Biogen Inc. (NASDAQ: BIIB) today announced new 12-month data for
tofersen, an investigational antisense drug for people with
superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS).
The data show that earlier initiation of tofersen compared to
delayed initiation (six months later in the open-label extension
[OLE] study) slowed declines in clinical function, respiratory
function, muscle strength, and quality of life. At the time of the
analysis, because the majority of participants survived without
permanent ventilation (PV), the median time to death or PV could
not be estimated. However, early survival data suggest a lower risk
of death or PV with earlier initiation of tofersen. These results
are based on new integrated data from the pivotal Phase 3 VALOR
study and its OLE study.
The data were presented today at the European Network to Cure
ALS (ENCALS) meeting in Edinburgh, Scotland between 9-10:25 a.m.
BST. An archived version of the presentation will be available on
the Investors section of Biogen’s website
at investors.biogen.com.
Clinical ResultsAs previously reported in
October 2021, VALOR, a six-month Phase 3 randomized study, did not
meet the primary endpoint of change from baseline to week 28 in the
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale
(ALSFRS-R). However, trends of reduced disease progression across
multiple secondary and exploratory endpoints were observed. The new
12-month data further build on the results previously observed in
the initial readout.
“The initial six-month and now 12-month results show that
tofersen had an impact on important measures critical to people
with SOD1-ALS,” said Timothy Miller, M.D., Ph.D., principal
investigator of VALOR and ALS Center co-Director at Washington
University School of Medicine, St. Louis. “These new 12-month data
showed tofersen consistently slowed disease progression across
endpoints and, if approved, may meaningfully change the lives of
people living with SOD1-ALS.”
The 12-month data compare early initiation of tofersen (at the
start of VALOR) to delayed initiation of tofersen (six months
later, in the OLE). Over 12 months in the overall study population,
results favored earlier start tofersen on measures of:
- Clinical function as measured by ALSFRS-R (difference of 3.5
points; 95% confidence interval [CI]: 0.4, 6.7)
- Respiratory function as measured by slow vital capacity
(difference of 9.2 percent-predicted; 95% CI: 1.7, 16.6)
- Muscle strength as measured by the handheld dynamometry
megascore (difference of 0.28; 95% CI: 0.05, 0.52)
- Quality of life as measured by the 5-item amyotrophic lateral
sclerosis assessment questionnaire (ALSAQ-5) (difference of 10.3
points; 95% CI: -17.3, -3.2)
At the time of the analysis, because the majority of
participants survived without PV, the median time to death or PV
and median time to death, could not be estimated. However, early
survival data suggest a lower risk of death or PV (Hazard ratio
[HR] 0.36; 95% CI: 0.137, 0.941) and death (HR 0.27; 95% CI: 0.084,
0.890) with earlier initiation of tofersen.
Biomarker ResultsThe latest 12-month results
show that reductions in total SOD1 protein (a marker of target
engagement) and neurofilament (a marker of axonal injury and
neurodegeneration) were sustained over time.
“In ALS, people with more rapidly progressing disease have
higher neurofilament levels, most likely because their neurons and
axons are degenerating more quickly,” said Merit Cudkowicz, M.D.,
co-principal investigator of the VALOR trial and co-founder of the
Northeast ALS Consortium, Director of the Healey & AMG Center
for ALS and Chair of Neurology at Massachusetts General Hospital
and the Julieanne Dorn Professor of Neurology at Harvard Medical
School. “Tofersen lowered neurofilament levels by approximately
40-50 percent. The combination of these biomarker results and the
clinical outcomes data provide additional evidence of tofersen's
potential to effectively slow the relentless progression of
SOD1-ALS.”
Tofersen reduced total CSF SOD1 protein and plasma neurofilament
levels in both early- and delayed-start groups as follows:
- 33 percent and 21 percent reduction in SOD1 protein, the
intended target for tofersen, respectively
- 51 percent and 41 percent reduction in plasma neurofilament, a
marker of neuron injury, respectively
Safety ResultsThe most common adverse events
(AEs) in participants receiving tofersen in VALOR and the OLE study
were headache, procedural pain, fall, back pain and pain in
extremity. Most AEs in both VALOR and the OLE were mild to moderate
in severity. Serious AEs were reported in 36.5 percent of
participants who received tofersen in VALOR and/or the OLE and 17.3
percent of participants discontinued treatment due to an AE.
Serious neurologic events including myelitis, radiculitis, aseptic
meningitis, and papilledema, were reported in 6.7 percent of
participants receiving tofersen in VALOR and its OLE. There were 14
deaths reported in tofersen-treated participants in VALOR and the
OLE, all of which were determined not to be related to
tofersen.
About VALOR and the OLEVALOR was a 28-week
Phase 3, randomized, double-blind, placebo-controlled study to
evaluate the effects of tofersen 100 mg in 108 adults with ALS
associated with a SOD1 mutation. In total, 108 participants were
randomized in VALOR (n=72 to tofersen 100 mg and n=36 to placebo).
Of these participants, 95 enrolled in the ongoing OLE. At the time
of the analysis all participants had an opportunity for at least 12
months of follow-up, with a median exposure to tofersen of
approximately 20 months (range: 1 – 34 months).
To account for disease heterogeneity, the planned clinical
analyses adjusted for neurofilament levels as a marker of the
disease progression rate at baseline. Neurofilaments are proteins
that increase in blood and cerebrospinal fluid when neurons or
their axons are damaged. Neurofilaments have been shown to be a
prognostic marker of disease progression and survival in ALS.
“For more than a decade Biogen has pursued new medicines for
ALS. These additional data further reinforce our belief in tofersen
and we will continue to follow the science to change the course of
this cruel and deadly disease,” said Toby Ferguson, M.D., Ph.D.,
Vice President and Head of the Neuromuscular Development Unit at
Biogen. “Biogen is engaging with FDA and regulators around the
world, the medical community and patient advocacy
groups and will provide updates on next steps when
appropriate.”
ENCALS Annual Meeting DetailsFriday, June 3,
2022, 9-10:25 a.m. BST - Evaluating the Efficacy and Safety of
Tofersen in Adults with ALS and a SOD1 Mutation: Results from the
Phase 3 VALOR Trial and Open-Label Extension, presented by Timothy
Miller, M.D., Ph.D., principal investigator of VALOR and ALS Center
co-Director at Washington University School of Medicine, St. Louis.
ENCALS is an annual scientific meeting to review advancements in
ALS.
About TofersenTofersen is an antisense drug
being evaluated for the potential treatment of SOD1-ALS. Tofersen
binds to SOD1 mRNA, allowing for its degradation by RNase-H in an
effort to reduce synthesis of SOD1 protein production. In addition
to the ongoing open label extension of VALOR, tofersen is being
studied in the Phase 3 ATLAS study designed to evaluate whether
tofersen can delay clinical onset when initiated in presymptomatic
individuals with a SOD1 genetic mutation and biomarker evidence of
disease activity. Biogen licensed tofersen from Ionis
Pharmaceuticals, Inc. under a collaborative development and license
agreement.
About Amyotrophic Lateral Sclerosis and
SOD1-ALSAmyotrophic lateral sclerosis (ALS) is a rare,
progressive and fatal neurodegenerative disease that results in the
loss of motor neurons in the brain and the spinal cord that are
responsible for controlling voluntary muscle movement. People with
ALS experience muscle weakness and atrophy, causing them to lose
independence as they steadily lose the ability to move, speak, eat,
and eventually breathe. Average life expectancy for people with ALS
is three to five years from time of symptom onset.1
Multiple genes have been implicated in ALS. Genetic testing
helps determine if a person’s ALS is associated with a genetic
mutation, even in individuals without a family history of the
disease. Currently, there are no genetically targeted treatment
options for ALS. Mutations in the SOD1 gene are responsible for
approximately 2 percent of the estimated 168,000 people who have
ALS globally (SOD1-ALS).2 Life expectancy in SOD1-ALS varies
widely, from less than one year to more than 20 years.3
Biogen’s Continuous Commitment to ALSFor over a
decade, Biogen has been committed to advancing ALS research to
provide a deeper understanding of all forms of the disease. The
company has continued to invest in and pioneer research despite
making the difficult decision to discontinue a late-stage ALS asset
in 2013. Biogen has applied important learnings to its portfolio of
assets for genetic and other forms of ALS, with the goal of
increasing the probability of bringing a potential therapy to
patients in need. These applied learnings include evaluating
genetically validated targets in defined patient populations,
pursuing the most appropriate modality for each target and
employing sensitive clinical endpoints. Today, the company has a
pipeline of investigational drugs being evaluated in ALS, including
tofersen and BIIB105.
About BiogenAs pioneers in neuroscience, Biogen
discovers, develops, and delivers worldwide innovative therapies
for people living with serious neurological 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, Sir Kenneth Murray, and Nobel Prize
winners Walter Gilbert and Phillip Sharp. Today, Biogen has a
leading portfolio of medicines to treat multiple sclerosis, has
introduced the first approved treatment for spinal muscular
atrophy, and developed the first and only approved treatment to
address a defining pathology of Alzheimer’s disease. Biogen is also
commercializing biosimilars and focusing on advancing one of the
industry’s most diversified pipeline in neuroscience that will
transform the standard of care for patients in several areas of
high unmet need.
In 2020, Biogen launched a bold 20-year, $250 million initiative
to address the deeply interrelated issues of climate, health, and
equity. Healthy Climate, Healthy Lives™ aims to eliminate fossil
fuels across the company’s operations, build collaborations with
renowned institutions to advance the science to improve human
health outcomes, and support underserved communities.
We routinely post information that may be important to investors
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Biogen Safe Harbor StatementThis news release
contains forward-looking statements, including statements made
pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995, including statements about results
from the Phase 3 VALOR study of tofersen or its OLE; the potential
clinical effects of tofersen; the potential benefits, safety and
efficacy of tofersen; the clinical development program for
tofersen; the identification and treatment of ALS; our research and
development program for the treatment of ALS; the potential of our
commercial business and pipeline programs, including tofersen; and
risks and uncertainties associated with drug development and
commercialization. These forward-looking statements may be
accompanied by words such as “aim,” “anticipate,” “believe,”
“could,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,”
“potential,” “possible,” “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, uncertainty of
success in the development and potential commercialization of
tofersen; the risk that we may not fully enroll our clinical trials
or enrollment will take longer than expected; unexpected concerns
may arise from additional data, analysis or results obtained during
our clinical trials; regulatory authorities may require additional
information or further studies, or may fail or refuse to approve or
may delay approval of our drug candidates, including tofersen; the
occurrence of adverse safety events; the risks of unexpected
hurdles, costs or delays; failure to protect and enforce our data,
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impacts of the ongoing COVID-19 pandemic on our business, results
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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
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We do not undertake any obligation to publicly update any
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References:
- Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J
Med. 2017 Jul 13;377(2):162-172. doi: 10.1056/NEJMra1603471. PMID:
28700839.
- Brown CA, Lally C, Kupelian V, Flanders WD. Estimated
Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1
and C9orf72 Genetic Variants. Neuroepidemiology.
2021;55(5):342-353. doi: 10.1159/000516752. Epub 2021 Jul 9. PMID:
34247168.
- Bali T, et al. Defining SOD1 ALS
natural history to guide therapeutic clinical trial design. J
Neurol Neurosurg Psychiatry. 2017 Feb;88(2):99-105. doi:
10.1136/jnnp-2016-313521. Epub 2016 Jun 3. PMID: 27261500; PMCID:
PMC5136332.
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