On October 7, 2024, Scholar Rock announced that the Phase III clinical trial (SAPPHIRE) of Apitegromab (SRK-015) met its primary endpoint with a statistically significant and clinically meaningful enhancement in motor function. Apitegromab is a Growth Differentiation Factor 8 (GDF-8, also known as myostatin) antibody for the treatment of spinal muscular atrophy (SMA). Among patients treated with Apitegromab, 30% showed an improvement of 3 points in the HFMSE score, compared to only 12.5% in the placebo group.
Figure 1. Results summary of Apitegromab SAPPHIRE trial to treat spinal muscular atrophy (SMA) [1].
Scholar Rock plans to submit a Biologics License Application (BLA) and a Marketing Authorization Application (MAA) to the FDA and EMA in the first quarter of 2025. This means that Apitegromab is expected to become the first approved antibody drug for the treatment of SMA, offering a new therapeutic option for SMA patients. This success marks a significant milestone in the history of SMA treatment. Following this news, Scholar Rock's stock price surged by 362% on the same day, bringing its market value to $2.7 billion.
Function and Signaling Pathway of GDF-8
GDF-8, a protein primarily expressed by skeletal muscle cells, stands for Growth/Differentiation Factor 8, also known as Myostatin or MSTN. It belongs to the Transforming Growth Factor-β (TGF-β) superfamily and mainly controls muscle volume by inhibiting muscle cell proliferation, thereby reducing muscle mass and regulating skeletal muscle growth. Under various pathological conditions, such as muscle atrophy, chronic kidney disease, cancer, liver disease, obesity, and anterior cruciate ligament (ACL) tears, GDF-8 levels may increase.
Figure 2. Overview of myostatin (GDF-8) protein structure and maturation [2]
Mature GDF-8 undergoes a series of cleavage processes: the GDF-8 precursor is synthesized within the cell and first has its signal peptide removed by signal peptidase, resulting in Pro-GDF-8 (also known as precursor GDF-8). Subsequently, the proprotein convertase Furin recognizes and cleaves specific sequences within Pro-GDF-8, forming Latent GDF-8. This step is crucial for myostatin protein maturation. Finally, the metalloproteinases BMP-1 or Tolloid further process Latent GDF-8, which may involve cleavage of the prodomain, thereby activating GDF-8. Mature GDF-8 exists as a homodimer, a structural feature critical for its biological activity.
Activin type II receptors (ActRII) are the main downstream receptors for GDF-8. When GDF-8 binds to them, it recruits ActRI receptors, subsequently activating intracellular SMAD and AKT signaling pathways. This leads to changes in gene transcription and the degradation of related proteins, ultimately causing muscle loss.
Figure 3. GDF-8 (myostatin) Signaling Pathway [3]
Development of GDF-8 Targeted Drugs
As a critical regulator of muscle growth and disease progression, GDF-8 is currently a significant target for treating skeletal muscle diseases, neuromuscular diseases, obesity, and cancer. Scholar Rock's SRK-015 (Apitegromab) is a representative drug in this category. SRK-015 is a fully human monoclonal antibody that binds with high specificity to human Pro-GDF-8 or Latent GDF-8 without binding to mature GDF-8 and other closely related growth factors. It inhibits GDF-8 before release, offering high selectivity and minimal side effects. SRK-015 is currently in Phase 3 clinical trials (NCT05156320) for spinal muscular atrophy (SMA) and is the first potential muscle-directed therapy for SMA. Roche's RO7204239 (GYM329, RG6237) targets Latent myostatin and is being tested for SMA (NCT05115110) and facioscapulohumeral muscular dystrophy (NCT05548556).
Figure 4. Design Principle of Apitegromab [4]
Regeneron's REGN-1033 (Trevogrumab) targets the mature form of GDF-8. In collaboration with Eli Lilly, Phase 2 clinical trials are evaluating whether Trevogrumab combined with Semaglutide±Garetosmab (anti-Activin A) can maintain weight loss efficacy by increasing muscle mass. Similarly, Keros' KER-065 is designed for GDF-8, being a novel ligand trap drug [4] that can capture GDF-8 or Activin A, treating obesity by increasing muscle mass and reducing fat mass. It can be used as a standalone therapy or combined with GLP-1 receptor agonists.
Figure 5. KER-065 mechanism of action on activin A and myostatin (GDF-8) [6].
KACTUS High-Quality GDF-8 (Myostatin) Proteins
GDF-8 has become an important drug target for developing treatments that promote muscle growth and address muscle atrophy-related conditions. Many drugs target the non-mature form of GDF-8, which helps control the activation process of GDF-8 (myostatin) protein. In contrast, targeting the mature form of GDF-8 can more directly intervene in the regulation of muscle growth. The most suitable strategy for drug design depends on factors such as the mechanism of action, safety, efficacy, and potential side effects.
To support drug development in various fields, including muscle atrophy, KACTUS has developed high-quality recombinant GDF-8, Latent GDF-8, and related proteins such as Activin RIIA and Activin RIIB. These products cover multiple species and diverse tag designs. They are all rigorously quality tested and applicable to different research stages, such as drug screening and validation.
Product Validation Data
Figure 6. Bioactivity of Human/Mouse/Rat GDF-8 protein determined by its ability to inhibit the proliferation of MPC-11 cells. The expected ED50 for this effect is <30 ng/ml (QC Test).
Figure 7. Immobilized Human Latent GDF-8, His Tag at 1 ug/ml (100 ul/well) on the plate. Dose response curve for Anti-GDF8 Antibody, hFc Tag with the EC50 of 22.8 ng/ml determined by ELISA (QC Test).
Product List
| Catalog Number | Product Information |
| GDF-HM108 | Human Latent GDF-8, His Tag |
| GDF-HM008 | Human/Mouse/Rat GDF-8, No Tag |
| ACV-HM001 | Human Activin A, No Tag |
| ACV-HM101 | Human Latent Activin A, His Tag |
| ARA-HM12A | Human Activin RIIA, His Tag |
| ARA-HM22A | Human Activin RIIA, hFc Tag |
| ARA-HM52AB | Biotinylated Activin RIIA, hFc-Avi Tag |
| ARA-HM32A | Human Activin RIIA, mFc Tag |
| ARA-MM12A | Mouse Activin RIIA, His Tag |
| ARB-HM12B | Human Activin RIIB, His Tag |
| ARB-HM42BB | Biotinylated Human Activin RIIB, His-Avi Tag |
| ARB-HM52BB | Biotinylated Human Activin RIIB, hFc-Avi Tag |
| ARB-HM32B | Human Activin RIIB, mFc Tag |
| ARB-MM12B | Mouse Activin RIIB, His Tag |
| TGF-HM6R1 | Human TGFBR1, mFc-Avi Tag |
| TGF-HM6R1B | Biotinylated Human TGFBR1, mFc-Avi Tag |
| ALK-HM104 | Human ACVR1B/ALK-4, His Tag |
References
[1] https://investors.scholarrock.com/static-files/693dd276-5581-4b1a-9834-b24e16dbe17f
[2] Hoogaars WMH, Jaspers RT. Past, Present, and Future Perspective of Targeting Myostatin and Related Signaling Pathways to Counteract Muscle Atrophy. Adv Exp Med Biol. 2018;1088:153-206. doi: 10.1007/978-981-13-1435-3_8.
[3] Garber K. No longer going to waste. Nat Biotechnol. 2016 May 6;34(5):458-61. doi: 10.1038/nbt.3557.
[5] https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386654
[6] https://ir.kerostx.com/static-files/d666096b-07f9-47ea-b9ad-205f7c89895f
