Biogen (Nasdaq: BIIB) today announced that data from CS2/CS12, an
open-label study of the safety and tolerability of SPINRAZA in
individuals with later-onset spinal muscular atrophy (SMA), were
published in the peer-reviewed journal Neurology, the medical
journal of the American Academy of Neurology. The data show that
individuals with later-onset SMA, treated with SPINRAZA, regained
motor function that had been previously lost and that treatment
stabilized their disease activity leading to improvements in
activities of daily living.
“These data give us new insight on how long-term treatment
with SPINRAZA, over approximately three years, continues to help
individuals with later-onset SMA and
shows improved clinical efficacy,” said Basil Darras,
M.D., lead study author, professor of neurology at Harvard Medical
School. “A longitudinal analysis of this kind, which has not been
available until now, provides a wealth of information about the
ability to help prevent motor function loss, regain function and
safely treat individuals with later-onset SMA. As we change the
paradigm of living with SMA, long-term studies of this kind will be
essential to understanding the disease.”
“These results add to the body of evidence of SPINRAZA as the
foundation of care in SMA broadening its safety and efficacy
profile. The data underscore the ability of the therapy to help
improve the lives of people with SMA, including those with
later-onset SMA, who without treatment typically experience a
progressive decline in motor function,” said Wildon Farwell, M.D.,
executive medical director, clinical development at Biogen.
The full manuscript, “Nusinersen in later-onset spinal muscular
atrophy: long-term results from the phase 1/2 studies” is available
online and will appear in the May 21, 2019 print issue of
Neurology. The open-label study evaluated 28 patients, aged five to
19 at time of study completion, with later-onset SMA including
those most likely to develop SMA Type 2 (n=11) and 3 (n=17) that
were treated with SPINRAZA for more than three years.
In addition to safety, the study also evaluated motor function
measures through the Hammersmith Functional Motor Scale–Expanded
(HFMSE); Upper Limb Module (ULM); and Six-Minute Walk Test (6MWT).
The mean scores for each test showed clinically significant
improvements. Key highlights include:
- Participants with SMA Type 2 increased HFMSE scores by 10.8
points while those with SMA Type 3 improved by 1.8 points. This
compares to the natural history of the disease in which individuals
with SMA Type 2 and 3 who are not being treated typically
experience a 1.7-point decline in HFMSE scores after three
years.1
- All non-ambulant children with SMA Type 3 achieved a maximum
score of 18 points on the ULM assessment by day 350 and maintained
that level of function through day 1,150. This compares to the
natural history of the disease in which non-ambulant children with
SMA Type 2 and 3 have an average ULM score of 10.23 points with an
average 12-month gain of 0.04.2
- Individuals with SMA Type 2 had an average increase of 4.0
points in the ULM assessment up to three years after the baseline
assessment. In the natural history of the disease, individuals
experience a 0.04 gain over a 12-month period.2
- Participants with SMA Type 3 increased their distance walked by
92.0 meters in the 6MWT in comparison to a 1.5-meter decrease in
natural history in the same test after one year.3
- One of the 11 non-ambulant children with SMA Type 2 gained the
ability to walk independently through the course of the studies– an
achievement that has never been reported in individuals with SMA
Type 2 that are not undergoing treatment.
- Two of the four children with SMA Type 3, who had previously
lost the ability to walk, regained the ability to walk
independently during the course of the studies, suggesting that
reversal of motor function loss may be possible for later-onset
individuals treated with SPINRAZA.
- No participants discontinued treatment due to adverse events
and no new safety concerns were identified during the three-year
observation period.
The analysis is based on patients first treated during the CS2
study who continued treatment in the CS12 extension study. CS2 was
a 253-day, multiple ascending dose (3, 6, 9, 12 mg), open-label,
multicenter study that enrolled children with SMA aged two to 15
years. CS12 was a 715-day, single-dose level (12 mg) study. Time
between studies varied by participant.
The SPINRAZA clinical development program includes over six
years of data from 300 patients and is the largest body of evidence
in SMA. As of March 31, 2019, over 7,500 individuals with SMA have
been treated with SPINRAZA worldwide, based on patients across the
post-marketing setting, Expanded Access Program (EAP) and clinical
trial participants. For more information about SPINRAZA and
prescribing information in the United States, please
visit www.SPINRAZA.com. Prescribing information in the
European Union is available
at http://www.ema.europa.eu/ema/.
About SPINRAZA® (nusinersen)4-7SPINRAZA is the
first and only approved medicine for the treatment of spinal
muscular atrophy (SMA) and is currently available in more than 40
countries. As of March 31, 2019, over 7,500 individuals with SMA
are being treated with SPINRAZA worldwide, based on patients across
the post-marketing setting, Expanded Access Program (EAP) and
clinical trial participants.
SPINRAZA is an antisense oligonucleotide (ASO) developed using
Ionis’ proprietary antisense technology that is designed to treat
the root cause of SMA. SPINRAZA alters the splicing of SMN2
pre-mRNA in order to increase production of full-length SMN
protein. ASOs are short synthetic strings of nucleotides designed
to selectively bind to target RNA and regulate gene expression.
Through use of this technology, SPINRAZA has been shown to increase
the amount of full-length SMN protein in individuals with SMA.
SPINRAZA is administered via intrathecal injection, which delivers
therapies directly into the cerebrospinal fluid (CSF) around the
spinal cord, where motor neurons degenerate in individuals with SMA
due to insufficient levels of SMN protein.
In the clinical trial program, SPINRAZA demonstrated a favorable
benefit-risk profile. The most common adverse reactions that
occurred in the SPINRAZA group were respiratory infection and
constipation. Serious adverse reactions of atelectasis were more
frequent in SPINRAZA-treated patients. Coagulation abnormalities
and thrombocytopenia, including acute severe thrombocytopenia, have
been observed after administration of some ASOs. Individuals may be
at increased risk of bleeding complications. Renal toxicity has
been observed after administration of some ASOs. SPINRAZA is
present in and excreted by the kidney.
Biogen licensed the global rights to develop, manufacture and
commercialize SPINRAZA from Ionis Pharmaceuticals, Inc. (Nasdaq:
IONS), a leader in antisense therapeutics. Biogen and Ionis
conducted an innovative clinical development program, the largest
of its kind in SMA, that moved SPINRAZA from its first dose in
humans in 2011 to its first regulatory approval in five years.
About the SPINRAZA Clinical Program NURTURE is
an ongoing, open-label study of infants up to six weeks of age at
time of first dose, who were genetically diagnosed with SMA and had
not experienced any symptoms by the time of first dose. Data
presented at the World Muscle Society in October 2018 demonstrated
unprecedented efficacy in treating patients pre-symptomatically. In
that analysis, all NURTURE study participants were alive and did
not require permanent ventilation, in contrast to natural history
of SMA. Study participants achieved motor milestones with 100
percent sitting independently and 88 percent able to walk. All
NURTURE study participants were 14 months or older at the time of
the analysis.Participants included infants with two copies of the
SMN2 gene (n=15) who are likely to develop a fatal, early-onset
form of SMA known as Type 1, and infants with three copies of the
SMN2 gene (n=10) who typically develop SMA Type 2 or 3. People
living with SMA Types 2 and 3 may never be able to walk or will
lose that ability over time. No new safety concerns were
identified.
The ENDEAR study was a thirteen-month, international, phase 3,
multicenter, double-blind, sham-controlled study of 121 patients
with infantile-onset SMA (most likely to develop SMA Type 1).
Results from the pivotal study, which were published in The New
England Journal of Medicine, evaluated the efficacy and safety in
patients that onset of signs and symptoms of SMA before six months
of age. Patients treated with SPINRAZA in the ENDEAR study achieved
clinically meaningful improvement in achievement of motor
milestones compared to untreated study participants with 51 percent
vs. 0 percent demonstrating Hammersmith Infant Neurological
Examination section 2 (HINE-2) motor milestone response, an
assessment which evaluates eight motor-milestone categories, based
on the defined criteria.
CHERISH was a fifteen-month, phase 3, randomized, double-blind,
sham-controlled study investigating SPINRAZA in 126 non-ambulatory
patients with later-onset SMA (most likely to develop SMA Type 2 or
3). Patients included had onset of signs and symptoms at greater
than 6 months of age, and an age of 2 to 12 years at screening. The
final analysis of CHERISH data found that children receiving
SPINRAZA experienced a highly statistically significant and
clinically meaningful improvement in motor function compared to
those who did not receive treatment with a treatment difference of
4.9 points on the Hammersmith Functional Motor Scale Expanded.
SPINRAZA demonstrated a favorable benefit-risk profile in the
study.
About SMA8 SMA is a rare, genetic,
neuromuscular disease that is characterized by loss of motor
neurons in the spinal cord and lower brain stem, resulting in
severe and progressive muscle atrophy and weakness. About 1 in
10,000 live births have a diagnosis of SMA. Ultimately, individuals
with SMA can lose the ability to walk and have difficulty
performing the basic functions of life, such as breathing and
swallowing, which results in significant healthcare intervention
and caregiver assistance. Left untreated, the majority of infants
with the most severe form of the disease (Type 1) do not live
beyond their second birthday without respiratory intervention.
People with childhood or adult onset SMA (Type 2 or 3) produce
greater amounts of SMN protein resulting in less severe, but still
life-altering forms of the disease.
Due to a deletion of, or mutation in, the SMN1 gene, people with
SMA do not produce enough survival motor neuron (SMN) protein,
which is critical for the maintenance of motor neurons. The
severity of SMA correlates with the amount of SMN protein an
individual has. People with Type 1 SMA, the form that requires the
most intensive and supportive care, produce very little SMN protein
and do not achieve the ability to sit without support or typically
live beyond two years without respiratory support. People with Type
2 and Type 3 SMA produce greater amounts of SMN protein and have
less severe, but still life-altering forms of SMA.
About Biogen At Biogen, our mission is clear:
we are pioneers in neuroscience. Biogen discovers, develops, and
delivers worldwide innovative therapies for people living with
serious neurological and neurodegenerative diseases as well as
related therapeutic adjacencies. One of the world’s first global
biotechnology companies, Biogen was founded in 1978 by Charles
Weissmann, Heinz Schaller, Kenneth Murray, and Nobel Prize winners
Walter Gilbert and Phillip Sharp, and today has the leading
portfolio of medicines to treat multiple sclerosis, has introduced
the first and only approved treatment for spinal muscular atrophy,
and is focused on advancing neuroscience research programs in MS
and neuroimmunology, Alzheimer’s disease and dementia, movement
disorders, neuromuscular disorders, acute neurology, neurocognitive
disorders, pain, and ophthalmology. Biogen also commercializes
biosimilars of advanced biologics.
We routinely post information that may be important to investors
on our website at www.biogen.com. To learn more, please
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Biogen Safe Harbor This news release
contains forward-looking statements, including statements made
pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995, relating to the potential benefits,
safety and efficacy of SPINRAZA; the results of certain real-world
data; our research and development program for the treatment of
SMA; and availability of patient access and reimbursement pathways,
which may vary on a country-by-country basis. These statements may
be identified by words such as “aim,” “anticipate,” “believe,”
“could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,”
“plan,” “possible,” “potential,” “will,” “would” and other words
and terms of similar meaning. Drug development and
commercialization involve a high degree of risk, and only a small
number of research and development programs result in
commercialization of a product. Results in early stage clinical
trials may not be indicative of full results or results from later
stage or larger scale clinical trials and do not ensure regulatory
approval. You should not place undue reliance on these statements
or the scientific data presented.
These statements involve risks and uncertainties that could
cause actual results to differ materially from those reflected in
such statements, including without limitation the occurrence of
adverse safety events and/or unexpected concerns that may arise
from additional data or analysis; risks of unexpected costs or
delays; failure to protect and enforce our data, intellectual
property and other proprietary rights and uncertainties relating to
intellectual property claims and challenges; product liability
claims; and third party collaboration risks. The foregoing sets
forth many, but not all, of the factors that could cause actual
results to differ from our expectations in any forward-looking
statement. Investors should consider this cautionary statement, as
well as the risk factors identified in our most recent annual or
quarterly report and in other reports we have filed with the
Securities and Exchange Commission. These statements are based on
our current beliefs and expectations and speak only as of the date
of this news release. We do not undertake any obligation to
publicly update any forward-looking statements, whether as a result
of new information, future developments or otherwise.
Reference:1. Kaufmann P, McDermott MP, Darras BT, et al.
Prospective cohort study of spinal muscular atrophy types 2 and 3.
Neurology. 2012;79(18):1889-1897.
2. Sivo S, Mazzone E, De Sanctis, et al. Upper limb module in
non-ambulant patients with spinal muscular atrophy: 12 month
changes. Neuromuscul Disord. 2015;25(3):212-215.
3. Mazzone E, Bianco F, Main M, et al. Six minute walk test in
type III spinal muscular atrophy: a 12 month longitudinal study.
Neuromuscul Disord. 2013;23(8):624-628.
4. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF,
Krainer AR. Antisense correction of SMN2 splicing in the CNS
rescues necrosis in a type III SMA mouse model. Genes Dev. 2010 Aug
1; 24(15):16344-44.
5. Finkel R, Chiriboga C, Vajsar J, et al. Treatment of
infantile-onset spinal muscular atrophy with nusinersen: a phase 2,
open-label, dose-escalation study. Lancet.
2016;388(10063):3017-3026.
6. Evers MM, Toonen LJ, van Roon-Mom WM. Antisense
oligonucleotides in therapy for neurodegenerative disorders. Adv
Drug Deliv Rev. 2015;87:90-103.
7. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet.
2008;371(9630):2120-2133.
8. Darras B, Markowitz J, Monani U, De Vivo D. Chapter 8 -
Spinal Muscular Atrophies. In: Vivo BTD, ed. Neuromuscular
Disorders of Infancy, Childhood, and Adolescence (Second Edition).
San Diego: Academic Press; 2015:117-145.
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