Biogen SOD1 clinical trial

An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)

The multiple ascending dose (MAD) study – Part B – and  fixed dose component – Part C – is being conducted through the Motor Neurone Disease (MND) Care Centre at Sheffield and is open to eligible participants throughout the UK.

 

Study titleSingle and Multiple Dose Study of BIIB067 in Adults With Amyotrophic Lateral Sclerosis (ALS)

There is also an open-label extension study to this trial, which is only open to patients who have completed Part A, B or C of this trial.
UK Chief InvestigatorProfessor Dame Pamela Shaw
Research summaryAmyotrophic lateral sclerosis (ALS), is a rapidly progressive, invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles (muscle action we are able to control, such as those in the arms, legs, and face).

Although the majority of patients suffer from sporadic ALS (without family history), approximately 2%, have an inherited, or familial, form of ALS caused by a variety of genetic mutations known as superoxide dismutase 1 mutations (SOD1-ALS).

BIIB067 is an investigational drug which reduces the levels of the toxic protein that causes the genetic mutation. The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics (PK) of BIIB067, in adults with SOD1-ALS.

The study is randomised (participants are randomly allocated to treatment), double-blind (neither the participant nor study team will know which treatment is being given) and placebo-controlled (the study drug will be compared with an inactive “placebo”).
This is a 3-part study to examine the efficacy, safety, tolerability, PK and PD of BIIB067. Part A is the single ascending dose (SAD) component of the study, Part B is the multiple ascending dose (MAD) component of the study and Part C will be the fixed dose component of the study. Hence, the overall phase of development of the study is 1/2/3.

BIIB067 will be administered by intrathecal bolus injection (via an injection into the spinal canal) to up to approximately 144 adults with SOD1-ALS.

Approximately 17 sites are planned in the United States, Canada, and Western Europe.
This study is sponsored by Biogen Idec Research Limited.
Inclusion/exclusion criteriaKey Inclusion Criteria:
- Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2.
- A forced vital capacity (FVC) ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). Participants with stable FVC <50% but ≥45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator.
- If taking riluzole, Participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
- Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.

Key Exclusion Criteria:
- History of or positive test result for human immunodeficiency virus.
- History of, or positive test result at Screening, for hepatitis C virus antibody.
- Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study.
- Treatment with another investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed.
- Current enrollment in any other interventional study.
- Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) or pyrimethamine.
- Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.
- Tracheostomy
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Current statusActive – recruiting
LocationsSheffield
King’s College Hospital, London
Contact detailsIf you think you might be interested please contact Neurologist Professor Christopher McDermott via the study nurse on 0114 2222264 or h.wollff@sheffield.ac.uk
Recruitment group(s)Patients with MND
Recruitment target(s)144 participants worldwide
Key datesStudy start date: 31 January 2016 (global)
Target study completion date: 31 December 2025 (global)
Funder(s)Biogen Idec
SponsorBiogen Idec
Study designInterventional (clinical trial)
Intervention (if applicable)Drug: BIIB067
Other: Placebo
Phase (if applicable)Phase 1/2/3
Outcome measuresPrimary Outcome Measures:
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part A and B: Up to Day 169 ] An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.
Number of Participants With Clinically Significant Laboratory Assessment Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
Number of Participants With Clinically Significant Neurological Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) [ Time Frame: Part A and B: Up to Day 169 ]
PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) [ Time Frame: Part A and B: Up to Day 169 ]
PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) [ Time Frame: Part A and B: Up to Day 169 ]
PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) [ Time Frame: Part A and B: Up to Day 169 ]
PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
Slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Score [ Time Frame: Part C: Baseline to Day 197 ] There are 12 questions, each scored from 0 (no function) to 4 (full function). Total possible score is 48. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression.

Secondary Outcome Measures:
Change From Baseline in CSF Levels of SOD1 Protein. [ Time Frame: Part A, B and C: Up to Day 169 ]
Combined Assessment of Function and Survival (CAFS) Score [ Time Frame: Part C: Up to Day 197 ]
CAFS is clinical outcome based on survival time and change in ALSFRS-R score. A higher CAFS score indicates a better group outcome.

Change From Baseline in ALSFRS-R Score [ Time Frame: Part C: Baseline to Day 197 ]
There are 12 questions, each scored from 0 (no function) to 4 (full function). Total possible score is 48. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression.

Change From Baseline in Slow Vital Capacity (SVC) [ Time Frame: Part C: Baseline to Day 197 ]
Vital capacity will be measured by means of an SVC test, administered in the upright position.

Ventilation Assistance-free Survival (VAFS) [ Time Frame: Part C: Baseline to Day 225 ]
It is defined as the time to the earliest occurrence of one of the following events: death, first use of non-invasive ventilation (NIV) for ≥22 hours per day for ≥10 consecutive days, first use of permanent assisted ventilation (PAV) for ≥22 hours per day for ≥7 consecutive days.

Overall Survival [ Time Frame: Part C: Baseline to Day 225 ]
Overall survival is defined as the time from randomization until death due to any cause.

Change From Baseline in Muscle Strength Measured by Handheld Dynamometry (HHD) [ Time Frame: Part C: Baseline to Day 197 ]
Quantitative muscle strength will be evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning.

Change From Baseline in ALS Assessment Questionnaire (ALSAQ-5) Score [ Time Frame: Part C: Baseline to Day 197 ]
ALSAQ-5 is a disease-specific participant self-reported health status questionnaire used to assess ALS-related health quality. The ALSAQ-5 total score ranges from 0 to 100, with a lower score representing a better health-related status.

Change From Baseline in Fatigue Severity Scale (FSS) Score [ Time Frame: Part C: Baseline to Day 197 ]
FSS is a self-reported questionnaire designed to assess disabling fatigue. It will be used to assess ALS-related health quality.

Change From Baseline in EuroQol Five Dimension Five Level Questionnaire (EQ-5D-5L) Score [ Time Frame: Part C: Baseline to Day 197 ]
EuroQol Five Dimension (EQ-5D) will be used to assess ALS-related health quality and consists of 2 sections.

Change From Baseline in Work Productivity and Activity Inventory (WPAI) Score [ Time Frame: Part C: Baseline to Day 197 ]
WPAI questionnaire will measure participant's impairments in work and activities. It will be used to assess ALS-related health quality. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

Change From Baseline in Zarit Burden Interview (ZBI) Score [ Time Frame: Part C: Baseline to Day 197 ]
ZBI will be used to assess ALS-related health quality. It is a self-report that measures the response of caregivers to a series of 22 questions about the impact of the participant's disabilities on their lives.

Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score [ Time Frame: Part C: Baseline to Day 197 ]
SF-36 will be used to assess ALS-related health quality. It is a validated 36-item participant-completed questionnaire. Higher scores indicate better function.

Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part C: Baseline to Day 225 ]
Change From Baseline in Phosphorylated Axonal Neurofilament heavy chain (p-NFH) Concentration in CSF [ Time Frame: Part C: Baseline to Day 169 ]
p-NFH is a biomarker whose concentration will be assessed in CSF.
Publications / Results reports
Participant Information Sheet