Scholar Rock Demonstrates that Highly Specific TGFβ1 Inhibition Combined with Anti-PD1 Drives Tumor Regression and Survival ...
November 09 2018 - 7:00AM
Scholar Rock Holding Corporation (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 new preclinical data from its TGFβ1 cancer
immunotherapy program. In syngeneic mouse models of primary
resistance to checkpoint blockade therapy (CBT), combination
treatment with a highly specific inhibitor of TGFβ1, SRTβ1-Ab3, and
an anti-PD1 antibody resulted in tumor regression or tumor control
as well as significant survival benefit. In addition, adult rats
treated with SRTβ1-Ab3 with weekly doses up to 100mg/kg for 4 weeks
showed an improved preclinical toxicity profile compared to
pan-TGFβ inhibition. Detailed results are being presented at the
Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting in
Washington DC.
“We are proud to be presenting these exciting results that
demonstrate a highly specific TGFβ1 inhibitor overcomes primary
resistance to checkpoint blockade therapy while minimizing the
toxicities associated with pan-TGFβ inhibition,” said Nagesh
Mahanthappa, Ph.D., President and CEO of Scholar Rock. “Despite the
clinical breakthroughs achieved by cancer immunotherapy, there
remains significant unmet need with a majority of patients failing
to respond to checkpoint inhibition. These preclinical results,
using models that we believe better emulate human tumors resistant
to CBT, could potentially provide a new avenue in the pursuit of
novel therapies for patients with cancer.”
TGFβ1 is the predominant TGFβ isoform expressed in many human
tumors, particularly those for which CBT is an approved treatment.
Based on analyses of human tumors that are resistant to CBT, TGFβ1
is implicated as a key contributor to immune exclusion that leads
to primary resistance observed in patients. Scholar Rock
evaluated SRTβ1-Ab3, a highly specific inhibitor of TGFβ1, in
syngeneic mouse tumor models sharing key features that can be
observed in resistant human tumors: high expression of TGFβ1
over TGFβ2 and TGFβ3, active TGFβ signaling, immune exclusion, and
minimal to no response to anti-PD1/PDL1 therapy. In these
preclinical studies, treatment with SRTβ1-Ab3 drove effector cell
infiltration and expansion and rendered solid tumors vulnerable to
PD1 blockade.
Highlights from the preclinical data being presented at SITC for
the poster, titled “Defeating checkpoint resistance: Highly
specific inhibition of latent TGFβ1 activation renders resistant
solid tumors vulnerable to PD-1 blockade” (Poster #550),
include:
- SRTβ1-Ab3 is a fully human antibody that binds latent TGFβ1
with high selectivity and high affinity, potently blocking the
growth factor’s activation, and with minimal or no binding to TGFβ2
and TGFβ3 isoforms.
- In syngeneic mouse tumor models that reflect human primary
resistance to CBT, treatment with SRTβ1-Ab3 rendered the MBT-2
(bladder cancer) and Cloudman S91 (melanoma) tumors vulnerable to
anti-PD1 therapy.
- Combination treatment with SRTβ1-Ab3 and an anti-PD1 antibody
resulted in tumor regression or tumor control.
|
MBT-2
tumor model (Response*: %, N) |
Cloudman
S91 tumor model (Response**: %, N) |
Control |
0% (0/13) |
0% (0/11) |
Anti-PD1 monotherapy |
0% (0/13) |
17% (2/12) |
SRTβ1-Ab3 monotherapy |
0% (0/12) |
0% (0/12) |
Anti-PD1/ SRTβ1-Ab3, 3 mg/kg |
29% (4/14) |
83% (10/12) |
Anti-PD1/ SRTβ1-Ab3, 10 mg/kg |
57% (8/14) |
78% (7/9) |
Anti-PD1/ SRTβ1-Ab3, 30 mg/kg |
– |
73% (8/11) |
* For MBT-2: Response provides percentage of animals that
achieved a tumor volume at study end of less than 25% of the
1,200mm3 survival threshold.** For Cloudman S91: Response provides
percentage of animals that achieved a tumor volume at the interim
study cutoff of less than 25% of the 2,000mm3 survival threshold.
This study is ongoing to continue assessment of response
durability.
- Combination treatment with SRTβ1-Ab3 and an anti-PD1 antibody
in the syngeneic mouse tumor models resulted in statistically
significant survival benefit when compared to anti-PD1 monotherapy.
- In the MBT-2 study, median survival was not reached at study
end in the anti‑PD1/ SRTβ1-Ab3 10mg/kg combination group.
- In the ongoing Cloudman S91 study, median survival was not yet
reached in any of the three combination groups.
- In contrast to age-matched naïve mice, complete responders from
the anti-PD1/ SRTβ1‑Ab3 combination groups rejected re-challenge
with MBT-2 cells after a washout period of 7 weeks, demonstrating
durable immunological memory.
- Adult rats treated with SRTβ1-Ab3 up to a weekly dose of
100mg/kg for 4 weeks showed an improved preclinical toxicity
profile versus a pan-TGFβ antibody and an ALK5 inhibitor.
Scholar Rock will host an investor and analyst event
beginning at 2:00 p.m. ET on Saturday, November 10, 2018.
The live webcast may be accessed by visiting the Investors &
Media section of the Scholar Rock website
at http://investors.scholarrock.com. An archived replay
of the webcast will be available on the Company’s website for
approximately 90 days following the presentation.
The poster can be accessed
at: http://www.scholarrock.com/platform/publications/
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 StatementsThis 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 ability of its inhibitor
of TGFβ1 to render tumors vulnerable to checkpoint blockade
therapy, including the inhibitor’s ability, as a monotherapy or in
combination with other therapies, to affect tumor regression, tumor
control or survival; the toxicity profile of its inhibitor of
TGFβ1; and the ability of its inhibitor of TGFβ1 to be a
monotherapy or combination therapy for patients with cancer. 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 reproducibility of any preclinical data presented; the
inability to produce similar data in patients compared to the data
from preclinical studies; data generated from Scholar Rock’s
future nonclinical studies and clinical trials; and Scholar Rock’s
ability to obtain, maintain and protect its intellectual property
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, 2018, 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.
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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