Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis

Abstract

ObjectiveTo assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).MethodsParticipants (aged 36–85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co–primary outcome measures were 6-minute walk distance (6MWD) and safety.ResultsBetween November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24–104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).ConclusionExtended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.Clinical Trial RegistrationClinicaltrials.gov identifier NCT02573467.Classification of EvidenceThis study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases

“…Several progresses have been made towards this direction, with the identification of key molecular regulators of the myostatin pathway. Moreover, several myostatin modulators have already reached clinical trial phase for a broad range of indications, including muscular dystrophy, sporadic inclusion body myositis (IBM), cachexia, aging-related muscle atrophy, obesity, type 2 diabetes, and SMA [ 102 – 113 ].…”

“…Taking a look at the outcomes of the trials, it emerges that targeting myostatin signaling pathway in humans led to inconsistent increase in muscle mass and strength. Some trials described an increase in thigh muscle volume at Magnetic Resonance Imaging (MRI) between 5 and 9% and improvement in the 6-min walking test [ 112 , 114 ], while other studies did not witness an amelioration in these parameters [ 103 , 107 , 113 , 115 ]. Nonetheless, these effects, though significant, were substantially lower than those seen in mice, in which muscle mass increase spanned between 10 to 30% in case of myostatin-specific compounds [ 97 , 116 – 118 ].…”

Antibody Therapies in Autoimmune Inflammatory Myopathies: Promising Treatment Options

“…The extended treatment period up to 2 years with bimagrumab was well tolerated, but could not reach improvement in mobility [ 92 ]. Patients of the extension study showed an increase of lean body mass, but without any resulting clinical improvement [ 93 ].…”

Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs

“…The apparent prioritization of mass over functional metrics may have been a costly oversight as clinical testing of Bimagrumab consistently demonstrated an ability to improve muscle mass, but not function ( Table 2 ). This was most evident in the 2 largest clinical trials to date for any ActRII attenuator, both of which included 251 subjects with either IBM ( 368-370 ) or hip fracture. The latter trial has yet to be published (see clinicaltrials.gov for results); nevertheless, Bimagrumab failed to improve objective measures of muscle function in the IBM trial that included 6-minute walk distance, isometric quadricep strength, and short physical performance battery tests (eg, gait speed, maintain balance, chair rise time, etc.).…”