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Significant Opportunities to Target Iron-Restricted Anemias Across Multiple Indications 105 Chronic Kidney Disease (CKD) Anemia of Chronic Inflammation (AI) Myelofibrosis (MF) Targeting RGMc/HJV for anemia is well validated and relatively de-risked - High levels of hepcidin, the main regulator of systemic iron metabolism, are associated with anemia across various diseases Safe and convenient RGMc inhibitor has promise of improving patient outcomes across multiple indications as stand alone or in combination with SoC - Significant and clear unmet need given lack of approved treatments or severe limitations of current treatments - Well defined patient population Collectively, sizeable commercial opportunity given relatively large population - Potential for rapid POC with clear regulatory path - Opportunity to build an anemia franchise with initial POC and indication expansion in the future ANEMIA
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(! #!! #(! B!! B(! D!! D(! $!! IJ.L 12345S TUV:D(B!B 1 ;<. =S >L?@. A?BC 3Ca EAF d 1 ;<a =S !"# BCD(# )*HIJK/0/ 120P45S47 CHU !V# )*HIJK/0/ 120P45S47 CHU !"# :;<=P C<>?# )HIJK/0/ 120P45S47 CHU PK: HJV-35202 (10mg/kg, IV) PD: UIBC: HJV-35202 (10mg/kg, IV) PDF: Serum Iron: HJV-35202 (10mg/kg, IV) ! " #$ B# BC D( $B $) ( *D "! !H!# !H# # #! #!! #!!! !
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Nicholls S.B., et al. Poster: RGMc-selective antibodies modulate iron homeostasis in vivo, 12th International BMP Conference, Tokyo, October 2018 2. Scholar Rock, Data on File - High-affinity antibody - Specific to RGMc, with mechanism of specificity understood - Cross-reactive to human, mouse, rat and cyno - Sustained PD observed in healthy rats and cynos, with clear PK/PD relationship - Highly manufacturable framework with no sequence liabilities - Formulatable into a subcutaneous format (150 mg/mL) !
Wang CY and Babitt JL. (2016) Hepcidin Regulation in the Anemia of Inflammation. Curr Opin Hematol 23(3): 189-197. - Elevation of proinflammatory cytokines drives increased hepcidin expression and results in anemia due to functional iron deficiency4 Anemia of Inflammation/ Chronic Disease Hepcidin Serum iron Untreated Hepcidin Serum iron Ab treated - Human mutations in HJV/RGMc establish it as a central player in hepcidin regulation1 - Knockout phenotypes and tissue-specific expression pattern demonstrate that its predominant role is in iron homeostasis2 - Member of repulsive guidance molecule (RGM) family (RGMa, RGMb, RGMc/HJV) that act as BMP co-receptors to modulate BMP signaling3 HJV/RGMc is a key player in the regulation of hepcidin expression ANEMIA 2024 Scholar Rock, Inc.
Am J Physiol Cell Physiol 294(4):C994-C1003 2: Constante M, et al.. (2007) Repression of repulsive guidance molecule C during inflammation is independent of Hfe and involves tumor necrosis factor-alpha. Am J Pathol 170(2):497-504 3: Core A.B., et al. (2014) Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front Pharmacol. 5:104. 4.
SRK-181 has not been approved by the US FDA or any other health authority, and its safety and efficacy have not been established. Binding to latent TGF -1 delays maturity state allowing TGF -1 to accumulate in system Combination treatment with pembrolizumab did not appear to impact circulatory TGF -1 levels C1D2 C1D8 C1D15 C2D1* C3D1* C3D2 C3D8 C3D15 C4D1* C5D1* Baseline Circulatory TGF -1 (Fold-Change from Baseline) 2 3 4 6 5 Median Circulatory TGF -1 Increased Post-treatment with SRK-181 (Q3W, All Patients) SRK - 181 2024 Scholar Rock, Inc.
Circulatory TGF -1 and PF4 levels were quantitated by using validated ELISA kits from R&D System.12 Because platelet activation during sample processing can lead to elevated TGF -1 levels, samples with elevated PF4, a platelet activation biomarker, were excluded from the analysis based on a preliminary cutoff value. Pre-infusion. SRK-181 is an investigational drug candidate that is being evaluated for the treatment of cancer.
PD-L1) - Changes to intra-tumoral and/or circulating immune cell contexture (MDSC) - Show evidence of the SRK-181 target engagement e.g. circulating TGF -1 levels - TGF pathway modulation: e.g. Histochemical analysis of pSMAD e.g. RNA-based TGF gene signatures and pathway analyses - Paired biopsies from the head and neck cohort allow for a potential to accelerate the development path Immunophenotyping Assessment of immune landscape TGF -1 pathway evaluation Assessment of signaling pathway SRK - 181 2024 Scholar Rock, Inc.
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. NSCLC TMB Low High Substantial % of Solid Tumors Exhibit Immune Exclusion Immune Phenotype Inflamed Immune Excluded Immune Desert Tumor Type Melanoma RCC UBC TNBC Gastric CRC MSS Pancreatic SCLC HR+BC Prostate Inflamed Immune Excluded Immune Desert Cancer Genome Atlas RNAseq Analysis of >10,000 Samples Spanning 33 Tumor Types TGFB1 TGFB2 TGFB3 Scale % of patient samples (+) for TGF- isoform 100 80 60 40 20 0 SRK - 181 2024 Scholar Rock, Inc.
Toxicol Pathol. 2011;39: 916-924.; and Stauber AJ, et al. Nonclinical safety evaluation of a transforming growth factor Receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. J Clin Pract. 2014: 4:3. 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 PanTGF Ab 30 mg/kg Iv, 1 dose 10 mg/kg iv, qwk x 4 30 mg/kg iv, qwk x 4 100 mg/kg iv, qwk x 4 SRK-181 Selective TGF -1 Toxicity: Minimal Non-selective TGF Toxicity: Minimal, slight and moderate Unremarkable Minimal Slight Moderate Toxicology: Repeat Dose Pilot Toxicology Study Adult female Sprague Dawley rats Cardiac findings were exhibited in animals dosed with pan-TGF antibody or LY2109761 (inhibitor of ALK5, common TGF receptor kinase) as expected based on published data NO CARDIOTOXICITIES (valvulopathy) were noted with SRK-181 NOAEL for SRK-181: 100 mg/kg QW (highest dose evaluated) 4-week GLP toxicology studies RATS NOAEL for SRK-181: 200 mg/kg QW (highest dose evaluated) NON-HUMAN PRIMATES NOAEL for SRK-181: 300 mg/kg (highest dose evaluated) Not test article related SRK - 181 2024 Scholar Rock, Inc.
Martin CJ, et al. Sci Transl Med. 2020 Mar 25;12(536):eaay8456. https://scholarrock.com/platform/publications. Days after treatment initiation Monotherapy 3/12 Anti-PD1 (10 mg/kg BIW) Tumor volume (mm3) SRK-181-mIgG1 (30 mg/kg QW) Responders 0/12 Combination Therapy Led to tumor regression and survival benefit Anti-PD1/SRK-181-mIgG1 (30 mg/kg QW) 8/11 Days after treatment initiation Anti-PD1/SRK-181-mIgG1 (10 mg/kg QW) Tumor volume (mm3) 4/9 SRK - 181 2024 Scholar Rock, Inc.
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 (TGF -1/3 co-expressing) 0/13 Anti-PD1 (10 mg/kg BIW) 0/10 SRK-181-mIgG1 (10 mg/kg QW) Anti-PD1/ SRK-181-mIgG1 (10 mg/kg QW) 5/10 Responders 0/9 Control 0/9 Anti-PD1 (10 mg/kg BIW) SRK-181-mIgG1* (10 mg/kg QW) Responders 0/12 MBT-2 and EMT6 Models SRK - 181 2024 Scholar Rock, Inc.
Efficacy in Cohort MEL Clinical Responses in Anti-PD-1 Non-responders 90 Efficacy Intent To Treat N=11 ORR 3 (27.3%) Confirmed CR 1 (9.1%) Confirmed PR 1 (9.1%) mDoR (Months) 4.9 (1.8, 7.1) DCR 8 (72.7%) - Median lines of prior cancer therapy: 3 (range 1 7) All have SD or PD as BOR to the last prior anti-PD-1 9 (82%) had PD from the last prior anti-PD-1 BOR, best overall response; CR, complete response; DCR, disease control rate; mDoR, median duration of response; MEL, melanoma; ORR, objective response rate; PD, progressive disease; PD-1, programmed cell death protein 1; PR, partial response.
SRK-181 is an investigational drug candidate that is being evaluated for the treatment of cancer. SRK-181 has not been approved by the US FDA or any other health authority, and its safety and efficacy have not been established. - At 800 mg q3w, 1 partial response (PR) was observed in patient with anti-PD-1-resistant clear cell renal cell carcinoma (ccRCC) - 9 patients had best response of SD - 6 patients (green highlight) were stable beyond the 16-week cutoff - 1 ongoing patient with head and neck cancer had a 29.4% tumor reduction SRK - 181 2024 Scholar Rock, Inc.
Safety and Efficacy Results of SRK-181, a latent TGF 1 inhibitor, from a Phase 1 trial (DRAGON Trial); Presented at ESMO-TAT; March 7, 2023. *Clinical cutoff date: December 2, 2022. Response is assessed using RECIST v1.1 by PI; the scan is performed during screening, 6 weeks after first dose, every 9 weeks for the next 6 months of treatment, and every 12 weeks thereafter.
Safety and Efficacy Results of SRK-181, a latent TGF 1 inhibitor, from a Phase 1 trial (DRAGON Trial); Presented at ESMO-TAT; March 7, 2023. *Clinical cutoff date: December 2, 2022. Response is assessed using RECIST v1.1 by PI; the scan is performed during screening, 6 weeks after first dose, every 9 weeks for the next 6 months of treatment, and every 12 weeks thereafter.
Treatment-related Grade 3 AEs: - Alanine aminotransferase increased (1 patient) Treatment-related SAEs: - None No DLTs were observed up to 3000 mg q3w and 2000 mg q2w No Grade 4 or 5 treatment-related AEs occurred Treatment-related Grade 3 AEs: - Pruritus (2 patients), blister, immune-mediated lung disease, pemphigoid, rash, rash maculo-popular and rash vesicular (1 patient each) Treatment-related SAEs: - Blister, pruritus, and rash (all in 1 patient) and immune-mediated lung disease (1 patient) No DLTs were observed up to 2400 mg q3w No Grade 4 or 5 treatment-related AEs occurred Yap T et al.
PART B SRK-181 + pembrolizumab; non-responders to prior anti-PD-1 Non-small cell lung cancer SRK-181 + pembrolizumab Urothelial carcinoma SRK-181 + pembrolizumab Cutaneous melanoma SRK-181 + pembrolizumab Clear cell renal cell carcinoma** SRK-181 + pembrolizumab SRK-181 + pembrolizumab Head and neck squamous cell** carcinoma COHORT TREATMENT PART A SRK-181 80 mg (n=1) SRK-181 240 mg (n=1) SRK-181 800 mg (n=3) SRK-181 1600 mg (n=3) SRK-181 2400 mg (n=3) SRK-181 3000 mg (n=3)* SRK-181 all-comers A1 A2 SRK-181+anti-PD-(L)1; non-responders to prior anti-PD-(L)1 SRK-181 240 mg (n=3) SRK-181 800 mg (n=3) SRK-181 1600 mg (n=3) SRK-181 2400 mg (n=3) SRK - 181 2024 Scholar Rock, Inc.
The Lancet, Volume 402, Issue 10397, 2023, Pages 185-195, https://doi.org/10.1016/S0140-6736(23)00922-4 PD-1/PD-L1) SRK - 181 Enrollment completed December 2023 NEXT STEPS Present ongoing emerging data at future medical meetings Conduct an end of Phase 1 meeting with regulatory authorities to inform next steps - Monoclonal antibody selectively targeting latent and context-independent binding to TGF 1 - Novel and highly selective inhibition of TGF -1 targeting latent form - Offers potential to avoid toxicity and dose-limiting challenges of non-selective TGF inhibition approaches Differentiation Ph1 DRAGON Demonstrated Proof-of-Concept in multiple tumor types - Showed objective, durable clinical responses above what is expected from continuing PD-1 alone1 - Biomarker data supports proof-of-mechanism in multiple tumor types 85 2024 Scholar Rock, Inc.
Data generated from available post treatment biopsies that were evaluated using a multiplex fluorescent assay. ccRCC, clear cell renal cell carcinoma; CD, cluster of differentiation; GrmB, Granzyme B; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease; UC, urothelial carcinoma.
CD! ! D! ()G+,-.L0,1OPO45 0 S TO 9 4.: SO ; S T<P = > ? G @ S.A S =O ) B 4 = : S SRK-181 and Pembrolizumab Increased CD8+ Infiltration CD8+ Cytotoxic T-cells were Activated in Responding Patients Line indicates cutoff that defines infiltrated status. Data generated from available paired biopsies that were evaluated using a chromogenic assay. Data generated from available paired biopsies that were evaluated using a multiplex fluorescent assay.
AE, adverse event; ccRCC, clear cell renal cell carcinoma; HNSCC, head and neck squamous cell carcinoma; MEL, melanoma; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; PD-(L)1, PD-1/PD-L1; RECIST, response evaluation criteria in solid tumors; UC, urothelial carcinoma. Data cut date: Apr 10, 2024 SRK - 181 2024 Scholar Rock, Inc.
Sci Transl Med. 2020;12:eaay8456. Yap T, et al. J ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0780. AE, adverse event; ccRCC, clear cell renal cell carcinoma; DLT, dose-limiting toxicity; HNSCC, head and neck squamous cell carcinoma; MAD, maximum administered dose; MTD, maximum tolerated does; PK, Pharmacokinetic; PD, progressive disease; PR, partial response; q2w, every 2 weeks; q3w, every 3 weeks; SD, stable disease.
Tumor Nest Analysis CD8 Stain Melanoma, Pre and Post Treatment Primary Compartmental Analysis % CD8+ T cells per compartment ! " #! #" ! #!!! $!!! %!!! C!!! D() +(),-.)/- 0 12P D456-6T) +8. 4( /) 5- 569) :; )<< ; 48/-= !"#$%&D& ED)D*+ I-./$+0+D& ! "! #! $! %! ! "!!! #!!! $!!! CD() +,-.)/-0) 1 2P4 CD(5)56- +T/ D, 0-() (58- 9:-;; :DT0)< !"#$%&'& E)+$I-.I'& 0% 10% 20% 30% Whole Tissue Margin Stroma Tumor Pre Post Cutoff Post-Treatment Pre-Treatment SRK - 181 2024 Scholar Rock, Inc.
Part B: SRK-181 (1500mg q3w) + Pembrolizumab n=up to 40/cohort Dose Expansion Cohort HNSCC Cohort MEL Cohort UC Cohort NSCLC Cohort Any Other* Cohort ccRCC Key Eligibility Criteria - 18-year-old and ECOG 0-1 - Measurable disease per RECIST v1.1 - At least 1 prior line of anti-PD-1 antibody - Part B Cohort ccRCC and HNSCC: Must have had PD on the most recent prior anti-PD-1 - Part B Cohorts NSCLC, UC and MEL: Non-responders to all prior anti-PD-1 SRK - 181 2024 Scholar Rock, Inc.
Part A1: SRK-181 Single Agent (80-3000 mg q3w/2000 mg q2w) All advanced solid tumor n=19 Part A2: SRK-181 + anti-PD-(L)1 (SRK-181: 240-2400mg q3w) Advanced solid tumor non-responders to prior anti-PD-(L)1 n= 15 Dose Escalation (3+3) Study Endpoints Primary: - Safety and tolerability Secondary: - Anti-tumor activity (BOR, ORR, DoR, and DCR) - PK and ADA Exploratory: - Biomarker - PFS, OS, etc.
J Clin Invest. 1990 Dec;86(6):1976-84. doi: 10.1172/JCI114932. PMID: 2254455; PMCID: PMC329834. SRK-181: Latent TGF -1 Inhibitor Targets TGF -1 Potential to overcome CPI resistance SRK-181 inhibits the TGF -1 implicated in check point inhibitor resistance Selective to -1 isoform Highly selective to -1 isoform vs. 2 and 3 Increases therapeutic window and potentially avoids toxicities associated with non-selective TGF inhibition Other programs target multiple isoforms of TGF Context-independent Inhibits all sources of TGF -1 SRK-181 targets all TGF -1 sources (LRRC33, GARP and LTBP1 and 3) Some programs only target one source Targets the latent form of TGF -1 Selectively targeting the latent form shuts off the growth factor before activation Increases opportunity to inhibit TGF -1 Most other programs target the mature form of TGF -1 SRK - 181 2024 Scholar Rock, Inc.
Halligan3 , Michiel S. van der Heijden4 , Yohann Loriot5 , Jonathan E. Rosenberg6 , Lawrence Fong7 , Ira Mellman1 , Daniel S. Chen1 , Marjorie Green1 , Christina Derleth1 , Gregg D. Fine1, Priti S. Hegde1, Richard Bourgon1 & Thomas Powles8 Willy Hugo, Jesse M. Zaretsky, Lu Sun, Douglas B. Johnson, Antoni Ribas, Roger S. Lo Volume 165, Issue 1, 24 March 2016, Pages 35-44 Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma July 24, 2020: https://doi.org/10.1038/ s41571-020-0403-1 Nature Reviews , July 24, 2020 NATURE REVIEWS | CLINICAL ONCOLOGY TGF : biology in cancer progression and immunotherapy Rik Derynck1,2,3, Shannon J.
Astarita1, Rafael Cubas1, Suchit Jhunjhunwala1, Romain Banchereau1, Yagai Yang1, Yinghui Guan1, Cecile Chalouni1, James Ziai1, Yasin enbabao lu1, Stephen Santoro1, Daniel Sheinson1, Jeffrey Hung1, Jennifer M. Giltnane1, Andrew A. Pierce1, Kathryn Mesh1, Steve Lianoglou1, Johannes Riegler1, Richard A. D. Carano1 , Pontus Eriksson2 , Mattias H glund2 , Loan Somarriba3 , Daniel L.
Constance J. Martin, et al. Vol 12, Issue 536. DOI: 10.1126/scitranslmed.aay8456 Nature (online), February 14, 2018. TGF attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Sanjeev Mariathasan1 *, Shannon J. Turley1 *, Dorothee Nickles1 *, Alessandra Castiglioni1 , Kobe Yuen1 , Yulei Wang1 , Edward E. Kadel III1, Hartmut Koeppen1, Jillian L.
IQVIA. https://www.iqvia.com/library/white-papers/in-the-eye-of-the-storm-pd-l-1-inhibitors-weathering-turbulence 2. Source: Carretero-Gonzalez et al. (2018) Oncotarget 9:8706-8715 Meta-analysis of twelve randomized trials with control arm or adequate safety profile (includes nivolumab, pembrolizumab, and atezolizumab) Clinically derived rationale points to significant opportunity to increase checkpoint therapy responses by targeting TGF -1 7.9-10.41 MILLION US patients on CPI therapies First-line CPI therapy Second-line (or later) CPI therapy DID NOT respond 63%2 78%2 SRK - 181 2024 Scholar Rock, Inc.
Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. Pooled Nonambulatory Patients1 Mean Change from Baseline (+SE) n= 34 28 31 31 27 22 95% CI= (-0.2, 1.4) (0.2, 2.3) (1.2, 3.3) (1.1, 3.7) (2.0, 5.3) n= 28 22 25 25 22 18 95% CI= (-0.7, 1.1) (0.1, 2.4) (1.0, 3.5) (1.4, 4.2) (2.7, 6.3) SPINAL MUSCULAR ATROPHY Baseline mean age=7.3 | Time on SMN Rx=24.1m Baseline mean age=5.5 | Time on SMN Rx=24.6m Age 2-21 Years All Doses (N=35) Age 2-12 Years All Doses (N=29) 70 Mean Change from Baseline (+SE) 2024 Scholar Rock, Inc.
Visit windows were applied to utilize data from unscheduled or early termination visits if the patient was missing the RULM total score at the scheduled visit. One patient did not have baseline RULM due to young age. Error bars represent standard error (SE) and CI represents confidence interval. SMN Rx=SMN therapy. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy.
The analysis population pooled the nonambulatory patients (Cohorts 2 and 3) and included patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). A total of 11 patients in the population had scoliosis surgery during the study and their data was excluded from any RULM assessments at 48 months.
Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. Pooled Nonambulatory Patients1 Mean Change from Baseline (+SE) Mean Change from Baseline (+SE) SPINAL MUSCULAR ATROPHY 2.8 3.6 4.2 4.0 5.3 0 1 2 3 4 5 6 7 8 9 Baseline 6 months 12 months 24 months 36 months 48 months n= 35 29 32 29 28 23 95% CI= (1.4, 4.1) (1.2, 6.0) (1.9, 6.6) (1.0, 6.9) (1.5, 9.2) n= 29 23 26 23 23 19 95% CI= (1.8, 5.0) (1.8, 7.4) (2.3, 8.0) (1.3, 8.3) (1.8, 11.0) Baseline mean age=7.3 | Time on SMN Rx=24.1m Baseline mean age=5.5 | Time on SMN Rx=24.6m Age 2-21 Years All Doses (N=35) Age 2-12 Years All Doses (N=29) 69 2024 Scholar Rock, Inc.
Visit windows were applied to utilize data from unscheduled or early termination visits if the patient was missing the HFMSE total score at the scheduled visit. Error bars represent standard error (SE) and CI represents confidence interval. SMN Rx=SMN therapy. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy.
The analysis population pooled the nonambulatory patients (Cohorts 2 and 3) and included patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). A total of 11 patients in the population had scoliosis surgery during the study and their data was excluded from any HFMSE assessments at 48 months.
Significant Opportunities to Address High Unmet Need Across Multiple Fibrotic Indications 65 Alport Syndrome (AS) Focal Segmental Glomerulosclerosis (FSGS) IgA Nephropathy (IgAN) Primary Sclerosing Cholangitis (PSC) Diffuse Cutaneous Systemic Sclerosis (dcSSc) Idiopathic Pulmonary Fibrosis (IPF) Collectively, significant commercial potential given large patient population with clear high unmet need given poor outcomes and lack of effective therapeutics - Significant impact to delay or stop progression to end-stage disease and organ transplant - Expansion opportunities via other indications given shared etiologies FIBROSIS 2024 Scholar Rock, Inc.
Nath PNAS, February 24, 1986 Transforming growth factor type : Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro ANITA B. ROBERTS* MICHAEL B. SPORN*, RICHARD K. ASSOIAN*, JOSEPH M. SMITH*, NANETTE S. ROCHE*, LALAGE M. WAKEFIELD*, URSULA I. HEINE*, LANCE A. LIOTTA*, VINCENT FALANGA , JOHN H. KEHRL , AND ANTHONY S.
Preston, Chrisine M. Grinnell, Katherine M. Salte,* Anthony M. Giamis,* Yanping Luo,* Victor Sun, Andrew D. Goodearl, Murali Gopalakrishnan,* and Susan E. Lacy J Pathol, July 25, 2021 TGF- as a driver of fibrosis: physiological roles and therapeutic opportunities Erine H Budi1, Johanna R Schaub1, Martin Decaris1, Scott Turner1, Rik Derynck2 J Receptors Sign Trans, Feb 13, 2020 Inevitable role of TGF- in progression of nonalcoholic fatty liver disease Bhagyalakshmi Nair and Lekshmi R.
J. Mol. Sci. August 27, 2018 Targeting TGF- Signaling in Kidney Fibrosis Yoshitaka Isaka J. Am. Soc. Nephrol. December 3, 2017 Targeting Anti-TGF- Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach Steve McGaraughty,* Rachel A. Davis-Taber, Chang Z. Zhu,* Todd B. Cole,* Arthur L. Nikkel,* Meha Chhaya, Kelly J. Doyle,* Lauren M. Olson,* Gregory M.
Tirzepatide and semaglutide dose regimen will follow the United States Prescribing Information. Randomized, double-blind, placebo-controlled (n=102 enrolled) Enrolled patients who are overweight or obese Enrollment completed ahead of schedule; topline data expected in Q2 2025 Screening (Up to 4 weeks) - Male or female, age 18 and 65 years old at the time of informed consent - Stable body weight within 90 days of screening - BMI 30.0 kg/m2 to 45.0 kg/m2 or 27.0 kg/m2 to <30.0 kg/m2 with the presence of 1 or more weight-related comorbid condition(s) ENDPOINTS Primary Endpoint (Week 24) Change from baseline in lean mass by DEXA scan Secondary Endpoints Additional weight loss measures, safety & tolerability, PK/PD Treatment (24 weeks) Apitegromab Q4W + tirzepatide or semaglutide* QW Placebo Q4W + tirzepatide or semaglutide* QW ADDITIONAL Exploratory Endpoints (Week 24 and 32) Cardiometabolic profile (e.g., HbA1c), body composition, physical function R N=50 N=50 8 weeks (24 weeks) Primary endpoint (32 weeks) Exploratory endpoints 2025 Scholar Rock, Inc.
POC data readout Q2* Ph 2 proof-of-concept trial APITEGROMAB + tirzepatide 2025 IND* SRK-439 + GLP-1 RA Novel asset for cardiometabolic indication Phase 1 trial Cardiometabolic Disorders - EMBRAZE POC readout in Q2 2025 - SRK-439 IND submission in Q3 2025 Testing hypothesis of selective anti-myostatin antibody in obese population OBESITY 2025 Scholar Rock, Inc.
Control Control + Sema 0.3 1 3 10 0.3 1 3 20 Antibody Treatment (mg/kg) + Semaglutide (0.04mg/kg) SRK-439 Anti-ActRII* p < 0.01 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 -SRK-439 preserved semaglutide-driven lean mass loss dose-dependently and at lower doses than anti-ActRII -Highlights efficacy of SRK-439 and avoids potential liabilities of non-selective approach of anti-ActRII antibodies -Low target dose of SRK-439 supports subcutaneous and potentially best-in-class profile Key Observations *Murine chimera of Bimagrumab Study conducted in Diet Induced Obesity (DIO) mouse model utilizing a murine chimera of SRK-439 OBESITY 2024 Scholar Rock, Inc.
S ; 2 C4 <a@ Ec !d# !dG # G eS80LS> I %24: eS80LS> %C'(FG+ AL2:04280 ! ! ! SRK-439: Further Improvement of Metabolic Health 49 Key Observations SRK-439 Further Improved Fasting Glucose in Semaglutide Treated Animals - Semaglutide reduced fasting glucose levels as expected - Combination with SRK-439 led to further improvement in fasting glucose levels by ~20% in a dose-dependent manner - Highlights the role of muscle preservation in improving long term metabolic profile SRK-439 (mg/kg) + Semaglutide (0.04mg/kg) p < 0.05 p < 0.05 p < 0.05 Study conducted in Diet Induced Obesity (DIO) mouse model utilizing a murine chimera of SRK-439 OBESITY 2024 Scholar Rock, Inc.
HFD: High Fat Diet - SRK-439 attenuates regain of fat mass after withdrawal of semaglutide compared to IgG control - SRK-439 leads to higher lean mass proportion after withdrawal of semaglutide compared to IgG control Key Observations SRK-439 Improved Proportion of Lean and Fat Mass to Total Body Weight OBESITY !"#$ BCD (FG BCD (FG BCD HI-. (FG LM1 HI-. 2 32 L2 42 R2 SI7.89WI <I.= >.??
Day 7 is start of semaglutide and SRK-439 treatment. Day 35 is discontinuation of semaglutide treatment. - Considerable lean mass loss seen with semaglutide treatment as expected - Treatment with SRK-439 led to: - Preservation of lean mass during semaglutide treatment - Significant increase in lean mass upon semaglutide discontinuation - Attenuation of fat mass regain upon semaglutide discontinuation Key Observations SRK-439 Increased Absolute Lean Mass and Attenuated Regain of Absolute Fat Mass OBESITY !
Barrett et al. Adv Therapy. 2021; 2. Crawford T et al. Neurology. 2024; 3. Garito T et al. Clin Endocrinol (Oxf). 2018; 4. Amato AA et al. Neurology. 2021; 5. Heymsfield SB et al. JAMA. 2021; 6. Vanhoutte F et al. J Clin Pharmacol. 2020; 7. Attie KM et al. Muscle Nerve. 2013; 8. Attie KM et al. Am J Hematol. 2014; 9. Campbell C et al. Muscle Nerve. 2017; 10.
Diabetes Metab J. 2016;40: 147-153; 7. Roh E, Choi KM. Health consequences of sarcopenic obesity: a narrative review. Front. Endocrinol. 2020;11: 332; 8. Volpi E, Nazemi R, Fujita S. Muscle tissue changes with aging. Curr Opin Clin Nutr Metab Care. 2004;7(4): 405-410. - Improved strength - Improved insulin sensitivity - Increased basal metabolic rate - Improved metabolic profile - Reduced total body fat The preservation of lean mass has many benefits for overall health: OBESITY Better insulin sensitivity and lower risk of prediabetes3 Reduced visceral fat4 Increased bone density, strength, function, and longevity and decreased risk of injury, and disability6-8 Increased caloric expenditure post-exercise5 Enhanced glucose homeostasis2 Increased basal metabolic rate (BMR)1 2025 Scholar Rock, Inc.
Sports Med. 2022(Feb);52(2):287-300. doi: 10.1007/s40279-021-01562-2; 5. Zurlo, F., Larson, K., Bogardus, C., et al. Skeletal muscle metabolism is a major determinant of resting energy expenditure. J Clin Invest. 1990;86(5), 1423-1427; 6. Fukushima Y, Kurose S, Shinno H, et al. Importance of lean muscle maintenance to improve insulin resistance by body weight reduction in female patients with obesity.
Relative muscle mass is inversely associated with insulin resistance and prediabetes. Findings from the third National Health and Nutrition Examination Survey. J Clin Endocrinol Metab. 2011; 96:2898 903. doi: 10.1210/jc.2011-0435; 4. Wewege MA, Desai I, Honey C, et al. The effect of resistance training in healthy adults on Body fat percentage, fat mass and visceral fat: A systematic review and meta-analysis.
Eur J Clin Nutr.2015; 69, 831 836. https://doi.org/10.1038/ejcn.2014.216; 2. Lindegaard B, Hansen T, Hvid T, et al. The effect of strength and endurance training on insulin sensitivity and fat distribution in human immunodeficiency virus-infected patients with lipodystrophy. J Clin Endocrinol Metab. 2008; 93:3860 9; 3. Srikanthan P, Karlamangla AS.
Analysis n Results (vs Placebo, n=50) Unadjusted P-value Apitegromab 10+20 mg/kg combined 106 1.8 0.0192* Apitegromab 20 mg/kg 53 1.4 0.1149* Apitegromab 10 mg/kg 53 2.2 0.0121** Change from Baseline in HFMSE Total Score Primary Endpoint Met Clinically Meaningful and Statistically Significant Improvement in HFMSE SAPPHIRE APITEGROMAB IN SMA Achieved Statistical Significance Primary Analysis SPINAL MUSCULAR ATROPHY 2024 Scholar Rock, Inc.
The hierarchical testing procedure was applied to account for multiple confirmatory tests for the primary endpoint and key secondary endpoints. The testing procedure first evaluated the primary confirmatory test, followed by analyses of key secondary endpoints for apitegromab 20 mg/kg, and then the analyses of primary endpoint and key secondary endpoints for apitegromab 10 mg/kg.
SOC=standard of care. 188 Patients Underwent Randomization Ages 2-12 156 Completed SAPPHIRE Treatment Period 155 (99%) Apitegromab 20 mg/kg + SOC 53 Apitegromab 10 mg/kg + SOC 53 Placebo + SOC Group 50 Ages 13-21 32 Completed SAPPHIRE Treatment Period 31 (97%) Apitegromab 20 mg/kg + SOC 22 Placebo + SOC Group 10 SAPPHIRE APITEGROMAB IN SMA 98% of Patients Continue on Long-Term Extension ONYX Long-Term Extension Trial (Ongoing) 185* (98%) SPINAL MUSCULAR ATROPHY 2024 Scholar Rock, Inc.
Age at SMN therapy initiation (age < 5 vs. age 5) 2. SMN therapy (nusinersen vs. risdiplam) ENDPOINTS Primary Efficacy: Mean HFMSE change from baseline at 12 months Additional Efficacy Measures: RULM, WHO, other outcome measures Safety, PK/PD, ADA Additional Data Opportunities Exploratory population (age 13-21), in patients using SMN therapy Focused upon safety & exploratory efficacy (n=48; 2:1 randomization between apitegromab 20 mg/kg vs placebo) Separate open-label extension study (after patients complete 12-month treatment period) Focused upon safety & exploratory long-term efficacy ClinicalTrials.gov Identifier: NCT05156320 HFMSE=Hammersmith Functional Motor Scale Expanded; RULM=Revised Upper Limb Module; R=randomization; SMA=spinal muscular atrophy; SMN=survival motor neuron.
CONSISTENT clinically meaningful benefit observed across all age groups (2-21) FAVORABLE SAFETY profile consistent with >48 months experience in Phase 2 TOPAZ trial 30% of apitegromab patients ACHIEVED 3 POINT IMPROVEMENT IN HFMSE 1.8 POINT IMPROVEMENT (p=0.0192) in HFMSE* vs. placebo Positive Phase 3 Trial Using Gold Standard SMA Scale SUCCESSFUL PIVOTAL TRIAL On Track to Submit BLA and MAA in 1Q 2025 SPINAL MUSCULAR ATROPHY 2024 Scholar Rock, Inc.
Commercial Launch* Global expansion, starting with Europe SMA expansion with Ph 2 OPAL trial for patients under 2 and subcutaneous formulation Neuromuscular expansion of apitegromab into additional indications Unlocking value in our pipeline by targeting various aspects of neuromuscular diseases to help people living with rare, devastating diseases 22 SPINAL MUSCULAR ATROPHY 2025 Scholar Rock, Inc.
For illustrative purposes only. SPINAL MUSCULAR ATROPHY Apitegromab is a selective MUSCLE-TARGETED APPROACH designed to improve motor function*1,2 Myostatin is a negative modulator of muscle growth Strong clinical and preclinical evidence indicates upstream targeting of structurally differentiated pro- and latent myostatin avoids undesirable off-target effects Apitegromab Muscle fiber atrophy Apitegromab specifically and only inhibits myostatin and has the potential to build muscle and strength to improve patient outcomes Motor neuron degeneration3 2025 Scholar Rock, Inc.
CI=Confidence Interval; EXP=Exploration Subpopulation; HFMSE=Hammersmith Functional Motor Scale Expanded; LS=Least Squares; MEP=Main Efficacy Population; SOC=standard of care. - Despite effective SMN-targeted therapy, long-term trajectory of SMA patients remains that of progressive decline in motor function - Treatment with apitegromab has improved motor function vs. placebo KEY TAKEAWAYS Motor Function Over Time of Patients Treated with Nusinersen Placebo + SOC n= 50 50 50 48 50 49 48 Apitegromab + SOC n= 106 105 105 101 102 102 102 Motor Function Over Time of Patients in SAPPHIRE 16 SPINAL MUSCULAR ATROPHY 2024 Scholar Rock, Inc.
HFMSE, Hammersmith Functional Motor Scale Expanded; SE, standard error. MFM was primary efficacy endpoint of SUNFISH. HFMSE was a secondary endpoint. 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. Overall population age 2-25 Change in HFMSE Over Four Years with Risdiplam2 Risdiplam n= 120 120 119 117 109 106 89 99 101 97 Placebo n= 60 60 58 58 Risdiplam Placebo (months 0-12) Mean (+/-SE) Change in HFMSE Total Score From Baseline* 0 6 12 18 24 30 36 42 48 Visit, months Change in HFMSE Over Four Years with Nusinersen1 Overall population age 2-12 Mean (+SE) Change in HFMSE Total Score From Baseline Analysis Visit, days Initial Treatment CHERISH Chronic Maintenance Phase SHINE -4 -2 0 2 4 6 8 1 92 169253 350 450 690 930 1170 1410 1650 Nusinersen n= 84 82 84 84 83 76 83 83 79 61 20 Placebo n= 42 41 41 42 42 39 Nusinersen in CHERISH and SHINE Sham control in CHERISH SPINAL MUSCULAR ATROPHY 2025 Scholar Rock, Inc.
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. SPINAL MUSCULAR ATROPHY 0 20 40 60 80 Mean improvement in HFMSE experienced by patients in nusinersen Phase 3 CHERISH trial1 3.9-point increase in HFMSE from nusinersen (4.9 point increase relative to sham control) HFMSE Score at Month 15 Total Possible HFMSE Score of 66 Unmet need remains substantial Patients and caregivers want new therapies to address the following unmet needs2 : INCREASE muscle strength IMPROVE daily activities STABILIZE or GAIN new motor function REDUCE fatigue 2024 Scholar Rock, Inc.
Revenue as of Roche 3Q23 financial update; includes patients treated worldwide as of July 2023. 5. Revenue as of Novartis 3Q23 financial update; includes patients treated worldwide including clinical trials, commercially, and managed access programs as of August 2023. SPINAL MUSCULAR ATROPHY GLOBAL DISEASE: >20,000 affected in US and Europe1, 2 Three treatments to address SMN loss >13,000 patients treated WW $1.8 billion annual revenue (LTM)3 > 11,000 patients treated WW ~CHF1.4 billion annual revenue (LTM)4 > 3,500 patients treated WW ~$1.2 billion in revenues (LTM)5 Established market dynamics support Scholar Rock's first potential commercial launch 2024 Scholar Rock, Inc.
Lally et al. Indirect estimation of the prevalence of spinal muscular atrophy Type I, II, and III in the United States. Orphanet J Rare Dis. 2017 Nov 28;12(1):175. doi: 10.1186/s13023-017-0724-z. 3. Revenue as of Biogen 3Q23 financial update; includes patients treated worldwide in post-marketing setting, expanded access program, and clinical trials as of May 2022. 4.
If I could lift that 1L bottle of water at work instead of having to find a graduate student to move it for me things don't take a ton more muscle, but they are all muscle I still don't have. What may seem like minimal gains in strength actually translate to exponential gains in functional abilities. I often have to choose between taking a shower and doing homework because I don't have the energy to do both.
Hua Y, et al. Nature. 2011;478(7367):123-6. 2. Figure adapted from: SMA Foundation Overview. http://www.smafoundation.org/wp-content/uploads/2012/03/SMA-Overview.pdf.; Accessed April 18, 2021. SPINAL MUSCULAR ATROPHY ...but do not directly address muscle atrophy SMN therapies slow further degeneration of motor neurons1 Motor neuron degeneration2 Muscle fiber atrophy Spinal Muscular Atrophy Motor neuron impairment and loss due to SMN genetic deficiency leads to muscle atrophy and weakness There is further potential to regain vital muscle function by also addressing the progressive muscle atrophy and associated weakness of SMA 2024 Scholar Rock, Inc.
This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our future performance and the future performance of the markets in which we compete are necessarily subject to a high degree of uncertainty and risk. Apitegromab and SRK-181 are investigational drug candidates under evaluation.
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. This presentation may also contain estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry.
These risks and uncertainties include, without limitation, that preclinical and clinical data, including the results from the Phase 3 trial of apitegromab or Part A or Part B of the Phase 1 trial of linavonkibart, are not predictive of, may be inconsistent with, or more favorable than, data generated from future or ongoing clinical trials of the same product candidate; 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, including from the EMBRAZE clinical trial; 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's current 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; its ability to establish or maintain strategic business alliances; its ability to receive priority or expedited regulatory review or to obtain regulatory approval of apitegromab; its ability to expand globally and the anticipated commercial launch in the United States of apitegromab in the fourth quarter of 2025; as well as those risks more fully discussed in the section entitled "Risk Factors" in Scholar Rock's Form 10-K for the year ended December 31, 2023, and Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, as well as discussions of potential risks, uncertainties, and other important factors in Scholar Rock's subsequent filings with the Securities and Exchange Commission.
The use of words such as may, could, 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.
(collectively, 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 preclinical studies and clinical trials for apitegromab, SRK-439, linavonkibart 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.