UNITED
STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
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SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
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FORM
8-K
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CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
Date of Report (Date of earliest event Reported): January 10, 2022
(Exact Name of Registrant as Specified in Charter)
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(State or Other Jurisdiction of Incorporation)
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(Commission File Number)
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(I.R.S. Employer Identification Number)
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(Address of Principal Executive Offices) (Zip Code)
(857 ) 259-3860
(Registrant’s telephone number, including area code)
(Registrant’s telephone number, including area code)
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
Securities registered pursuant to Section 12(b) of the Act:
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Title of each class
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Trading Symbol(s)
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Name of each exchange on which registered
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (17 CFR §230.405) or Rule 12b-2 of the Securities Exchange Act of 1934 (17 CFR §240.12b-2). Emerging growth company
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If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange
Act. ☒
Item 7.01. Regulation FD Disclosure.
On January 10, 2022, Scholar Rock Holding Corporation (the “Company”) issued a press release announcing a corporate update and highlighting
priorities for 2022. A copy of the press release is being furnished as Exhibit 99.1 to this report on Form 8-K.
On January 4, 2022, the Company announced that management will present at the 40th Annual J.P. Morgan Healthcare Conference on
Tuesday, January 11, 2022 at 7:30 a.m. EST. A copy of the presentation slide deck that will be presented is being furnished as Exhibit 99.2 to this report on Form 8-K. A live webcast of the presentation may be accessed by visiting the Investors
& Media section of the Scholar Rock website at http://investors.scholarrock.com.
The information in this report furnished pursuant to Item 7.01 and Exhibits 99.1 and 99.2 shall not be deemed “filed” for the purposes of
Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section. It may only be incorporated by reference in another filing under the Exchange Act or the Securities Act of
1933, as amended, if such subsequent filing specifically references the information furnished pursuant to Item 7.01 and Exhibits 99.1 and 99.2 of this report.
Item 8.01. Other Events.
On December 19, 2018, Gilead Sciences, Inc. ("Gilead”) and
Scholar Rock, Inc. (“Scholar Rock”) entered into a three-year collaboration to discover and develop therapeutics that target TGFβ-driven
signaling, a central regulator of fibrosis (the “Collaboration Agreement”). On January 6, 2022, Scholar Rock entered into a letter agreement with Gilead which (i) confirmed that the collaboration period under the Collaboration Agreement had expired as of December 19, 2021, and (ii) the
parties agreed the option exercise period for all programs under the Collaboration Agreement had been terminated as of date of the letter agreement.
The foregoing description of the letter agreement does not purport to be complete and is qualified in its entirety by reference to the
letter agreement, which we intend to file as an exhibit to our Form 10-Q for the quarter ending March 31, 2022.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
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Exhibit
No.
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Description
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SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the
undersigned hereunto duly authorized.
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Scholar Rock Holding Corporation
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Date: January 10, 2022
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By:
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/s/ Junlin Ho
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Junlin Ho
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General Counsel and Corporate Secretary
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Exhibit 99.1
Scholar Rock Provides Corporate Update and Highlights Priorities for 2022
- Initiated Phase 3 SAPPHIRE Clinical Trial Evaluating Apitegromab in Non-Ambulatory Patients with Type 2 and Type 3 Spinal Muscular Atrophy (SMA)
- Advanced DRAGON Phase 1 Study into Part B to Evaluate Potential for SRK-181 to Overcome Checkpoint Inhibitor Resistance in Cancer Patients
- Concluded Partnership with Gilead and Regained Rights to Advanced Preclinical Assets with Multiple Distinct Pharmacological Profiles
- Ended 2021 with Approximately $253 Million in Cash, Cash Equivalents, and Marketable Securities
CAMBRIDGE, Mass.--(BUSINESS WIRE)--January 10, 2022--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 provided recent corporate updates and highlighted upcoming priorities for its pipeline programs in 2022.
“2021 was another transformative year for Scholar Rock, with positive data from both of our clinical programs, including from the TOPAZ Phase 2 trial for apitegromab, which is being developed for the improvement of motor function in patients with SMA; and Part A of the DRAGON Phase 1 proof-of-concept trial for SRK-181, being developed to overcome resistance to check point inhibitor therapy in cancer patients,” said Nagesh Mahanthappa, Ph.D., Interim CEO of Scholar Rock. “In 2022, we are thrilled to be advancing a pivotal Phase 3 trial of apitegromab and advancing our SRK-181 program to test our hypothesis that this highly selective and potent molecule can overcome resistance to checkpoint inhibitors thereby increasing the number of patients who may benefit from cancer immunotherapy. In addition, the preclinical pipeline has received a major boost as we have regained rights to assets discovered and developed during our research partnership with Gilead that have novel pharmacological profiles relevant to TGFβ-mediated diseases.”
2022 Priorities:
Apitegromab is a selective inhibitor of myostatin activation being developed as the potential first muscle-directed therapy for the treatment of spinal muscular atrophy (SMA).
- Robust Enrollment of the Phase 3 SAPPHIRE Trial Evaluating Apitegromab in Patients with Non-Ambulatory Type 2 and 3 Patients. Scholar Rock has initiated the SAPPHIRE study. The study design plans for approximately 156 patients aged 2-12 years old with non-ambulatory Type 2/3 SMA 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.
- Progress TOPAZ Long-Term Extension to Two Year Readout. As of January 6, 55 of 57 patients remain in the long-term extension trial of apitegromab in Type 2 and 3 SMA.
- Advance Development Activities to Include Patients with Type 1 and Ambulatory SMA.
SRK-181 is a potent and highly selective inhibitor of latent TGFβ1 activation being developed with the aim of overcoming primary resistance to and increasing the number of patients who may benefit from checkpoint inhibitor therapy.
- Advance Progress in Part B of DRAGON Phase 1 Proof-of-Concept Trial. Based on the safety and pharmacokinetic data from Part A of the DRAGON Phase 1 trial, Scholar Rock has initiated the Part B dose expansion portion of the trial,
which is evaluating SRK-181 dosed 1500 mg every three weeks (Q3W) in patients receiving an approved anti-PD-(L)1 therapy dosed Q3W and 1000 mg every two weeks (Q2W) in patients receiving an approved anti-PD-(L)1 therapy dosed Q2W. Part B will
enroll and dose patients in multiple proof of concept cohorts conducted in parallel, including;
- Urothelial carcinoma (UC),
- Cutaneous melanoma (MEL),
- Non-small cell lung cancer (NSCLC),
- Clear cell renal cell carcinoma (ccRCC),
- Other solid tumors.
Each cohort is expected to enroll up to 40 patients with various locally advanced or metastatic solid tumors who have demonstrated primary resistance to anti-PD-(L)1 therapy. Early efficacy and safety data are anticipated in 2022.
Advancing assets gained from the Gilead collaboration. In December 2018, Gilead Sciences and Scholar Rock entered into a three-year collaboration to discover and develop therapeutics that target TGFβ-driven signaling, a central regulator of fibrosis. Under the collaboration, Gilead had exclusive options to license worldwide rights to antibodies from certain TGFβ programs being developed by Scholar Rock. Scholar Rock received $80.0 million in proceeds upon signing the agreement and an additional $25.0 million preclinical milestone was achieved in December 2019 for the successful demonstration of efficacy in preclinical in vivo proof-of-concept studies. As of December 19, 2021 the collaboration period has concluded and on January 6, 2022, Gilead agreed that its option exercise period for all programs has been terminated.
- Scholar Rock regains rights to a suite of antibodies with novel pharmacological profiles that were discovered over the course of the collaboration.
- Of particular note, Scholar Rock has discovered antibodies that selectively inhibit the activation of latent TGFβ1 in the context of fibrotic extracellular matrix and that avoid perturbing TGFβ1 presented by cells of immune system. Such antibodies demonstrated significant antifibrotic activity in a variety of preclinical rodent models and safety at all doses tested in a non-GLP mouse safety study that we intend to publish in 2022.
“The novel anti-fibrotic antibodies discovered during this collaboration demonstrate the unique capabilities of the discovery platform we have built at Scholar Rock,” said Gregory Carven, CSO of Scholar Rock. “We are excited to continue the advancement of these assets as a part of the company’s growing preclinical pipeline.”
“We made great progress across our portfolio in 2021 and we’re carrying that momentum into 2022,” said Ted Myles, CFO and Head of Business Operations of Scholar Rock. “We recently strengthened our balance sheet through the use of our ATM and taking the $25 million second tranche of our debt facility with Silicon Valley Bank and Oxford Finance so that we have greater flexibility to continue to advance our clinical and pre-clinical programs. We have high conviction in our platform based on the exciting clinical data to date and we believe this puts us in a unique position as we advance our programs to serve patients’ needs.”
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, without limitation, that preclinical and clinical data, including the results from the Phase 2 trial of apitegromab, or Part A of the DRAGON clinical trial for SRK-181, are not predictive of, may be, inconsistent with, or more favorable than, data generated from future clinical trials of the same product candidate, including, without limitation, the Phase 3 trial of apitegromab in SMA or the Phase 1 trial of SRK-181, 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, without limitation, 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.
Contacts
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
Exhibit 99.2
Deep Insights Advancing Impactful Medicines 40th Annual J.P. Morgan Healthcare ConferenceJanuary 10-13,
2022
Disclaimers Various statements in this presentation concerning the future expectations, plans and
prospects of Scholar Rock, Inc. (“Scholar Rock”), including without limitation, Scholar Rock’s expectations regarding its strategy, its product candidate selection and development timing, including timing for the initiation of and reporting
results from its clinical trials for apitegromab, SRK-181, and other product candidates and indication selection and development timing, its cash runway, 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 for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of
1995. 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, without limitation, that preclinical and clinical data, including the results from the Phase 2 trial of apitegromab or Part A of the Phase 1 trial of
SRK-181, are not predictive of, may be inconsistent with, or more favorable than, data generated from future clinical trials of the same product candidate, including the Phase 3 trial of apitegromab in SMA and Part B of the Phase 1 trial of
SRK-181, respectively, 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, the success of Scholar Rock’scurrent and potential future collaborations, Scholar Rock’s dependence on third parties for development and manufacture of product candidates including, without limitation, 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 importantfactors in Scholar Rock’s subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent Scholar Rock’sviews 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, Inc. All rights reserved. January 2022.
3 Bringing a Revolutionary Approach to Highly Sought-AfterGrowth Factors Implicated in Devastating
Diseases Scholar Rock’s TargetGrowth Factor Precursor (Latent Form) Scholar Rock’s R&D PlatformTransform Medical Practice Pursue important targets with well-validated biology but are difficult to drugApply revolutionary approach to tough
targetsLeverage deep insights into structureand functionEngineer antibodies to deliver differentiated therapeutic profiles (i.e. exquisite selectivity)TOPAZ demonstrated the therapeutic potential of inhibiting the latent forms of growth factors
DRAGON Part A: dose escalation and continued follow-up Apitegromab Spinal Muscular Atrophy
(SMA) SRK-181Immuno-Oncology and Oncology Preclinical/ Platform SAPPHIRE Phase 3 Trial Portfolio Spanning All Stages of Discovery and Development TOPAZ extension (55 of the 57 patients who completed TOPAZ 12-month period continue to
participate in the extension) Continue to discover and advance preclinical programsTGFβ1 in Fibrosis (LTBP)RGMc (BMP6 Co-Receptor)Additional Early Programs Multiple opportunities for additional myostatin-related indications beyond SMA and
muscular dystrophies DRAGON Part B: parallel POC evaluations in multiple tumor typesUrothelial CarcinomaMelanomaNon-small Cell Lung Cancer (NSCLC)Clear Cell Renal Cell Carcinoma (ccRCC)Other Solid Tumor Types ApitegromabOther
Indications Continued Studies to Explore Opportunities to Serve Broader SMA Population (e.g., Type 1 and ambulatory SMA) 2021 Q4 2022 Q1 Q2 Q3 Q4 4
Apitegromab Positioned to be Next Potential Transformative Therapy for Patients with SMA
6 Potential to Pioneer a New Treatment Era: Opportunity for Muscle-Directed Therapy to Complement SMN
Upregulators Phase 3 Trial Design Indication Market Penetration Non-ambulatory Type 2/32-12 years of agePrimary endpoint: Mean change from baseline in HFMSE at 15 months >11,000* patients treated WW$2+ billion in revenues
(LTM) ~1,200*** patients treated WW~$1.2 billion in revenues (LTM) ~4,000** patients treated WW~CHF243 million in revenues (1H21) Type 1, 2, and 3 SMA in pediatricand adult patients Type 1, 2, 3 SMA in patients 2 months of age and older SMA
in patients less than 2 years of age Non-ambulatory Type 2/32-25 years of agePrimary endpoint: Mean change from baseline in MFM-32 at 12 months Infantile-onset Type 1<6 months of agePrimary endpoints: Ability to sit independently and
event-free survival *As of Biogen 2Q21 financial update on 7/22/21; includes patients treated worldwide in post-marketing setting, expanded access program, and clinical trials.**As of Roche 1H21 financial update on 7/22/21; includes patients
treated worldwide between clinical trials, commercial, and compassionate use program.***As of Novartis 2Q21 financial update on 7/21/21; commercially, via managed access programs and in clinical trials HFMSE = Hammersmith Functional Motor Scale
Expanded; MFM-32 = Motor Function Measure – 32 items Patients continue to experience major functional impairments despite utilization of SMN upregulators
7 Spinal Muscular Atrophy Overview Significant, progressive motor function impairment; many lose
ambulation Infantile onset; unable to sit upindependently Severe, progressive disabilities and unable to walk independently Type 114% Type 251% Type 335% Global disease with 30,000-35,000 affected in U.S. and Europe alone TOPAZ* 12-month
results showed transformative potential in non-ambulatory Type 2 and 3 patients Represents ~2/3 of overall patient population Motor neuron impairment and loss due to SMN genetic deficiency, leading to muscle atrophy and weakness *TOPAZ Phase
2 trial evaluated patients with Type 2 and 3 SMA (did not include Type 1) Lallyet al, OrphanetJournal of Rare Diseases, 2017
8 TOPAZ Top-Line Data Showed Apitegromab’sTransformative Potential in Patients with Type 2/3 SMA ✔
Apitegromab led to HFMSE improvements in both non-ambulatory cohorts (including patients started on nusinersen at age > 5) * Pooled cohorts of non-ambulatory patients treated with apitegromab 20 mg/kg and 2 mg/kg**Non-ambulatory patients who
initiated background nusinersen at a young age of <5 years and treated with apitegromab 20 mg/kg dose At 12 months Mean HFMSE increase ≥1-point increase ≥3-point increase Initiated background nusinersen age <5** +7.1 points 88% (7/8)
of patients 63% (5/8) of patients Initiated background nusinersen age ≥5 +0.6 points 64% (9/14) of patients 29% (4/14) of patients ✔ Majority of non-ambulatory patients* experienced HFMSE increases from apitegromab as add- on during chronic
maintenance phase of SMN therapy 20151050-5-10 HFMSE change from baseline
SAPPHIRE Phase 3 Design Optimized by Insights from TOPAZ 9 TOPAZ Learnings SAPPHIRE Design
Elements Largest HFMSE gains observed in the non- ambulatory Type 2/3 SMA cohorts Study population: Non-ambulatory Type 2/3 SMAPrimary efficacy endpoint: HFMSE Exploratory age 2-12 analysis in non-ambulatory Type 2/3 showed transformative
potential Age 2-12 will be main efficacy population HFMSE gains evident by 12 months of treatment 12 month treatment duration Dose response seen (greater effect observed with 20 mg/kg over 2 mg/kg) 20 mg/kg apitegromab doseTo explore
potential that dose between 2 and 20 mg/kg may be comparable to 20 mg/kg, will also evaluate 10 mg/kg arm
SAPPHIRE Phase 3 Design Optimized by Insights from TOPAZ 10 TOPAZ Learnings SAPPHIRE Design
Elements Largest HFMSE gains observed in the non- ambulatory Type 2/3 SMA cohorts Study population: Non-ambulatory Type 2/3 SMAPrimary efficacy endpoint: HFMSE Exploratory age 2-12 analysis in non-ambulatory Type 2/3 showed transformative
potential Age 2-12 will be main efficacy population HFMSE gains evident by 12 months of treatment 12 month treatment duration Dose response seen (greater effect observed with 20 mg/kg over 2 mg/kg) 20 mg/kg apitegromab doseTo explore
potential that dose between 2 and 20 mg/kg may be comparable to 20 mg/kg, evaluating 10 mg/kg arm
SAPPHIRE (Phase 3) Trial Overview Apitegromab (20 mg/kg IV q4w) + SMN upregulator N = 5252 weeks
treatmentRandomized, double-blind, placebo-controlled, parallel arm designAdd-on to background SMN therapy (enrolling patients on nusinersen as well as patients on risdiplam)Primary efficacy endpoint: mean HFMSE change from baseline at 12
monthsStudy start-up activities commenced11 MainPopulationPatients (age 2-12) with Non-ambulatory Type 2/3 SMA Apitegromab (10 mg/kg IV q4w) + SMN upregulator Placebo + SMN upregulator N = 52 N = 52
Additional Therapeutic Opportunities May Be Pursued With Separate Development Strategies Global disease
with 30,000-35,000 affected inU.S. and Europe alone A Ambulatory patients Smaller population but high unmet need as benefits of SMN regulators not well-establishedTOPAZ suggests potential clinicalbenefit in a subset of
patients C Type 1 SMA, including those treated with gene therapyHighest incidence population and growing prevalence due toSMN upregulator treatmentTOPAZ showed benefits of early treatment suggesting potential in Type 1 patients B Type
114% Type 251% Type 335% Apitegromab in non-ambulatory Type 2 and 3 SMA with background SMN upregulatorsRepresents 2/3 of overall patientsPatients already treated with or eligible forSMN upregulator therapyImprovements in motor function on top
of SMN upregulators observed in TOPAZ 12
SRK-181: Potential Transformative Backbone for a New Era ofCancer Immunotherapy
SRK-181: Unique TGFβ1-Selective Approach to OvercomingCheckpoint Inhibitor Resistance 14 Scholar
Rock’s TargetSRK-181: Latent TGFβ1 InhibitorInhibits TGFβ1 pathway - implicated in CPI resistanceHighly selective targeting - avoids inhibiting latent TGFβ2 and TGFβ3 isoformsAimed at increasing therapeutic window – potentially avoids toxicities
associated with non-selective TGFβ inhibitionTherapeutic flexibility - pair with any CPI and optimizedosing of each component of combination therapyTraditional target:“Mature” growth factor
SRK-181 Therapeutic Hypothesis: Potential Advantages of Latent TGFβ1
Inhibitor 15 SRK-181* BifunctionalTGFβ/CPI ALK5Inhibitor NonselectiveTGFβ antibody Selectivity for TGFβ1: potential for widertherapeutic window and improved safety ✔ X X X Ability to combine with any anti-PD-(L)1 ✔ X ✔ ✔ Ability
to optimize dosing of eachcomponent of combination therapy ✔ X ✔ ✔ Activity spatially distinct from anti-PD-(L)1 in tissue ✔ X ✔ ✔ SRK-181 is an investigational product candidate currently being evaluated in DRAGON phase 1 clinical
trial. The efficacy and safety of SRK-181 have not been established.
16 TGFβ1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible to Anti-PD1
Therapy Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med. 2020 Mar 25;12(536):eaay8456. https://scholarrock.com/platform/publications. Anti-PD1/SRK-181-mIgG1(10 mg/kg
QW) Anti-PD1/SRK-181-mIgG1(30 mg/kg QW) 4/9 8/11 3/12 SRK-181-mIgG1 (30 mg/kg QW) Anti-PD1 (10 mg/kg BIW) *P<0.01.†P<0.05 Log-rank (Mantel-Cox test) vs anti-PD1. * * † Melanoma (Cloudman S91) model: Combination treatment led to
tumor regression and survival benefitTumor Regression: Monotherapy Tumor Regression: Combination Therapy Days after treatment initiation Days after treatment initiation Days after treatment initiation Survival Benefit Anti-PD1/ SRK-
181-mIgG1 led to influx of CD8+ cells in preclinical bladder tumor model Anti-PD1 Overcoming immune exclusion Tumor volume (mm3) Responders 0/12
TGFβ1 Isoform Specificity of SRK-181 Improved Preclinical Toxicity Profile Preclinical data
published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med 2020 Mar 25;12(536): eaay8456.*Source: Anderton MJ, et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol. 2011;39: 916-924.; and
Stauber AJ, et al. Nonclinical safety evaluation of a transforming growth factor β Receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. J Clin Pract. 2014: 4:3. Selectivity of SRK-181 offers potential to overcome toxicity and
dose-limiting challenges of non-selective TGFβ pathway approaches Microscopic observations in heart Valvulopathy Atrium—Mixed cell infiltrate Myocardium—Degeneration/necrosis Myocardium—Hemorrhage Myocardium—Mixed cell infiltrate,
base Coronary artery—Necrosis with inflammation Cardiomyocyte—Necrosis/inflammatory cell infiltrate Control Vehicle iv, qwk x
4 LY2109761 300 mg/kg po, qd x 8 PanTGFβAb 30
mg/kg Iv, 1 dose SRK-181 LEGENDUnremarkable MinimalSlight Moderate 10 mg/kg 30 mg/kg 100
mg/kg iv, qwk x 4 iv, qwk x 4 iv, qwk x
4 Repeat
dose pilot toxicology study in adult female Sprague Dawley rats: Cardiac findings were exhibited in animals dosed with a pan- TGFβ antibody or LY2109761 (inhibitor of ALK5, common TGFβ receptor kinase) as expected based on published data†No
cardiotoxicities (valvulopathy) were noted with SRK-181– NOAEL for SRK-181 was the highest dose evaluated of 100 mg/kg QW 4-week GLP toxicology studies:Rats: NOAEL for SRK-181 was up to highest evaluated dose of 200 mg/kg QWNon-human primates:
NOAEL for SRK-181 was up to highest evaluated dose of 300 mg/kg QW 17
DRAGON Phase 1 POC Trial to Evaluate SRK-181’s Abilityto Overcome Primary Resistance to Checkpoint
Inhibitors Note: In Part A, SRK-181 is administered q3w, with the exception of a 2000 mg q2w cohort in Part A1. In Part B, SRK-181 is administered at 1500 mg q3w for combination with anti-PD-(L)1 therapy dosed q3w (or at 1000 mg q2w for
combination with anti-PD-[L]1 therapy dosed q2w)* A cohort of 2000 mg Q2W (n=3) was also evaluated.**The clear cell RCC cohort will also explore the effects of SRK-181 in patients with relapsed response after anti-PD-(L)1 treatment.18NCT04291079
on www.clinicaltrials.gov. Part AA2: SRK-181+anti-PD-(L)1; non-responders to prior anti-PD-(L)1 Part BSRK-181 + anti-PD-(L)1; non-responders to prior anti-PD-(L)1n=up to 40/cohort Cohort: Non-small celllung cancer A1:
SRK-181all-comers SRK-181 80 mg (n=1) SRK-181 240 mg (n=1) SRK-181 1600 mg (n=3) SRK-181 800 mg (n=3) SRK-181 2400 mg (n=3) SRK-181 3000 mg (n=3)* SRK-181 240 mg (n=3) SRK-181 800 mg (n=3) SRK-181 1600 mg (n=3) SRK-181 2400 mg
(n=3) Cohort: Urothelial carcinoma Cohort: Cutaneous melanoma Cohort: Clear cell renal cell carcinoma** SRK-181 +pembrolizumab SRK-181 +pembrolizumab SRK-181 +pembrolizumab SRK-181pembrolizumab Cohort: Other solid tumor
types SRK-181 + anyanti-PD-(L)1
DRAGON Part A: Preliminary Anti-Tumor Effects* 19 Part A1 (n=19)8 patients had best response of stable
disease (SD)3 ovarian cancer patients had best response of SD, with tumor regressions in 2 of these individualsPart A2 (n=10)At 800 mg q3w, 1 partial response (PR) was observed in patient with anti-PD-1-resistant renal cell carcinoma (RCC)4
patients had best response of SD including 1 oropharynx cancer patient with tumor regression *Preliminary anti-tumor effects were assessed using RECIST1.1 and reported based upon local investigator reads
Part B dose selected based upon Part A data & PK modeling: 1500 mg q3w*Estimated to offer drug
exposure at levels exceeding those hypothesized as needed for anti-tumor effect based on preclinical data and PK modelingPart B encompasses multiple POC cohorts (enrolling up to 40 patients each)Enrolling patients with primary resistance to
anti-PD-(L)1 therapyEnriched with solid tumor types for which it is hypothesized there may be higher potential for early efficacy signals based upon translational and preclinical insightsAdditional Part B cohort of clear cell renal cell carcinoma
(ccRCC) being added based on emerging insights, including preliminary data from Part A DRAGON Has Advanced to Part B to Test Proof of Conceptfor SRK-181 in Overcoming Anti-PD-(L)1 Resistance 20 *For patients receiving anti-PD-(L)1 therapy
dosed at q2w frequency, SRK-181 will be dosed at 1000 mg q2wNCT04291079 on www.clinicaltrials.gov.
Biomarker Strategies Employed in DRAGON Trial 21 ImmunophenotypingAssessment of immune
landscapeExamples:Histochemical characterization tumor immune contexture (e.g. CD8+)Classification of inflamed, excluded or immune desert tumors and tumor nestsAbility of SRK-181 to overcome tumor immune exclusionAnalysis of immune response
markers (e.g.PD-L1)Changes to intra-tumoral and/or circulating immune cell contexture (MDSC) Show evidence of the SRK-181 targetengagemente.g. circulating TGFβ1 levels TGFβ pathway modulation:e.g. Histochemical analysis ofpSMADe.g. RNA based
TGFβ gene signatures and pathway analyses Multiple tissue-based and circulating biomarker analyses to be evaluated in DRAGON study TGFβ1 pathway evaluationAssessment of signaling pathway
Preclinical data provide scientific rationale to evaluateperipheral samples for evidence of SRK-181
activity ImmunophenotypingAssessment of immune landscapeMeasurement of MDSCs in circulation may provide indirect evidence of drug action on the tumorMyeloid-derived suppressor cells (MDSCs) have immune suppressive functionsSRK-181 plus
anti-PD1 combination drive MDSC levels down significantly in the tumor microenvironmentCirculating MDSC levels inversely correlate with tumor volume following SRK-181 and anti-PD1 treatment in MBT-2 tumor modelBoth tumoral and circulatory MDSC
are being evaluated in the DRAGON study 0 500 1000Tumor Volume (mm3)MBT-2 bladder tumor model IgG, anti-PD-1 and SRK-181-mIgG1 dosed d1,
d7 0 20 40 60 80 Circulating gMDSC (%CD45) IgG Ctrl
SRK-181Anti-PD-1Anti-PD-1+SRK-1811 mpk3 mpk10 mpk Circulating MDSC inversely correlate with tumor volume 22 Analysis on day 10
New Horizons in TGFβ Selectivity
Selectively Targeting Large Latent Complexes To AchieveContext-Dependent TGFβ1 Inhibition Immune
CellsGARP presents TGFβ1on Tregs LRRC33 presents TGFβ1on macrophages Fibrotic TissueLTBP1 and LTBP3present TGFβ1 in connective tissue GARPorLRRC33 Large latent complexes present TGFβ1 thoughcovalent interaction with “presenting
molecules”which are cell-type specificLTBP1 and LTBP3 present TGFβ in connective tissueGARP and LRRC33 present TGFβ on the cell surface of immune cellsAntibodies that selectively block TGFβ1 activation in different contexts may allow fine-tuning
of therapeutic indexLTBP-selective targeting for fibrosisGARP/LLRC33-selective targeting for immunomodulationScholar Rock has identified a portfolio of antibodies that selectively bind TGFβ1 in a context dependent manner 24
Specificity for LTBP-Selective Context Maintains Anti-Fibrotic Activity Antifibrotic efficacy and safety
demonstrated in multiple rodent models of kidney fibrosis with context selective LTBP-TGF�1 antibodyLTBP-selective inhibition is as effective as context-dependent inhibition suggesting that LTBP-driven TGF�1 is driving fibrosisRat
adenine-deficient diet model: Reduction of fibrosis observed via decrease in collagen and hydroxyproline stainingImproved kidney function observed via reduction ofplasma BUN and creatinineSignificant reduction in multiple TGF� related pro-
fibrotic gene expression Mouse model of Alport’s Disease (Col4A3-/-):Suppression of SMAD2 phosphorylation; indicative ofinhibition of TGF� signaling IgG 30 mg/kg IgG Ctrl 30 mg/kg 30 mg/kg) 10 mg/kg 3
mg/kg 0 2 4 6 %pSMAD2+ Nuclei *** * * Het (Col4A3
KO) Anti-LTBP-TGF�1 suppresses TGF�1 signaling in Alport mouse kidneyAlport mice Anti-LTBP-TGF�1 * P < 0.05** P <0.01***P<0.001vs. IgG 25
DRAGON Part A: dose escalation and continued follow-up Apitegromab Spinal Muscular Atrophy
(SMA) SRK-181Immuno-Oncology and Oncology Preclinical/ Platform SAPPHIRE Phase 3 Trial Portfolio Spanning All Stages of Discovery and Development TOPAZ extension (55 of the 57 patients who completed TOPAZ 12-month period continue to
participate in the extension) Continue to discover and advance preclinical programsTGFβ1 in Fibrosis (LTBP)RGMc (BMP6 Co-Receptor)Additional Early Programs Multiple opportunities for additional myostatin-related indications beyond SMA and
muscular dystrophies DRAGON Part B: parallel POC evaluations in multiple tumor typesUrothelial CarcinomaMelanomaNon-small Cell Lung Cancer (NSCLC)Clear Cell Renal Cell Carcinoma (ccRCC)Other Solid Tumor Types ApitegromabOther
Indications Continued Studies to Explore Opportunities to Serve Broader SMA Population (e.g., Type 1 and ambulatory SMA) 2021 Q4 2022 Q1 Q2 Q3 Q4 26
Appendix
Key Characteristics ofSpinal Muscular Atrophy (SMA) Scholar Rock’s Guiding Principles
forNeuromuscular Indication SelectionYounger populationAt least partially intact innervation andno structural muscle abnormalitiesNeed for increase in fast-twitchmuscle fibersClinical trial endpoint driven by fast-twitch fiber function Genetic
disorder with onset in childhoodPartial neural connectivity and atrophiedmuscles that largely retain structural integritySubstantial deficit in fast-twitch fibersFast-twitch fiber function has a prominent role in SMA outcome
measures 28 Apitegromab: Pairing the latent form with important translational insights
Apitegromab: Muscle-Directed Therapy Aimed at Complementing SMN Upregulators 29 Adapted from images
courtesy of the SMA Foundation Myostatin is a negative regulator of skeletal muscle growthApitegromab is a fully human, mAb that specifically binds to proforms of myostatin and inhibits myostatin activation Apitegromab is a muscle-directed
approach aimed at improving motor function Apitegromab SMN upregulators prevent further degeneration of motor neurons...but do not directly addressmuscle atrophy Motor neurondegeneration Muscle fiber atrophy
Apitegromab Phase 2 Trial Design 30 Patients with Type 2 and 3 SMA Ambulatory Type 3 patients
(ages 5-21)Apitegromab 20 mg/kg IV Q4W monotherapy or with chronic nusinersen maintenance Key objectives: RHS and safety at 12 months Non-ambulatory Type 2 patients (ages ≥2) on chronicmaintenance nusinersen (initiated <5 years of
age)Apitegromab 2 mg/kg and 20 mg/kg IV Q4W + nusinersen Key objectives: HFMSE and safety at 12 months Non-ambulatory Type 2/3 patients (ages 5-21) on chronicmaintenance nusinersen (initiated ≥5 years of age)Apitegromab 20 mg/kg IV Q4W +
nusinersen Key objectives: HFMSE and safety at 12 months Patients on background SMN therapy were in chronic maintenance phase of nusinersen(~5 mean maintenance doses at baseline) *Excludes one patient from Cohort 1 that discontinued from the
trial 55 of the 57* patients who completed TOPAZ 12-month period continue to participate in the extension
Baseline CharacteristicsNusinersen-treated patients well into chronic maintenance
phase 31 Non-Ambulatory,Ages ≥2 and initiated nusinersen <5 years Non-Ambulatory, Ages 5-21 Ambulatory, Ages 5-21 20 mg/kg+nusinersen 2 mg/kg+nusinersen Pooled 20 mg/kg+nusinersen 20 mg/kgmonotherapy 20
mg/kg+nusinersen Pooled N 10 10 20 15 11 12 23 Mean age at baseline (min, max) 3.8 (2, 6) 4.1 (2, 6) 4.0 (2, 6) 11.7 (8, 19) 12.1 (7, 19) 13.1 (7, 21) 12.6 (7, 21) Mean RHS score (min, max) 47.6 (26, 63) 51.3 (43,
62) 49.6 (26, 63) Mean HFMSE score (min, max) 23.5 (14, 42) 26.1 (12, 44) 24.8 (12, 44) 22.7 (13, 39) Mean # of nusinersen maintenancedoses (min, max) 5.4 (3, 8) 5.5 (2, 9) 5.5 (2, 9) 5.1 (2, 9) N/A 5.6 (2, 8) N/A SMN2 Gene
Copy* (#, %) 2 1 (10%) 1 (10%) 2 (10%) 1 (9%) 0 (0%) 1 (4%) 3 8 (80%) 8 (80%) 16 (80%) 11 (73%) 4 (36%) 9 (75%) 13 (57%) 4 0 (0%) 1 (10%) 1 (5%) 2 (13%) 4 (36%) 1 (8%) 5
(22%) Discontinuation(s) 0 0 0 0 0 1** 1** *Data not available for all patients**Patient who discontinued study for reasons unrelated to study drug HFMSE=Hammersmith Functional Motor Scale Expanded; RHS=Revised Hammersmith Scale Data on
file. Scholar Rock, Inc. Cambridge, MA
Non-Ambulatory Type 2 Cohort:Initiated nusinersen age <5 32 Apitegromab (20 mg/kg) +
nusinersen n=8 Mean change from baseline in HFMSE (95% CI) +7.1(1.8, 12.5) # (%) patients achieving: ≥1-pt increase in HFMSE 7/8 (88%) ≥3-pt increase in HFMSE 5/8 (63%) ≥5-pt increase in HFMSE 5/8 (63%) Baseline characteristics: mean
(min, max) n=10 Age 3.8 (2, 6) HFMSE score 23.5 (14, 42) # of nusinersen maintenance doses 5.4 (3, 8) Sizable increases in HFMSE observed in patients already treated with chronic maintenance nusinersen88% (7/8) improved63% (5/8) with
≥5-point increase38% (3/8) with >10-point increaseContinuous and durable improvements observed through 12-months of treatment Data on file. Scholar Rock, Inc. Cambridge, MA
Non-Ambulatory Type 2/3 Cohort:Initiated nusinersen age ≥5 Apitegromab (20 mg/kg) + nusinersen Per
Protocol Population* (n=13) Intent-to-Treat Population (n=14) Mean change from baseline in HFMSE (95% CI) +1.2(-0.5, 2.9) +0.6(-1.4, 2.7) # (%) patients achieving: ≥1-pt increase in HFMSE 9/13 (69%) 9/14 (64%) ≥3-pt increase in
HFMSE 4/13 (31%) 4/14 (29%) ≥5-pt increase in HFMSE 2/13 (15%) 2/14 (14%) Baseline characteristics: mean (min, max) n=15 Age 11.7 (8, 19) HFMSE score 22.7 (13, 39) # of nusinersen maintenance doses 5.1 (2, 9) 33 Majority of
patients improved in HFMSE (despite initiating background nusinersen age ≥5)~2/3 with ≥1-point increase~30% with ≥3-point increaseDurability of effect observedthrough 12-months of treatment *Patient had concomitant exposure to an
acetylcholinesterase inhibitor, which was not permitted per the TOPAZ trial protocolData on file. Scholar Rock, Inc. Cambridge, MA
Majority of Ambulatory Patients Maintained or Improved in RHS Score from Baseline 34 Apitegromab 20
mg/kg monotherapy Apitegromab 20 mg/kg + nusinersen Mean change from baseline in RHS (95% CI) -0.4 (-3.9, 3.1) -0.3 (-2.0, 1.4) # (%) patients achieving: ≥0-pt increase in RHS 6/11 (55%) 7/12 (58%) ≥1-pt increase in RHS 4/11
(36%) 5/12 (42%) ≥3-pt increase in RHS 3/11 (27%) 2/12 (17%) Baseline characteristics: mean (min, max) n=11 n=12 Age 12.1 (7, 19) 13.1 (7, 21) HFMSE score 47.6 (26, 63) 51.3 (43, 62) # of nusinersen maintenance doses n/a 5.6 (2,
8) Majority maintained or improved57% (13/23) with ≥0-point increase39% (9/23) with ≥1-point increaseUp to 8-point increase observedResults contrast with declines typically observed with natural history of ambulatory patients Data on file.
Scholar Rock, Inc. Cambridge, MA
Dose-proportional and sustained drug exposure following chronic administration of
apitegromab Pharmacokinetic and Pharmacodynamic Data areSupportive of Clinically Observed Effects Both 2 mg/kg and 20 mg/kg doses yielded high levels of target engagement (>100-fold increase from baseline)20 mg/kg dose offers relatively
higher magnitude of target engagement than 2 mg/kg dose High levels of target engagement achieved by both doses, with relatively higher absolute levels with high dose 35 *Starting at day 28, measures are pre-dose trough levels Data on file.
Scholar Rock, Inc. Cambridge, MA Pharmacokinetics* (PK) Pharmacodynamics (PD)
HFMSE Improvements Observed Across Age Range of Non-Ambulatory Patients with Relatively Larger Gains
from Earlier Treatment *Pooled cohorts of non-ambulatory patients treated with apitegromab 20 mg/kg and 2 mg/kg; excludes 4 patients who each missed 3 doses of apitegromabdue to COVID-19-related site access restrictions and were not included in
the primary (intent-to-treat) analysis. Data on file. Scholar Rock, Inc. Cambridge, MA HFMSE change from baseline Youngest (2 years) Oldest (19 years) Age of patient at baseline in TOPAZ 36
Analysis overview*:Pooled patients (n =16) of age 2-12 years from the intent-to-treat population of the
two non-ambulatory cohortsNusinersen initiated at age < 5 years: n = 8Nusinersen initiated at age > 5 years: n = 812 months of apitegromab 20 mg/kg as add-on to background nusinersenPatients were all in chronic maintenance phase of
nusinersenHFMSE change from baseline TOPAZ Age 2-12 Exploratory Analysis (Non-Ambulatory Type 2/3 SMA) 37 *Exploratory, post hoc analysis
Mean HFMSE increase of 4.4 points, with majority experiencing > 3-point increases on top of background
SMN therapyHFMSE gains also notable in subset of individuals in this analysis who had started background nusinersen at age > 5: 75% (6/8) with > 1-point increase and 50% (4/8) with > 3-point increase*Exploratory, post hoc analysis TOPAZ
Age 2-12 Analysis* in Pooled Non-Ambulatory CohortsTransformative Potential as Add-on for Apitegromab Non-Ambulatory Type 2/3 SMA(Apitegromab 20 mg/kg; Intent-to-Treat Population) Age 2-12 years (n=16) Mean HFMSE change from baseline (95%
CI) +4.4(1.3, 7.4) # (%) patients with ≥1-pt increase in HFMSE 13/16 (81%) # (%) patients with ≥3-pt increase in HFMSE 9/16 (56%) 38
39 SAPPHIRE Details Main population Endpoints Analysis Additional Data Opportunities Primary
efficacy: HFMSEAdd’l efficacy measures: RULM, WHO, other outcome measuresSafety, PK/PD, ADA Topline readout based upon main efficacy population (age 2-12) and focused upon apitegromab 20 mg/kg* vs. placeboInterim analysis opportunity when >
50% of patients in main efficacy population have completed 12 months Open-label extension (after patients complete 12-month period); focused upon safety &exploratory longer-term efficacyExploratory population (age 13-21): n=48 (2:1
randomization between apitegromab 20 mg/kg vs placebo, as add-on to background SMN Rx); focused upon safety & exploratory efficacy Age 2-12, non-ambulatory Type 2 and Type 3 SMAChronic maintenance phase of SMN Rx (minimum prior duration of
treatment before screening of 10 mo’s for nusinersen or 6 mo’s for risdiplam)Stratified randomization to ensure balanced allocation: 1) age at SMN Rx initiation (age < 5 vs age > 5) 2) background SMN Rx (nusinersen vs. risdiplam) *To
control type I error caused by multiple comparisons, the efficacy analysis will first compare the apitegromab 20 mg/kg arm againstplacebo before any testing of apitegromab 10 mg/kg against placebo
Increases in HFMSE Not Correlated with Duration of PriorNusinersen Treatment Change in HFMSE Not
Correlated With Number of Nusinersen Maintenance Doses(post-hoc analysis of TOPAZ non-ambulatory patients) Further data suggesting increases in HFMSE may be attributable to apitegromab No correlation between duration of prior nusinersen
treatment and change in HFMSEPatients in TOPAZ were already in chronic maintenance phase of nusinersen (mean of~2 years at enrollment) Data on file. Scholar Rock, Inc. Cambridge,
MA -10 -5 0 5 10 15 20 HFMSE change from baseline 2(~10 months) 9(~3 years) # of maintenance nusinersen doses 5(~2 years) 40
WHO Motor DevelopmeSupport Apitegromab nt Milesto’s Potential ne Achievementto Improve Mot s Furtheror
Function Non-ambulatory Type 2/3 Patients Pooled Initiated nusinersen age <5 Initiated nusinersen age ≥5 # of patients gaining ≥1 WHO motor milestone(s) 7/35 4/20 3/15 41 WHO motor milestone analysis included all patients who
completed the 12-month treatment period, including 4 patients who missed 3 doses of apitegromabdue to COVID-19-related site access restrictions. Median baseline score for both non-ambulatory cohorts was 1.0.1 patient (initiated nusinersen age ≥5)
gained 2 new motor milestones and 1 patient (initiated nusinersen age <5, 20 mg/kg) gained 3 new motor milestonesPictures are not of patients with SMA and are not meant to be representative of patients with SMA. Data on file. Scholar Rock,
Inc. Cambridge, MA. Sitting without support Hands & knees crawling Standing with assistance Walking with assistance Standing alone Walking alone ✔✔ ✔✔✔ ✔✔✔ ✔ ✔ Following 12 months ofapitegromab
treatment...
Inhibition of TGFβ1: Multipronged Approach forImmuno-Oncology 42 TGFβ1 Tumor Associated
Macrophage Cancer Associated Fibroblasts (Stromal cells) Tumor cells TGFβ1 is a key driver of immune system evasion by cancer cellsRegulatory T cell Pathway analysis in patienttumors points to TGFβ1 as major determinant of primary resistance
to anti-PD-(L)1 therapy TGFβ1 creates ‘immune excluded’tumor microenvironment
TGFβ1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible to Anti-PD1 Therapy Days
after treatment initiation Tumor volume (mm3) Anti-PD1/SRK-181-mIgG1(10 mg/kg QW) Anti-PD1/SRK-181-mIgG1(3 mg/kg QW) 4/14 8/14 Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med. 2020 Mar
25;12(536):eaay8456. https://scholarrock.com/platform/publications/.*SRK-181-mIgG1 is the murine version of SRK-181; responder defined as tumor size <25% endpoint volume at study end. Bladder Cancer Breast Cancer (TGFβ1/3
co-expressing) Responders SRK-181-mIgG1* (10mg/kg QW) 0/13 Anti-PD1 (10 mg/kg BIW) 0/12 0/10 SRK-181-mIgG1* (10 mg/kg QW) Anti-PD1/ SRK-181-mIgG1(10 mg/kg QW) 5/10 Responders 0/9 0/9 Control Anti-PD1 (10 mg/kg BIW) 43
44 “Longer-term treatment with nusinersen: results in later-onset spinal muscular atrophy from the SHINE
study” P.257, World Muscle Society Congress 2020 This third-party information is provided for background only and is not intended to convey or imply a comparison to the TOPAZ clinical trial results. Plateauing of HFMSE gains apparent following
initial treatment effects for nusinersen... Mean (+ SE) Change in HFMSE Total Score From Baseline 690 930Analysis Visit, days 1170 1410 1650 -41 92 169 253 350 450 876543210-1-2-3 <1-point increase in HFMSE after~ first year of
treatment +3.9-points +4.6-points Unmet Need for Motor Function Gains Initial treatmentCHERISH Chronic maintenance phaseSHINE Patients with Type 2 and 3 SMA Continue to Experience MajorFunctional Deficits Despite Improvement from SMN
Therapy* Mean improvement in HFMSE experienced in nusinersen Phase 3 CHERISH trial 3.9-point HFMSE increase from baseline(4.9 point increase relative to sham ctrl) 0 20 40 60 80 HFMSE Score at Month 15 Total Possible HFMSE
Score of 66 Motor function impairment Significant motor function deficits still present...
†Source: Mercuri E, et.al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N
Engl J Med. 2018;378:625-635. † †Efficacy and safety of risdiplam (RG7916) in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA) Roche/PTC Therapeutics *This third-party information is provided for background only and is
not intended to convey or imply a comparison to the TOPAZ clinical trial results In patients with later-onset SMA who were age >5 at screening…Primary benefit of nusinersen - stabilization of motor functionMajority of patients do not
experience HFMSE increases 45 Low percentage of patients over the age of 5 achieved ≥3-point increase on MFM32 scale, even with risdiplam treatmentHFMSE secondary endpoint showed a mean 0.58-point improvement over placebo (not statistically
significant) % of patients with >3 change inMFM32 total at Month 12 2-5 years 18-25 years 6-11 years 12-17 yearsChange in MFM32 total score Risdiplam Placebo 100806040200 Non-Ambulatory Type 2/3 SMA: Majority of Patients Started
on SMN Rx After Age 5 Do Not ExperienceMotor Function Increases*Nusinersen CHERISH Trial in Later-Onset SMA† Risdiplam SUNFISH Trial in Later-Onset SMA††
Safety Results fromSupport Evaluation TOPAZ 12-Montof Apitegromab h Top-Line Anin Phase 3
Tria alysisl Treatment-emergent adverse events (TEAEs) Apitegromab 2 mg/kg (n=10) Apitegromab 20 mg/kg (n=48) Total (n=58) Any TEAE 9 (90.0%) 44 (91.7%) 53 (91.4%) Any Serious TEAE 1 (10.0%) 4 (8.3%) 5 (8.6%) Any TEAE leading to
study drug discontinuation 0 (0.0%) 1 (2.1%) 1 (1.7%) Any Grade 3 (severe) or higher TEAE 0 (0.0%) 3 (6.2%) 3 (5.2%) 46 Treatment-emergent adverse events (TEAEs) are defined as AEs that start after the first dose of study drug or start
prior to the administration of study drug and worsen in severity/grade or relationship to investigational medication after the administration of study drug.*TEAE rates are across all patients in TOPAZ trial Data on file. Scholar Rock, Inc.
Cambridge, MA Five most frequently reported TEAEs*: Headache (24%), pyrexia (22%), upper respiratory tract infection (22%), cough (22%), and nasopharyngitis (21%).SAEs, Grade 3 AEs and AE leading to early study discontinuation were all
assessed by investigators as unrelated to study drugAnti-drug antibodies (ADA) were present at low titers following apitegromab treatment in 3 out of 58 enrolled patients. No apparent impact on drug exposure was observed and was not associated
with any hypersensitivity reactions.Incidence and severity of AEs were consistent with the underlying patient population and background therapy
Significant Interest in Potential Role of TGFβ Inhibition inImmuno-Oncology Nature (online), Feb.
14, 2018. AuthorsWilly Hugo, Jesse M. Zaretsky, Lu Sun, Douglas B. Johnson, Antoni Ribas, Roger S. LoVolume 165, Issue 1, 24 March 2016, Pages 35-44 July 24, 2020: https://doi.org/10.1038/ s41571-020-0403-1 February 2019: “GSK and
Merck KGaA, Darmstadt, Germany announce global alliance to jointly develop and commercialise M7824, a novel immunotherapy with potential in multiple difficult-to-treat cancers”€300 million upfront and up to €3.7 billion total June 2019:
“Merck to Acquire Tilos Therapeutics: Merck Gains Portfolio of Investigational Antibodies Modulating TGFβ”$773 million total potential deal value 47 August 2020: “Bristol Myers Squibb Enters Agreement toAcquire Forbius TGF-beta Program”
Cancer Genome Atlas RNAseq analysis of>10,000 samples spanning 33 tumor types* Substantial % of
solid tumors exhibit immune exclusion Emerging Evidence Implicates TGFβ1 as Driving Primary Resistance to Checkpoint Inhibitors Human Tumor Analyses Reveal TGFβ1 as Most Likely Driver of TGFβ Signaling Pathway in Cancers 48 †Priti H, et
al. Top 10 challenges in cancer immunotherapy. Immunity. 2020 Jan 14:52(1):17-35. https://doi.org/10.1016/j.immuni.2019.12.011.*Source: National Cancer Institute - Cancer Genome Atlas Program.
DRAGON Part A: Dose Escalation Update and Safety Data 49 Median number of prior lines of therapy was 4
(range 1, 9) for Part A1 and 4 (range 2, 6) for Part A2No dose-limiting toxicities have been observed with SRK-181 in Part A (as of Oct. 12, 2021), evaluating doses as high as the following thus far:Part A1 : doses up to 3000 mg Q3W and 2000 mg
Q2W as a monotherapyPart A2: 1600 mg Q3W in combination with anti-PD-(L)1 therapyMost common (>10%) treatment-related TEAEs* of any grade were fatigue,decreased appetite, and nausea (Part A1) and rash maculo-papular (Part A2)*TEAE =
treatment-emergent adverse event
DRAGON Part A: Preliminary Pharmacokinetics (PK)Summary of SRK-181 50 SRK-181 displayed typical
monoclonal antibody PK characteristicsBased on a power model, dose- proportional PK was observed for SRK-181The T1/2 of SRK-181 was 5.4 to 10.7days