Dimitris A Papanicolaou’s research while affiliated with United States Naval Research Laboratory and other places

Background: Bimagrumab is a human monoclonal antibody binding to the activin type II receptor with therapeutic potential in conditions of muscle wasting and obesity. This phase I study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of various dose regimens of bimagrumab and routes of administration in healthy older adults. Methods: This was a randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose study in older adult men and women (aged ≥ 70 years, body mass index [BMI] 18-34 kg/m2) with stable health and diet. The study comprised seven treatment groups (Cohorts 1-7). Participants received bimagrumab or placebo treatment every 4 weeks for three doses (Cohorts 1 [700 mg] and 2 [210 mg] intravenous infusion; Cohorts 3 [1500 mg] and 4 [525 mg] subcutaneous infusion), or every week for 12 doses (Cohorts 5 [300 mg], 6 [150 mg], and 7 [52.5 mg] subcutaneous bolus injection) and were followed up until week 20. Blood samples were collected for bimagrumab PK analysis. PD were assessed by dual energy X-ray absorptiometry to quantify the change from baseline in lean body mass (LBM) and fat body mass (FBM) compared with placebo. Safety was assessed throughout the study. Results: Eighty-four of 91 (92.3%) randomized participants (mean age 74.5 years; BMI 28.0 kg/m2) completed the study. Demographic characteristics were generally balanced across the groups. A target-mediated drug disposition profile was observed following both intravenous and subcutaneous administration. The absolute subcutaneous bioavailability was estimated at approximately 40%. LBM increased by 4-6% (1.5-2 kg) from baseline throughout the treatment period for intravenous and subcutaneous regimens, except for the 52.5 mg subcutaneous dose, which did not differ from placebo. Concurrently, there was a decrease in FBM (approximately 2-3 kg) for all intravenous and subcutaneous regimens. Bimagrumab was generally safe and well tolerated; adverse events were mostly mild to moderate in severity. Conclusions: Dose levels of bimagrumab administered weekly subcutaneously resulted in PK profiles and PD effects comparable with monthly intravenous dosing, which supports the feasibility of the subcutaneous route of administration for bimagrumab for future clinical development.

Background and objectives Limited data suggests that quantitative MRI (qMRI) measures have potential to be used as trial outcome measures in sporadic inclusion body myositis (sIBM), and as a non-invasive assessment tool to study sIBM muscle pathological processes. Our aim was to evaluate changes in muscle structure and composition using a comprehensive multi-parameter set of quantitative MRI (qMRI) measures and to assess construct validity and responsiveness of qMRI measures in people with sIBM. Methods Prospective observational cohort study with assessments at baseline (n=30) and 1-year (n=26). qMRI assessments: thigh muscle volume (TMV), inter/intramuscular adipose tissue (IMAT), muscle fat fraction (FF), muscle inflammation (T2 relaxation time), IMAT from T2* relaxation (T2*-IMAT), intermuscular connective tissue from T2* relaxation (T2*-IMCT), and muscle macromolecular structure from the magnetization transfer ratio (MTR). Physical performance assessments: sIBM Physical Functioning Assessment (sIFA), 6-minute walk distance, and quantitative muscle testing of the quadriceps. Correlations assessed using the Spearman correlation coefficient. Responsiveness assessed using the standardised response mean (SRM). Results After one year, we observed a reduction in TMV (6.8%, p<0.001) and muscle T2 (6.7%, p=0.035), an increase in IMAT (9.7%, p<0.001), FF (11.2%, p=0.030), connective tissue (22%, p=0.995) and T 2 *-IMAT (24%, p<0.001), and alteration in muscle macromolecular structure (ΔMTR=-26%, p=0.002). Decrease in muscle T2 correlated with increase in T2*-IMAT (r=-0.47, p=0.008). Deposition of connective tissue and IMAT correlated with deterioration in sIFA (r=0.38, p=0.032; r=0.34, p=0.048; respectively), while decrease in TMV correlated with decrease in QMT (r=0.36, p=0.035). The most responsive qMRI measures were T2*-IMAT (SRM=1.50), TMV (SRM=-1.23), IMAT (SRM=1.20), MTR (SRM=-0.83) and T2 relaxation time (SRM=-0.65). Discussion Progressive deterioration in muscle quality measured by qMRI is associated with decline in physical performance. Inflammation may play a role in triggering fat infiltration into muscle. qMRI provides valid and responsive measures that might prove valuable in sIBM experimental trials and assessment of muscle pathological processes. Classification of evidence This study provides Class I evidence that qMRI outcome measures are associated with physical performance measures in sIBM.

Background Older adult patients (ie, those aged ≥60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. Methods This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15–35 kg/m² who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. Findings Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0·2 kg [SD 2·0]) in the bimagrumab 210 mg group (1·9 kg [1·7]; p<0·0001) and in the bimagrumab 700 mg group 2·8 kg [2·2]; p<0·0001) but not in the bimagrumab 70 mg group (0·6 kg [SD 2·2]; significance not assessed). Changes in habitual gait speed and short physical performance battery scores between baseline and week 24 were not significantly different across the treatment groups, suggesting no enhancement of physical recovery with bimagrumab over placebo. Bimagrumab was safe and well tolerated. The most frequently reported treatment-emergent adverse events were falls (six [18%] of 34 participants in the bimagrumab 70 mg group; 12 [17%] of 69 participants in the bimagrumab 210 mg group; 14 [19%] of 75 participants in the bimagrumab 700 mg group; and 13 [18%] of 72 participants in the placebo group), muscle spasms (two [6%] in the bimagrumab 70 mg group; 17 [25%] in the bimagrumab 210 mg group; 12 [16%] in the bimagrumab 700 mg group; and six [8%] in the placebo group), and arthralgia (five [15%] in the bimagrumab 70 mg group; six [9%] in the bimagrumab 210 mg group; nine [12%] in the bimagrumab 700 mg group; and five [7%] in the placebo group). Six deaths were reported during the study, none of which were considered by investigators as related to the study drug. Interpretation Bimagrumab treatment for 24 weeks led to dose-dependent, significant increases in lean body mass in older patients recovering from hip fracture surgery when compared with placebo. However, no functional benefit was observed in recovery of mobility or lower extremity function following bimagrumab treatment compared with placebo. Funding Novartis Pharma.

Objective: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis. Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT) were invited to join an extension study. Individuals continued on same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab, or matching placebo administered as intravenous infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. Results: Between 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) 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 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). Conclusion: Extended 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. Classification of evidence: This 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. Clinical trial registration: Registered at ClinicalTrials.gov: NCT02573467.

Importance The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, −4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001). Conclusions and Relevance This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise. Trial Registration ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25

Background: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. Methods: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. Findings: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. Interpretation: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. Funding: Novartis Pharma.

Background Bimagrumab is a human monoclonal antibody inhibitor of activin type II receptors (ActRII), with anabolic action on skeletal muscle mass by blocking binding of myostatin and other negative regulators of muscle growth. Bimagrumab is under evaluation for muscle wasting and associated functional loss in hip fracture and sarcopenia, and in obesity. Bimagrumab also blocks other endogenous ActRII ligands, such as activins, which act on the neurohormonal axes, pituitary, gonads and adrenal glands. Aim To evaluate the effect of bimagrumab on the pituitary‐gonadal and pituitary‐adrenal axes in humans. Methods Healthy men and women, aged 55 to 75 years, received bimagrumab intravenously 10 mg/kg or placebo on Day 1 and Day 29. Pituitary‐gonadal and ‐adrenal function was evaluated with basal hormone measurement and standard gonadotropin releasing hormone (GnRH) and adrenocorticotropic hormone (ACTH) stimulation tests at baseline, Week 8 and at the end of study (EOS) ‐ Week 20. Results At Week 8, follicle‐stimulating hormone (FSH) levels were reduced by 42.16 IU/L (p<0.001) and luteinizing hormone (LH) levels were increased by 2.5 IU/L (p=0.08) over placebo in response to bimagrumab in women but not in men. Effects that were reversible after bimagrumab was cleared. Gonadal and adrenal androgen levels were not affected by exposure to bimagrumab. Conclusion Bimagrumab alters the function of pituitary gonadotroph cells, consistent with blockade of activin on local ActRII. This effect is reversible with clearance of bimagrumab. Bimagrumab did not impact gonadal and adrenal androgen secretion. This article is protected by copyright. All rights reserved.