– Phase 3 trial is a randomized, double-blind,
placebo-controlled trial of apitegromab as add-on to background SMN
therapy in non-ambulatory Type 2/3 SMA
– Trial design is informed by the positive
results from the prior TOPAZ trial, including a new exploratory
analysis of patients 2-12 years old with non-ambulatory Type 2/3
SMA
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 the
study design for SAPPHIRE, a Phase 3 trial of apitegromab, a
selective inhibitor of the activation of latent myostatin. This
pivotal trial will evaluate the efficacy and safety of apitegromab
in patients with non-ambulatory Type 2 and Type 3 spinal muscular
atrophy (SMA), which is estimated to represent approximately
two-thirds of the overall SMA patient population. Study start-up
activities for SAPPHIRE have commenced.
“Despite the important progress in SMA treatment offered by SMN
therapies, there continues to be significant unmet medical need,
and we believe that apitegromab has the potential to improve motor
function as add-on to background SMN therapy and transform the
lives of patients with SMA,” said Nagesh Mahanthappa, Ph.D.,
Interim CEO. “We are excited to advance to the pivotal trial phase
of apitegromab development through SAPPHIRE.”
SAPPHIRE Trial Design
SAPPHIRE is a randomized, double-blind, placebo-controlled,
phase 3 clinical trial. Approximately 156 patients aged 2-12 years
old with non-ambulatory Type 2/3 SMA are anticipated to be enrolled
in the main efficacy population. Patients will be randomized 1:1:1
to receive for 12 months either apitegromab 10 mg/kg, apitegromab
20 mg/kg, or placebo by intravenous (IV) infusion every 4 weeks
added on top of background SMN treatment. Patients receiving the
background SMN treatment of nusinersen as well as patients
receiving background SMN treatment of risdiplam will both be
eligible for enrollment.
Additional key elements of the study design include the
following:
- At baseline, all patients will be required to be in the chronic
maintenance phase of SMN treatment, corresponding to > 6 months of prior treatment in the case of
risdiplam or > 10 months of prior
treatment in the case of nusinersen.
- Randomization will be stratified by both the background SMN
treatment (nusinersen vs. risdiplam) as well as the age at which
SMN treatment had been initiated (< 5 years vs. > 5 years).
- The primary efficacy endpoint will evaluate the mean change
from baseline in the Expanded Hammersmith Functional Motor Scale
(HFMSE) total score after 12 months of treatment.
- Additional endpoints will evaluate safety, proportion of
patients with >3-point HFMSE
increase, Revised Upper Limb Module (RULM), and World Health
Organization (WHO) motor developmental milestones,
pharmacokinetics, pharmacodynamics, anti-drug antibody, and other
outcome measures.
In addition, the trial provides the opportunity for an interim
analysis when at least 50% of patients in the main efficacy
population (age 2-12 years) have completed 12 months of
treatment.
Separately from the main efficacy population, an exploratory
population of 48 patients aged 13-21 years old with non-ambulatory
Type 2/3 SMA will be evaluated. These patients will be randomized
2:1 to receive either apitegromab 20 mg/kg or placebo added to
background SMN treatment with nusinersen or risdiplam. In this
subpopulation of older individuals with SMA, the safety and
tolerability of apitegromab will be characterized, and efficacy
will also be evaluated in an exploratory, nonpowered manner.
To further characterize apitegromab in SMA, upon completion of
the 12-month treatment period, all patients will be offered the
option of enrolling in an open-label extension study. In this
open-label extension, the safety and tolerability of apitegromab
will be evaluated, along with an exploratory characterization of
longer-term efficacy. In addition, the TOPAZ extension continues to
follow patients from TOPAZ and evaluate the longer-term efficacy
and safety of apitegromab. Among the 57 patients who completed the
12-month TOPAZ treatment period, 55 patients continue to
participate in the extension period as of November 30, 2021.
SAPPHIRE is planned to enroll across 55 sites globally,
including in the U.S. and Europe, and study start-up activities
have commenced. For more information about SAPPHIRE, visit
www.clinicaltrials.gov.
“We are encouraged and motivated by the positive results of the
TOPAZ Phase 2 proof of concept trial, which informed the design of
SAPPHIRE to evaluate the therapeutic potential of apitegromab in
SMA,” said Yung Chyung, M.D., CMO. “Building on the solid
foundation of TOPAZ, our Phase 3 trial and the broader program are
aimed at advancing the development of apitegromab towards our
aspiration of transforming the lives of patients with SMA.”
TOPAZ Insights Inform Key Elements of
the SAPPHIRE Design
The SAPPHIRE design was informed by results from the TOPAZ phase
2 proof of concept trial of apitegromab in patients with Type 2 and
Type 3 SMA. Key features of the SAPPHIRE design include the
following:
- SAPPHIRE enrolls patients with non-ambulatory Type 2/3 SMA,
which was the population of individuals observed to have the
largest HFMSE increases from baseline in TOPAZ.
- Selection of the age 2-12 population in SAPPHIRE was informed
by the positive efficacy results of an exploratory post hoc
analysis from TOPAZ, as described in further detail below.
- SAPPHIRE will use the same primary efficacy endpoint (mean
HFMSE change from baseline) as had been used in TOPAZ.
- SAPPHIRE will use the same treatment duration (12 months) as
had been used in TOPAZ.
- SAPPHIRE will evaluate apitegromab at 20 mg/kg, which was
observed in TOPAZ to have a greater effect than the 2 mg/kg dose
both in terms of efficacy and pharmacodynamics. As it is possible
that an intermediate dose of apitegromab between 2 and 20 mg/kg may
offer comparable effects as the 20 mg/kg dose, SAPPHIRE will
include an apitegromab 10 mg/kg arm. To control type I error caused
by multiple comparisons, the efficacy analysis will first compare
the apitegromab 20 mg/kg arm against placebo before any testing of
apitegromab 10 mg/kg against placebo.
Exploratory Analysis of Age 2-12
Non-Ambulatory Patients from TOPAZ
This exploratory post hoc analysis from TOPAZ pooled together
patients from both non-ambulatory cohorts (patients who had
initiated their background nusinersen therapy at the age of < 5
years and patients who had initiated their background nusinersen
therapy at the age of > 5 years).
Patients in this subset of the intent-to-treat population were in
the age range of 2-12 years old and had been treated with 20 mg/kg
of apitegromab.
The 12-month apitegromab results from this age 2-12 years old
exploratory analysis of the pooled non-ambulatory cohorts in TOPAZ
include the following:
- N= 16 total, with 50% of these patients being from the cohort
of background nusinersen initiated at age < 5 years and 50% of
these patients being from the cohort of background nusinersen
initiated at age > 5 years
- All patients were in the chronic maintenance phase of
nusinersen treatment. Data from the SHINE study suggest that the
effects of nusinersen upon HFMSE generally plateau after initial
increases.1
- Mean HFMSE change from baseline was 4.4-point increase (95% CI
of 1.3, 7.4)
- 81% (13/16) of patients had >
1-point increase in HFMSE
- 56% (9/16) of patients had >
3-point increase in HFMSE
- Among the older subset of patients (individuals who had started
their background nusinersen at the age of > 5 years) in this analysis, 75% (6/8) of
patients had > 1-point increase in
HFMSE and 50% (4/8) of patients had > 3-point increase in HFMSE
About Apitegromab
Apitegromab is a selective inhibitor of the activation of
myostatin and is an investigational product candidate for the
treatment of patients with 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,
including humans. Scholar Rock believes that inhibiting myostatin
activation with apitegromab may promote a clinically meaningful
improvement in motor function in patients with SMA. The U.S. Food
and Drug Administration (FDA) has granted Fast Track (FTD), Orphan
Drug (ODD) and Rare Pediatric Disease (RPD) designations, and the
European Medicines Agency (EMA) has granted Priority Medicines
(PRIME) and Orphan Medicinal Product designations, 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 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 and Europe. 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. While there has been
progress in the development of therapeutics that address the
underlying SMA genetic defect, via SMN-dependent pathways, there
continues to be a high unmet need for therapeutics that directly
address muscle function.
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, and
fibrosis. 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 www.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 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, SRK-181, and other product candidates and indication
selection and development timing, the ability of any product
candidate to perform in humans in a manner consistent with earlier
nonclinical, preclinical or clinical trial data, and the potential
of its product candidates and proprietary platform. 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
preclinical and clinical data, including the 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
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 and expectations, as well
as those risks more fully discussed in the section entitled "Risk
Factors" in Scholar Rock’s Quarterly Report on Form 10-Q for the
quarter ended September 30, 2021, 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.
1 This information from a third-party study is provided for
background purposes only and is not intended to convey or imply a
comparison to the TOPAZ clinical trial results.
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Scholar Rock Contacts: Investors Stephanie Ascher
Stern Investor Relations, Inc. Stephanie.Ascher@sternir.com
212-362-1200
Media Ariane Lovell Finn Partners
ariane.lovell@finnpartners.com 917-565-2204
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