Preliminary evidence suggest the potential for
dose-dependent disease stabilization in MPS IIIB patients treated
with SBC-103 at six months
Data Presented at 14th International Symposium
on MPS and Related Diseases 2016
Alexion Pharmaceuticals, Inc. (Nasdaq:ALXN) announced today that
researchers presented new data from an ongoing open-label, Phase
1/2 trial of intravenous (IV) SBC-103 (rhNAGLU enzyme), an
investigational enzyme replacement therapy, in children with
mucopolysaccharidosis IIIB (MPS IIIB, also known as Sanfilippo
syndrome type B), a genetic, progressive, and devastating rare
lysosomal storage disease. Preliminary evidence, based on brain
scans (MRI) and neurocognitive assessments at 24 weeks, showed the
potential for disease stabilization in patients with MPS IIIB
treated with SBC-103.1 These data were presented at the 14th
International Symposium on MPS and Related Diseases in Bonn,
Germany.
MPS IIIB is caused by genetic mutations that result in a marked
decrease in N-acetyl-α-D-glucosaminidase (NAGLU) enzyme activity,
leading to abnormal accumulation of heparan sulfate (HS) in the
brain and other organs, as well as progressive brain atrophy with
cortical gray matter (CGM) volume loss.2-5 This results in severe
neurocognitive decline, behavioral disturbances, speech loss,
increasing loss of mobility, and premature death.6 At present there
is no treatment for this disorder. MPS IIIB typically presents in
children during the first few years of life, and these children
have a greater than 50 percent mortality rate by 17 years of
age.7
“MPS IIIB is a devastating and life-threatening disorder, with
no available treatments, and has a severe and progressive impact on
the cognitive function of children suffering with the disease,”
said Martin Mackay, Ph.D., Executive Vice President and
Global Head of R&D at Alexion. “These new data presented today
suggest the potential of SBC-103 to cross the blood-brain barrier
when administered intravenously and provide preliminary evidence of
potential dose-dependent disease stabilization at 24 weeks in
children with MPS IIIB.”
Researchers presented preliminary results for volumetric brain
MRI and neurocognitive assessments performed after 24 weeks of IV
SBC-103 at 0.3, 1, or 3 mg/kg every other week (QOW). MRI scans for
those dosed at 3 mg/kg showed that 3 out of 4 patients had an
increase or no change (-1% to +1%) in CGM volume compared to
baseline suggesting a potential for disease stabilization at this
dose. In the 1 mg/kg group and 0.3 mg/kg group, MRI scans showed
that 2 out of 3 and 0 out of 3 patients respectively had an
increase or no change in CGM volume compared to baseline. In the
neurocognitive assessments for the 3 mg/kg group, 3 out of 4
patients had an increase in both mental age equivalent (AEq) and
developmental quotient (DQ) compared to baseline. For the 1 mg/kg
group, 2 out of 4 patients had an increase in both AEq and DQ
compared to baseline, and for 0.3 mg/kg group, 1 out of 3 patients
had an increase in both AEq and DQ compared to baseline. Overall,
response profiles among the 3 mg/kg treatment groups suggest a
potential dose effect as compared to the 0.3 mg/kg and 1 mg/kg
groups.1
“These new preliminary data from the brain MRI and
neurocognitive assessments of children with MPS IIIB show, for the
first time, the potential for disease stabilization following
intravenous administration of SBC-103,” said Chester B. Whitley,
Ph.D., M.D., Department of Pediatrics, University of Minnesota,
Minneapolis, U.S. “In addition to the evidence of heparan sulfate
reduction in cerebrospinal fluid, these findings support the
continued advancement of this clinical program, and dose escalation
to 5 mg/kg and 10 mg/kg for all patients in the study with this
severe and progressive rare disease.”
Eleven children with MPS IIIB (ages 2 years to 10 years at study
entry) were enrolled in this first-in-human study, which included
three parallel dosing groups of intravenous SBC-103 (0.3, 1.0 and
3.0 mg/kg QOW). The primary endpoint of the ongoing trial is safety
and tolerability, and key secondary endpoints presented at MPS 2016
include effect of SBC-103 on total HS levels in cerebrospinal fluid
(CSF) and serum, brain structures (MRI) and neurocognitive status,
and pharmacokinetic (PK) profile of SBC-103.
During 24 weeks of treatment with SBC-103 at the highest dose of
3 mg/kg, most adverse events (AEs) were mild in severity and no
patient discontinued the study. Two patients experienced a total of
four serious AEs (bacteremia, pyrexia, staphylococcal bacteremia,
and cyanosis [pre-treatment]) that were deemed not related to
SBC-103. Seven infusion-associated reactions occurred in three
patients (pyrexia, chills, hypertension, and tachycardia).1
As previously presented at the 12th Annual WORLDSymposiumTM,
patients treated with SBC-103 had a 26.2 percent mean reduction
from baseline in total HS levels in CSF at 24 weeks in the highest
dose studied (3 mg/kg QOW). Additionally, at week 24, patients in
the 0.3 mg/kg and 1.0 mg/kg groups had a 10.9 percent mean increase
and a 0.4 percent mean decrease in HS CSF, respectively. HS
reduction in CSF was linearly correlated with SBC-103 serum PK
exposures. Total change from baseline in serum HS was -39.6
percent, -53.9 percent and -40.5 percent for 0.3 mg/kg, 1 mg/kg,
and 3 mg/kg groups, respectively.8
About Mucopolysaccharidosis IIIB (MPS IIIB)
MPS IIIB (also known as Sanfilippo syndrome type B) is a
genetic, progressive, and devastating rare lysosomal storage
disease. In patients with MPS IIIB, genetic mutations result in a
marked decrease in N-acetyl-α-D-glucosaminidase (NAGLU) enzyme
activity, which leads to the accumulation of heparan sulfate (HS)
in the brain and other organs, as well as progressive brain atrophy
with cortical gray matter (CGM) volume loss.2-5 The accumulation of
abnormal HS results in neurocognitive decline, behavioral
disturbances, speech loss, increasing loss of mobility, and
premature death.6 MPS IIIB typically presents in children during
the first few years of life, and patients have a greater than 50
percent mortality rate by 17 years of age.7
There are no approved treatments for patients with MPS IIIB.
Current supportive care is palliative for behavioral problems,
sleep disturbances, seizures, and other complications, and does not
address the root cause of MPS IIIB or stop disease
progression.6,7
About SBC-103
SBC-103 (rhNAGLU enzyme) is an enzyme replacement therapy (ERT)
being investigated in a Phase 1/2 trial for patients with MPS IIIB.
It is a recombinant form of the N-acetyl-α-D-glucosaminidase
(NAGLU) enzyme intended to reduce accumulated heparan sulfate by
replacing the missing or deficient NAGLU enzyme. SBC-103 was
granted orphan designation by the U.S. Food and Drug Administration
(FDA) in April 2013 and by the European Commission in June 2013. It
received Fast Track designation by the FDA in January 2015.
SBC-103 utilizes Alexion’s proprietary protein expression
platform, a novel production process that has the potential to
enable ERTs to cross the blood-brain barrier. Alexion is evaluating
the use of this platform in the development of ERTs for severe and
devastating lysosomal storage diseases, including those that have
central nervous system manifestations.
About Alexion
Alexion is a global biopharmaceutical company focused on
developing and delivering life-transforming therapies for patients
with devastating and rare disorders. Alexion is the global leader
in complement inhibition and has developed and commercializes the
first and only approved complement inhibitor to treat patients with
paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic
uremic syndrome (aHUS), two life-threatening ultra-rare disorders.
In addition, Alexion’s metabolic franchise includes two highly
innovative enzyme replacement therapies for patients with
life-threatening and ultra-rare disorders, hypophosphatasia (HPP)
and lysosomal acid lipase deficiency (LAL-D). Alexion is advancing
the most robust rare disease pipeline in the biotech industry with
highly innovative product candidates in multiple therapeutic areas.
This press release and further information about Alexion can be
found at: www.alexion.com
[ALXN-G]
Forward-Looking Statements
This news release contains forward-looking statements, including
statements related to potential medical benefits of SBC-103 for
mucopolysaccharidosis IIIB (MPS IIIB). Forward-looking statements
are subject to factors that may cause Alexion's results and plans
to differ from those expected, including for example, risks and
uncertainties of drug development, decisions of regulatory
authorities regarding marketing approval or material limitations on
the marketing of SBC-103 for MPS IIIB, delays in arranging
satisfactory manufacturing capabilities and establishing commercial
infrastructure for SBC-103 for MPS IIIB, the possibility that
results of clinical trials are not predictive of safety and
efficacy results of SBC-103 in broader or different patient
populations, the risk that estimates regarding the number of
patients with MPS IIIB are inaccurate, the possibility that
clinical trials of our product candidates could be delayed or that
additional research and testing is required by regulatory agencies,
and a variety of other risks set forth from time to time in
Alexion's filings with the Securities and Exchange Commission,
including but not limited to the risks discussed in Alexion's
Quarterly Report on Form 10-Q for the period ended March 31, 2016
and in our other filings with the U.S. Securities and Exchange
Commission. Alexion does not intend to update any of these
forward-looking statements to reflect events or circumstances after
the date hereof, except when a duty arises under law.
References
1.
Whitley CB, Escolar ML, Vijay S, et al.
Initial, 24 Week Results of Heparan Sulfate Levels in Cerebrospinal
Fluid (CSF) and Serum, Brain Structural MRI and Neurocognitive
Evaluations in a Phase I/II, First-in-Human Clinical Trial of
Intravenous SBC-103 in Mucopolysaccharidosis IIIB. Poster presented
at 14th International Symposium on MPS and Related Diseases 2016,
Bonn, Germany, July 14-17. Abstract 99.
2.
Cressant A, et al. Improved behavior and
neuropathology in the mouse model of Sanfilippo type IIIB disease
after adeno-associated virus-mediated gene transfer in the
striatum. J Neurosci. 2004 Nov 10;24(45):10229-39.
3.
Malinowska M, et al. The Use of Elevated
Doses of Genistein-Rich Soy Extract in the Gene Expression-Targeted
Isoflavone Therapy for Sanfilippo Disease Patients. JIMD Rep. 2012;
5: 21–25.
4.
Zafeiriou DI, et al. Mucopolysaccharidosis
type IIIB (MPS IIIB) masquerading as a behavioural disorder. BMJ
Case Rep. 2013; 2013: bcr2013009592.
5.
Nestrasil I, et al. A Prospective Natural
History Study of Mucopolysaccharidosis Type IIIA. Journal of
Pediatrics. 2016; (Vol 170):278–287.e4.
6.
Wijburg FA, Wegrzyn G, Burton BK,
Tylki-Szymanska A. “Mucopolysacchardosis type III (Sanfilippo
syndrome) and misdiagnosis of idiopathic developmental delay,
attention deficit/hyperactivity disorder or autism spectrum
disorder.” Acta Paediatr. 2013;102(5):462-70.
7.
Heron B, et al. Incidence and natural
history of mucopolysaccharidosis type III in France and comparison
with United Kingdom and Greece. Am. J. Med. Genet Part A.
2011;155:58-68.
8.
Whitley CB, Escolar ML, Vijay S, et al.
Initial, 24 Week Results of Heparan Sulfate Levels in Cerebrospinal
Fluid (CSF) and Serum in an Open Label, Phase I/II, First-in-Human
Clinical Trial of Intravenous SBC-103 in Mucopolysaccharidosis
IIIB. Poster presented at WORLDSymposium Annual Meeting 2016, San
Diego, February 29-March 4. Abstract LB-33.
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Alexion Pharmaceuticals, Inc.MediaStephanie Fagan,
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CommunicationsorLauren Cettier, +41 (0)79 572 25 83Associate
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+1-203-699-7722Vice President, Investor Relations
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