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

Phase 2

Completed

Conditions: Spinal and Bulbar Muscular Atrophy

Interventions: Drug: Placebo
Drug: BVS857

Registration Number: NCT02024932

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 37

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Part B double blind (Cohort 5)	Placebo	Participants received matching placebo i.v. to BVS857 weekly for 12 weeks.
Placebo Part A double blind (Cohort 2)	Placebo	Participants received single doses of matching placebo i.v. on day 1 and matching placebo s.c. on days 15, 29, 43 and 57.
BVS857 Part B open-label (Cohort 4)	BVS857	Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks.
BVS857 Part A Open label (Cohort 1)	BVS857	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.
BVS857 Part A double blind (Cohort 2)	BVS857	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.)
BVS857 Part B double blind (Cohort 5)	BVS857	Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability	After 78 days in Part A and after 85 days in Part B.	Safety was monitored throughout the study.
Number of Mild, Moderate and Severe Adverse Events as a Measure of Safety and Tolerability	After 78 days in Part A and after 85 days in Part B.	Safety was monitored throughout the study.
Mean Percent Change From Baseline in Thigh Muscle Volume in Part B, Cohort 5	Baseline, Day 85	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.

Secondary Outcome Measures

Name	Time	Method
Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part A, Cohort 2	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	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part A, Cohort 2	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	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part A, Cohort 1	Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose	Serum samples were obtained for PK assessment.
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	Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose	Serum samples were obtained for PK assessment.
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	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	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part A, Cohort 1	Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose	Serum samples were obtained for PK assessment.
Mean Change From Baseline in Score on the Adult Myopathy Assessment Tool (AMAT) in Part B, Cohort 5	Baseline, Day 85	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.
Mean Change From Baseline in Total Lean Body Mass (LBM) in Part B, Cohort 5	Baseline, Day 85	LBM was assessed by dual-energy X-ray (DXA) absorptiometry. A positive change from baseline indicate improvement.
Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part B, Cohort 4	Days 1: pre-dose, 1, 4, 24, 48 hours post-dose	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) 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.	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: The Terminal Elimination Half-life (T1/2)	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.	Serum samples were obtained for PK assessment.
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	Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose	Serum samples were obtained for PK assessment.
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	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	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part B, Cohort 4	Days 1: pre-dose, 1, 4, 24, 48 hours post-dose	Serum samples were obtained for PK assessment.
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	Day 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose.	Serum samples were obtained for PK assessment.
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	Days 1: pre-dose, 1, 4, 24, 48 hours post-dose	Serum samples were obtained for the PK assessment.
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)	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.	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf)	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.	Serum samples were obtained for PK assessment.
Compare Dose Normalized Log-transformed AUCinf Following IV and SC Administrations	In Part A: days 1 and 15, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose.	Serum samples were obtained for PK assessment.
Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) 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.	Serum samples were obtained for PK assessment.