Myostatin, a member of the transforming growth factor beta (TGF-β) superfamily, is a secreted protein that negatively regulates skeletal muscle mass in animals and humans throughout the lifecycle. Myostatin acts via the activin receptor type II (mainly via ActRIIB) and its proposed signaling is through the SMAD 2/3 pathway, which is involved in the inhibition of protein synthesis, and myocyte differentiation and proliferation. Myostatin inhibition or genetic ablation increases muscle mass and strength (Lee et al 2005, Lee and McPherron 2001, Whittemore et al 2003).
Bimagrumab (BYM338) or is a monoclonal antibody developed to bind competitively to activin receptor type II (ActRII) with greater affinity than myostatin or activin, its natural ligands. Bimagrumab is a fully human antibody (modified IgG1, 234-235-Ala-Ala, λ2) which binds to the ligand binding domain of ActRII, thereby preventing binding and subsequent signaling of its ligands, including myostatin and activin that act as natural inhibitors of skeletal muscle growth. Myostatin, a member of the transforming growth factor beta (TGF-β) superfamily, is a secreted protein that negatively regulates skeletal muscle mass in animals and humans. Myostatin signaling occurs at ActRII and its proposed mechanism of action is through the Smad 2/3 pathway to inhibit protein synthesis and myocyte differentiation and proliferation. Myostatin inhibition or genetic ablation increases muscle mass and strength (Lee et al 2005; Lee and McPherron 2001; Whittemore et al 2003).
Bimagrumab is cross-reactive with human and mouse ActRIIB and effective on human, cynomolgus, mouse and rat skeletal muscle cells. Bimagrumab is formulated for intravenous (i.v.) administration.
Myostatin, ActRIIB Receptor and ActRIIB Receptor Antibodies
Bimagrumab, also known as BYM338, is a human monoclonal antibody developed to bind competitively to activin receptor type II B (ActRIIB) with greater affinity than myostatin, its principal natural ligand. Bimagrumab is disclosed in WO2010/125003, which is incorporated by reference herein in its entirety. Myostatin, a member of the transforming growth factor beta (TGF-β) superfamily, is a secreted protein that negatively regulates skeletal muscle mass in animals and humans, throughout the lifecycle. Myostatin signaling occurs at ActRIIB and its proposed mechanism of action is through the Smad 2/3 pathway to inhibit protein synthesis and myocyte differentiation and proliferation. The absence of myostatin in developing animals and humans results in a hypermuscular phenotype with an increased number and size of muscle fibers. Reducing the level of myostatin postpartum results in the hypertrophy of skeletal muscle due to an increase in the size of existing myofibers. In the adult, myostatin is produced in skeletal muscle and circulated in the blood in part as a latent inactive complex.
Consistent with the role of myostatin as an endogenous inhibitor of skeletal muscle mass, bimagrumab dramatically increased skeletal muscle mass in preclinical murine models of disuse and steroid-induced atrophy and in toxicology studies with healthy cynomolgus monkeys. In addition, the increased mass in mouse and rat resulted in a corresponding increase in muscle strength (force production). Following i.v. and s.c. administration to mice and cynomolgus monkey, bimagrumab showed a consistent IgG1 pharmacokinetic (PK) profile with target mediated drug disposition (TMDD) and was well tolerated.
An analysis of the six dose levels of the first in human, single ascending dose study, suggests that single i.v. doses of 0.1, 0.3, 1, 3, 10 and 30 mg/kg of bimagrumab are safe, well tolerated, and produce a PK profile that is predictable from modeled preclinical data. At four weeks doses of 3-30 mg/kg result in a measurable increase in thigh muscle volume of 2.7-5.2% from baseline over placebo.
Role of Body Composition in the Determination of Mobility and Hip Fracture Risk
It is well established that even in the healthy elderly, declines in muscle strength cannot fully be explained by loss of skeletal muscle mass (Frontera et al 2000, Vandervoort 2002). Further, maintenance or even gains in muscle mass do not necessarily prevent the loss of muscle strength (Goodpaster et al 2006); and the force produced by skeletal muscle per unit of muscle mass decreases with advancing age (Goodpaster et al 2006; Brooks and Faulkner 1994). While these facts do not diminish the importance of maintaining muscle mass during aging, they do underscore that there is more than the loss of muscle tissue to understand and treat to address age-related decline in mobility.
In addition to loss of muscle mass, there is also infiltration of muscle tissue by lipids and other non-contractile components. Emerging evidence suggests that skeletal muscle lipid content directly influences muscle strength and mobility function (Goodpaster et al 2001; Visser et al 2002) as well as the increased risk of future mobility loss in older men and women (Visser et al 2005). Beavers et al (2013) showed that high/increasing inter-muscular adipose tissue (IMAT) area in the thigh, as well as the decreasing total thigh muscle area, is an important predictor of walking speed decline. Baseline thigh IMAT predicts the annual gait speed decline in both men and women. In longitudinal analyses, changes in thigh IMAT and total thigh muscle are the only body-composition measures that predict gait-speed decline in both men and women (FIG. 1).
Age-related adipose infiltration of muscle tissue as well as reduced muscle strength combined with reduced lower extremity performance confer increased risk of outcomes, such as loss of mobility, falls, and skeletal fractures, including hip fracture (Lang et al 2010).
Mechanisms Underlying the Impact of Intermuscular Fat Mass on Skeletal Muscle
Mechanisms underlying the links between increased IMAT and walking speed decline may include the endocrine nature of adipose tissue. Excessive fat accumulation in the muscle may be associated with excessive secretion of proinflammatory cytokines (Fantuzzi et al 2005). Chronic inflammation is associated with lower muscle strength (Visser et al 2002), and predicts disability in older adults (Verghese et al 2011), potentially as a result of impaired muscle-fiber contractility (Pahor & Kritchevsky 1998). Excessive adiposity may also down-regulate the anabolic actions of insulin, testosterone and growth hormone (Chevalier et al 2006, Schaap et al 2005, Waters et al 2008), all of which may contribute to muscle loss and functional decline.
Changes of Body Composition After Hip Fracture
Clinical observations indicate that elderly subjects sustaining a hip fracture and subsequently undergoing major surgery for fracture repair are subject to additional rapid changes in body composition, in a vicious cycle due to exacerbating postoperative mobility limitations (Wehren et al 2005; D'Adamo et al 2014). The immediate or rapidly evolving changes include neurogenic muscle weakness, skeletal muscle loss (disuse atrophy), increase in fat mass and accelerated bone loss (D'Adamo et al 2014, Fox et al 2000, Daguet et al 2011). Importantly, these changes can be apparent from as early as Day 10 and can reach maximum by approximately 2 months after surgery.
Collectively, the acute complication of frailty and fragility—hip fracture—further worsens body composition that contributed to the occurrence of the complication in the first place. In addition, it diminishes the rate and magnitude of postoperative functional recovery, which in turn increases the risk of mobility-related complications (injurious falls, fractures, and related re-hospitalizations). The net result of this vicious cycle is the alarming mortality rate of patients after hip fracture, ranging from 8.4-36% during the first year (Abrahamsen et al 2009).
Early Need for Preventing Postoperative Complications
Importantly, the bulk of complications tend to occur in the first 6 months after surgery increasing the need for measures that can both accelerate and increase the magnitude of general mobility to prevent mobility-related complications, re-hospitalizations and ultimately decrease the fairly high mortality rate in this population.
Unmet Medical Needs
Current standard of care encompassing dietary measures (protein, vitamin D and Ca supplementation), early post-op mobilization and resistance training combined with antiresorptive therapies leave considerable room for optimization. Compliance to rehabilitation is limited and the effect of current pharmacological treatment (bisphosphonates, denosumab, vitamin D) is relatively small and slow in onset.
Requirements to the Ideal Pharmacological Agent
In light of these demands, there is a definite unmet need for a pharmacological agent that can accelerate and boost the efficacy of current standard of care without posing significant safety issues in this frail population with common presence of comorbidities. Thus, the ideal drug candidate would fulfill the following requirements:                A. Can rapidly achieve maximal benefits in terms of reversing the adverse alterations of body composition        B. Can induce muscle mass changes that are clinically meaningful, which can translate into increases in muscle strength and physical performance        C. Can substantially reduce fat infiltration of skeletal muscle thereby improving muscle quality and improvement of muscle strength and mobility        D. No significant safety or tolerability issues limiting the delivery of the intended 6 months treatment        
Evidence that Bimagrumab has the Best Chances to Deliver on those 3 Requirements
Applicant has evidence that of the current approaches to prevent myostatin signaling (anti-myostatin antibody, soluble activin receptor type IIB, and antibody against cell-bound activin type II receptors), activin receptor antagonism is providing the best balance between efficacy and safety (highest benefit/risk ratio), hence being able to induce rapid and substantial muscle growth with concomitant decreases in inter-muscular adipose tissue (i.e. improved muscle quality), which are both contribute directly to improvements of muscle contraction and ultimately mobility.
Preclinical Evidence
ActRII Blockade Induces the Largest Increases in Muscle Mass
The applicant has investigated whether inhibition of other ligands that signal via ActRII were playing a significant role in the hypertrophy induced by bimagrumab by comparing the antibody with an inhibitor that neutralizes only myostatin in the circulation (Lach-Trifilieff 2014). For this purpose a stabilized myostatin propeptide (D76A) was used, which was validated to be a myostatin-specific inhibitor. Both bimagrumab and the myostatin-propeptide were administered weekly for 5 weeks to young SCID mice; bimagrumab was administered at 10 mg/kg, and the myostatin propeptide was administered at 30 mg/kg.
Body weight increased throughout the treatment period, reaching significance upon bimagrumab treatment only (36% versus 15% for myostatin propeptide). The 15% increase induced by the myostatin propeptide is in line with that described in a prior publication (Trendelenburg et al 2009); the ActRII antibody was over 2-fold more efficacious (FIG. 2, left panel). Muscle weights increased significantly in most muscles examined, with more pronounced increases demonstrated with bimagrumab (FIG. 2, middle panel). This greater increase in total muscle mass was further corroborated by analyzing the fiber cross-sectional area distribution, demonstrating that the factors were acting by increasing fiber diameter, as opposed to fiber number (FIG. 2, right panel).
The considerably higher efficacy of activin type II receptor blockade versus neutralization of the circulating myostatin pool clearly demonstrates that there are ligands beyond myostatin that are able to promote muscle loss via activin type IIB receptors.
The third approach to blocking myostatin signaling is by the soluble activin type IIB receptor trap/decoy (ActRIIB-Fc) that can capture all possible ligands of this receptor in the circulation, including myostatin. The efficacy of this approach in terms of induction of muscle growth is probably comparable with that of bimagrumab. Results from a Phase 2 study with the ActRIIB-Fc (ACE-031) on boys with Duchenne muscular dystrophy showed an increase in LBM and attenuation of declines in TMV and the six-minute walk distance (Campbell et al 2012). However, observations of reversible nosebleeds and skin telangiectasias in the healthy volunteer MAD study as well as in the Phase 2 muscular dystrophy study have led to the termination of these trials and the clinical development of this pharmacological approach (Smith and Lin 2013). The fundamental difference of bimagrumab from this latter approach is that it only blocks ligand trafficking through receptors on the target tissue (e.g. muscle) and does not eliminate the opportunity of circulating ligands from reaching their own alternative receptors to exert effects which may be critical for safety (e.g. the signaling of BMPs through ActRIIB located on skeletal muscle will be blocked but BMP can reach and signal through their own BMP receptors, which is not an option with the decoy that prevents action).
Although the activin receptor IIB trap can evoke muscle volume increases comparable with those evoked by blockade of the membrane-bound ActRIIB, and results from a Phase 2 study with the ActRIIB-Fc (ACE-031) in Duchenne muscular dystrophy boys showed an increase in lean body mass and attenuation of declines in thigh muscle volume and six minute walk distance (Campbell et al 2012), the observation of reversible nosebleeds and skin telangiectasias in the healthy volunteer MAD study as well as in the Phase 2 muscular dystrophy study has led to the termination of these trials (Smith and Lin 2013). The fundamental difference between the two approaches is that while the ActRIIB-Fc captures and neutralizes all possible ligands of the receptor in the circulation preventing their binding to other possible target receptors, bimagrumab only blocks ligand trafficking through the ActRIIB on target tissue (e.g. muscle). For example BMPs that bind to ActRIIB may continue to signal through their BMP receptors.
Responsiveness to ActRII Inhibition in Younger and Older Animals
Animal studies demonstrated that a single administration of bimagrumab at 20 mg/kg I.V. significantly increased body weight over 2-3 weeks in both 6 and 21 month old rats pointing to promotion of anabolic muscle actions. This was indeed confirmed by MRI-based evaluation of hind leg muscle volume, which demonstrated that a single dose bimagrumab administration promoted muscle hypertrophy in both 6 and 21 month old rats (FIG. 3).
The hypertrophic action of bimagrumab was prominent 2 weeks after the single administration of the compound, where it reached a 13-15% increase over the control group. Importantly, the maximal response to bimagrumab was similar in 6 and 21 month old rats, demonstrating that old animals are still equally responsive to ActRII inhibition and able to generate the same volume increase in skeletal muscle as young animals when compared in a parallel setting.
Clinical Evidence
Reversal of Disuse Atrophy in Healthy Young Volunteers: Full-Length Leg Casting Model
The applicant has evidence that bimagrumab is capable of triggering rapid reversal of disuse-associated muscle loss in young healthy volunteers (average age 24 years) who underwent full-length casting of one leg for 2 weeks. This immobilization (i.e. deactivation of muscles) induced rapid muscle loss of ˜5% in the course of 2 weeks. A single i.v. dose of bimagrumab (30 mg/kg) yielded almost full recovery (to −0.8% of pre-casting) of thigh muscle volume within 2 weeks after cast removal, whereas it took seemingly 12 weeks to return to baseline for the group that recovered muscle mass just by returning to normal daily activities (no targeted rehabilitation program). This observation clearly demonstrates the rapid onset of action of ActRII blockade by bimagrumab as reflected by increases in skeletal muscle mass during the early period of remobilization.
Further to the normalization, thigh muscle mass continued to increase from Week 2 to Week 12 after cast removal ending with approximately 5% more volume than the group not receiving bimagrumab (FIG. 4). Hence, all in all a total of ˜10% increase in thigh muscle volume to a single intravenous dose of the drug could be evidenced over a 12-week observation period.
Regaining Muscle Mass in Sarcopenic Patients
In a recently completed study on elderly patients with sarcopenia and physical frailty, a single dose of 30 mg/kg intravenous bimagrumab could trigger thigh muscle volume increases, which were comparable with the magnitude of muscle growth seen in the experimental model of disuse atrophy, i.e. >8% increase from baseline in eight weeks (FIG. 5). This increase in mass preceded a significant increase in 6 minute walking distance (6 MWD) in the most mobility limited patients, those who started with 6 MWD<300 m (+76 meters, p=0.02).
Accordingly, bimagrumab was able to induce comparable responses regardless whether it was administered to young subjects with disuse atrophy or elderly subjects who have substantial muscle atrophy due to aging.
Marked Decreases in Intermuscular Adipose Tissue (IMAT)
In a randomized, six treatment, double blind, placebo controlled, single ascending dose design trial on 49 healthy women and men up to 65 years of age single i.v. doses of 0.1, 0.3, 1, 3, 10, and 30 mg/kg were administered in a staggered fashion. In this trial, in addition to safety, tolerability and pharmacokinetics, effects of bimagrumab on thigh muscle volume as well as intermuscular adipose tissue measured by magnetic resonance imaging were also assessed. As shown in FIG. 6, bimagrumab induced dose-dependent decreases in inter-muscular adipose tissue. The effect of 10 and 30 mg/kg was comparable at Week 10 after the drug injection, both exceeding 10% decrease from baseline.
Bimagrumab Treatment is Associated with Significant Improvements in Functional Performance
As illustrated by data from patients with sporadic inclusion body myositis, a progressive muscle degenerative disease, the rapid increases in lean body mass (>5% from baseline) induced by a single injection of bimagrumab (30 mg/kg) are able to trigger significant increases in physical performance (FIG. 7). Importantly, improvement of functional following muscle mass increase require a period of lag time possibly reflecting the structural/functional remodeling of skeletal muscle before becoming fully matured and ready to serve increased contractile activities.
Collectively, bimagrumab seems to possess the properties of a capable pharmacological agent that can reverse both age-related changes of body composition as well as the reactive changes (disuse atrophy) following hip fracture surgery. The applicant also has growing evidence arguing that the drug candidate can trigger functional improvement in muscle wasting diseases. Thus, with relatively rapid and pronounced effects on both muscle and IMAT, bimagrumab offers an innovative approach to accelerate recovery after hip fracture.