIII activity levels that are in
or near to the normal range with both median and mean values of
49%. Median annualized bleed and factor VIII use rates for
the 4e13 vg/kg cohort were zero after Week 4 and when their Factor
VIII activity rose above 5%. Mean annualized bleed and factor
VIII use rates for the 4e13vg/kg cohort were 0.6 and 2.0,
respectively. With the 6e13 vg/kg dose, at 78 weeks post
infusion, the median and mean Factor VIII levels of the 6e13 vg/kg
cohort were 90 and 89%, respectively. Median annualized bleed
and factor VIII use rates for the 6e13 vg/kg were zero after Week
4. Mean annualized bleed and factor VIII use rates for the
6e13 vg/kg cohort were 0.5 and 6.1, respectively. Please see
full release issued December 9, 2017
here for details.
"The confluence of new medicines and advanced treatment
approaches for hemophilia has created an unprecedented opportunity
to improve outcomes for patients today and in the future," said
Hank Fuchs, M.D., President,
Worldwide Research and Development at BioMarin. "We are very
encouraged that our findings to date suggest a one-time infusion of
valoctocogene roxaparvovec has the potential to eliminate bleeds,
the need for exogenous factor VIII infusions and achieve FVIII
levels in the normal range for patients with severe hemophilia A,
with a very acceptable safety profile. We are entering a new
era for the treatment of severe hemophilia and look forward to
advancing an innovative therapeutic platform for our patients."
New England Journal of Medicine Publishes 1
Year Data on 6e13 vg/kg Dose Data
The company also announced that the New England Journal of
Medicine (NEJM) published an independent, peer-reviewed article
on the ongoing Phase 1/2 study of valoctocogene roxaparvovec, an
investigational gene therapy, in men with severe hemophilia
A. The article assessed the safety and efficacy of
valoctocogene roxaparvovec at the 6e13 dose, after 52 weeks.
The NEJM article, "AAV Gene Transfer in Patients with Severe
Hemophilia A," reported "sustained normalization" of Factor VIII
activity over the 52-week period for six of seven study
participants who received the 6e13 vg/kg dose of valoctocogene
roxaparvovec. In addition, all seven participants
demonstrated stabilization of hemostasis and a "profound" reduction
in Factor VIII use. Safety findings were limited to
elevations in liver function tests, noting the relatively small
sample size. For additional safety data, see the
Safety section below in the press release.
Abstract (poster) #3332, titled, "Impact of Pre-Existing
Immunogenicity to AAV on Vector Transduction by BMN 270, an
AAV5-Based Gene Therapy Treatment for Hemophilia A"
As presented at ASH on December
10, the objective of this study was to determine the
comparative pharmacodynamics of valoctocogene roxaparvovec when
given as a single intravenous bolus injection to cynomolgus monkeys
with varying baseline anti-AAV5 total antibody (TAb) levels and
transduction inhibition (TI) titers. The results demonstrated
no evidence for decreased FVIII expression in animals with
non-antibody based transduction inhibition, while baseline AAV5
antibody positive animals had a range of FVIII expression.
These data suggest a reasonable likelihood that valoctocogene
roxaparvovec may be efficacious for individuals with baseline
anti-AAV5 TAb. Importantly, the threshold for a positive AAV5
TAb assay result may be lower than baseline anti-AAV5 TAb levels
that impact efficient vector transduction. These data support
the initiation of the Phase 1/2 BMN 270-203 study, which will
evaluate the safety and efficacy of valoctocogene roxaparvovec in
severe hemophilia A subjects who have various baseline anti-AAV5
TAb levels.
Abstract (poster) #4611, titled, "Interim Analysis of
Immunogenicity to the Vector Capsid and Transgene-Expressed Human
FVIII in a Phase-1/2 Clinical Study of BMN 270, an AAV5-Mediated
Gene Therapy for Hemophilia A"
As presented at ASH on December
11, this study analyzed both the cellular and humoral immune
responses to the AAV5 capsid and the hFVIII transgene product in
subjects in the Phase 1/2 study BMN 270-201 with valoctocogene
roxaparvovec. No FVIII inhibitor (by Nijmegen Bethesda assay)
or sustained non-neutralizing FVIII TAb responses have been
detected in any valoctocogene roxaparvovec treated patients.
As anticipated, all patients developed an antibody specific for the
AAV5 capsid by week 8 post-infusion. No significant cellular
immune responses specific for the AAV5 capsid or FVIII were
detected, which is distinct from results from non-AAV5 vector
studies that correlated capsid immune responses to temporal
elevations in alanine transaminase levels as well as loss of factor
activity. The absence of adaptive immune responses observed
to valoctocogene roxaparvovec that impacted clinical safety or
efficacy suggest that certain immune responses may be specific to
AAV serotypes and are not a class effect.
Valoctocogene Roxaparvovec Safety
Overall, valoctocogene roxaparvovec has been well-tolerated by
patients across all doses, including the two patients who received
the lowest doses of 6e12 and 2e13 vg/kg, respectively. 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)
elevation (11 patients, 73%); arthralgia (9 patients, 60%);
aspartate aminotransferase elevation (8 patients, 53%); headache (7
patients, 47%); back pain, fatigue and upper respiratory tract
infection (5 patients, 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 valoctocogene
roxaparvovec. 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 valoctocogene
roxaparvovec. The other SAE was assessed as not related to
valoctocogene roxaparvovec, attributed to a planned knee surgery to
treat hemophilic arthropathy, and Grade 1 in severity. No
complications were reported.
Regulatory Status
The U.S. Food and Drug Administration (FDA) granted
valoctocogene roxaparvovec Breakthrough Therapy Designation.
The FDA's Breakthrough Therapy Designation program is intended to
facilitate and expedite development and review of new drugs to
address unmet medical need in the treatment of a serious
condition. To qualify for Breakthrough Therapy Designation,
preliminary clinical evidence must show that that the drug may
demonstrate substantial improvement over existing
therapies.
The European Medicines Agency (EMA) has granted access to
its Priority Medicines (PRIME) regulatory initiative for
valoctocogene roxaparvovec. 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).
BioMarin's valoctocogene roxaparvovec has also received orphan
drug designation from the FDA and EMA for the treatment of severe
hemophilia A. The Orphan Drug Designation program is intended
to advance the evaluation and development of products that
demonstrate promise for the diagnosis and/or treatment of rare
diseases or conditions.
Gene Therapy Manufacturing
BioMarin has constructed one of the largest gene therapy
manufacturing facilities in the world, which is located in
Novato, California. Good
Manufacturing Practices (GMP) production of valoctocogene
roxaparvovec has commenced and will support clinical development
activities and anticipated commercial demand. This facility
is capable of supporting approximately 2,000 patients per year, and
the production process was developed in accordance with
International Conference on Harmonisation guidance for
Pharmaceuticals for Human Use facilitating worldwide registration
with health authorities.
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. As an
X-linked disorder, hemophilia A mostly affects males, occurring in
approximately 1 in 5,000 male births. 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. Even with prophylactic regimens, many patients still
experience microbleeds and spontaneous bleeding events that result
in progressive joint damage.
About BioMarin
BioMarin is a global biotechnology company that develops and
commercializes innovative therapies for patients with serious and
life-threatening rare and ultra-rare genetic diseases. 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
valoctocogene roxaparvovec program generally, the impact of
valoctocogene roxaparvovec gene therapy for treating patients with
severe hemophilia A, the potential for valoctocogene roxaparvovec
to bring Factor VIII levels to normal and to reduce or eliminate
bleeds, the planned Phase 3 studies, the planed Phase 1/2 study, or
other possible future clinical studies of valoctocogene
roxaparvovec. 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
valoctocogene roxaparvovec, 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 September 30, 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 trademarks of BioMarin Pharmaceutical
Inc.
Contacts:
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BioMarin
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(415)
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455-7451
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SOURCE BioMarin Pharmaceutical Inc.