- Data further demonstrate proof-of-concept for
the therapeutic potential of apitegromab in patients with Type 2
and Type 3 SMA
- Phase 3 registrational trial initiation
expected by the end of 2021
- European Medicines Agency (EMA) granted
Priority Medicines (PRIME) designation to apitegromab, recognizing
unmet medical needs of patients with SMA
- Scholar Rock to host webcast today at 8:00am
ET
Scholar Rock (NASDAQ:SRRK), a clinical-stage biopharmaceutical
company focused on the treatment of serious diseases in which
protein growth factors play a fundamental role, today announced
positive top-line data from the TOPAZ Phase 2 clinical trial
evaluating apitegromab (SRK-015) in patients with Type 2 and Type 3
spinal muscular atrophy (SMA).
“These top-line 12-month data provide further support towards
establishing apitegromab as a potential first muscle-directed
therapy for patients with SMA,” said Yung Chyung, M.D., Chief
Medical Officer of Scholar Rock. “The findings also offer important
insights into myostatin biology and our scientific approach of
targeting the latent forms of growth factors. We look forward to
advancing the development and investigation of apitegromab as we
plan to initiate a pivotal trial in SMA by the end of 2021 and
explore its potential in additional disease areas.”
Key findings from the 12-month top-line
analysis include:
- Cohort 1: 5-21 years of age, ambulatory Type 3, 20 mg/kg
dose monotherapy and in conjunction with nusinersen:
- Observed a mean change from baseline in Revised Hammersmith
Scale (RHS) of a 0.3-point decline.
- Majority of patients across the cohort (57%, 13/23 of patients)
maintained or improved their motor function, as reflected by a
>0-point change from baseline in
RHS score, and 22% of patients (5/23) attained a >3-point increase from baseline.
- Results suggest potential clinical effect in certain patients
in this population.
- Cohort 2: 5-21 years of age, Type 2 and non-ambulatory
Type 3 who initiated nusinersen ≥5 years old, 20 mg/kg dose:
- Observed a mean change from baseline in Hammersmith Functional
Motor Scale Expanded (HFMSE) of a 0.6-point improvement.
- Majority of patients (64%, 9/14 of patients) attained a
>1-point increase from baseline and
29% of patients (4/14) attained a >3-point increase from baseline.
- Results support the potential durability of the improvements in
motor function observed at the six-month interim analysis.
- Cohort 3: ≥2 years of age, Type 2 who initiated
nusinersen <5 years of age:
- Observed a mean change from baseline in HFMSE of 7.1-point and
5.3-point improvements in the 20 mg/kg dose and the 2 mg/kg dose
arms, respectively.
- Across the full cohort, 59% of patients (10/17) attained a
>5-point increase and 35% of
patients (6/17) attained a >10-point increase from
baseline.
- Results demonstrate further improvements in motor function
beyond what had been observed at the six-month interim
analysis.
- Dose response continued to be observed based upon clinical
efficacy (HFMSE improvements) and pharmacodynamics (target
engagement).
- No safety signals for apitegromab were identified as of the
12-month top-line analysis. The five most frequently reported
treatment-emergent adverse events (TEAEs) were headache, pyrexia,
upper respiratory tract infection, cough, and nasopharyngitis.
- All 57 patients who completed the 12-month TOPAZ trial have
opted into the extension period.
“These 12-month results from the Phase 2 apitegromab TOPAZ trial
have built upon the previously announced exciting 6-month interim
results,” said Thomas Crawford, M.D., Professor of Neurology at the
Johns Hopkins School of Medicine and Lead Investigator of the TOPAZ
trial. “There looks to be promising potential for a muscle-directed
therapy that will complement the unmet need still evident, and
likely emerging, in many individuals with SMA who receive
SMN-enhancing therapies. Though much work remains to be done, I
believe the results are wonderful news for the SMA community, and I
am enthusiastic about the potential that apitegromab may offer for
further meaningful functional improvements.”
Detailed summary of the TOPAZ 12-month
top-line results by cohort Apitegromab is a selective
inhibitor of the activation of latent myostatin. The TOPAZ Phase 2
proof-of-concept trial enrolled 58 patients with Type 2 and Type 3
SMA across 16 study sites in the United States and Europe. The
trial evaluated the safety and efficacy of intravenous apitegromab
dosed every four weeks (Q4W) over a 12-month treatment period. Four
patients (one in Cohort 2 and three in Cohort 3) each missed three
consecutive doses of apitegromab over the course of the 12-month
treatment period due to COVID-19-related site access restrictions
and are excluded from the prespecified intent-to-treat primary
analysis.
Cohort 1: This open-label,
single-arm cohort enrolled 23 patients with ambulatory Type 3 SMA.
Patients were treated with 20 mg/kg of apitegromab either as a
monotherapy or in conjunction with an approved SMN upregulator
therapy (nusinersen). The primary objectives of Cohort 1
were to assess safety and the mean change from baseline in RHS
following 12 months of treatment.
In Cohort 1 (pooled population), the mean change from baseline
in RHS score was a 0.3-point decline. The Cohort 1 efficacy data suggest a potential
clinical effect of apitegromab in certain patients in this
population, as 57% of patients observed a maintenance or
improvement in RHS score (>0-point change from baseline) and 22%
of patients achieved at least a 3-point increase in RHS score from
baseline.
Cohort 1 (Intent-to-treat
population)
Apitegromab 20 mg/kg
monotherapy (n=11)
Apitegromab 20 mg/kg +
nusinersen (n=12)
Apitegromab pooled
(n=23)
Mean change from baseline in RHS score
(95% CI)
-0.4 (-3.9, +3.1)
-0.3 (-2.0, +1.4)
-0.3 (-2.1, +1.4)
% of patients attaining ≥0-point increase
in RHS score
6/11 (55%)
7/12 (58%)
13/23 (57%)
% of patients attaining ≥1-point increase
in RHS score
4/11 (36%)
5/12 (42%)
9/23 (39%)
% of patients attaining ≥3-point increase
in RHS score
3/11 (27%)
2/12 (17%)
5/23 (22%)
% of patients attaining ≥5-point increase
in RHS score
1/11 (9%)
0/12 (0%)
1/23 (4%)
Cohort 2: This open-label,
single-arm cohort enrolled 15 patients with Type 2 or
non-ambulatory Type 3 SMA and who were already receiving treatment
with an approved SMN upregulator (nusinersen) initiated at age five
years or older. One patient missed three consecutive doses
of apitegromab due to COVID-19-related site access restrictions and
was excluded from the prespecified intent-to-treat primary
analysis. The primary objectives of the cohort were to assess
safety and the mean change from baseline in HFMSE following 12
months of treatment.
Cohort 2 efficacy data
demonstrate improvement of motor function from baseline. The mean
change from baseline in HFMSE score was a 0.6-point increase. The
majority (64%) of patients achieved at least a 1-point increase in
HFMSE and 29% of patients achieved at least a 3-point increase in
HFMSE from baseline. Potential durability of effect was observed up
to 12 months of treatment.
One patient in Cohort 2 was
identified as having received concomitant treatment with an
acetylcholinesterase inhibitor before and during the study, which
was not permitted by the trial protocol. This patient experienced a
7-point decline in HFMSE score at the 12-month timepoint. In the
per protocol analysis conducted in accordance with the prespecified
approach, which excludes this patient as well as the patient who
missed three consecutive doses due to COVID-19-related site access
restrictions, the mean change from baseline in HFMSE score for
Cohort 2 was a 1.2-point improvement.
Cohort 2
Apitegromab 20 mg/kg +
nusinersen
Intent-to-treat (n=14)
Per Protocol (n=13)
Mean change from baseline in HFMSE score
(95% CI)
+0.6 (-1.4, +2.7)
+1.2 (-0.5, 2.9)
% of patients attaining ≥1 point increase
in HFMSE score
9/14 (64%)
9/13 (69%)
% of patients attaining ≥3 point increase
in HFMSE score
4/14 (29%)
4/13 (31%)
% of patients attaining ≥5 point increase
in HFMSE score
2/14 (14%)
2/13 (15%)
Cohort 3: This randomized,
double-blind, parallel arm portion of the trial enrolled patients
with Type 2 SMA who had initiated treatment with an approved SMN
upregulator (nusinersen) before five years of age. Twenty patients
were randomized in a 1:1 ratio to receive the low dose (apitegromab
2 mg /kg Q4W) or high dose (apitegromab 20 mg/kg Q4W); both
treatment arms were in conjunction with an approved SMN upregulator
therapy (nusinersen). Three patients (two in high-dose arm
and one in low-dose arm) each missed three consecutive doses of
apitegromab due to COVID-19-related site access restrictions and
were excluded from the prespecified intent-to-treat primary
analysis. The primary objectives of the cohort were to assess
safety and the mean change from baseline in HFMSE following 12
months of treatment.
Cohort 3 efficacy data
demonstrate further improvements in motor function relative to what
was observed at the six-month interim analysis. The mean change
from baseline in HFMSE score was a 7.1-point and a 5.3-point
improvement for the 20 mg/kg and 2 mg/kg dose arms, respectively.
The majority (59%) of patients in Cohort 3 achieved at least a
5-point increase in HFMSE and 35% of patients achieved greater than
a 10-point increase in HFMSE over baseline.
Dose response was observed; the 20 mg/kg dose achieved
numerically greater mean improvements from baseline in HFMSE scores
than the 2 mg/kg dose across all assessed timepoints in the
12-month treatment period. The clinically observed dose response
was consistent with the pharmacodynamic (target engagement)
results. Both the 20 mg/kg and 2 mg/kg doses yielded high levels of
target engagement (>100-fold increase from baseline), but the 20
mg/kg dose led to a relatively higher absolute level of target
engagement.
Cohort 3 (Intent-to-treat
population)
Apitegromab 20 mg/kg +
nusinersen (n=8)
Apitegromab 2 mg/kg +
nusinersen (n=9)
Apitegromab pooled
(n=17)
Mean change from baseline in HFMSE score
(95% CI)
+7.1 (+1.8, +12.5)
+5.3 (-1.5, +12.2)
+6.2 (+2.2, +10.1)
% of patients attaining ≥1-point increase
in HFMSE score
7/8 (88%)
7/9 (78%)
14/17 (82%)
% of patients attaining ≥3-point increase
in HFMSE score
5/8 (63%)
5/9 (56%)
10/17 (59%)
% of patients attaining ≥5-point increase
in HFMSE score
5/8 (63%)
5/9 (56%)
10/17 (59%)
% of patients attaining >10-point
increase in HFMSE score
3/8 (38%)
3/9 (33%)
6/17 (35%)
Overall safety and tolerability profile:
- Incidence and severity of adverse events were consistent with
the underlying patient population and background therapy.
- Five most frequently reported TEAEs: Headache (24%), pyrexia
(22%), upper respiratory tract infection (22%), cough (22%), and
nasopharyngitis (21%).
- Five patients experienced a serious treatment-emergent adverse
event, all assessed by the respective trial investigator as
unrelated to apitegromab:
- One patient treated with 2 mg/kg dose (Cohort 3) hospitalized
due to adenoidal hypertrophy and tonsillar hypertrophy to perform
scheduled adenotonsillectomy (Grade 2). Event resolved without
sequelae.
- Two patients treated with 20 mg/kg dose (both Cohort 1) with
gait inability considered a significant disability (both Grade 3).
Events remain ongoing.
- One patient treated with 20 mg/kg dose (Cohort 1) hospitalized
with post lumbar puncture syndrome (Grade 2). Event resolved
without sequelae.
- One patient treated with 20 mg/kg dose (Cohort 1) hospitalized
due to viral upper respiratory tract infection (Grade 2). Event
resolved without sequelae.
- One patient (Cohort 1) presented with a non-serious Grade 3
post lumbar puncture syndrome; assessed by trial investigator as
unrelated to apitegromab. Event resolved without sequelae.
- One patient (Cohort 1) discontinued from the trial due to Grade
2 muscle fatigue that started prior to initiation of dosing with
study drug; assessed by the trial investigator as unrelated to
apitegromab.
- Anti-drug antibodies (ADA) were present at low titers following
apitegromab treatment in three out of the 58 enrolled patients. No
apparent impact on drug exposure was observed and was not
associated with any hypersensitivity reactions.
Additional potential disease areas for apitegromab:
Scholar Rock believes apitegromab has potential for applicability
across multiple SMA types, as well as in other neuromuscular
indications. Based upon ongoing indication assessments, the Company
has identified Becker Muscular Dystrophy (BMD), which affects
approximately 20,000 individuals in the US and EU(a), as the next
potential indication for apitegromab. The Company is in the process
of planning a proof-of-concept trial with an aim to initiate the
trial in 2022. Scholar Rock is continuing to explore other
myostatin-related indications for which fast-twitch fibers may play
an important role in motor function.
Conference call/webcast: Scholar Rock will host a
conference call and audio webcast to discuss the apitegromab TOPAZ
Phase 2 clinical trial top-line results today at 8:00 a.m. Eastern
Time. To participate in the call, please dial 833-519-1308
(domestic) or 914-800-3874 (international) and refer to conference
ID: 4196782. A webcast of the call will also be available on the
Investors & Media section of the Scholar Rock website at
http://investors.scholarrock.com. An archived replay of the webcast
will be available on Scholar Rock’s website at:
https://scholarrock.com/ for approximately 180 days following the
presentation.
(a) “Muscular Dystrophy: Disease Landscape and Forecast.” DRG
Reports, June 2020
About SMA Spinal muscular atrophy (SMA) is a rare, and
often fatal, genetic disorder that typically manifests in young
children. An estimated 30,000 to 35,000 patients are afflicted with
SMA in the United States(1) and Europe(2). It is characterized by
the loss of motor neurons, atrophy of the voluntary muscles of the
limbs and trunk and progressive muscle weakness. The underlying
pathology of SMA is caused by insufficient production of the SMN
(survival of motor neuron) protein, essential for the survival of
motor neurons, and is encoded by two genes, SMN1 and SMN2(3). While
there has been progress in the development of therapeutics that
address the underlying SMA genetic defect, there continues to be a
high unmet need for therapeutics that directly address muscle
atrophy.
(1) Lally, C. et al. Indirect estimation of the prevalence of
spinal muscular atrophy Type I, II, and III in the United States.
Orphanet Journal of Rare Diseases. (2017) 12:175. (2) Briefing
Document to the Clinical Trial Readiness in Spinal Muscular Atrophy
(SMA) SMA Europe, TREAT-NMD and European Medicines Agency meeting.
Prepared by SMA Europe and TREAT-NMD. November 11, 2016. (3)
Parente, V. and Corti, S. Advances in spinal muscular atrophy
therapeutics. Therapeutic Advances in Neurological Disorders.
(2018) 11:1.
About Apitegromab Apitegromab (SRK-015) is a selective
inhibitor of the activation of latent myostatin and is an
investigational product candidate for the treatment of patients
with spinal muscular atrophy (SMA). Myostatin, a member of the TGFβ
superfamily of growth factors, is expressed primarily by skeletal
muscle cells, and the absence of its gene is associated with an
increase in muscle mass and strength in multiple animal species.
Scholar Rock believes the inhibition of the activation of latent
myostatin with apitegromab may promote a clinically meaningful
improvement in motor function.
The TOPAZ Phase 2 clinical trial in patients with Type 2 and
Type 3 SMA is ongoing in the extension phase (NCT03921528). The
U.S. Food and Drug Administration (FDA) has granted Orphan Drug
Designation (ODD) and Rare Pediatric Disease (RPD) designation, and
the European Medicines Agency (EMA) has granted Priority Medicines
(PRIME) Designation and Orphan Medicinal Product Designation, to
apitegromab for the treatment of SMA. The efficacy and safety of
apitegromab have not been established and apitegromab has not been
approved for any use by the FDA or any other regulatory agency.
About Scholar Rock Scholar Rock is a clinical-stage
biopharmaceutical company focused on the discovery and development
of innovative medicines for the treatment of serious diseases in
which signaling by protein growth factors plays a fundamental role.
Scholar Rock is creating a pipeline of novel product candidates
with the potential to transform the lives of patients suffering
from a wide range of serious diseases, including neuromuscular
disorders, cancer, fibrosis and anemia. Scholar Rock’s approach to
targeting the molecular mechanisms of growth factor activation
enabled it to develop a proprietary platform for the discovery and
development of monoclonal antibodies that locally and selectively
target these signaling proteins at the cellular level. By
developing product candidates that act in the disease
microenvironment, the Company intends to avoid the historical
challenges associated with inhibiting growth factors for
therapeutic effect. Scholar Rock believes its focus on biologically
validated growth factors may facilitate a more efficient
development path. For more information, please visit
https://scholarrock.com/ or follow Scholar Rock on Twitter
(@ScholarRock) and LinkedIn
(https://www.linkedin.com/company/scholar-rock/).
Scholar Rock® is a registered trademark of Scholar Rock,
Inc.
Forward-Looking Statements This press release contains
"forward-looking statements" within the meaning of the Private
Securities Litigation Reform Act of 1995, including, but not
limited to, statements regarding the potential of apitegromab,
Scholar Rock’s future expectations, plans and prospects, including
without limitation, Scholar Rock’s expectations regarding its
growth, strategy, progress and timing of its clinical trials for
apitegromab, the potential of its proprietary platform, and its
intellectual property protection. The use of words such as “may,”
“might,” “will,” “should,” “expect,” “plan,” “anticipate,”
“believe,” “estimate,” “project,” “intend,” “future,” “potential,”
or “continue,” and other similar expressions are intended to
identify such forward-looking statements. All such forward-looking
statements are based on management's current expectations of future
events and are subject to a number of risks and uncertainties that
could cause actual results to differ materially and adversely from
those set forth in or implied by such forward-looking statements.
These risks and uncertainties include the possibility that
preclinical and clinical data, including the 12-month top-line
results from the Phase 2 trial of apitegromab, are not predictive
of, are inconsistent with, or more favorable than, data generated
from future clinical trials of the same product candidate,
including the planned Phase 3 registrational trial of apitegromab
in SMA, Scholar Rock’s ability to provide the financial support,
resources and expertise necessary to identify and develop product
candidates on the expected timeline, the data generated from
Scholar Rock’s nonclinical and preclinical studies and clinical
trials, information provided or decisions made by regulatory
authorities, competition from third parties that are developing
products for similar uses, Scholar Rock’s ability to obtain,
maintain and protect its intellectual property, Scholar Rock’s
dependence on third parties for development and manufacture of
product candidates including to supply any clinical trials, Scholar
Rock’s ability to manage expenses and to obtain additional funding
when needed to support its business activities and establish and
maintain strategic business alliances and new business initiatives,
and the impacts of public health pandemics such as COVID-19 on
business operations including its clinical trials, as well as those
risks more fully discussed in the section entitled "Risk Factors"
in Scholar Rock’s Annual Report on Form 10-K for the year ended
December 31, 2020, as well as discussions of potential risks,
uncertainties, and other important factors in Scholar Rock’s
subsequent filings with the Securities and Exchange Commission. Any
forward-looking statements represent Scholar Rock’s views only as
of today and should not be relied upon as representing its views as
of any subsequent date. All information in this press release is as
of the date of the release, and Scholar Rock undertakes no duty to
update this information unless required by law.
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Scholar Rock: Investors: Catherine Hu
chu@scholarrock.com
Media: Ariane Lovell Finn Partners
ariane.lovell@finnpartners.com 917-565-2204
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