Safety, Tolerability, and Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy

Study Overview
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Brief Summary
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The purpose of this study was to determine if BVS857 is safe, tolerable and increases thigh muscle thickness in patients with spinal bulbar and muscular atrophy (SBMA).

Official Title
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A Two-part Placebo-controlled Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy (SBMA)

Conditions
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Spinal and Bulbar Muscular Atrophy

Intervention / Treatment
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* Drug: BVS857
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Genetic diagnosis of SBMA with symptomatic muscle weakness Able to complete 2 minute timed walk Serum IGF-1 level less than or equal to 170 ng/mL Key Exclusion Criteria: Medically treated diabetes mellitus or known history of hypoglycemia History of Bell's palsy Treatment with systemic steroids > 10 mg/day (or equivalent dose); androgens or androgen reducing agents; systemic beta agonists; or other muscle anabolic drugs within the previous 3 months History of cancer, other than non-melanomatous skin cancer Retinopathy Papilledema Other protocol defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BVS857 Part A Open label (Cohort 1)<br>Participants received single doses of 0.01 mg/kg BVS857 intravenously (i.v.) on day 1, 0.01 mg/kg BVS857 subcutaneously (s.c.) on day 15, 0.03 mg/kg BVS857 s.c. on day 29, 0.06 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57. | Drug: BVS857<br>* BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..<br>|
| Experimental: BVS857 Part A double blind (Cohort 2)<br>Participants received single doses of 0.03 mg/kg BVS857 i.v on day 1, 0.03 mg/kg BVS857 s.c. on day 15, 0.06 mg/kg BVS857 s.c. on day 29, 0.10 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57. (BVS857 concentrations differed on days 43 and 57.) | Drug: BVS857<br>* BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..<br>|
| Placebo Comparator: Placebo Part A double blind (Cohort 2)<br>Participants received single doses of matching placebo i.v. on day 1 and matching placebo s.c. on days 15, 29, 43 and 57. | Drug: Placebo<br>* Placebo lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..<br>|
| Experimental: BVS857 Part B open-label (Cohort 4)<br>Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks. | Drug: BVS857<br>* BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..<br>|
| Experimental: BVS857 Part B double blind (Cohort 5)<br>Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks. | Drug: BVS857<br>* BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..<br>|
| Placebo Comparator: Placebo Part B double blind (Cohort 5)<br>Participants received matching placebo i.v. to BVS857 weekly for 12 weeks. | Drug: Placebo<br>* Placebo lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability | Safety was monitored throughout the study. | After 78 days in Part A and after 85 days in Part B. | 
| Number of Mild, Moderate and Severe Adverse Events as a Measure of Safety and Tolerability | Safety was monitored throughout the study. | After 78 days in Part A and after 85 days in Part B. | 
| Mean Percent Change From Baseline in Thigh Muscle Volume in Part B, Cohort 5 | Thigh muscle volume was assessed by magnetic resonance imaging (MRI). Change from baseline was calculated from the ratio of the post-baseline mean value to the baseline mean value: [(Day 85/baseline) - 1)] x 100. A positive change from baseline indicates improvement. | Baseline, Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Score on the Adult Myopathy Assessment Tool (AMAT) in Part B, Cohort 5 | The AMAT rated physical function and muscle endurance, with higher scores indicating better performance. The tool includes 7 timed functional tasks rated on a scale from 0 - 21 and 6 endurance tasks rated on a scale from 0 - 24. The range for the total score was from 0 (worst) to 45 (best). A positive change from baseline indicates improvement. | Baseline, Day 85 | 
| Mean Change From Baseline in Total Lean Body Mass (LBM) in Part B, Cohort 5 | LBM was assessed by dual-energy X-ray (DXA) absorptiometry. A positive change from baseline indicate improvement. | Baseline, Day 85 | 
| Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part A, Cohort 1 | Serum samples were obtained for PK assessment. | Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part A, Cohort 2 | Serum samples were obtained for PK assessment. | Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part A, Cohort 1 | Serum samples were obtained for PK assessment. | Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part A, Cohort 2 | Serum samples were obtained for PK assessment. | Day 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) in Part A, Cohort 1 | Serum samples were obtained for PK assessment. | Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) in Part A, Cohort 2 | Serum samples were obtained for PK assessment. | Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part A, Cohort 1 | Serum samples were obtained for PK assessment. | Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part A, Cohort 2 | Serum samples were obtained for PK assessment. | Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part B, Cohort 4 | Serum samples were obtained for PK assessment. | Days 1: pre-dose, 1, 4, 24, 48 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part B, Cohort 5 | Serum samples were obtained for PK assessment. | Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. | 
| Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part B, Cohort 4 | Serum samples were obtained for PK assessment. | Days 1: pre-dose, 1, 4, 24, 48 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part B, Cohort 5 | Serum samples were obtained for PK assessment. | Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. | 
| Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) in Part B, Cohort 5 | Serum samples were obtained for PK assessment. | Day 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. | 
| Plasma Pharmacokinetics (PK) of BVS857:The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part B, Cohort 4 | Serum samples were obtained for the PK assessment. | Days 1: pre-dose, 1, 4, 24, 48 hours post-dose | 
| Plasma Pharmacokinetics (PK) of BVS857:The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part B, Cohort 5 |  | Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. | 
| Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) | Serum samples were obtained for PK assessment. | Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. | 
| Plasma Pharmacokinetics (PK) of BVS857: The Terminal Elimination Half-life (T1/2) | Serum samples were obtained for PK assessment. | Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. | 
| Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) | Serum samples were obtained for PK assessment. | Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. | 
| Compare Dose Normalized Log-transformed AUCinf Following IV and SC Administrations | Serum samples were obtained for PK assessment. | In Part A: days 1 and 15, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. |