Multiple Sclerosis
Conditions
Keywords
Relapsing Forms of Multiple Sclerosis, GNbAC1, Human Endogenous Retrovirus Type W, HERV-W, Temelimab
Brief summary
Randomized, double-blind, placebo-controlled Phase IIa clinical study, assessing safety, tolerability, pharmacodynamic effects and pharmacokinetics of temelimab, administered at three different dose levels (18 mg/kg or 36 mg/kg or 54 mg/kg). In this study temelimab is administered subsequently to rituximab therapy, i.e. no co-administration of rituximab and temelimab is done in this study.
Interventions
temelimab 18 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total).
DRUGtemelimab 36 mg/kg
temelimab 36 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total).
temelimab 54 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total).
DRUGPlacebo
Placebo will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total).
Sponsors
GeNeuro Innovation SAS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Current diagnosis of RMS, based on McDonald 2017 criteria * Having received treatment with rituximab, as per local clinical routine for at least 12 months prior to the Screening Visit * Having received their last dose of rituximab not more than 8 weeks and not less than 4 weeks before Randomization (Study Day 1) * Having expanded disability status scale (EDSS) 2.5 - 5.5 inclusive at Screening * Present clinical worsening in one or more neurological domains as assessed by EDSS, ambulatory function as assessed by 6MWT or T25FW, cognitive functioning as assessed by SDMT or increased need of walking aids or pharmacological/procedures for bowel and bladder functions over the last year. Main
Exclusion criteria
* Current diagnosis of primary progressive MS (PPMS) * Any disease other than MS (e.g. myelitis and /or bilateral optic neuritis) that could better explain the patient's signs and symptoms * Usage of any of the following medications prior to the Screening visit: * Any usage of interferon beta, glatiramer acetate, IV immunoglobulin (IVIG), dimethyl fumarate or teriflunomide within 12 months prior to Screening, * Any history of exposure to mitoxantrone, cladribine, alemtuzumab, cyclophosphamide, systemic cytotoxic therapy, total lymphoid irradiation, and/or bone marrow transplantation at any time, * Any usage of natalizumab within 24 months prior to Screening, * Any usage of highly potent immune modulating therapy, such as: ocrelizumab, ofatumumab, fingolimod, siponimod, ozanimod or anti-cytokine therapy, plasmapheresis or azathioprine within 12 months prior to Screening, * Any usage of any experimental treatment if not washed out for ≥ 5 half-lives or ≥ 12 months (whichever is longer), except rituximab which is allowed before the study. * CTCAE Grade 2 or greater lymphopenia * Any major medical or psychiatric disorder that would affect the capacity of the patient to fulfill the requirements of the study * History or presence of serious or acute heart disease such as uncontrolled cardiac dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure (NYHA class 3 or 4) * Any history of cancer with the exceptions of basal cell carcinoma and/or carcinoma in situ of the cervix, and only if successfully treated by complete surgical resection, with documented clean margins and any medically unstable condition as determined by the investigator * Pregnant or breastfeeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | 48 weeks | Analysis of Adverse Events (AEs) focused on Treatment Emergent AEs (TEAEs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuroimaging | 48 weeks | Change in magnetization transfer saturation (MT Sat) in periventricular NAWM at Week 48 compared to Baseline. The MT Sat represents the fraction of free water, as transformed to per-unit scale, saturated by a single Magnetization transfer (MT) pulse during repetition time (TR). |
Countries
Sweden
Participant flow
Pre-assignment details
Screening details: Subjects who met the inclusion criteria at the Screening visit (within 3 weeks prior to dosing) and at the Baseline visit (Study Day 1 (SD1)) were considered eligible to participate in the clinical study.
Participants by arm
| Arm | Count |
|---|---|
| Temelimab 18 mg/kg Monthly IV repeated dose
Temelimab 18 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total). | 11 |
| Temelimab 36 mg/kg Monthly IV repeated dose
Temelimab 36 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total). | 10 |
| Temelimab 54 mg/kg Monthly IV repeated dose
temelimab 54 mg/kg will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total). | 10 |
| Placebo Monthly IV repeated dose
Placebo will be given as monthly (4-weekly) intravenous (IV) infusions over 48 weeks (12 administrations in total). | 10 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Temelimab 18 mg/kg | Temelimab 36 mg/kg | Temelimab 54 mg/kg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 10 Participants | 10 Participants | 10 Participants | 41 Participants |
| Age, Continuous | 43.2 years STANDARD_DEVIATION 7.3 | 47.9 years STANDARD_DEVIATION 6.3 | 45.2 years STANDARD_DEVIATION 10.2 | 45.6 years STANDARD_DEVIATION 9.4 | 45.4 years STANDARD_DEVIATION 8.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 10 Participants | 9 Participants | 10 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Sweden | 11 participants | 10 participants | 10 participants | 10 participants | 41 participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 3 Participants | 6 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 7 Participants | 4 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 10 / 11 | 9 / 10 | 10 / 10 | 9 / 10 |
| serious Total, serious adverse events | 1 / 11 | 0 / 10 | 0 / 10 | 1 / 10 |
Outcome results
Primary
Safety and Tolerability
Analysis of Adverse Events (AEs) focused on Treatment Emergent AEs (TEAEs)
Time frame: 48 weeks
Population: Safety set (SAF): all patients having taken at least one dose of IMP. Patients were allocated to the group based on treatment they received
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temelimab 18 mg/kg | Safety and Tolerability | 10 Participants with at least one TEAE |
| Temelimab 36 mg/kg | Safety and Tolerability | 9 Participants with at least one TEAE |
| Temelimab 54 mg/kg | Safety and Tolerability | 10 Participants with at least one TEAE |
| Placebo | Safety and Tolerability | 9 Participants with at least one TEAE |
Secondary
Neuroimaging
Change in magnetization transfer saturation (MT Sat) in periventricular NAWM at Week 48 compared to Baseline. The MT Sat represents the fraction of free water, as transformed to per-unit scale, saturated by a single Magnetization transfer (MT) pulse during repetition time (TR).
Time frame: 48 weeks
Population: Per protocol (PP) set: All patients of the RS with no major protocol deviations and with at least 9 infusions performed. All protocol deviations were assessed and documented on a case-by-case basis prior to database lock, and deviations considered to have a serious impact on the efficacy results led to the relevant patient being excluded from the set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Temelimab 18 mg/kg | Neuroimaging | -0.011 per unit | Standard Deviation 0.097 |
| Temelimab 36 mg/kg | Neuroimaging | -0.060 per unit | Standard Deviation 0.081 |
| Temelimab 54 mg/kg | Neuroimaging | -0.016 per unit | Standard Deviation 0.194 |
| Placebo | Neuroimaging | 0.008 per unit | Standard Deviation 0.113 |
p-value: 0.508495% CI: [-0.124, 0.063]ANCOVA
Comparison: Bayesian analysis is done using a non-informative prior on the mean observed difference.95% CI: [-0.121, 0.057]Bayesian
Secondary
Neuroimaging
Change in magnetization transfer saturation (MT Sat) in cortex at Week 48 compared to Baseline. The MT Sat represents the fraction of free water, as transformed to per-unit scale, saturated by a single Magnetization transfer pulse during repetition time.
Time frame: 48 weeks
Population: PP set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Temelimab 18 mg/kg | Neuroimaging | 0.037 per unit | Standard Deviation 0.058 |
| Temelimab 36 mg/kg | Neuroimaging | 0.044 per unit | Standard Deviation 0.044 |
| Temelimab 54 mg/kg | Neuroimaging | -0.013 per unit | Standard Deviation 0.077 |
| Placebo | Neuroimaging | 0.018 per unit | Standard Deviation 0.04 |
p-value: 0.947295% CI: [-0.052, 0.049]ANCOVA
Comparison: Bayesian analysis is done using a non-informative prior on the mean observed difference.95% CI: [-0.036, 0.059]Bayesian
Secondary
Neuroimaging
Change in T1 and T2 lesion volume at Week 48 compared to Baseline
Time frame: 48 weeks
Population: PP set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Temelimab 18 mg/kg | Neuroimaging | Change in T2 lesion volume | 0.028 mL | Standard Deviation 0.085 |
| Temelimab 18 mg/kg | Neuroimaging | Change in T1 lesion volume | -0.055 mL | Standard Deviation 0.315 |
| Temelimab 36 mg/kg | Neuroimaging | Change in T2 lesion volume | 0.029 mL | Standard Deviation 0.088 |
| Temelimab 36 mg/kg | Neuroimaging | Change in T1 lesion volume | -0.032 mL | Standard Deviation 0.686 |
| Temelimab 54 mg/kg | Neuroimaging | Change in T2 lesion volume | 0.023 mL | Standard Deviation 0.061 |
| Temelimab 54 mg/kg | Neuroimaging | Change in T1 lesion volume | 0.227 mL | Standard Deviation 0.405 |
| Placebo | Neuroimaging | Change in T1 lesion volume | -0.044 mL | Standard Deviation 0.185 |
| Placebo | Neuroimaging | Change in T2 lesion volume | 0.027 mL | Standard Deviation 0.075 |
Comparison: ANCOVA analysis for T1 lesion volume parameterp-value: 0.402795% CI: [-0.216, 0.524]ANCOVA
Comparison: ANCOVA analysis for T2 lesion volume parameterp-value: 0.742895% CI: [-0.051, 0.071]ANCOVA
Secondary
Neuroimaging
Change in brain parenchymal volume fraction at Week 48 compared to Baseline. The brain parenchymal fraction is defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour.
Time frame: 48 weeks
Population: Per protocol (PP) set
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Temelimab 18 mg/kg | Neuroimaging | -0.013 Ratio | Standard Deviation 0.011 |
| Temelimab 36 mg/kg | Neuroimaging | -0.021 Ratio | Standard Deviation 0.032 |
| Temelimab 54 mg/kg | Neuroimaging | -0.011 Ratio | Standard Deviation 0.013 |
| Placebo | Neuroimaging | -0.019 Ratio | Standard Deviation 0.017 |
p-value: 0.731495% CI: [-0.013, 0.018]ANCOVA
Comparison: Bayesian analysis is done using a non-informative prior on the mean observed difference.95% CI: [-0.01, 0.023]Bayesian
Secondary
Neuroimaging
Change in thalamic volume fraction at Week 48 compared to Baseline. The thalamic volume fraction is the ratio of the legitimate (i.e. thalamic) brain tissue volume to the total volume within the brain surface contour.
Time frame: 48 weeks
Population: PP set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Temelimab 18 mg/kg | Neuroimaging | -0.000 Ratio | Standard Deviation 0 |
| Temelimab 36 mg/kg | Neuroimaging | -0.000 Ratio | Standard Deviation 0 |
| Temelimab 54 mg/kg | Neuroimaging | -0.000 Ratio | Standard Deviation 0 |
| Placebo | Neuroimaging | -0.000 Ratio | Standard Deviation 0 |
p-value: 0.766295% CI: [0, 0]ANCOVA