Scholar Rock Holding Corporation (Scholar Rock), a late-stage biopharmaceutical company, focuses on the discovery, development and delivery of innovative medicines for the treatment of serious diseases in which signaling by protein growth factors plays a fundamental role.
The company has discovered and progressed the development of:
Apitegromab, an investigational, fully human monoclonal antibody that inhibits myostatin activation by selectively binding the pro- and latent forms of myostatin i...
Scholar Rock Holding Corporation (Scholar Rock), a late-stage biopharmaceutical company, focuses on the discovery, development and delivery of innovative medicines for the treatment of serious diseases in which signaling by protein growth factors plays a fundamental role.
The company has discovered and progressed the development of:
Apitegromab, an investigational, fully human monoclonal antibody that inhibits myostatin activation by selectively binding the pro- and latent forms of myostatin in skeletal muscle, and is being developed for the treatment of spinal muscular atrophy (‘SMA’).
SRK-439, a novel, preclinical, investigational myostatin inhibitor that has high in vitro affinity for pro- and latent myostatin, and maintains myostatin specificity, and is being developed for the treatment of cardiometabolic disorders.
SRK-181, an investigational inhibitor of the activation of latent transforming growth factor beta-1 (‘TGFß1’), that is being developed for the treatment of cancers that are resistant to anti-PD-(L)1 antibody therapies.
SRK-373, a novel, preclinical, investigational TGFß inhibitor that selectively inhibits the activation of latent TGFß1 isoform in the context of fibrotic extracellular matrix, and avoids perturbing TGFß1 presented by cells of the immune system, and is being developed for the treatment of fibrotic diseases.
SRK-256, a novel, preclinical, investigational inhibitor that selectively inhibits RGMc or hemojuvelin, the co-receptor of bone morphogenic protein 6 (‘BMP6’), and hence inhibits BMP6 signaling. BMP6 signaling is critical for iron homeostasis, and SRK-256 has wide potential applicability in states of iron-restricted anemias.
Additional discovery and early preclinical programs related to the selective modulation of growth factor signaling.
The company’s first product candidate, apitegromab, is a highly selective, fully human, monoclonal antibody, with a unique mechanism of action that results in inhibition of the activation of the growth factor, myostatin, in skeletal muscle. Apitegromab is being developed as a potential first muscle-targeted therapy for the treatment of SMA. The company completed SAPPHIRE, a pivotal Phase 3 clinical trial to evaluate the efficacy and safety of apitegromab in patients with nonambulatory Type 2 and Type 3 SMA (which is estimated to represent the majority of the current prevalent SMA patient population in the U.S. and Europe), and announced positive top-line results in October 2024. The study achieved its primary endpoint. The company submitted a U.S. Biologics License Application (‘BLA’) to the FDA in January 2025, and is planning to submit a European Union marketing authorization application to the European Medicines Agency (‘EMA’) in the first quarter of 2025.
Apitegromab was evaluated in the company’s Phase 2 TOPAZ proof-of-concept clinical trial for the treatment of patients with Type 2 and Type 3 SMA. Positive 12-month top-line results were initially announced in April 2021. The company has subsequently presented data from the TOPAZ trial over 24 months (2022), 36 months (2023), and 48 months (2024). At 48 months, over 90% of TOPAZ patients with nonambulatory Type 2 and 3 SMA receiving a survival motor neuron (‘SMN’) therapy remained on apitegromab treatment, and showed sustained clinical benefit, a continued favorable safety profile with no new safety findings. Additionally, the company is conducting a long-term extension study, ONYX, for patients from both the TOPAZ and SAPPHIRE studies, who were receiving apitegromab in conjunction with an approved SMN therapy. The FDA granted Fast Track designation, Rare Pediatric Disease designation, and Orphan Drug designation to apitegromab for the treatment of SMA in May 2021, August 2020, and March 2018, respectively. The EMA granted Priority Medicines (‘PRIME’) designation in March 2021, and the EC granted orphan medicinal product designation in December 2018 to apitegromab for the treatment of SMA.
In October 2023, the company announced an expansion of its therapeutic focus into cardiometabolic disorders by advancing its anti-myostatin program with SRK-439, a novel, fully human anti-myostatin monoclonal antibody, for evaluation in cardiometabolic disorders, including obesity. The company is developing SRK-439 towards a potential investigational new drug application (‘IND’) submission in the third quarter of 2025. In 2024, the company presented preclinical data at scientific conferences which support the potential of SRK-439 to increase lean mass and contribute to a favorable body composition in conjunction with a GLP-1 receptor agonist (‘GLP-1 RA’) treatment. To inform the development of SRK-439, in May 2024, the company initiated the Phase 2 EMBRAZE proof-of-concept trial, designed to assess the safety and efficacy of apitegromab to preserve muscle mass in individuals living with obesity and on background therapy of a GLP-1 RA. In September 2024, the company announced that it completed enrollment in the Phase 2 EMRAZE proof-of-concept trial. Top-line results from this trial are expected in the second quarter of 2025.
The company has identified multiple other diseases for which the selective inhibition of the activation of myostatin may offer therapeutic benefit, including additional patient populations in SMA (such as patients with SMA under 2 years of age) and indications for other neuromuscular disorders beyond SMA.
The company’s second product candidate, SRK-181, is a highly selective inhibitor of the activation of latent TGFß1, and is being developed for the treatment of cancers that are resistant to checkpoint inhibitor therapies (‘CPI therapies’), such as anti-PD-1 or anti-PD-L1 antibody therapies (referred to together as anti-PD-(L)1 antibody therapies). SRK-181 is being evaluated in the company’s Phase 1 DRAGON proof-of-concept clinical trial in patients with locally advanced or metastatic solid tumors that exhibit resistance to anti-PD-(L)1 antibody therapies. The company completed enrollment of the DRAGON trial in December 2023, and continues to treat patients who remain on study. This two-part clinical trial consists of a dose escalation portion (Part A) and a dose expansion portion evaluating SRK-181 in combination with an approved anti-PD-(L)1 antibody therapy (Part B).
The company integrates these insights with sophisticated protein expression, monoclonal antibody discovery capabilities, and assay development to test the characteristics of its monoclonal antibodies.
Proprietary Platform
The company’s proprietary platform is designed to generate highly selective antibodies that target the growth factor’s latent precursor form prior to its activation within the disease microenvironment, or tissue where it is localized.
The company has built a proprietary platform that is rooted in its structural biology insights into the activation of latent growth factor precursors. The company integrates these insights with sophisticated protein expression, monoclonal antibody discovery capabilities, and assay development to test the characteristics of its monoclonal antibodies. In addition to this know-how, the company’s proprietary platform is covered by patents projected to expire well into the 2030s, excluding any patent term adjustments or extensions. The key elements of the company’s proprietary platform include the following: focusing on growth factor targets with a high degree of evidence implicating them in a disease process or processes; utilizing structural biology insights to generate recombinant versions of the latent forms of targeted growth factors, as well as versions of closely related growth factors utilizing proprietary technology and in-house expertise; developing proprietary assays in which the company is able to recapitulate the natural activation mechanism that these growth factors undergo in the human body; designing sophisticated selection strategies utilizing recombinant antibody libraries, such as phage and yeast display that allow the company to identify monoclonal antibodies, a well-established therapeutic modality, that can modulate the activation of these growth factors without having an effect on the activation of other closely related growth factors; and optimizing the output of such selections to ensure that the company’s product candidates have the appropriate characteristics for manufacturability and further development.
Strategy
The company’s strategies are to continue advancing apitegromab in SMA to characterize its potential to offer meaningful benefit to patients; identify the next indication(s) for apitegromab; leverage anti-myostatin expertise to expand into cardiometabolic disorders; advance the company’s TGFß1 product candidate, SRK-181, through clinical proof-of-concept; continue to leverage the company’s proprietary platform to expand its pipeline beyond lead programs; and selectively seek strategic collaborations to maximize the value of its proprietary platform and pipeline.
Pipeline
Using the company’s innovative approach and proprietary platform, the company is creating a differentiated pipeline of novel product candidates that selectively inhibit the activation of latent growth factors to be important drivers in a variety of diseases, including neuromuscular disorders, cardiometabolic disorders, cancer, fibrosis, and iron-restricted anemia. The company’s proprietary platform includes the company’s know-how enabling expression and purification of latent protein growth factor complexes in quantity and quality sufficient to enable antibody discovery; strategies to identify rare antibodies that selectively bind targeted latent protein growth factor complexes; and assays developed by the company to test the highly selective antibodies’ ability to modulate the activation of specific latent growth factors. The company has worldwide rights to its proprietary platform and all of its product candidates.
Product Candidates
Latent Myostatin
Utilizing the company’s proprietary platform, the company targeted the precursor form of myostatin and generated two novel antibodies, each with a design tailored for specific patient populations: apitegromab for SMA and SRK-439 for obesity. Both antibodies are novel, highly selective inhibitors of the activation of myostatin from its inactive precursor in skeletal muscle, where myostatin resides and signals upon activation.
In preclinical studies, the company has shown that apitegromab selectively avoids interaction with other closely related growth factors that play distinct physiological roles. The company observed multi-fold increases in serum latent myostatin levels in mouse models of both early and late SMN restoration, and that apitegromab promoted increased strength (as measured by torque generation) in SMN-deficient mice. In a Phase 1 clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic (‘PK’)/ pharmacodynamic (‘PD’) profile of apitegromab in adult healthy volunteers, there were no dose-limiting toxicities, and the company observed robust and sustained target engagement following administration of apitegromab.
Key disease features of SMA are aligned with Scholar Rock’s guiding principles for neuromuscular indication selection for apitegromab.
The company is developing apitegromab as a selective muscle-targeted therapy for the treatment of SMA. Myostatin, a member of the TGFß superfamily of growth factors, is expressed primarily in skeletal muscle cells, and the absence of its gene is associated with an increase in muscle mass and strength in multiple animal species.
Apitegromab was evaluated in the company’s Phase 2 TOPAZ proof-of-concept clinical trial for the treatment of patients with Type 2 and Type 3 SMA, and positive 12-month top-line results were announced in April 2021. The company has subsequently presented data from the TOPAZ trial over 24 months (2022), 36 months (2023), and 48 months (2024). In October 2024, the company announced positive top-line results from SAPPHIRE, a pivotal Phase 3 clinical trial to evaluate the efficacy and safety of apitegromab in patients with nonambulatory Type 2 and Type 3 SMA receiving SMN therapy. The company reported that the study achieved its primary endpoint. The company submitted a BLA to the FDA in January 2025 and requested priority review, and plans to submit a marketing authorization application to the EMA in the first quarter of 2025.
Clinical Development Overview
The company completed SAPPHIRE, a pivotal Phase 3 clinical trial to evaluate the efficacy and safety of apitegromab in patients with nonambulatory Type 2 and Type 3 SMA being treated with SMN therapy. In October 2024, the company announced positive top-line results that showed the study achieved its primary endpoint.
Beyond Type 2 and Type 3 SMA, apitegromab has the potential for therapeutic benefit in patients with either more or less severe forms of SMA, as well as pre-symptomatic patients receiving early intervention with an SMN therapy.
Phase 3 SAPPHIRE Pivotal Trial
On October 7, 2024, the company announced positive top-line data from its Phase 3 SAPPHIRE clinical trial evaluating the efficacy and safety of apitegromab, an investigational muscle-targeted therapy, in patients with SMA.
SAPPHIRE was a randomized, double-blind, placebo-controlled, Phase 3 clinical trial that evaluated the safety and efficacy of apitegromab in nonambulatory patients with Types 2 and 3 SMA who are receiving current standard of care therapies (either nusinersen or risdiplam). SAPPHIRE enrolled 156 patients ages 2–12 years old in the main efficacy population. These patients were randomized 1:1:1 to receive either apitegromab 10 mg/kg, apitegromab 20 mg/kg, or placebo by intravenous infusion every 4 weeks. An exploratory population that enrolled 32 patients ages 13–21 years old was also evaluated. These patients were randomized 2:1 to receive either apitegromab 20 mg/kg or placebo.
Patients receiving apitegromab in the main efficacy population (ages 2–12) demonstrated early motor function improvement compared to placebo from the first measured time point at 8 weeks, and clinical benefit expanded at 52 weeks as measured by HFMSE.
Treatment with apitegromab was well-tolerated across all age groups. There were no clinically relevant differences in the adverse event profile by dose, 10 mg/kg versus 20 mg/kg. No new safety findings were observed in the SAPPHIRE clinical trial; the profile was consistent with that observed in the Phase 2 TOPAZ clinical trial, including an extension study which had over four years of treatment as of the cut-off date. Serious adverse events (‘SAEs’) were consistent with the underlying disease and the current standard of care received by patients; no SAEs were assessed as related to apitegromab.
The company is also continuing its long-term extension study, ONYX, for patients from both the TOPAZ and SAPPHIRE studies, who are receiving apitegromab in conjunction with the current standard of care. Following trial completion, 98% of SAPPHIRE patients (185/188) enrolled in the ONYX open-label expansion study.
Phase 2 TOPAZ Proof-of-Concept Trial
The company completed enrollment in its Phase 2 TOPAZ proof-of-concept trial of apitegromab in January 2020. TOPAZ was a Phase 2 active treatment study evaluating the safety, efficacy, PK, and PD of apitegromab 2 and 20 mg/kg in 58 patients ages 2 to 21 years old with Type 2 and Type 3 SMA (nonambulatory and ambulatory). One patient discontinued from the 12-month treatment period for reasons that were determined to be unrelated to apitegromab treatment. All remaining patients completed the 12-month treatment period and opted into the extension period.
The clinical trial consisted of three distinct cohorts of patients with Type 2 or Type 3 SMA and evaluated the safety and efficacy of apitegromab over a 12-month treatment period. All patients in the clinical trial received apitegromab dosed every four weeks (Q4W) either as a monotherapy or in conjunction with an approved SMN therapy. The primary efficacy objectives evaluated in the TOPAZ trial, HFMSE and Revised Hammersmith Scale (‘RHS’), are clinically meaningful outcome measures validated for SMA. The HFMSE is a validated measure for the assessment of gross motor function in SMA, while the RHS is a revised version and used for ambulatory patients in TOPAZ.
In August 2024, the company reported that long-term apitegromab data continued to show sustained motor function benefit over 48 months (Crawford WMS 2024). Over 90 percent of nonambulatory patients remained on treatment in the extension study over 48 months.
Phase 1 Healthy Volunteer Clinical Trial Results
The randomized, double-blind, placebo-controlled, first-in-human, Phase 1 clinical trial was designed to evaluate the safety and tolerability, immunogenicity, PK, and PD of IV administered apitegromab in adult healthy volunteers. A total of 66 subjects were enrolled, including 40 subjects in the single ascending dose (‘SAD’) and 26 subjects in the multiple ascending dose portions of the study. Full results from the Phase 1 clinical trial were presented at the Cure SMA Annual Conference in June 2019.
Safety and immunogenicity results. Apitegromab was shown to be well-tolerated with no apparent safety signals. There were no dose-limiting toxicities identified up to the highest tested dose of 30 mg/kg, treatment-related serious adverse events or hypersensitivity reactions. Immunogenicity was assessed by anti-drug antibody testing, and all subjects tested negative.
Pharmacokinetics and pharmacodynamics results. Apitegromab displayed a PK profile generally consistent with that commonly observed with monoclonal antibodies. Drug exposure was dose proportional, and the serum half-life was approximately 23 to 33 days across the apitegromab dose groups. The findings supported the investigation of a once every 4-week dosing regimen in the Phase 2 TOPAZ clinical trial.
Mean serum concentrations of latent myostatin in the SAD were < 20 ng/ml in the pre-treatment baselines for apitegromab treated subjects, as well as in placebo subjects throughout the study.
SRK-439: A Novel Anti-myostatin Antibody for the Treatment of Obesity
In addition to the company’s work to advance apitegromab in SMA, the company has leveraged its expertise in anti-myostatin and its effect on increasing muscle mass to develop myostatin-selective inhibitors for cardiometabolic disorders, including obesity.
SRK-439, a novel anti-myostatin antibody developed by the company, has attractive properties that make it specifically suited for the patient population with obesity. These properties include high in vitro affinity for pro- and latent myostatin, maintenance of myostatin specificity (i.e., no GDF11 or Activin-A binding), and a developability profile, including suitability for subcutaneous dosing and a low dosing volume.
In addition to these properties, SRK-439 has shown robust preclinical efficacy. In two models of DIO mice, SRK-439 maintained lean mass when combined with a GLP-1 RA therapy, either semaglutide or liraglutide. In both cases, adding SRK-439 to semaglutide or liraglutide alone demonstrated dose-dependent increases and reversals of lean muscle mass loss, with improvements in fat mass loss as well compared to a GLP-1 RA alone. These results provide the scientific rationale and support the hypothesis that inhibition of myostatin in combination with GLP-1 RA-driven weight loss may lead to retention of lean muscle.
The company is advancing this preclinical program and plans to submit an IND in the third quarter of 2025.
To inform the development of SRK-439, in May 2024, the company initiated the Phase 2 EMBRAZE proof-of-concept trial, designed to assess the safety and efficacy of apitegromab to preserve muscle mass in individuals living with obesity and on background therapy of a GLP-1 RA. In September 2024, the company announced that it completed enrollment, and top-line results from this trial are expected in the second quarter of 2025.
Inhibiting TGFß – SRK-181 (context-independent latent TGFß1 inhibitor) and LTBP (matrix-selective latent TGFß1 inhibitor).
The company has been a pioneer in developing a differentiated approach to harnessing the therapeutic potential of the TGFß superfamily of growth factors. The foundation of the company’s industry-leading platform is targeting the TGF superfamily of growth factors with the desired selectivity for both the target (i.e., latent- or pro- form) and disease-specific context. While the company is building its experience from this approach with its anti-myostatin pipeline, the company has also observed promising preclinical and early clinical data that supports targeting other forms of TGFß, including for oncology and fibrosis.
In March 2019, the company selected SRK-181 as a product candidate in its TGFß1 cancer immunotherapy program based on the strength of preclinical data and human translational insights. In vitro and in vivo studies of SRK-181 showed that it binds to latent TGFß1 with high affinity and high selectivity, which is evidenced by minimal or no binding to latent TGFß2 or latent TGFß3 isoforms.
SRK-181 in Cancer Immunotherapy - Inhibitor of Latent TGFß1 Activation
The company’s second product candidate, SRK-181, a highly selective inhibitor of the activation of latent TGFß1, is in clinical development for the treatment of locally advanced or metastatic solid tumors that are resistant to anti-PD-(L)1 therapies.
The company has observed multiple mouse models that recapitulate the immune-excluded phenotype and are resistant to PD-1 blockade become responsive to the combination of SRK-181-mIgG1, the murine analog of SRK-181, and an anti-PD-1 antibody. These models, including the MBT-2 bladder cancer model, the Cloudman S91 melanoma model, and the EMT6 breast cancer model, were poorly responsive or unresponsive to single agent treatment with either anti-PD-1 or SRK-181-mIgG1, with little or no effect on tumor growth. However, in representative experiments, the combination of SRK-181-mIgG1 and anti-PD-1 resulted in tumor regressions of 72%, 57%, and 70% in these three mouse models, respectively.
The company’s Phase 1 DRAGON clinical trial is intended to initially evaluate its therapeutic hypothesis that SRK-181 in combination with anti-PD-(L)1 therapy may overcome resistance to anti-PD-(L)1 therapy and lead to anti-tumor responses. This clinical trial in patients with locally advanced or metastatic solid tumors is ongoing and investigates the safety, PK, and efficacy of SRK-181. The DRAGON trial consists of two parts: Part A (dose escalation of SRK-181 as a single-agent or in combination with an approved anti-PD-(L)1 therapy) and Part B (dose expansion evaluating SRK-181 in combination with an approved anti-PD-(L)1 antibody therapy). Part B encompasses five active cohorts, including urothelial carcinoma, cutaneous melanoma, non-small cell lung cancer, clear cell renal cell carcinoma, and head and neck squamous cell carcinoma, and commenced in 2021 and completed enrollment in December 2023. The company continues to treat patients who remain on study. Safety, efficacy, and biomarker data were presented in June 2024 at the ASCO annual meeting and in November 2024 at the SITC 39th Annual Meeting. The data showed encouraging responses in heavily pretreated and anti-PD-(L)1 resistant patients across multiple tumor types. Data presented continues to support proof-of-concept for SRK-181 in 30 heavily pretreated patients with ccRCC resistant to anti-PD-1. SRK-181 was generally well tolerated and showed promising anti-tumor activity in this patient population. Of 30 patients in the ccRCC cohort, seven patients treated with SRK-181 in combination with pembrolizumab had documented responses, achieving a best tumor reduction of 40% to 100%, with an objective response rate of 23.3%. In the biomarker analysis, SRK-181 combined with pembrolizumab established proof of mechanism in patients by creating a proinflammatory tumor microenvironment across multiple tumor types. Safety data from the ccRCC cohort continue to show that SRK-181 is generally well tolerated. In ccRCC patients, responders had higher basal levels of activated CD8+ T cells, higher T-regs, as well as higher TGFß1 expression. The data cutoff for all analyses was September 9, 2024.
The DRAGON trial achieved its study objectives by showing objective, durable clinical responses in patients with ccRCC resistant to PD-1 therapy beyond what is expected from continuing PD-1 alone.
Potential Applications of SRK-181 in Additional Oncology Settings
In addition to cancer immunotherapy, SRK-181 has the potential for use in other oncology settings, such as in immunotherapy-naïve patients, in combination with other therapies beyond checkpoint inhibitors, and in myelofibrosis.
Fibrosis: LTBP-49247
Fibrosis is a pathological feature of many diseases and can occur in virtually all organs. It is characterized by excessive accumulation of extracellular matrix in the affected tissue, and accounts for substantial morbidity and mortality. The TGFß signaling pathway is a well-established central driver in the pathogenesis of fibrotic diseases, and inhibition of this pathway has been shown to improve outcomes in relevant animal models of hepatic, renal, pulmonary, and other fibrotic diseases. In addition, a non-selective inhibitor of TGFß signaling that inhibits all three isoforms (isoform 1, 2, and 3) of TGFß showed clinical improvement in patients with systemic sclerosis, a fibrotic connective tissue disease. However, non-selective inhibition of all TGFß isoforms is known to be associated with serious safety findings, most notably bleeding episodes, and cardiac toxicities. Based on knockout animal models (a model where researchers have inactivated, or ‘knocked out,’ an existing gene by replacing it or disrupting it with an artificial piece of DNA), these safety findings are to be associated with inhibition of the TGFß2, and TGFß3 isoforms. These data suggest that novel approaches to targeting TGFß signaling may have broad applicability to the treatment of fibrotic disease, where more selective approaches may offer an improved safety profile. In addition, given that immune cell activation may play a key role in fibrotic disease development, selective targeting of only matrix-associated TGFß1, at the primary site of fibrosis manifestation, while avoiding immune cell-associated TGFß1 is key to maintaining efficacy while avoiding potential long-term liabilities of immune cell activation.
Based on this scientific rationale, the company utilized its platform to discover and develop antibodies that selectively inhibit the activation of latent TGFß1 in the context of fibrotic extracellular matrix, and that avoid perturbing TGFß1 presented by cells of the immune system. The company selected SRK-373, a highly potent, anti-latent TGFß1 antibody that selectively inhibits TGFß1 activation within the extracellular matrix by targeting latent TGFß1 associated with latent TGFß-binding proteins (LTBPs), thus enabling specific inhibition of TGFß1 in fibrotic tissue. This antibody demonstrated significant antifibrotic activity in a variety of preclinical rodent models. It also demonstrated a robust therapeutic index at all doses tested in a non-GLP mouse safety study. The company plans to advance this program to IND-enabling studies.
SRK-256: A High-Affinity Antibody Demonstrating Selective Inhibition of HJV/RGMc
A number of disease states, as well as rare genetic mutations, can cause disruptions in iron homeostasis, and can result in either iron deficiency or overload. These imbalances in iron levels can lead to detrimental complications, and are the basis of mortalities and morbidities in many diseases. Hepcidin is a peptide hormone that is produced in the liver and plays a major role in regulating systemic iron homeostasis. Aberrantly increased hepcidin expression is a hallmark of several chronic and devastating diseases, where it causes iron-restricted anemia, contributing to the morbidity and mortality of these diseases. Hepcidin expression is controlled via the bone morphogenetic protein (BMP) signaling pathway, with BMP2/6 being the predominant ligands signaling through a large protein receptor complex containing BMP receptors (BMPR) and a BMP co-receptor, repulsive guidance molecule c/hemojuvelin (RGMc/HJV). The RGM family consists of three members, RGMa, RGMb, and RGMc/HJV, and owing to their role as BMP co-receptors, has been shown to be involved in the development and maintenance of many tissues and organs throughout the body. Human mutations, as well as knockout animal studies, have demonstrated the predominant role of RGMc/HJV to be in the regulation of iron homeostasis.
In contrast to the far-reaching roles of BMP-BMPRs throughout the body, the specific role of RGMc/HJV isoform in iron homeostasis provided an opportunity to utilize the company’s platform to discover and develop antibodies that selectively bind to and inhibit RGMc. The company selected SRK-256, a highly potent and selective RGMc/HJV inhibitor that has demonstrated significant suppression of hepcidin expression and resultant mobilization of stored iron in vivo in mice, rats, and non-human primates. SRK-256 may provide a novel approach to treating iron-restricted anemia in patients with chronic diseases driven by hepcidin overexpression. The company plans to advance this program to IND-enabling studies.
Additional Potential Areas of Exploration
Additional therapeutic areas and targets in which the company could potentially apply its scientific platform and expertise include:
Exploring opportunities to develop other context-dependent inhibitors of TGFß1 to modulate immune cell activation within the context of specific immune diseases.
Exploring opportunities in modulating metabolic physiology, including understanding the important role of skeletal muscle in modulating metabolism. This is highlighted by potential therapeutic opportunity for myostatin blockade. For example, evidence is emerging that blockade of the myostatin pathway can reduce the mass of visceral fat, a significant driver of cardiometabolic pathophysiology. The company has efforts underway to evaluate these opportunities, including preclinical and translational research, development path assessments, and commercial evaluations.
The company continues to enhance its internal biologics discovery capabilities, including the acquisition and development of its own proprietary single-domain antibody libraries. These new capabilities allow the company to more efficiently discover antibodies, and furthers the company’s.
License Agreements
Gilead Collaboration
On December 19, 2018 (the ‘Effective Date’), the company entered into a three-year collaboration with Gilead to discover and develop therapeutics that target TGFß-driven signaling, a central regulator of fibrosis (‘the Collaboration Agreement’).
Adimab Agreement
On March 12, 2019, the company entered into an amended and restated collaboration agreement (‘Adimab Agreement’) with Adimab, LLC (‘Adimab’).
Intellectual Property
As of December 31, 2024, the company had 30 pending patent families across multiple programs. Among the pending families, 24 have been nationalized, from which 24 applications have matured into U.S. issued patents with additional issued patents in multiple jurisdictions globally. Collectively, there are 337 national or direct utility applications pending or issued. In addition, there are four patent family filings which are in the priority year.
As of December 31, 2024, three granted patents, EP2981822, EP2981822, and EP3368069, were the subject of ongoing opposition proceedings before the European Patent Office (‘EPO’).
Platform
The company’s novel approach to generating selective modulators of supracellular activation of growth factors is broadly embodied in its earliest ‘platform’ patent family, PCT/US2014/036933 (published as WO 2014/182676). This patent family is directed to methods for modulating the activation of the TGFß superfamily of growth factors, and methods for screening for a monoclonal antibody that specifically targets an inactive form of the growth factor, thereby preventing activation (e.g., release) of mature growth factor. The TGFß superfamily is a group of more than 30 related growth factors/cytokines that mediate diverse biological processes and includes TGFß1 and myostatin (also known as GDF-8). Issued U.S. patents in the platform family include: U.S. Patents Nos. 9,573,995 (issued 02/21/2017); 9,758,576 (issued 09/12/2017); 9,580,500 (issued 02/28/2017); 9,399,676 (issued 07/26/2016); 9,758,577 (issued 09/12/2017); 10,597,443 (issued 03/24/2020); 10,981,981 (issued 04/20/2021); and 11,827,698 (issued 11/28/2023). There is also a granted European (‘EP’) platform patent: EP2981822 (granted on 09/02/2020). These U.S. and EP patents are projected to expire in 2034.
Specifically, EP2981822 originally granted with composition of matter claims directed to an antibody capable of binding a recombinant antigen comprising pro-TGFß1 or a growth factor-prodomain complex which comprises the TGFß1 LAP complex, in addition to claims directed to methods of making such antibodies. EP2981822 is the subject of ongoing opposition proceedings before the EPO. It was revoked by the opposition division in November 2024, but the revocation decision is subject to appeal.
The U.S. Patent No. 9,573,995 has issued composition of matter claims directed to an antibody that specifically binds to GARP associated with a human TGFß1 LAP complex.
The U.S. Patent No. 9,758,576 has issued composition of matter claims directed to an isolated monoclonal antibody, or a fragment thereof, that specifically binds the prodomain of a pro/latent GDF-8/myostatin complex, thereby preventing proteolytic cleavage between residues Arg 75 and Asp 76 of GDF-8/myostatin prodomain, so as to inhibit the release of mature GDF-8/myostatin growth factor from the complex.
The U.S. Patent No. 9,580,500 has issued claims directed to phage display library-based antibody production methods for identifying an antibody that binds a GARP/proTGFß1 complex.
The U.S. Patent No. 9,399,676 has issued claims directed to phage display library-based antibody production methods for identifying an antibody that binds a pro/latent GDF-8 complex that has been subjected to enzymatic cleavage. Related product-by-process claims are included in issued U.S. Patent No. 9,758,577.
The U.S. Patent No. 10,597,443 has issued claims that broadly cover manufacturing methods for a pharmaceutical composition containing an antibody that binds a large latent complex of TGFß, thereby modulating TGFß signaling.
The U.S. Patent No. 10,981,981 has issued claims that broadly cover manufacturing methods for a pharmaceutical composition containing an antibody that binds pro/latent GDF-8, but does not bind to mature GDF-8, and inhibits GDF-8 signaling.
In addition, U.S. Patent No. 11,827,698 has issued claims that broadly cover manufacturing methods for a pharmaceutical composition containing an antibody that binds pro/latent GDF-8, and inhibits the release of mature GDF8 from the pro/latent GDF8 complex.
Myostatin Activation Inhibitors
Three families are directed to composition of matter claims that cover the company’s proprietary antibodies. PCT/US2015/059468 (published as WO 2016/073853) broadly covers a class of monoclonal antibodies that specifically bind inactive precursors, thereby preventing activation of myostatin. This patent family is projected to expire in November 2035. U.S. Patents 10,307,480, 11,135,291, and 11,925,683 issued in June 2019, October 2021, and March 2024, respectively, with claims directed to the company’s proprietary antibodies that specifically bind pro/latent myostatin, including 29H4, the parental clone of apitegromab, and variants, as well as host cells and methods of making antibodies with pH-sensitive binding to pro/latent myostatin.
A second family, PCT/US2016/052014 (published as WO 2017/049011), discloses the specific amino acid sequence of apitegromab and is projected to expire in September 2036. U.S. Patent 10,751,413 issued in August 2020, with claims directed to antibodies and pharmaceutical compositions comprising the heavy and light chain sequences of apitegromab, while U.S. Patent 11,439,704 issued in September 2022, with claims directed to a method of preventing muscle loss and/or reducing muscle atrophy or treating SMA by administering an antibody having the heavy and light chain sequences of apitegromab. The European counterpart also granted as EP 3350220 B1 in May 2021. The granted claims relate to antibodies comprising the heavy and light chain variable region and full chain sequences of apitegromab, and pharmaceutical compositions of the antibodies.
A third family, PCT/US2023/085574 (published as WO2024138076), was filed with claims directed to specific amino acid sequences of additional antibodies in the company’s proprietary myostatin inhibitor portfolio. If granted, patents from this family are projected to expire in December 2043.
The following patent families are directed to therapeutic uses/methods:
PCT/US2017/012606 (published as WO 2017/120523) broadly covers treatment methods for a number of muscle and neuromuscular diseases and disorders using an antibody that specifically blocks the activation step of myostatin. This family is projected to expire in September 2036. The first U.S. application issued in May 2019 as U.S. Patent 10,287,345 with claims drawn to methods for inhibiting myostatin activation using the company’s proprietary activation inhibitors (such as apitegromab) to cause specified pharmacological effects to treat a variety of conditions, including muscle and metabolic disorders. A second U.S. application issued as U.S. Patent 10,882,904 in January 2021. The issued claims recite methods for inhibiting myostatin activation using an antibody comprising the heavy and light chain sequences of apitegromab for various indications. A third U.S. application issued as U.S. Patent 12,006,359 in June 2024. The issued claims are directed to a method of improving body composition by administering an antibody comprising heavy and light chain sequences of its proprietary activation inhibitors (such as apitegromab) or variants thereof.
PCT/US2017/037332 (published as WO 2017/218592) is directed to methods for treating neuromuscular diseases and selecting patient populations that are likely to respond to myostatin inhibition. This filing includes the treatment of SMA in patients who are on SMN therapies (e.g., SMN correctors/upregulators). This patent family is projected to expire in June 2037. The PCT application was nationalized in 11 jurisdictions, and applications in the three key jurisdictions (i.e., U.S., Europe, and Japan) have granted, as well as in other countries. Specifically, the U.S. application granted in March of 2021 as U.S. Patent 10,946,036. The granted claims are directed to add-on or combination therapy for treating spinal muscular atrophy with a myostatin inhibitor and a neuronal corrector (such as SMN upregulator therapy). Similar claims have also granted in other countries including Japan (JP Patent No. 6823167, JP Patent No. 7161554, and JP Patent No. 7344337). Likewise, the European counterpart granted as EP 3368069B1 and has been validated in 37 states. The originally granted European claims are directed to add-on therapy and combination therapy for the treatment of SMA using a myostatin-selective inhibitor, in conjunction with an SMN corrector therapy. EP 3368069B1 is currently the subject of ongoing opposition proceedings before the EPO. It was revoked by the opposition division in April 2024, but the revocation decision is being appealed.
PCT/US2018/012686 (published as WO 2018/129395) relates to the treatment of metabolic diseases with a myostatin activation inhibitor and is projected to expire in January 2038. The PCT was nationalized in 2019 and is in the early stages of prosecution. A U.S. patent issued in October of 2021 as U.S. 11,155,611, with claims directed to methods of making a pharmaceutical composition comprising a myostatin-selective inhibitor, comprising screening for an antibody that is capable of decreasing expression of pyruvate dehydrogenase kinase 4 (PDK4) and increasing expression of pyruvate dehydrogenase phosphatase 1 (PDP1). A Japanese patent (JP 7198757) issued in December 2022 with claims directed to a pro/latent myostatin-specific inhibitor for use in treating or preventing obesity or metabolic disorder in a subject on a calorie restriction diet. Similar claims have issued in Europe in 2023 (EP 3565592).
In addition to the five pending patent families listed, there are also two PCT applications related to the phase 2 and phase 3 clinical trials of apitegromab in SMA. PCT/US2021/056517 (published as WO2022/093724) is directed to inventions deriving from the phase 2 clinical trial of apitegromab. This PCT was nationalized broadly. If granted, patents deriving from this PCT would expire in 2041. Another PCT application was filed in 2023, PCT/US2023/020843 (published as WO 2023/215384) with claims directed to therapeutic methods for treating SMA deriving from the phase 2 and phase 3 clinical trials of apitegromab. If granted, patents from this family would expire in 2043. Both of these families are in early stages of prosecution.
A further PCT application, PCT/US2022/034588 (published as WO2022/2271867), was filed with claims directed to a myostatin pathway inhibitor for use in treating metabolic disorders. If granted, patents deriving from this PCT would expire in 2042.
Finally, five other myostatin-related patent families have been filed and are in the priority year.
TGFß1 Activation Inhibitors
In addition to the patent families in the ‘Intellectual Property-Platform’ section that generically cover certain aspects of the TGFß1 program, fifteen patent families have been filed to date, covering various specific aspects of its TGFß1 programs.
Isoform-specific inhibitors of TGFß1 which confer improved safety profile and related methods are described in PCT/US2017/021972 (published as WO 2017/156500). A U.S. patent (11,643,459) issued in May 2023, with claims directed to methods for identifying TGFß1-specific inhibitors. A European patent granted in May of 2023 as EP3365368, with claims to the use of isoform-selective and context-independent anti-TGFß1 antibodies, defined by CDR sequences or by cross-competition, in the treatment of cancer or myelofibrosis. EP3365368 is the subject of ongoing opposition proceedings before the EPO. Additional patents in this family have been granted in other jurisdictions. This family is projected to expire in March 2037.
Among TGFß1 inhibitors, one of the company’s context-independent antibodies is separately claimed and related preclinical data are described in PCT/US2018/012601 (published as WO 2018/129329). This patent application is projected to expire in January 2038. For this latter family, a Japanese patent (JP Patent No. 7157744) issued in October 2022 with claims covering certain isoform-selective, context-independent antibodies and their use in the treatment of fibrotic diseases.
In addition, high-affinity, isoform-selective TGFß1 inhibitors are disclosed in PCT/2019/041373 (published as WO US2020/014460, and patents have issued in April 2024 in Columbia, June 2024 in the Gulf Cooperation Council, and August of 2024 in Japan). Patents of this family are projected to expire in 2039. Separately, direct national/regional applications covering related subject matter have been filed, in the U.S., Europe, and Hong Kong, and are projected to expire in 2039. Two U.S. patents issued in September of 2021 as U.S. 11,130,803 and in October of 2024 as U.S. 12,122,823, with claims which cover the SRK-181 clinical candidate and pharmaceutical compositions thereof; and a European patent issued in November of 2021 as EP3677278; and the corresponding Hong Kong patent issued in June of 2022, with claims that cover the SRK-181 clinical candidate, pharmaceutical compositions, use for treating cancer and myelofibrosis, and methods for manufacturing. Additionally, PCT/US2021/012969 (published as WO 2021/142448) discloses data related to biomarkers for the high-affinity, isoform-selective TGFß1 inhibitors, and, if granted, patents deriving from this PCT application are projected to expire in 2041. Additional biomarkers are disclosed in PCT/US2022/022063 (published as WO2022/204581). If granted, patents deriving from these PCT applications would expire in 2042. Another PCT application, PCT/US2024/018970 (published as WO 2024/187051) discloses methods of treating certain cancers and identification of patient populations using biomarkers. If granted, patents derived from this PCT are expected to expire in 2044. One additional patent family to the company’s TGFß1 inhibitor program is currently in the priority year. Antibodies claimed in these patent families protect the company’s SRK-181 clinical candidate.
Separately, other improved isoform-selective, context-independent inhibitors of TGFß1 are disclosed in PCT/US2019/041390 (published as WO 2020/014473). This family is projected to expire in 2039. PCT/US2021/12930 (published as WO 2021/142427) is directed to optimized isoform-selective, context-independent inhibitors of TGFß1. This family is projected to expire in 2041.
LTBP complex-specific inhibitors of TGFß1 are described in four patent families: PCT/US2018/44216 (published as WO 2019/023661) which is expected to expire in July of 2038; and PCT/US2020/15915 (published as WO2020/160291), which is expected to expire in 2040; PCT/US2022/73740 (published as WO 2023/288277), which is expected to expire in 2042. Three U.S. patents (U.S. Pat. Nos. 11,214,614, 11,365,245, and 12,173,059) and one Columbian patent have been issued in the second patent family with claims directed to antibodies and pharmaceutical compositions.
LRRC33-specific inhibitors are described in a further patent family: PCT/US2018/031759 (published as WO 2018/208888) which is expected to expire in May of 2038. EP3621694 granted in July 2023, with claims directed to therapeutic use of LRRC33 inhibitors for the treatment of various indications. PCT/US2017/042162 (published as WO 2018/013939) was exclusively licensed to Janssen, but the license agreement was terminated in July 2022. The company is now in control of prosecution. This patent family covers antibodies that specifically inhibit GARP-associated TGFß, and is projected to expire in July 2037. A Japanese patent (JP Patent No. 7128801) issued in August 2022 with claims directed to antibodies and antigen-binding fragments which specifically bind human pro-TGFß1-GARP complex, a process for their production, and related compositions. Additional patents have also granted in other jurisdictions including in Australia (AU 2017294772).
RGMc-Selective Inhibitors
PCT/US2019/057687 (published as WO2020/086736) is directed to RGMc-selective inhibitors and is projected to expire in 2039. A Japanese patent application was allowed in December 2024 and will grant in early 2025. The Japanese patent will have claims which cover a pharmaceutical composition comprising the SRK-256 clinical candidate and the use thereof for treating anemia, including anemia of chronic disease and anemia in subjects diagnosed with cancer, such as myelofibrosis. Also, a Chinese patent application was allowed in December 2024, with similar claims. Applications are pending in other jurisdictions, including the U.S. and EP.
Intellectual Property Protection
The company cannot predict whether the patent applications it pursues will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide any proprietary protection from competitors. Even if the company’s pending patent applications are granted as issued patents, those patents, as well as any patents the company licenses from third parties, may be challenged, circumvented, or invalidated by third parties. Three granted patents, EP2981822, EP3365368, and EP3368069, were the subject of ongoing opposition proceedings before the EPO, as of December 31, 2024. While there are no contested proceedings or third-party claims relating to any of the other patents, as of December 31, 2024, the company could not provide any assurances that it will not have such proceedings or third-party claims at a later date.
Additionally, the Unitary Patent/Unified Patent Court system in Europe became fully operational in June 2023. As such, European patents which are subject to the jurisdiction of the Unified Patent Court (‘UPC’) face limited precedent for the court, increasing the uncertainty of any litigation.
Government Regulation
Where state laws are more protective than The Health Insurance Portability and Accountability Act of 1996 (‘HIPAA’), the company must comply with the state laws it is subject to, in addition to HIPAA.
In the event the company continues to conduct clinical trials in the European Economic Area (‘EEA’), the company must also ensure that it maintains adequate safeguards to enable the transfer of personal data outside of the EEA, in particular to the U.S., in compliance with European data protection laws.
Research and Development
The company’s research and development expenses were $184.6 million for the year ended December 31, 2024.
History
Scholar Rock Holding Corporation was founded in 2012. The company was incorporated in 2017.
