Bimagrumab (DB12584): A Comprehensive Report on an Investigational Activin Receptor Type II Inhibitor

Table of Contents

1. Executive Summary
2. Introduction to Bimagrumab
3. Drug Identity, Properties, and Development History

• [3.1. Key Identifiers and Basic Properties]
• [3.2. Developer History and Strategic Shifts]

4. Mechanism of Action

• [4.1. Molecular Target: Activin Type II Receptors (ActRIIA and ActRIIB)]
• [4.2. Downstream Signaling Modulation]

5. Pharmacodynamics (PD)

• [5.1. Effects on Muscle Mass and Composition]
• [5.2. Effects on Muscle Strength and Physical Function]
• [5.3. Effects on Fat Mass]
• [5.4. Effects on Metabolic Parameters]
• [5.5. Effects on Bone Metabolism]
• [Table: Overview of Bimagrumab Pharmacodynamic Effects in Humans]

6. Pharmacokinetics (PK)

• [6.1. Administration and Bioavailability]
• [6.2. Distribution, Metabolism, Elimination, Half-life]
• [6.3. Anti-Drug Antibodies (ADAs)]

7. Clinical Development Program

• [7.1. Sporadic Inclusion Body Myositis (sIBM)]
• [7.2. Sarcopenia]
• [7.3. Obesity and Type 2 Diabetes Mellitus (T2DM)]
• [7.4. Other Investigated Indications]
• [Table: Summary of Key Bimagrumab Clinical Trials]

8. Safety and Tolerability Profile

• [8.1. Overview from Pooled Analyses and Multiple Studies]
• [8.2. Specific Adverse Event Profile in Key Indications]
• [8.2.1. Sporadic Inclusion Body Myositis (sIBM)]
• [8.2.2. Sarcopenia]
• [8.2.3. Obesity and Type 2 Diabetes]
• [8.2.4. Healthy Older and Obese Adults (Phase I)]
• [8.3. Effects on Pituitary Hormonal Axes]

9. Regulatory Status

• [9.1. FDA Breakthrough Therapy Designation]
• [9.2. Orphan Drug Designations]

10. Discussion and Future Perspectives
11. Conclusion

1. Executive Summary

[Bimagrumab (BYM338, LY3985863) is an investigational human monoclonal antibody that targets activin type II receptors (ActRIIA and ActRIIB), primarily ActRIIB, thereby blocking ligands like myostatin and activin that negatively regulate muscle growth. Originally developed by MorphoSys and Novartis for muscle-wasting conditions such as sporadic inclusion body myositis (sIBM) and sarcopenia, bimagrumab demonstrated consistent increases in lean body mass and thigh muscle volume across multiple clinical trials. However, it largely failed to translate these muscle mass gains into significant improvements in muscle strength or physical function in these populations, leading to the discontinuation of its development for these indications.]

[Despite these setbacks, clinical studies also revealed a significant and consistent effect of bimagrumab in reducing total body fat mass, including visceral and hepatic fat, and improving metabolic parameters such as insulin sensitivity and HbA1c in individuals with obesity and type 2 diabetes. This dual action of promoting muscle gain while reducing fat mass presented a unique therapeutic profile. Consequently, bimagrumab was licensed by Versanis Bio, which focused its development on obesity. In 2023, Eli Lilly and Company acquired Versanis Bio, integrating bimagrumab into its prominent obesity pipeline. Current development focuses on bimagrumab as a monotherapy and in combination with incretin-based therapies (e.g., semaglutide, tirzepatide) to enhance the quality of weight loss by preserving or increasing muscle mass alongside fat reduction.]

[Pharmacokinetic studies indicate non-linear, target-mediated drug disposition, with an estimated subcutaneous bioavailability of around 40%. The incidence of anti-drug antibodies has generally been low and predominantly non-neutralizing. Bimagrumab has demonstrated a generally acceptable safety profile, with common adverse events including transient muscle spasms, diarrhea, and rash. The future of bimagrumab hinges on its ability to demonstrate clinically meaningful benefits in obesity, particularly in preserving muscle mass during weight loss, a key differentiator in a competitive therapeutic landscape.]

2. Introduction to Bimagrumab

Bimagrumab is an investigational biologic therapeutic agent that has garnered considerable attention and undergone a notable evolution in its clinical development pathway. It is a human monoclonal antibody designed to modulate critical signaling pathways involved in muscle and fat regulation.[1] Initially, the primary therapeutic focus for bimagrumab centered on conditions characterized by pathological muscle loss and weakness, such as sporadic inclusion body myositis (sIBM) and sarcopenia, where the unmet medical need remains high.[1]

Over several years of clinical investigation, while bimagrumab consistently demonstrated an ability to increase muscle mass, its efficacy in improving muscle function and strength in these primary indications proved insufficient, leading to shifts in its development strategy.[1] However, compelling data emerged from these trials indicating a significant effect on reducing body fat and improving metabolic parameters, which prompted a strategic pivot towards indications such as obesity and type 2 diabetes mellitus (T2DM).[13]

[This report aims to provide a comprehensive overview of bimagrumab, drawing upon available scientific literature and clinical trial information. The scope includes its fundamental drug identity and properties, a detailed account of its complex development history involving multiple pharmaceutical entities, its mechanism of action, pharmacodynamic effects on muscle, fat, and metabolism, pharmacokinetic profile, and an extensive review of its clinical development program across a spectrum of indications. Furthermore, the safety and tolerability profile, regulatory milestones, and future perspectives for this intriguing therapeutic candidate will be discussed.]

3. Drug Identity, Properties, and Development History

3.1. Key Identifiers and Basic Properties

[Bimagrumab is a biologic drug candidate with the following key identifiers and properties:]

• Name (English):[ Bimagrumab [User Query]]
• DrugBank ID: DB12584 [18]
• CAS Number: 1356922-05-8 [1]
• Type: Biotech [18]
• Specific Nature: Bimagrumab is a human monoclonal antibody [1], specifically an IgG1 subtype.[20][ The IgG1 isotype is relevant as it influences Fc-mediated effector functions and pharmacokinetic properties like half-life, although bimagrumab's primary therapeutic effect is derived from its antigen-binding and receptor-blocking activity.]
• Synonyms: The most common synonym is BYM338, used extensively during its development by Novartis.[1] Eli Lilly and Company later designated it LY3985863.[20] Other identifiers include O81T794R34 and Anti-ACVR2B Reference Antibody.[20]
• Molecular Formula: C6306​H9732​N1684​O1990​S46​ [1]
• Molar Mass: Approximately 142451.78 g/mol [1]
• Sequence Origin: Human [21]

3.2. Developer History and Strategic Shifts

[The development trajectory of bimagrumab is marked by collaborations, strategic pivots based on clinical findings, and high-value acquisitions, reflecting the dynamic nature of pharmaceutical research and development.]

Bimagrumab was initially created by MorphoSys AG, utilizing its proprietary Human Combinatorial Antibody Library (HuCAL) technology, and was subsequently licensed to Novartis for further development and clinical investigation.[4] This partnership model, leveraging the discovery expertise of a biotech company with the development capabilities of a large pharmaceutical firm, is a common paradigm in the industry. Novartis spearheaded the early to mid-stage clinical trials, primarily focusing on bimagrumab's potential in treating muscle-wasting disorders. These included sporadic inclusion body myositis (sIBM), sarcopenia, cachexia associated with conditions like chronic obstructive pulmonary disease (COPD) and cancer, and muscle atrophy due to disuse or hip fracture.[1]

Despite showing promise in increasing muscle mass, bimagrumab failed to meet primary functional endpoints in key trials for sIBM (the RESILIENT study, NCT01925209).[1][ This led Novartis to discontinue its development for sIBM and tempered enthusiasm for other muscle-wasting indications where functional improvement is paramount.]

However, an important observation from Novartis's clinical program was bimagrumab's consistent effect on reducing fat mass while concurrently increasing lean mass.[13] This dual effect on body composition, particularly the fat reduction, opened a new avenue for development. In 2021, Versanis Bio, a company founded by Aditum Bio with a model of in-licensing and developing promising but deprioritized assets from larger pharmaceutical companies, licensed bimagrumab from Novartis.[13][ Versanis Bio's strategy was to reposition bimagrumab for the treatment of obesity and related metabolic diseases, capitalizing on its unique ability to improve body composition.]

The potential of bimagrumab in the burgeoning obesity market attracted further significant interest. In July 2023, Eli Lilly and Company announced its acquisition of Versanis Bio for a sum potentially reaching $1.925 billion, thereby adding bimagrumab (now also known by Lilly's designation LY3985863) to its formidable cardiometabolic and obesity pipeline.[27] Lilly's interest likely stems from bimagrumab's potential to offer a differentiated approach to weight management, possibly in combination with its existing incretin-based therapies, by addressing the quality of weight loss (i.e., maximizing fat loss while preserving or increasing muscle mass).[30][ This addresses a common concern with GLP-1 receptor agonists, which can lead to the loss of lean muscle mass along with fat.]

[The intricate development history of bimagrumab is summarized in Table 1, highlighting the evolving understanding of its therapeutic potential and the strategic decisions made by different developers. This journey from a muscle-wasting treatment to a promising obesity candidate illustrates the complexities and serendipitous discoveries often encountered in drug development.]

Table 1: Developer History and Key Milestones for Bimagrumab

Company	Role/Contribution	Key Dates/Events
MorphoSys AG	Originator (HuCAL antibody library)	Early 2000s (antibody discovery)
Novartis	Licensed from MorphoSys; Extensive clinical development for muscle-wasting diseases	2000s-2010s: Development for sIBM, sarcopenia, COPD, cachexia, etc..4 Aug 2013: FDA Breakthrough Therapy Designation for sIBM.1 Apr 2016: Announced RESILIENT (sIBM) Phase IIb/III study did not meet primary endpoint.1 Later studies revealed fat loss potential.13
Versanis Bio	Licensed from Novartis; Repositioned for obesity and metabolic diseases	2021: Licensed bimagrumab from Novartis.13 Initiated Phase IIb BELIEVE study for obesity (alone and with semaglutide).22
Eli Lilly and Company	Acquired Versanis Bio; Current developer for obesity	Jul 2023: Acquired Versanis Bio, integrating bimagrumab (LY3985863) into obesity pipeline.27 Initiated TRIUMPH program, including combination trials with tirzepatide.23

4. Mechanism of Action

[Bimagrumab exerts its pharmacological effects by targeting activin type II receptors, which are key regulators of muscle and fat homeostasis.]

4.1. Molecular Target: Activin Type II Receptors (ActRIIA and ActRIIB)

Bimagrumab is a fully human IgG1 monoclonal antibody that specifically binds to activin type II receptors (ActRII).[1] It exhibits high affinity for both subtypes, ActRIIA and ActRIIB, which are transmembrane serine/threonine kinases.[35] However, its binding affinity for human ActRIIB (dissociation constant, KD​=1.7 pM) is substantially greater than for human ActRIIA (KD​=434 pM).[19][ This approximately 250-fold higher affinity for ActRIIB suggests that the pharmacological effects of bimagrumab are predominantly mediated through the blockade of this specific receptor subtype. Such selectivity is crucial, as it implies that at therapeutic concentrations optimized for ActRIIB saturation, the engagement of ActRIIA might be less complete, potentially influencing the breadth of biological responses and the side-effect profile.]

Bimagrumab functions as a competitive antagonist by binding to ActRII with greater affinity than the receptors' natural ligands.[2] These endogenous ligands include myostatin (also known as GDF-8), activin A, activin B, and growth and differentiation factor 11 (GDF11), all of which are members of the transforming growth factor-beta (TGF-β) superfamily and act as negative regulators of skeletal muscle mass.[2]

4.2. Downstream Signaling Modulation

The binding of bimagrumab to ActRIIA/B sterically hinders the interaction of myostatin, activins, and other related ligands with these receptors. This blockade prevents the activation of the canonical downstream signaling pathway, which involves the phosphorylation of SMAD2 and SMAD3 transcription factors.[20][ Under normal physiological conditions, ligand binding to ActRII leads to the recruitment and phosphorylation of type I activin receptors (e.g., ALK4, ALK5, ALK7), which then phosphorylate SMAD2/3. Phosphorylated SMAD2/3 proteins form complexes with SMAD4, translocate to the nucleus, and regulate the transcription of target genes, ultimately leading to inhibition of muscle growth and, in some contexts, promotion of muscle atrophy.]

[By inhibiting this ActRII-SMAD signaling cascade, bimagrumab effectively "releases the brakes" on muscle growth. This leads to a net anabolic effect characterized by:]

• Increased protein synthesis and decreased protein degradation within skeletal muscle cells.[2]
• Stimulation of myoblast differentiation and fusion, leading to the formation of new muscle fibers and the hypertrophy (increase in size) of existing ones.[2]

Furthermore, activin receptors are known to be expressed on adipocytes (fat cells).[29] The blockade of ActRII signaling by bimagrumab is also hypothesized to directly impact adipose tissue metabolism, contributing to the observed reductions in fat mass. This dual effect on muscle anabolism and fat catabolism is a distinctive feature of bimagrumab's mechanism and underpins its current investigation for obesity. While traditional weight loss methods, including some pharmacological interventions like GLP-1 receptor agonists, often lead to a concomitant loss of lean muscle mass along with fat [29][, bimagrumab offers the potential to preserve or even increase muscle mass during fat loss. This "quality weight loss" is highly desirable for maintaining metabolic health, physical function, and potentially preventing weight regain.]

5. Pharmacodynamics (PD)

[The pharmacodynamic effects of bimagrumab have been extensively studied across various human populations, revealing consistent impacts on body composition and metabolic parameters, although functional improvements have been more variable.]

5.1. Effects on Muscle Mass and Composition

[A hallmark effect of bimagrumab is its ability to increase skeletal muscle mass.]

• Lean Body Mass (LBM): Numerous studies have demonstrated significant increases in LBM following bimagrumab treatment in diverse populations, including older adults with sarcopenia, patients with sIBM, individuals with T2D and obesity, and patients with COPD.[5] For instance, in a study of patients with T2D and obesity (Heymsfield et al., 2021; NCT03723134), bimagrumab treatment for 48 weeks resulted in a 3.6% (1.70 kg) increase in LBM, compared to a 0.8% decrease in the placebo group.[15] In healthy older adults, LBM increased by 4-6% (1.5-2 kg) from baseline.[28] The RESILIENT study in sIBM patients also reported LBM increases.[5]
• Thigh Muscle Volume (TMV): Consistent with LBM increases, bimagrumab has been shown to significantly increase TMV, a more direct measure of muscle hypertrophy in a specific region.[9] A 2024 meta-analysis focusing on sarcopenia patients found that bimagrumab treatment led to a mean difference in TMV increase of 5.29% compared to control groups.[37] In patients with COPD and muscle depletion, TMV increased by 5.9% at Week 4 and 7.0% at Week 8 with bimagrumab treatment.[36]

5.2. Effects on Muscle Strength and Physical Function

[Despite the consistent increases in muscle mass, the translation of these gains into improved muscle strength and physical function has been a significant challenge in bimagrumab's development, particularly for its initial target indications.]

• Sporadic Inclusion Body Myositis (sIBM): The Phase IIb/III RESILIENT study (NCT01925209) did not meet its primary endpoint of improving the 6-minute walk distance (6MWD) at week 52.[5] While the 10 mg/kg dose showed a statistically significant improvement in the patient-reported sIBM Functional Assessment (sIFA) total score, improvements in objective muscle strength measures were not clinically meaningful, and functional benefits were not sustained in the long-term extension study (NCT02573467).[5]
• Sarcopenia: In the Phase II study by Rooks et al. (2020) (NCT02333331), bimagrumab combined with diet and exercise did not show a significant improvement in the Short Physical Performance Battery (SPPB) score, 6MWD, or gait speed compared to placebo plus diet and exercise, even though LBM increased significantly.[6] The Novartis clinical trial results summary for CBYM338E2202 (NCT02333331) also concluded that bimagrumab did not have a meaningful effect on participants' strength and walking.[9] A meta-analysis confirmed these findings, noting no significant improvement in muscle strength, gait speed, or 6MWD, except potentially in participants with slower baseline walking speeds.[37]
• COPD with Muscle Wasting: A study in patients with COPD and reduced skeletal muscle mass (NCT01669174) showed that bimagrumab increased skeletal muscle mass but did not lead to improvements in functional capacity, as measured by 6MWD.[36]

[This consistent observation across different muscle-wasting conditions—that increased muscle mass does not automatically translate to enhanced strength or physical function—highlights the complexity of these disorders. Factors such as muscle quality, neuromuscular activation, underlying inflammatory processes, and the specific pathology of the disease likely play roles that are not solely addressed by increasing muscle bulk through ActRII blockade. This disconnect was a primary driver for the shift in bimagrumab's development focus away from these conditions.]

5.3. Effects on Fat Mass

[One of the most striking and consistent pharmacodynamic effects of bimagrumab is its ability to reduce fat mass.]

• Total Body Fat Mass (FM): Significant reductions in FM have been observed in diverse populations, including individuals with T2D and obesity, older adults with sarcopenia, and insulin-resistant individuals.[2] In the Phase II trial in T2D and obese patients (Heymsfield et al., 2021; NCT03723134), bimagrumab treatment led to a -20.5% (approximately -7.5 kg) reduction in FM over 48 weeks, compared to a -0.5% reduction with placebo.[15] A pooled analysis of non-diabetic subjects showed a 14.6% loss of total body fat mass in the highest dose group at 24 weeks, contrasting with a 2.4% gain in the placebo group.[57]
• Waist Circumference: Correspondingly, reductions in waist circumference have been consistently reported.[15]
• Regional Fat Deposits: Bimagrumab has demonstrated effects on specific fat depots, including reductions in abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).[15] Notably, in a subset of patients from the T2D/obesity study (NCT03723134), a 34% decrease in abdominal VAT and a 52% reduction in hepatic fat fraction were observed at week 48.[15]

5.4. Effects on Metabolic Parameters

[Alongside changes in body composition, bimagrumab has shown beneficial effects on key metabolic parameters.]

• Insulin Sensitivity: Improvements in insulin sensitivity have been reported in insulin-resistant individuals and those with T2D and obesity.[15] A study in insulin-resistant individuals showed that a single dose of bimagrumab improved insulin sensitivity by approximately 20-40%, as assessed by hyperinsulinemic-euglycemic clamp and intravenous glucose tolerance test (IVGTT).[48]
• Glycated Hemoglobin (HbA1c): In patients with T2D and obesity, bimagrumab treatment has led to reductions in HbA1c levels.[2] The Heymsfield et al. (2021) study reported a reduction of 0.76 percentage points in HbA1c with bimagrumab compared to a 0.04 percentage point reduction with placebo.[15]

5.5. Effects on Bone Metabolism

Emerging research, primarily from preclinical (murine) models but with direct relevance to ongoing and future human clinical trials, suggests that bimagrumab may have positive effects on bone metabolism. Studies indicate that bimagrumab can increase bone tissue amount and promote new bone formation, particularly in the cortical (shell) of long bones and in the area around the femoral head.[40][ This effect is particularly noteworthy because significant weight loss, especially if rapid, can sometimes be associated with a reduction in bone mineral density, increasing fracture risk. If bimagrumab can concurrently promote fat loss, preserve/increase muscle mass, and also support bone health, it would offer a significant advantage, particularly for older individuals or those at risk for osteoporosis. This potential to mitigate a common adverse effect of aggressive weight-loss strategies could make combination therapies involving bimagrumab particularly valuable from a comprehensive health standpoint.]

[Table 2 provides a consolidated overview of the principal pharmacodynamic effects of bimagrumab observed in human clinical trials.]

Table 2: Overview of Bimagrumab Pharmacodynamic Effects in Humans

Parameter	Direction of Effect	Magnitude of Effect (Representative)	Studied Population/Condition	Key Reference(s)
Lean Body Mass (LBM)	Increase	3.6% to 6% (1.5-2.0 kg)	T2D/Obesity, Sarcopenia, sIBM	5
Thigh Muscle Volume (TMV)	Increase	5-8%	Sarcopenia, COPD, Older Adults	36
Total Body Fat Mass (FM)	Decrease	14.6% to 20.5% (approx. 2-7.5 kg)	T2D/Obesity, Sarcopenia, Insulin-Resistant	15
Visceral Adipose Tissue (VAT)	Decrease	~34% (MRI subset)	T2D/Obesity	15
Hepatic Fat Fraction	Decrease	~52% (MRI subset)	T2D/Obesity	15
Waist Circumference	Decrease	~9.0 cm	T2D/Obesity	15
6-Minute Walk Distance (6MWD)	No significant change / Decline	Variable, often not clinically meaningful	sIBM, Sarcopenia, COPD	6
Gait Speed	No significant change	Not clinically meaningful	Sarcopenia	6
SPPB Score	No significant change	Not clinically meaningful	Sarcopenia	6
Muscle Strength	No significant change	Not clinically meaningful	sIBM, Sarcopenia	5
HbA1c	Decrease	~0.76 percentage points	T2D/Obesity	15
Insulin Sensitivity	Increase	~20-40% improvement	Insulin-Resistant, T2D/Obesity	15
Bone Formation	Potential Increase	Preclinical data promising	Osteoporosis (mice), Weight Loss context	40

6. Pharmacokinetics (PK)

[The pharmacokinetic profile of bimagrumab has been characterized in several clinical studies, revealing aspects typical of monoclonal antibody therapeutics, including target-mediated drug disposition.]

6.1. Administration and Bioavailability

Bimagrumab has been administered via both intravenous (IV) infusion and subcutaneous (SC) injection in clinical trials.1

A Phase I study in healthy older adults (aged ≥70 years) evaluated multiple dose regimens and routes. The absolute subcutaneous bioavailability was estimated to be approximately 40%.28 This study also concluded that weekly subcutaneous administration of bimagrumab could achieve pharmacokinetic profiles and pharmacodynamic effects (LBM increase, FBM decrease) comparable to monthly intravenous dosing, supporting the feasibility of SC administration for future clinical development.28

6.2. Distribution, Metabolism, Elimination, Half-life

Bimagrumab exhibits non-linear pharmacokinetics due to target-mediated drug disposition (TMDD).[28][ TMDD is a phenomenon common to many monoclonal antibodies that bind with high affinity to their targets. At lower concentrations, a significant portion of the drug binds to the activin type II receptors, and the drug-receptor complex is internalized and degraded, leading to a faster clearance rate. As drug concentrations increase and saturate the receptors, non-specific, linear clearance pathways (typical for IgG antibodies, such as catabolism by the reticuloendothelial system) become more dominant, resulting in slower clearance and a longer apparent half-life.]

This non-linear PK profile means that classical pharmacokinetic parameters like a single elimination half-life, clearance rate, or volume of distribution are not constant across different dose levels and can be challenging to define simply.[28] Despite this, general observations indicate a long duration of action. For instance, Wikipedia notes a "long half-life" allowing for once-monthly administration.[1] A study in patients with sIBM (Amato et al., Neurology 2014) reported that a single 30 mg/kg IV dose of bimagrumab resulted in serum concentrations considered to be above the level required for saturation of the ActRIIB receptor for at least 56 days.[61][ This sustained target engagement is consistent with the observed long-lasting pharmacodynamic effects on muscle and fat mass.]

6.3. Anti-Drug Antibodies (ADAs)

The immunogenicity of bimagrumab, specifically the development of anti-drug antibodies (ADAs), has been assessed in its clinical trials.

In the Phase II study by Heymsfield et al. (2021) involving patients with T2D and obesity (NCT03723134), two out of 37 patients (5.4%) in the bimagrumab group developed treatment-emergent, non-neutralizing ADAs. Importantly, these ADAs did not appear to have an impact on the systemic exposure levels of bimagrumab.15 The low incidence of ADAs, and their non-neutralizing character in this particular study, are generally favorable observations for a therapeutic antibody intended for chronic or long-term administration. However, comprehensive ADA data from larger and longer-duration trials, especially in the context of its new focus on obesity, will be critical to fully understand its immunogenicity profile. Data regarding ADAs from the sIBM studies (e.g., RESILIENT) were not detailed in the provided summary snippets.61

7. Clinical Development Program

[Bimagrumab has been investigated in a broad range of clinical trials across multiple indications, reflecting its evolving therapeutic hypothesis from muscle-wasting disorders to metabolic conditions like obesity and T2D.]

7.1. Sporadic Inclusion Body Myositis (sIBM)

sIBM is a rare, progressive inflammatory myopathy causing muscle weakness and atrophy, primarily in older adults, with no currently approved effective treatments.[12][ Bimagrumab was initially a key focus for Novartis in this area.]

• RESILIENT Study (Phase IIb/III, NCT01925209): This was the largest randomized, double-blind, placebo-controlled, dose-finding study in sIBM patients (N=251).[5][ Participants received IV infusions of bimagrumab (10, 3, or 1 mg/kg) or placebo every 4 weeks for 52 weeks.]
• Primary Endpoint: The study did not meet its primary endpoint of improving the 6-Minute Walk Distance (6MWD) at week 52 compared to placebo for any bimagrumab dose.[7]
• Secondary/Other Endpoints: While LBM increased, there was no improvement in muscle strength.[5] The 10 mg/kg dose of bimagrumab did show a statistically significant improvement (p=0.03) in the sIBM Functional Assessment (sIFA) total score, a patient-reported outcome, compared to placebo at week 52. Lower doses showed a positive numerical trend.[10]
• Outcome: Due to the failure to meet the primary functional endpoint, Novartis and MorphoSys announced the discontinuation of bimagrumab development for sIBM in April 2016.[1]
• Long-Term Extension Studies (NCT02250443 / CBYM338X2205E1; NCT02573467 / RESILIENT EXT): These studies assessed the long-term (up to 2 years) safety, tolerability, and efficacy of bimagrumab in sIBM patients who participated in previous trials.[5]
• Results: Bimagrumab continued to demonstrate a good safety profile and was well-tolerated over the extended period. Increases in muscle mass (TMV, LBM) were noted or sustained.[12] However, there was no evidence of clinical improvement in functional outcomes; for example, 6MWD showed a progressive decline in all treatment groups, including placebo, over 104 weeks.[5] Differences in muscle strength were not clinically meaningful.[5]

[The experience in sIBM highlighted a critical challenge in muscle-wasting diseases: increasing muscle mass through anabolic agents like bimagrumab does not inherently guarantee an improvement in muscle function or overall physical performance. The complex pathophysiology of sIBM, involving inflammatory and degenerative processes beyond simple muscle atrophy, likely contributed to this disconnect.]

7.2. Sarcopenia

Sarcopenia, the age-related decline in muscle mass, strength, and function, is a major contributor to frailty and disability in older adults.[4]

• Phase II Dose-Range Finding Study (NCT02333331 / CBYM338E2202; Rooks et al., 2020): This trial evaluated bimagrumab (70 mg, 210 mg, 700 mg IV Q4W) versus placebo for 24-28 weeks in community-dwelling adults aged ≥70 years with sarcopenia, all of whom also received diet and exercise counseling.[6]
• Primary Outcome: Change in Short Physical Performance Battery (SPPB) score. No statistically significant difference was observed between bimagrumab and placebo groups; both groups showed improvement, likely due to the diet and exercise intervention.[6]
• Secondary Outcomes: No significant improvements in 6MWD or usual gait speed were seen with bimagrumab compared to placebo.[6] However, bimagrumab significantly increased LBM and appendicular skeletal muscle index (ASMI), and decreased fat body mass.[6] The Novartis patient summary for this trial (CBYM338E2202) confirmed that bimagrumab did not meaningfully impact strength or walking but was found to be safe, with the 210 mg and 700 mg doses increasing muscle amount.[9]
• Off-Drug Extension Study (NCT02468674):[ This study followed participants from NCT02333331 for an additional 24 weeks off-drug. Detailed results from snippets are limited but likely confirmed the durability of LBM changes and the lack of sustained functional improvement.]
• Meta-analysis (2024): A meta-analysis of RCTs in sarcopenia patients confirmed that bimagrumab significantly increased TMV and fat-free body mass, and decreased fat body mass. However, it did not show significant improvements in muscle strength or physical performance measures like gait speed and 6MWD, except for a potential benefit in participants with slower baseline walking speeds or distances.[37][ This observation in slower walkers suggests that the baseline functional status might be an important factor in detecting treatment effects, or that the drug's impact is more discernible in individuals with greater initial impairment.]

7.3. Obesity and Type 2 Diabetes Mellitus (T2DM)

[The observation of significant fat mass reduction and lean mass preservation/gain in earlier trials led to the repositioning of bimagrumab for obesity and T2DM.]

• Phase II Study in T2DM and Obesity (NCT03723134, also referred to as NCT03005288 in some contexts; Heymsfield et al., 2021, JAMA Network Open): This 48-week, double-masked, placebo-controlled trial randomized 75 adults with T2DM (HbA1c 6.5%-10.0%) and BMI 28-40 kg/m2 to bimagrumab (10 mg/kg IV Q4W, up to 1200 mg) or placebo, with both groups receiving diet and exercise counseling.[15]
• Primary Endpoint (Fat Mass): Bimagrumab treatment resulted in a least square mean change from baseline in total body fat mass of -20.5% (-7.49 kg) versus -0.5% (-0.18 kg) for placebo (P<.001).[15]
• Secondary Endpoints:
• Lean Mass: +3.6% (1.70 kg) for bimagrumab vs -0.8% (-0.44 kg) for placebo (P<.001).[15]
• Waist Circumference: -9.0 cm for bimagrumab vs +0.5 cm for placebo (P<.001).[15]
• HbA1c: -0.76 percentage points for bimagrumab vs -0.04 percentage points for placebo (P=.005).[15]
• Body Weight: -6.5% (-5.90 kg) for bimagrumab vs -0.8% (-0.79 kg) for placebo (P<.001).[15]
• Exploratory MRI substudy showed reductions in hepatic fat fraction (-52% at week 48) and abdominal VAT (-34% at week 48) with bimagrumab.[57]
• [This study was pivotal in demonstrating bimagrumab's potential in metabolic diseases.]
• BELIEVE Phase IIb Study (NCT05616013; Versanis Bio/Eli Lilly): This study is evaluating bimagrumab alone and in combination with the GLP-1 receptor agonist semaglutide in adults who are overweight or obese (non-diabetic).[22] The primary outcome is change in body weight, with numerous secondary outcomes assessing body composition (including % body fat, VAT, SAT, trunk fat mass), waist circumference, BMI, and quality of life.[22] The rationale is to improve the quality of weight loss by preserving or increasing lean mass while losing fat, which is a concern with GLP-1 agonists alone.[29] Top-line results were expected in mid-2024 [22]; subsequent press releases from Eli Lilly [88][ likely pertain to these results, suggesting positive findings on fat mass reduction.]
• TRIUMPH Clinical Trial Program (Eli Lilly):[ This program encompasses several Phase II studies evaluating bimagrumab (LY3985863).]
• NCT06009720 (TRIUMPH-1): Bimagrumab in combination with tirzepatide (Lilly's GIP/GLP-1 agonist) in adults with obesity.[93]
• NCT06009694 (TRIUMPH-2): Bimagrumab as monotherapy in adults with obesity.[96]
• NCT06009707 (TRIUMPH-3): Bimagrumab in older adults (≥65 years) with obesity.[99]
• NCT06643728 (also referred to as J4Z-MC-GIDF or part of TRIUMPH program):[ A Phase 2 study evaluating bimagrumab and tirzepatide, alone or in combination, in adults with obesity or overweight (without T2D). It plans to enroll 240 participants and is expected to complete by January 2027.]
• NCT06901349 (J4Z-MC-GIDI): A Phase 2 study of bimagrumab and tirzepatide, alone or in combination, in participants with obesity or overweight and T2D. It aims to enroll 180 participants, with an estimated start in June 2025 and completion in January 2027.[27]

[The extensive TRIUMPH program signifies Lilly's strong commitment to exploring bimagrumab's full potential in obesity, both as a standalone therapy and, crucially, in combination with its leading incretin agent, tirzepatide. The focus on older adults also addresses a specific demographic where muscle preservation during weight loss is particularly important.]

7.4. Other Investigated Indications (Brief Overview)

[Bimagrumab was explored in several other conditions characterized by muscle loss or weakness:]

• COPD with Muscle Wasting (NCT01669174): A Phase 2 trial (N=67) was completed. Bimagrumab (30 mg/kg IV, two doses at Weeks 0 and 8) increased thigh muscle volume but did not improve 6MWD or functional capacity over 24 weeks.[27]
• Cachexia:
• Diffuse Large B-Cell Lymphoma (DLBCL) related cachexia (NCT01423110): A Phase IIa study was conducted.[107] The development for cachexia appears to be discontinued.[4]
• Cancer Cachexia (NCT01311466): A study to assess safety, tolerability, PK, and PD.[111]
• Hip Fracture Recovery (NCT03336375): A Phase 2a/b trial in older adults (≥60 years) post-hip fracture surgery showed that bimagrumab (70 mg, 210 mg, or 700 mg IV Q4W for 24 weeks) resulted in significant increases in LBM but no functional benefit in recovery of mobility or lower extremity function compared with placebo.[11]
• Mechanical Ventilation / ICU Acquired Weakness (NCT01868685): Mentioned as an investigated area.[43] A Phase 2 trial was planned/conducted.[43]
• Muscle Wasting Due to Prolonged Disuse (Bed Rest - NCT01524041): A Phase 2 study was completed.[50] A single dose of bimagrumab accelerated the recovery of thigh muscle volume and reversed intermuscular adipose tissue accumulation after 2 weeks of cast immobilization in healthy men.[44]
• Age-Related Loss of Skeletal Muscle Mass (NCT01601600): A Phase 2 multicenter study to assess effects on skeletal muscle in sarcopenic adults (N=40), completed.[54]

[Table 3 provides a summary of key clinical trials involving bimagrumab.]

Table 3: Summary of Key Bimagrumab Clinical Trials

NCT Number	Phase	Status	Condition(s)	Key Efficacy Outcomes (LBM/FM/Function)	Participants	Key Reference(s)
sIBM
NCT01925209 (RESILIENT Core)	IIb/III	Completed	Sporadic Inclusion Body Myositis (sIBM)	LBM ↑; FM NC/↓; 6MWD No change; sIFA ↔/↑ (dose-dependent)	251	10
NCT02250443 (RESILIENT Ext.)	II/III	Terminated	Sporadic Inclusion Body Myositis (sIBM)	LBM ↑; 6MWD ↓ (all groups)	10 (from this specific report) / 211 (overall ext.)	5
Sarcopenia
NCT02333331 (CBYM338E2202)	II	Completed	Sarcopenia (Age-Related Muscle Loss)	LBM ↑; FM ↓; SPPB/6MWD/Gait Speed No change vs PBO+Ex	159 (completed) / 217 (enrolled)	6
NCT02468674 (Extension of NCT02333331)	II	Completed	Sarcopenia	LBM changes likely sustained; Functional outcomes likely similar to core	N/A from snippets	74
Obesity / T2DM
NCT03723134 (Heymsfield 2021)	II	Completed	Obesity and Type 2 Diabetes	LBM ↑ (3.6%); FM ↓ (-20.5%); HbA1c ↓ (-0.76%)	75	15
NCT05616013 (BELIEVE)	IIb	Completed Enrollment (Results mid-2024)	Overweight/Obesity (non-diabetic)	Primary: Body Weight Change. Secondary: Fat Mass, Lean Mass, etc.	~500	22
NCT06643728 (TRIUMPH / J4Z-MC-GIDF)	II	Recruiting	Obesity/Overweight (without T2D)	Efficacy/Safety of Bimagrumab +/- Tirzepatide	240	32
NCT06901349 (TRIUMPH / J4Z-MC-GIDI)	II	Not yet recruiting (Starts Jun 2025)	Obesity/Overweight with T2D	Efficacy/Safety of Bimagrumab +/- Tirzepatide	180	33
COPD
NCT01669174	II	Completed	COPD with Muscle Wasting/Cachexia	TMV ↑; 6MWD No change	67	36
Hip Fracture
NCT03336375	IIa/b	Completed	Hip Fracture Recovery (Older Adults)	LBM ↑; Mobility/Function No change	N/A from snippets	44
Disuse Atrophy
NCT01524041	II	Completed	Muscle Wasting due to Prolonged Disuse	TMV recovery ↑; Intermuscular Adipose Tissue ↓	N/A from snippets	44
Mechanical Ventilation
NCT01868685	II	Phase 2	Mechanical Ventilation / ICU Acquired Weakness	N/A from snippets	N/A from snippets	43
Healthy Volunteers / PK/PD
NCT01230410	I	Completed	Healthy Volunteers & Myostatin-Related Muscle Atrophy	Safety, PK, PD	N/A from snippets	[User Query]
NCT01420326	I	Completed	Healthy Volunteers (Multiple Ascending Doses)	Safety, PK, PD	N/A from snippets	[User Query]
NCT06890611	I	Planned (Starts Apr 2025)	Healthy Participants	Bioavailability of SC Bimagrumab	N/A from snippets	27

LBM = Lean Body Mass; FM = Fat Mass; TMV = Thigh Muscle Volume; 6MWD = 6-Minute Walk Distance; SPPB = Short Physical Performance Battery; sIFA = sporadic Inclusion Body Myositis Functional Assessment; PBO+Ex = Placebo + Exercise/Diet counseling. Status and participant numbers are based on available snippets and may have been updated.

8. Safety and Tolerability Profile

Bimagrumab has been administered to over 1,000 patients across more than 20 clinical studies and has generally demonstrated an acceptable safety and tolerability profile.[22][ Adverse events (AEs) have been mostly mild to moderate in severity.]

8.1. Overview from Pooled Analyses and Multiple Studies

[Across various studies and patient populations, some common AEs have emerged:]

• Muscle-related symptoms: Muscle spasms or involuntary muscle contractions are frequently reported, particularly in bimagrumab-treated groups compared to placebo.[5] These are thought to be related to the rapid muscle tissue accretion induced by the drug.[62]
• Gastrointestinal issues: Diarrhea is another commonly reported AE, often more frequent in bimagrumab groups.[5] Nausea has also been noted.[15]
• Skin-related events: Rash and acne have been observed, believed to be due to the presence of ActRII on hair follicles and skin.[5]
• Falls: Particularly in studies involving older adults or patients with muscle weakness (e.g., sIBM, sarcopenia), falls were frequently reported across both bimagrumab and placebo groups, often being the most common AE overall, reflecting the underlying condition of the participants.[7]
• Transient elevations in enzymes: Early, transient elevations in levels of serum lipase, amylase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and γ-glutamyl transferase (GGT) have been observed in some studies, particularly in the bimagrumab group, tending to subside after the first few doses.[15]

Serious adverse events (SAEs) have generally been comparable between bimagrumab and placebo groups in larger studies, and deaths reported in trials have typically not been considered related to the study drug by investigators.[5][ Discontinuation rates due to AEs have varied but have often been relatively low.]

8.2. Specific Adverse Event Profile in Key Indications

8.2.1. Sporadic Inclusion Body Myositis (sIBM)

• RESILIENT Study (NCT01925209): At week 52, at least one AE was reported by 100% of participants in each bimagrumab group and 98% in the placebo group.[7] Falls were the most frequent AE overall (76-87% across bimagrumab doses, 84% placebo). AEs more frequent with bimagrumab included muscle spasms (e.g., 51% in 10mg/kg group vs 21% placebo) and diarrhea (e.g., 52% in 10mg/kg group vs 18% placebo).[7] SAEs were reported by 17-33% across bimagrumab doses and 32% in the placebo group. No significant adverse cardiac effects were noted.[7]
• Long-Term Extension (NCT02573467, NCT02250443): The most frequently reported AEs (>5% incidence) in the pooled bimagrumab group were diarrhea (14.7%), muscle spasm (9.6%), and rash (5.1%).[5] In an open-label extension (N=10), common AEs were muscle spasms and falls (both 90%), diarrhea (60%), acne, and skin eruption (both 50%).[12] Three discontinuations due to AEs (myocardial infarction, esophageal carcinoma, dementia) were not considered treatment-related.[12]

8.2.2. Sarcopenia

• NCT02333331 (Rooks et al. 2020): Bimagrumab 700 mg was generally safe and well-tolerated. Most frequent AEs were falls, involuntary muscle contractions, and diarrhea. Muscle spasms and diarrhea were more frequent with bimagrumab. Most AEs were mild/moderate. Five discontinuations due to AEs (4 bimagrumab, 1 placebo). No SAEs in the bimagrumab group were considered drug-related.[6] The Novartis patient summary (CBYM338E2202) reported AE-related discontinuations as 5% (70mg), 0% (210mg), 4% (700mg), and 2% (placebo).[9]

8.2.3. Obesity and Type 2 Diabetes

• NCT03723134 (Heymsfield et al. 2021): AEs were reported by 83.8% of bimagrumab patients and 81.6% of placebo patients.[15]
• [Most frequent AEs in bimagrumab group: diarrhea (41%), muscle spasms (41%), upper respiratory tract infection (16%), increased lipase (11%), nausea (11%). Diarrhea was most frequent after the first dose and diminished.]
• [SAEs: 3 patients (8%) in bimagrumab group (elevated lipase/epigastric pain/cholelithiasis; pancreatitis; pneumonia) and 3 patients (8%) in placebo group.]
• AEs leading to discontinuation: 5 patients in bimagrumab group (pancreatitis, H. pylori[ infection, muscle spasms [2 patients], increased lipase/abdominal pain/cholelithiasis), none in placebo.]
• [Transient elevations in liver enzymes, lipase, and amylase were noted, mostly after the first dose. Decreased FSH and urate, and increased creatine kinase were observed with bimagrumab.]

8.2.4. Healthy Older and Obese Adults (Phase I)

• Rooks et al. (2017, pub. 2020 JCSM; NCT01230410 / NCT01420326 likely precursors): Bimagrumab was safe and well-tolerated.[50]
• [Older adults: Most common AEs were upper respiratory tract infection, rash, and diarrhea (each 19%). Muscle spasms/myalgia in 25% (bimagrumab) vs 0% (placebo).]
• [Obese adults: Most common AEs were muscle spasms and rash (both 63%). Muscle spasms in 83% (bimagrumab) vs 0% (placebo).]
• [AEs were mostly mild, transient, and resolved spontaneously. No discontinuations due to AEs or deaths. No clinically significant ECG changes.]

8.3. Effects on Pituitary Hormonal Axes

A study by Garito et al. (2018) investigated the effects of bimagrumab on pituitary neurohormonal axes in healthy volunteers.[125] The study [15][ noted that patients treated with bimagrumab had decreased levels of follicle-stimulating hormone (FSH) and urate, and increased levels of creatine kinase. A comprehensive review of Garito et al. would be needed for full details on ACTH, cortisol, TSH, fT4, GH, IGF-1, LH, testosterone, estradiol, and prolactin. The general safety profile across trials has not highlighted major, persistent hormonal disturbances as a primary concern leading to discontinuation of overall programs, though specific changes like decreased FSH warrant noting.]

9. Regulatory Status

[Bimagrumab has received certain regulatory designations acknowledging its potential in specific unmet medical need areas, though it is not yet an approved medication.]

9.1. FDA Breakthrough Therapy Designation

On August 20, 2013, Novartis announced that the U.S. Food and Drug Administration (FDA) had granted Breakthrough Therapy designation to bimagrumab (BYM338) for the treatment of sporadic inclusion body myositis (sIBM).[1][ This designation was based on promising Phase II study results suggesting substantial benefit over available therapy for sIBM. However, as the subsequent Phase IIb/III RESILIENT trial did not meet its primary endpoint, this designation did not lead to an accelerated approval for this indication.]

9.2. Orphan Drug Designations

• Sporadic Inclusion Body Myositis (sIBM):
• FDA: Bimagrumab received orphan drug designation from the FDA for sIBM. While snippet [123][ did not directly confirm the date, other sources indicate this was granted around August 1, 2012 [User Query]. The sponsor was Novartis Pharmaceuticals Corporation.]
• EMA: Bimagrumab (BYM338) received orphan designation (EU/3/13/1173) from the European Medicines Agency (EMA) for the treatment of inclusion body myositis.[4][ The sponsor was Novartis Europharm Limited. The designation was granted on September 12, 2013. The status of this designation would likely be impacted by the discontinuation of development for sIBM.]

[No marketing authorizations have been granted for bimagrumab by the FDA or EMA for any indication to date.]

10. Discussion and Future Perspectives

[Bimagrumab's journey is a compelling case study in pharmaceutical development, characterized by initial promise in one therapeutic area, subsequent setbacks, and strategic repositioning based on unexpected but significant clinical observations. Originally pursued for its muscle-building potential in devastating conditions like sIBM and sarcopenia, the consistent failure to translate increased muscle mass into meaningful functional improvements was a critical learning point. This disconnect underscores the complexity of muscle pathophysiology in these diseases, where factors beyond mere muscle bulk (e.g., muscle quality, innervation, inflammatory milieu, and underlying degenerative processes) are crucial determinants of function. Simply making muscles larger via ActRII blockade did not suffice to overcome these multifaceted deficits.]

The serendipitous and consistent finding of significant fat mass reduction, coupled with lean mass preservation or even increase, across multiple studies, became the cornerstone of bimagrumab's revival.[13] This unique "body recompositioning" effect is highly attractive in the context of obesity and T2DM management. Current obesity treatments, including highly effective GLP-1 receptor agonists, often lead to a loss of lean muscle mass alongside fat loss, which can be detrimental to long-term metabolic health, physical function, and can contribute to weight regain.[29][ Bimagrumab's ability to potentially counteract this muscle loss, or even build muscle while promoting fat reduction, offers a distinct advantage and a strong rationale for its current development by Eli Lilly.]

The ongoing TRIUMPH program, particularly the trials combining bimagrumab with tirzepatide, will be pivotal.[23][ If these combinations demonstrate superior "quality" of weight loss (i.e., greater fat loss with muscle preservation/gain) and favorable metabolic outcomes compared to incretin monotherapy, bimagrumab could carve out a significant niche. The focus on older adults with obesity (NCT06009707) is also strategically sound, as this population is particularly vulnerable to sarcopenic obesity and the adverse consequences of muscle loss during weight reduction efforts.]

The emerging data on potential positive effects on bone metabolism further enhances bimagrumab's profile.[40][ If confirmed in human trials, this could offer an additional benefit, particularly for postmenopausal women or older individuals at risk of osteoporosis, who are also often candidates for weight loss therapies.]

Challenges remain. The long-term safety of sustained ActRII blockade, especially concerning potential off-target effects or unforeseen consequences of chronic muscle anabolism and fat modulation, needs continued scrutiny in larger, longer trials. The optimal dosing, route of administration (IV vs. SC), and frequency for obesity indications are still being refined. The immunogenicity profile, while thus far appearing manageable with low rates of non-neutralizing ADAs [15][, will require ongoing monitoring. Furthermore, the commercial landscape for obesity is becoming increasingly competitive, and bimagrumab will need to demonstrate clear differentiation and value, likely as part of a combination strategy, to succeed.]

11. Conclusion

[Bimagrumab is a human monoclonal antibody targeting activin type II receptors (ActRIIA/B) that has transitioned from a primary focus on muscle-wasting diseases to a promising candidate for obesity and type 2 diabetes. Its potent ability to increase lean body mass and, more strikingly, reduce fat mass, including visceral and hepatic fat, while improving metabolic parameters like insulin sensitivity and HbA1c, forms the basis of its current development by Eli Lilly.]

[While initial efforts in sIBM and sarcopenia were hampered by a lack of translation from muscle mass gains to functional improvements, these studies were instrumental in revealing bimagrumab's profound effects on body composition. The ongoing clinical trials, particularly those evaluating bimagrumab in combination with incretin-based therapies, aim to leverage its unique muscle-preserving and fat-reducing properties to achieve higher quality weight loss and better long-term metabolic outcomes. The safety profile observed to date appears generally acceptable, though continued monitoring in larger populations is essential. If future trials confirm its efficacy and safety, particularly in combination regimens, bimagrumab could become an important therapeutic option for individuals with obesity and related cardiometabolic conditions, addressing not just the quantity but also the quality of weight loss.]

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