- Retrospective analyses of clinical tumor samples identify
TGFβ1 as the most prevalent TGFβ isoform in most solid cancers
- Preclinical results demonstrate highly selective inhibition of
TGFβ1 activation with SRK-181-mIgG1 overcomes key mechanism of
primary resistance to checkpoint inhibition therapy
- Selective inhibition of latent TGFβ1 activation with SRK-181
has demonstrated an improved preclinical safety profile compared to
conventional inhibitors of TGFβ signaling
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
publication in the peer-reviewed journal Science Translational
Medicine of preclinical data that established the therapeutic
rationale for evaluating a potent and highly selective inhibitor of
transforming growth factor-beta 1 (TGFβ1) activation to overcome
primary resistance to checkpoint inhibitor therapy.
“With this publication, we are sharing the strong body of
preclinical evidence we have built supporting the
clinically-derived rationale for evaluating TGFβ1’s key role in
primary resistance to checkpoint inhibitor therapy and the
potential of a highly specific inhibitor of TGFβ1 activation to
overcome this challenge. In the second half of this year, we may
gain early insights from our Phase 1 proof-of-concept trial in
patients with solid tumors on SRK-181’s potential to overcome the
immune exclusion that we believe leads to primary resistance to
anti-PD-(L)1 therapy,” said Alan Buckler, Ph.D., Chief Scientific
Officer of Scholar Rock. “Moreover, these published data provide
further validation of Scholar Rock’s proprietary platform to
develop antibodies that locally and selectively target the
precursor form of growth factors with the aim of avoiding the
dose-limiting toxicities that have hindered traditional approaches
to targeting growth factors.”
The introduction of immunotherapy, including checkpoint
inhibitor therapy, has revolutionized the treatment of a wide
variety of cancers, delivering profound and durable responses for
many patients. Unfortunately, this therapeutic approach is only
effective in a small subset of patients; even at the outset of
treatment, some tumors show primary resistance to anti-PD-(L)1.
Human tumor profiling and several preclinical studies have
implicated TGFβ signaling activity as a potential point of
intervention to overcome primary resistance to checkpoint
inhibition. However, the development of therapies targeting TGFβ
signaling has been hindered by dose-limiting cardiotoxicities,
potentially due to non-selective inhibition of multiple TGFβ
isoforms.
As detailed in the Science Translational Medicine publication
“Selective inhibition of TGFβ1 activation overcomes primary
resistance to checkpoint blockade therapy by altering tumor immune
landscape,” SRK-181 inhibits TGFβ1 activation with high selectivity
and has demonstrated in preclinical studies the potential to
overcome primary resistance and meaningfully expand the number of
patients who could benefit from checkpoint inhibitor therapy.
(Martin et al., Sci. Transl. Med. 12: 25 March 2020)
- Based on RNAseq data from the Cancer Genome Atlas (TCGA), TGFβ1
is the most prevalent isoform expressed in the majority of human
cancer types, with the exception of breast cancer, mesothelioma,
and prostate cancer, where TGFβ3 is also expressed. This finding
was also observed in examination of individual samples.
- TGFβ1 is likely expressed by multiple cell types within the
tumor microenvironment and each cell type produces TGFβ1 in
different large latent complexes (LLCs). This is supported by TCGA
data, which indicates essentially all tumor types express mRNA
encoding all four LLC-presenting molecules, namely LTBP1, LTBP3,
GARP, and LRRC33. By targeting the precursor form of TGFβ1, SRK-181
achieves exquisite isoform specificity, inhibiting latent TGFβ1
activation in all known molecular contexts without binding to
latent TGFβ2, latent TGFβ3, or any of the three active TGFβ growth
factors.
- Scholar Rock identified three syngeneic mouse tumor models that
recapitulate key features of human primary resistance to checkpoint
inhibitor therapy: MBT-2 (bladder cancer), Cloudman S91 (melanoma)
and the EMT-6 (breast cancer) mouse models. Combination treatment
with SRK-181-mIgG1 and an anti-PD-1 therapy resulted in tumor
regression or control and survival benefit across these three
identified cancer models. This tumor response was also shown to be
durable, where mice with no measurable tumor at treatment cessation
remained tumor free.
MBT-2 bladder cancer model
(Response**: %, N)
Cloudman S91 melanoma model
(Response***: %, N)
EMT-6 breast cancer model
(Response*: %, N)
Control
0% (0/12)
0% (0/11)
0% (0/9)
Anti-PD1 monotherapy
0% (0/13)
25% (3/12)
0% (0/9)
SRK-181-mIgG1 monotherapy
0% (0/12)
0% (0/12)
0% (0/10)
Anti-PD-1/SRK-181-mIgG1, 3
mg/kg
29% (4/14)
75% (9/12)
NT
Anti-PD-1/SRK-181-mIgG1, 10
mg/kg
57% (8/14)
44% (4/9)
50% (5/10)
Anti-PD-1/SRK-181-mIgG1, 30
mg/kg
NT
73% (8/11)
NT
* For EMT-6: Response is defined as animals that achieved a
tumor volume at study end of less than 25% of the 2,000mm3 survival
threshold. ** For MBT-2: Response is defined as animals that
achieved a tumor volume at study end of less than 25% of the
1,200mm3 survival threshold. *** For Cloudman S91: Response is
defined as animals that achieved a tumor volume at study end of
less than 25% of the 2,000mm3 survival threshold. NT: Not
tested
- The tumor regression and control demonstrated in the EMT-6
breast cancer model, which expresses both TGFβ1 and TGFβ3, suggest
TGFβ1 is the key isoform contributing to checkpoint resistance and
highlights the possibility that selective TGFβ1 inhibition may have
therapeutic potential in overcoming primary resistance across a
broad spectrum of cancers, irrespective of the expression of other
TGFβ isoforms.
- Dose-limiting cardiotoxicities have challenged the therapeutic
development of TGFβ pathway inhibitors. Selective inhibition of
latent TGFβ1 activation with SRK-181 has demonstrated an improved
safety profile as compared to pan-TGFβ inhibitors. In a 4-week
repeat-dose rat toxicology study, the
no-observed-adverse-effect-level (NOAEL) was the highest dose
tested of 100 mg/kg once weekly, which is well above the doses
necessary to elicit robust anti-tumor responses when combined with
anti-PD-1 antibody.
- Following combination treatment with SRK-181-mIgG1 and
anti-PD-1, there were significant increases in intratumoral
effector T cells and decreases in immunosuppressive myeloid cells,
suggesting TGFβ1's multiple contributions to primary resistance to
checkpoint inhibition.
- Overall percentage of the CD45+ immune compartment did not
change.
- Ten-fold increase in CD8 T cell representation (average of 34%
vs. control average of 3.5%). Single-agent treatment with anti-PD-1
or SRK-181-mIgG1 only resulted in modest increases that did not
reach significance in the study.
- Significant reduction in immunosuppressive M2-like macrophages
(14% vs. control average of 47%) and myeloid-derived suppressor
cells (MDSC; 1.4% vs. control average of 10.9%).
About SRK-181
SRK-181 is a potent and highly selective inhibitor of TGFβ1
activation and is an investigational product candidate being
developed to overcome primary resistance to checkpoint inhibitor
therapy, such as anti-PD-(L)1 antibodies. TGFβ1 is the predominant
TGFβ isoform expressed in many human tumors, particularly for those
tumors where checkpoint therapies are currently approved. Based on
analyses of human tumors that are resistant to anti-PD-(L)1
therapy, TGFβ1 is implicated as a key contributor to exclude immune
cell entry into the tumor microenvironment, thereby preventing
normal immune function. By overcoming this immune cell exclusion,
Scholar Rock believes SRK-181 has the potential to induce tumor
regression when administered in combination with anti-PD-(L)1
therapy. A Phase 1 proof-of-concept clinical trial in patients with
locally advanced or metastatic solid tumors is ongoing. The
effectiveness and safety of SRK-181 have not been established and
SRK-181 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 newly elucidated understanding
of 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.
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 the timing of its
clinical trials for SRK-181; the potential of SRK-181 to address
certain patient unmet needs; and the ability of any product
candidate to perform in humans in a manner consistent with
nonclinical or preclinical study data. 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 Scholar Rock’s ability to
provide the financial support, resources and expertise necessary to
identify and develop product candidates on the expected timeline;
preclinical data and results may not be predictive of clinical
results; Scholar Rock’s dependence on third parties for development
and manufacture of product candidates including to supply any
clinical trials; and 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, 2019, 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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version on businesswire.com: https://www.businesswire.com/news/home/20200326005203/en/
Scholar Rock Contact: Investors/Media Catherine Hu
chu@scholarrock.com 917-601-1649
Media Contact: The Yates Network Kathryn Morris
kathryn@theyatesnetwork.com 914-204-6412
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