What clinical trials have been conducted for Apitegromab?

Introduction to Apitegromab
Apitegromab (formerly known as SRK-015) is an investigational, fully human monoclonal antibody that has been developed as a muscle-targeted therapeutic agent. It functions by selectively binding to the precursor (pro- and latent) forms of myostatin, a key negative regulator of muscle growth, thereby preventing its activation and ultimately enhancing muscle mass and strength. The drug is primarily being developed for conditions where muscle atrophy is a central feature, with spinal muscular atrophy (SMA) being the foremost therapeutic indication. However, its mechanism suggests potential utility in other neuromuscular and metabolic indications, such as obesity-related muscle impairment. Regulatory agencies worldwide have recognized its innovative approach by granting designations like Fast Track, Orphan Drug, Rare Pediatric Disease, and Priority Medicines (PRIME) to accelerate its development and evaluation.

Mechanism of Action
Apitegromab’s mechanism is based on the inhibition of myostatin activation. In normal physiology, myostatin is secreted as an inactive pro-protein that is subsequently cleaved to release its active form. Once activated, myostatin binds to receptors, such as ActRIIB, to negatively regulate skeletal muscle growth. Apitegromab intervenes upstream in this cascade by binding selectively to the pro- and latent forms of myostatin, which prevents the proteolytic conversion to its active state. This inhibition leads to sustained increases in serum latent myostatin levels and correlates with improvements in muscle mass and function. Preclinical evaluations confirmed its dose-dependent pharmacodynamics, and early-phase clinical trials demonstrated that single and multiple administrations of apitegromab resulted in robust target engagement, as evidenced by the increases in serum latent myostatin levels.

Therapeutic Indications
While the principal focus of apitegromab development has been on improving outcomes in spinal muscular atrophy (SMA)—a debilitating neuromuscular disorder characterized by progressive muscle weakness due to insufficient SMN protein—its therapeutic potential may extend further. In SMA, current SMN-targeted therapies (such as nusinersen and risdiplam) help to stabilize neurological decline; however, muscle atrophy often remains a persistent clinical problem. By directly targeting the muscle component via myostatin inhibition, apitegromab offers a complementary approach to enhance residual motor function. Additionally, a Phase 2 trial has been conducted in an overweight/obese adult population, exploring its potential benefit in conditions where muscle mass improvement could address metabolic challenges. These diverse approaches underscore the versatility of apitegromab as a therapeutic agent in both rare neuromuscular diseases and potentially other conditions related to muscle dysfunction.

Overview of Clinical Trials
Clinical development for apitegromab has followed the conventional multi-phase pathway—from early-phase assessments in healthy volunteers to extended proof-of-concept and pivotal registrational trials in patient populations. The design of these clinical trials adheres to rigorous regulatory and scientific standards that ensure both safety and efficacy are thoroughly evaluated while also obtaining critical pharmacokinetic (PK) and pharmacodynamic (PD) data.

Phases of Clinical Trials
Apitegromab has been evaluated through several key phases:
- Phase 1 Trials: These initial studies primarily focused on safety, tolerability, and the pharmacokinetic profile of the antibody in healthy adults using single and multiple ascending dose regimens. The findings were fundamental in confirming the drug’s mechanism of action and its capacity for robust target engagement through dose-dependent increases in serum latent myostatin levels.
- Phase 2 Trials: Moving forward into the proof-of-concept stage, the Phase 2 trials, notably the TOPAZ study, evaluated the efficacy and safety of apitegromab in patients with later-onset SMA. This phase also included sub-studies and extension trials that assessed long-term outcomes over 12, 24, and even 36 months. Additionally, a Phase 2 trial in adults with overweight or obesity was conducted to assess if the muscle-enhancing effects could translate into clinical benefits for a metabolic indication.
- Phase 3 Trials: The pinnacle of the clinical trial process for SMA has been the ongoing registrational Phase 3 SAPPHIRE trial, which is a randomized, double-blind, placebo-controlled study. This pivotal trial seeks to provide definitive evidence of apitegromab’s efficacy and safety in nonambulatory patients with Types 2 and 3 SMA when used in conjunction with SMN-targeted therapies such as nusinersen or risdiplam.

Regulatory Considerations
Given the innovative nature of apitegromab’s mechanism, regulatory agencies have shown significant interest in its development. Its designation as an Orphan Drug and receipt of Rare Pediatric Disease status by the FDA, along with PRIME designation by the EMA, reflect its potential to address unmet medical needs in SMA. These designations facilitate enhanced communication with regulatory bodies, expedited review processes, and incentives that support further clinical development. All clinical trials, from Phase 1 through Phase 3, have been registered on international trial registries like ClinicalTrials.gov, ensuring transparency and adherence to global regulatory and ethical standards.

Detailed Analysis of Apitegromab Trials
A deeper examination of the individual clinical trials for apitegromab reveals a robust and methodically sound clinical development program characterized by progressive phases that build upon each other in terms of safety and efficacy data.

Phase 1 Trials
The Phase 1 clinical study of apitegromab was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of the drug in healthy adult volunteers. This study used a randomized, double-blind, placebo-controlled design with single and multiple ascending doses.
- Key Findings:
- Pharmacokinetics: The drug demonstrated linear, dose-proportional pharmacokinetics with maximum plasma concentrations observed within 8 hours after a 120-minute intravenous infusion. The terminal half-life ranged approximately from 24 to 31 days, which contributed to the rationale for infrequent dosing regimens in later trials.
- Pharmacodynamics: Both single and multiple doses exhibited dose-dependent and sustained increases in serum latent myostatin, confirming the robust target engagement necessary for clinical efficacy.
- Safety Profile: The Phase 1 trial showed that apitegromab was well tolerated with only mild adverse events reported—headache being the most common with no dose-limiting toxicities detected. There were no clinically significant changes in vital signs, laboratory parameters, or ECG results, which supported moving forward into patient-based Phase 2 studies.

Overall, the Phase 1 study established a solid safety and PK/PD profile for apitegromab, which was critical for justifying subsequent clinical trials in patient populations.

Phase 2 Trials
The Phase 2 trials of apitegromab represent the pivotal proof-of-concept stage, particularly in patients with later-onset spinal muscular atrophy (SMA). The most notable among these is the TOPAZ trial, which has been conducted in multiple cohorts and has provided a wealth of efficacy and safety data.
- TOPAZ Trial Design:
- Population and Cohorts: The TOPAZ trial enrolled patients with Types 2 and 3 SMA who were already receiving SMN-targeted therapies (nusinersen). It included multiple cohorts differentiated by ambulatory status and age. One cohort focused on nonambulatory patients with later-onset SMA, while another included ambulatory patients, and a third cohort evaluated different dosing regimens (2 mg/kg vs. 20 mg/kg) in younger patients.
- Endpoints: The primary efficacy endpoints centered on changes in motor function as measured by validated scales such as the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Hammersmith Scale (RHS). For instance, statistically significant improvements in HFMSE scores were observed, with some cohorts showing mean increases ranging from approximately 5 to 7.1 points.
- Long-term Extension: Beyond the primary 12-month treatment period, extension phases (up to 36 months) were implemented to evaluate the durability of response. These extension studies have shown that sustained and even progressive improvements in motor function are achievable, with quality-of-life measures such as patient-reported outcomes (e.g., PROMIS for fatigue) consistently improving over extended treatment periods.
- Additional Indication: In parallel with the SMA studies, a separate Phase 2 randomized, double-blind, placebo-controlled trial has been conducted to assess the efficacy and safety of apitegromab in overweight and obese adults. Although this trial targets a different therapeutic area, its design mirrors the rigorous approach used in the SMA studies, evaluating efficacy, safety, and pharmacokinetic outcomes in a controlled setting.

- Key Findings from Phase 2:
- Efficacy: Evidence from the TOPAZ trial demonstrated that apitegromab significantly improved motor function scores relative to baseline, and data indicated a dose response in the randomized cohorts. A substantial proportion of patients achieved clinically meaningful improvements—for instance, in one analysis, 82% of patients attained a ≥1-point increase in HFMSE, and around 59% achieved ≥5-point increases.
- Safety and Tolerability: Both the TOPAZ trial and its extensions confirmed that the safety profile of apitegromab was consistent with expectations. The incidence of treatment-emergent adverse events (TEAEs) such as headache, pyrexia, upper respiratory tract infection, cough, and nasopharyngitis was in line with the underlying patient population and typical background therapies. Importantly, serious adverse events (SAEs) were uncommon and, when they did occur, they were not attributed to apitegromab.
- Long-Term Impact: The extended observation periods provided compelling evidence that the improvements in motor function are not transient. Sustained improvements over 24 to 36 months suggest that apitegromab could offer durable clinical benefits, which is a highly desirable characteristic for a disease like SMA where progressive decline is expected.

The Phase 2 data, especially from the TOPAZ trial and its long-term extension studies, have been instrumental in demonstrating the therapeutic promise of apitegromab in SMA, thereby providing the justification for advancing to Phase 3.

Phase 3 Trials
The transition to Phase 3 represents the final step in the clinical evaluation process for apitegromab, where the focus shifts to confirming efficacy and safety in a larger, diverse patient population through a randomized, double-blind, placebo-controlled design.
- SAPPHIRE Trial Design:
- Study Population: The SAPPHIRE trial is specifically designed for nonambulatory patients with Types 2 and 3 SMA who are receiving background SMN-targeted therapy (either nusinersen or risdiplam). Approximately 156 patients aged 2–12 years have been enrolled for the main efficacy population, while an exploratory cohort targets patients aged 13–21 years.
- Randomization and Dosing: Patients in the main efficacy cohort are randomized in a 1:1:1 ratio to receive either 10 mg/kg, 20 mg/kg of apitegromab, or placebo, with intravenous infusions administered every 4 weeks. The trial is powered to detect statistically significant differences in motor function improvements, primarily using the HFMSE score as the primary endpoint.
- Extension and Follow-Up: In addition to the 12-month primary treatment period, the study design includes multiple 12-month extension periods to gather long-term efficacy and safety data. This approach mirrors what was seen in the Phase 2 trial, where extended dosing periods revealed sustained improvements in motor function.
- Interim and Top-Line Data: Although the primary results from the Phase 3 SAPPHIRE trial were anticipated for release in the later half of 2024, preliminary findings have shown early signals of improvement in motor function as early as 8 weeks, with trends supporting the favorable efficacy profile observed in earlier phases.

- Significance of Phase 3 Data:
- Efficacy Confirmation: The Phase 3 trial is critical for confirming that the improvements in motor function observed in the TOPAZ Phase 2 trial are reproducible in a larger, multicenter setting. The trial’s design permits a rigorous, head-to-head comparison between apitegromab and placebo, thereby providing the definitive evidence needed for regulatory approval.
- Regulatory Readiness: A successful Phase 3 trial will pave the way for the submission of a Biologics License Application (BLA) in the United States and marketing authorization application (MAA) in the European Union. Scholar Rock intends to leverage the robust data generated from SAPPHIRE to support imminent regulatory submissions, with the potential for a commercial launch as early as 2025.
- Broader Patient Impact: The inclusion of an exploratory cohort of older patients (aged 13–21 years) expands the understanding of apitegromab’s efficacy across a broader age range, which is vital for addressing the heterogeneity inherent in SMA. This approach may help refine dosing strategies and optimize the overall therapeutic benefit for different patient demographics.

The Phase 3 SAPPHIRE trial, therefore, represents a culmination of the clinical development strategy for apitegromab, aiming to definitively establish its role in the treatment paradigm for SMA.

Outcomes and Implications
The comprehensive clinical program of apitegromab has generated a wealth of data that have significant implications not only for SMA treatment but also for the broader field of muscle-targeted therapies.

Efficacy Results
- Phase 1 Outcomes: In healthy adult volunteers, the Phase 1 trial confirmed the dose-dependent pharmacokinetics and pharmacodynamics of apitegromab. The linear and predictable profile provided a strong foundation for dosing strategies in patient populations and verified that the mechanism of action—robust target engagement as indicated by increased serum latent myostatin—is operational.
- Phase 2 (TOPAZ) Efficacy: The TOPAZ trial, which is the cornerstone Phase 2 study for SMA, yielded promising improvements in motor function. Statistically significant improvements in HFMSE scores were documented, with mean changes reaching up to 7.1 points in certain dosing cohorts. A notable proportion of the study population achieved clinically meaningful improvements, such as a ≥3-point or even ≥5-point increase compared to baseline. Furthermore, long-term extension data (up to 36 months) indicated that these benefits were not transient but were maintained or even augmented over time.
- Phase 3 (SAPPHIRE) Efficacy: While full top-line results are pending, early indications from the ongoing SAPPHIRE trial suggest that apitegromab continues to demonstrate robust improvements in motor function. These results are consistent with the earlier-phase data and have been observed as early as 8 weeks after treatment initiation. The consistency of efficacy across multiple phases reinforces the potential for apitegromab to become a critical addition to the treatment regimen for SMA.

Safety and Adverse Effects
- Overall Safety Profile: Across all clinical phases, apitegromab has consistently exhibited a strong safety profile. In the Phase 1 study, minimal adverse events were reported, and no dose-limiting toxicities were observed.
- Phase 2 Safety Data: The TOPAZ trial and its extensions confirmed that the adverse events encountered—primarily headache, pyrexia, upper respiratory tract infections, cough, and nasopharyngitis—were generally consistent with the expected background incidence in the SMA population. Importantly, serious adverse events were rare and were determined by investigators to be unrelated to apitegromab treatment. This favorable safety profile is crucial in a patient population often susceptible to complications and underscores the potential for long-term treatment without an undue burden of side effects.
- Phase 3 Safety Considerations: Early data from the SAPPHIRE trial continue to support the initial findings, with no new or alarming safety signals emerging. In addition, the lack of significant differences in adverse event incidence between the two dosing regimens (10 mg/kg and 20 mg/kg) suggests a broadly tolerable dose range, an important consideration for a chronic disease like SMA.

Potential Impact on Treatment Landscape
- Addressing Unmet Needs in SMA: Current treatment modalities for SMA largely focus on increasing SMN protein levels; however, they do not fully mitigate the muscle atrophy that underlies the functional decline in SMA patients. Apitegromab, by directly targeting the myostatin pathway, offers a novel approach that complements existing therapies. The sustained improvements in motor function observed in the TOPAZ trial suggest that combining apitegromab with SMN-targeted therapies could substantially enhance patient outcomes, potentially altering the natural progression of the disease.
- Long-Term Benefits and Quality of Life: The extended trial data (24 and 36 months) indicate that continuous treatment with apitegromab may yield durable improvements in motor function and patient-reported outcomes, including fatigue and activities of daily living. Such long-term benefits have the potential to improve the overall quality of life and functional independence for patients, which is particularly impactful in a condition characterized by progressive decline.
- Broader Implications and Future Directions: Beyond SMA, the investigational program for apitegromab also includes trials in populations with metabolic dysfunction (overweight/obesity), suggesting that its muscle-enhancing properties could be leveraged in other therapeutic areas. This broadens the potential impact of the drug and could stimulate further research into muscle-directed therapies in conditions where muscle atrophy contributes to morbidity. Additionally, the demonstrated safety profile and sustained efficacy may encourage exploration in other neuromuscular disorders, expanding the clinical utility of apitegromab well beyond its current indications.

Conclusion
In summary, the clinical development program for apitegromab has been comprehensive and methodical, following a traditional yet rigorous multi-phase pathway. The journey began with Phase 1 trials in healthy volunteers, which confirmed the safety, predictable pharmacokinetics, and robust pharmacodynamics of the drug through demonstrated increases in serum latent myostatin. Building upon this foundation, the Phase 2 TOPAZ trial in patients with later-onset SMA provided critical proof-of-concept data that not only demonstrated significant improvements in motor function—as evidenced by increases in HFMSE and RHS scores—but also confirmed that these benefits could be sustained over extended treatment periods of up to 36 months. Furthermore, additional Phase 2 studies in overweight and obese adults have extended our understanding of apitegromab’s potential in muscle-targeted therapy beyond the neuromuscular disease spectrum.

The pivotal Phase 3 SAPPHIRE trial is now underway, designed as a randomized, double-blind, placebo-controlled study specifically for nonambulatory SMA patients receiving concomitant SMN-directed therapy. This trial is critical for fulfilling the requirements for regulatory approval and is poised to provide definitive evidence of the drug’s efficacy and safety in a larger patient population. Early interim data have provided encouraging signals of robust and clinically meaningful improvements in motor function, which are consistent with the results from earlier studies.

Across all phases, the safety profile of apitegromab has been consistently favorable, with common adverse events being mild and manageable. The absence of new safety signals in both short-term and long-term studies supports the drug’s potential for chronic use—a key consideration in a condition like SMA where lifelong treatment may be necessary.

From a broader perspective, the integration of apitegromab into the treatment paradigm for SMA represents a transformative approach. By addressing the underlying muscle atrophy through myostatin inhibition—a mechanism distinct from the SMN-targeted therapies currently available—apitegromab has the potential to fill a significant unmet need in the management of SMA. Its ability to be administered alongside existing therapies could lead to a paradigm shift, offering enhanced motor function improvements and improved quality of life for patients. Additionally, its application in other indications, such as metabolic disorders, underscores the versatility and broader potential impact of muscle-directed therapies.

In conclusion, the clinical trials conducted for apitegromab have been extensive and multifaceted, encompassing early-phase safety and mechanistic studies, proof-of-concept efficacy trials in SMA (and beyond), and an ongoing pivotal Phase 3 trial designed for regulatory submission. The data generated thus far have consistently demonstrated that apitegromab is a well-tolerated and effective muscle-targeted therapy, capable of producing sustained improvements in motor function. These findings not only bolster the case for its use in SMA but also highlight its potential to revolutionize the treatment landscape for neuromuscular diseases. Future regulatory reviews and subsequent product approvals based on these trials could pave the way for its widespread clinical use, representing a major advance in the therapeutic options available for patients with SMA and potentially other muscle-impairing conditions.