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

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)

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).

Study Overview

• Status: Completed
• Conditions: Spinal and Bulbar Muscular Atrophy
• Intervention / Treatment: Drug: BVS857; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Novartis Investigative Site
• Germany
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Italy
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
• United States
  • California
    • Orange, California, United States, 92868
      • Novartis Investigative Site
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BVS857 Part A Open label (Cohort 1); 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; BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..
Experimental: BVS857 Part A double blind (Cohort 2); 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; BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..
Placebo Comparator: Placebo Part A double blind (Cohort 2); 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; Placebo lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..
Experimental: BVS857 Part B open-label (Cohort 4); Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks.	Drug: BVS857; BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..
Experimental: BVS857 Part B double blind (Cohort 5); Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks.	Drug: BVS857; BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..
Placebo Comparator: Placebo Part B double blind (Cohort 5); Participants received matching placebo i.v. to BVS857 weekly for 12 weeks.	Drug: Placebo; Placebo lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Grunseich C, Miller R, Swan T, Glass DJ, El Mouelhi M, Fornaro M, Petricoul O, Vostiar I, Roubenoff R, Meriggioli MN, Kokkinis A, Guber RD, Budron MS, Vissing J, Soraru G, Mozaffar T, Ludolph A, Kissel JT, Fischbeck KH; BVS857 study group. Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial. Lancet Neurol. 2018 Dec;17(12):1043-1052. doi: 10.1016/S1474-4422(18)30320-X. Epub 2018 Oct 15.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2014
• Primary Completion (Actual): April 13, 2016
• Study Completion (Actual): April 13, 2016

Study Registration Dates

• First Submitted: December 29, 2013
• First Submitted That Met QC Criteria: December 29, 2013
• First Posted (Estimate): December 31, 2013

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Motor Neuron Disease; Muscular Atrophy, Spinal; Muscular Atrophy; Atrophy; Bulbo-Spinal Atrophy, X-Linked
• Other Study ID Numbers: CBVS857X2202