Abstract
Objective
Elezanumab is a monoclonal antibody that binds repulsive guidance molecule a (RGMa), an inhibitor of central nervous system regeneration after inflammation or injury. The aim was to assess the safety and efficacy of elezanumab in relapsing and progressive forms of multiple sclerosis (MS).
Methods
RADIUS‐R and RADIUS‐P were phase 2 trials in relapsing (RADIUS‐R) or progressive (RADIUS‐P) MS. Participants were randomized to intravenous elezanumab 400mg, 1800mg, or placebo every 4 weeks through week 48. The primary endpoint was the mean Overall Response Score (ORS).
Results
In RADIUS‐R, 208 participants received elezanumab 400mg (n = 69), elezanumab 1800mg (n = 69), or placebo (n = 70). In RADIUS‐P, 123 participants received elezanumab 400mg (n = 40), elezanumab 1800mg (n = 40), or placebo (n = 43). The primary endpoint of ORS was not met in either study. For RADIUS‐R, mean ORS was −0.2 with effect size of −0.2 for elezanumab 400mg and −0.2 with effect size of −0.2 for elezanumab 1800mg. For RADIUS‐P, mean ORS was 0.0 with effect size of 0.0 for elezanumab 400mg and 0.1 with effect size of 0.1 for elezanumab 1800mg.
Elezanumab was well tolerated; the rate of serious adverse events was similar across treatment groups in both studies. Adverse events with ≥10% of elezanumab population were falls, urinary tract infections, headaches in RADIUS‐R and RADIUS‐P, and also fatigue, infusion‐related reactions, and muscular weakness in RADIUS‐P.
Interpretation
Elezanumab was safe and well tolerated, but did not meet the primary endpoint in either study. ANN NEUROL 2025;98:590–602
In multiple sclerosis (MS), immunotherapies decrease relapse frequency and slow disability accumulation; however, loss of physical and cognitive function is common and can occur even with complete relapse suppression. 1 , 2 Despite available treatments, patients with MS report lower health‐related quality of life, have an estimated 7‐year shorter life expectancy, and experience almost 3‐fold higher mortality than the general population. 3 , 4 Therefore, an unmet need exists for neurorestorative therapies with the potential to stop or reverse disease progression and improve physical function.
Repulsive guidance molecule a (RGMa) is a glycoprotein first identified as an axon guidance molecule in the chick visual system. 5 , 6 Although predominately expressed in the central nervous system (CNS) during embryological development, under conditions of CNS damage, RGMa is upregulated within and adjacent to lesions following ischemic stroke, 7 spinal cord injury, 8 and traumatic brain injury. 9 RGMa also accumulates in Alzheimer's disease amyloid plaques 10 and Parkinson's disease substantia nigra 11 and is present in active and chronic MS lesions, normal‐appearing gray and white matter, and the cerebrospinal fluid (CSF) of progressive MS patients. 12
In several CNS preclinical inflammatory disease models, monoclonal antibodies targeting RGMa inhibition promote axon regeneration, neuroprotection, and immune modulation. 7 , 8 , 9 , 10 , 11 , 12 Elezanumab (AbbVie, North Chicago, IL) is a high‐affinity human monoclonal antibody that selectively targets soluble and membrane‐bound forms of RGMa. 13 In 2 phase 1, double‐blind, placebo‐controlled, randomized, multiple‐dose studies, elezanumab showed an acceptable safety profile in healthy volunteers and participants with relapsing MS. 14 These results supported investigation of elezanumab in a larger cohort of participants with relapsing and progressive forms of MS. Here, we report the primary results from the phase 2 hypothesis‐generating pilot clinical trials, RADIUS‐R (NCT03737851) and RADIUS‐P (NCT03737812), assessing the safety and efficacy of elezanumab in patients with MS when added to standard‐of‐care therapy.
Methods
Study Design and Participants
RADIUS‐R and RADIUS‐P were randomized, double‐blind, placebo‐controlled, parallel‐group, signal‐seeking phase 2 clinical trials. Participants were enrolled at 49 (RADIUS‐R) and 37 (RADIUS‐P) sites across the United States and Canada. Participants eligible for RADIUS‐R were age 18 to 65 years, with a diagnosis of relapsing–remitting MS (RRMS) with no relapse 6 months before screening or relapsing secondary progressive MS (rSPMS) with clinical relapse occurring 6 to 24 months before screening (no relapses occurring 6 months before enrolment), magnetic resonance imaging (MRI) demonstrating lesion(s) consistent with MS, and evidence of a physical disability (based on Expanded Disability Status Scale [EDSS], timed 25 foot walk [T25FW], or 9‐hole peg test [9HPT]). Participants eligible for RADIUS‐P were age 18 to 65 years with a diagnosis of primary progressive MS (PPMS) or non‐relapsing secondary progressive MS (nrSPMS) with no relapses for at least 24 months, MRI demonstrating lesion(s) consistent with MS, and evidence of a physical disability based on EDSS, T25FW, or 9HPT. Ongoing use of MS disease‐modifying therapy (DMT) was permitted. Before initiating screening or study‐specific procedures, study participants or their legally authorized representatives were required to review and sign a written informed consent, approved by an independent ethics committee/institutional review board. Full eligibility criteria are available in Table S1.
Randomization and Masking
Participants were randomized (1:1:1) to receive elezanumab 400mg, elezanumab 1800mg, or placebo. Participants were stratified by disease course (RADIUS‐R, RRMS or rSPMS; RADIUS‐P, PPMS or nrSPMS) and use of background MS immunotherapy, with block randomization within each stratum providing balanced treatment assignments. An interactive response technology system was used to assign participant numbers and treatment assignments. Participants, investigators, and study site staff (except an unblinded pharmacist) were masked to assignments throughout the study. The unblinded pharmacist prepared the study drug and was responsible for maintaining drug preparation and accountability records. Identical commercial 0.9% sodium chloride injection/solution for infusion bags was used in the placebo and elezanumab arms.
Procedures
RADIUS‐R and RADIUS‐P consisted of a 30‐day screening period, a 52‐week double‐blind treatment period, and a 24‐week follow‐up period (35 weeks for women of childbearing potential) (Fig S1). Following randomization, elezanumab (AbbVie Deutschland, KG, Ludwigshafen, Germany) or placebo was administered intravenously every 4 weeks (with a treatment window of ±7 days) for the duration of the double‐blind treatment period (final dose at week 48).
The EDSS, T25FW, and 9HPT were assessed at screening, baseline (week 0), weeks 12, 24, 36, and 52 (or within 2 weeks of early discontinuation [ED]), and at follow‐up weeks 64 and 76. The oral symbol‐digit modality test (SDMT), low‐contrast visual acuity (LCVA), and the Modified Fatigue Impact Scale 5‐item version (MFIS‐5) were assessed at baseline and weeks 12, 24, 36, and 52/ED. The MS Individualized Outcome Assessment (MSIOA) was assessed at baseline and weeks 24 and 52/ED. 15
MRI scans were acquired at screening, week 24, and week 52 using standardized protocols on 1.5 Tesla (T) and 3 T scanners. Brain MRI sequences included T1‐weighted imaging with and without gadolinium, proton density (PD)‐ and T2‐weighted imaging, magnetization transfer (MT) imaging, and diffusion tensor imaging (DTI). MRI scans from all time points required by the protocol were qualitatively interpreted by local radiologists and reviewed by site investigators for assessment of disease activity (gadolinium+ lesions and T2 lesions) and participant safety. Clario (Philadelphia, PA) provided central reading of quantitative MRI data. To assess gadolinium+ and T2 lesion counts and volumes, T1‐weighted post‐gadolinium, T2‐weighted fluid‐attenuated inversion recovery, and PD/T2‐weighted images were evaluated centrally by radiology reviewers. Magnetization transfer ratio (MTR) indicated myelin content, DTI assessed demyelination and axonal loss, and the fractional anisotropy (FA) component of DTI assessed myelin and axonal microstructural integrity. Brain atrophy was measured using T1‐weighted images.
Neurological exams were performed at screening, baseline, week 24, and week 52/ED. Serum (pharmacokinetic analysis) and whole blood samples (biomarker analysis) were collected before infusion at baseline, weeks 12, 24, 36, and 52/ED, and at follow‐up weeks 64 and 76 for pharmacokinetic analysis. Samples for clinical laboratory safety and tolerability assessments (hematology, chemistry, and urinalysis) were taken at screening, baseline, and weeks 4, 8, 12, 24, 36, and 52/ED.
In the United States, wearable biosensors (BioStamp nPoint, Medidata/MC10, New York, NY, USA) were used to record parameters including gait cadence, moving duration, walking duration, number of steps, and resting duration. Participants were trained to apply biosensors at the baseline visit by study staff. Home actigraphy data were collected over 7‐day periods beginning at baseline and at weeks 24, 36, 52, and at follow‐up week 64. Sensors were worn on the chest, thigh, and lateral lower calf. The sensors on the chest and thigh also measured vital signs and posture. The primary assessment of movement via actigraphy was moving steps (average steps per hour, normalized to hours of biosensor wear). Because of the coronavirus disease 2019 (COVID‐19) pandemic, modifications following local regulations were incorporated into the study protocol to ensure continuity of care and participant safety (Table S2).
Outcomes
The primary endpoint was the mean Overall Response Score (ORS) in the modified intent‐to‐treat population (mITT) at week 52 (Fig S2). 16 ORS is a 4‐component composite score derived from the EDSS, T25FW, and 9HPT‐dominant (9HPT‐D) and non‐dominant (9HPT‐ND) hand. 16 Scoring and clinically significant change thresholds are described in Table S3. ORS components were scored (−1 to +1) relative to baseline and summed for a possible range of −4 (worsening in all components) to +4 (improvements in all components). If data for any individual component was absent, the ORS for that visit was considered missing. Secondary efficacy endpoints were ORS at weeks 12, 24, and 36, and the disability improvement response rate, based on the percentage of participants with improvement from baseline on the EDSS Plus (EDSS+) at week 52, indicated by clinically significant improvement in at least one of the following: EDSS, T25FW, 9HPT‐D, or 9HPT‐ND. 17
Safety variables, including adverse events, serious adverse events, adverse events of special interest, vital sign measurements, electrocardiogram variables, Columbia Suicide Severity Rating Scale assessments, clinical laboratory testing, and MS relapses were monitored by the sponsor study team and an independent internal data monitoring committee. Relapses were defined as a new or worsening neurological symptom(s) occurring in the absence of fever, lasting for more than 24 hours, and preceded by at least 30 days of clinical stability or improvement. All suspected relapses were assessed by the blinded investigator and adjudicated by an external committee. Adverse events were reported for the duration of the study. Women of childbearing potential completed monthly pregnancy tests throughout treatment and for 39 weeks (5 half‐lives) after the last study drug administration.
The overall goals of these phase 2 hypothesis‐generating clinical trials included the identification of clinical improvement across multiple doses, MS subtypes, and domains of interest, including cognitive processing speed, the patient‐reported outcome of fatigue and its effect on quality of life, visual acuity, the impact of treatment on a patient's activities of daily living, physical activity, MRI assessment of disease burden (lesion burden, tissue integrity), and biomarker levels indicative of neurologic tissue damage or elezanumab mechanism of action. The following exploratory endpoints were included in this report: SDMT, MFIS‐5, LCVA, MSIOA, activity measured by home actigraphy, change from baseline in MRI measures, and blood biomarker levels (neurofilament light [NfL] and glial fibrillary acidic protein [GFAP]).
Statistical Analysis
The goal of these studies was to optimize detection of treatment signal rather than powering for statistical analysis because no significance‐based hypothesis testing was being performed. Sample sizes were selected based on operational feasibility (number of trial sites and patients per trial) and on posterior probability analysis rather than traditional power calculations. See Supplementary Materials, Statistical Analysis section for additional information on sample size calculations.
Efficacy analyses were performed on the mITT population, all participants who received at least 1 dose of study drug. The primary efficacy endpoint was summarized using a mixed‐effect model for repeated measures relying on a missing at random assumption, with visits within blocks of the covariate matrix identified by participant nested within treatment group and an unstructured covariance structure used. If a component of the ORS was missing, the entire score was treated as missing. The responder analyses also used the mITT population and imputed missing responses using a non‐responder imputation approach. See Supplementary Materials, Statistical Analysis for statistical analysis details.
The safety dataset included all participants who received at least 1 dose of the study drug and were grouped according to treatment received. SAS Version 9.2 or higher (SAS Institute, Cary, NC) was used for statistical analysis. RADIUS‐R (NCT03737851) and RADIUS‐P (NCT03737812) are registered with ClinicalTrials.gov.
Results
Between February 27, 2019, and December 26, 2019, 208 of 282 participants screened for RADIUS‐R received elezanumab 400mg (n = 69), elezanumab 1800mg (n = 69), or placebo (n = 70). Between March 6, 2019, and January 2, 2020, 123 of the 148 participants screened for RADIUS‐P received elezanumab 400mg (n = 40), elezanumab 1800mg (n = 40), or placebo (n = 43) (Fig 1). The proportion of participants who discontinued treatment was similar across groups and consistent between studies (26 of 208 [13%] in RADIUS‐R and 15 of 123 [12%] in RADIUS‐P).
FIGURE 1.
Trial profile. (A) RADIUS‐R enrolled participants with relapsing forms of multiple sclerosis (RRMS and rSPMS). (B) RADIUS‐P enrolled participants with progressive forms of multiple sclerosis (includes PPMS and nrSPMS), respectively. aPrimary reason for discontinuation, participants may have more than one reason for discontinuation. bAll randomized participants who received at least 1 dose of study drug were included in the mITT populations. COVID‐19 = coronavirus disease 19; mITT = modified intent‐to‐treat; nrSPMS = non‐relapsing secondary progressive multiple sclerosis; PPMS = primary progressive multiple sclerosis; RRMS = relapsing remitting multiple sclerosis; rSPMS = relapsing secondary progressive multiple sclerosis.
In each trial, demographics and baseline characteristics were generally comparable across the 3 treatment arms (Tables 1 and S4). Participants in RADIUS‐R predominantly had RRMS and accounted for 199 of the 208 (96%) participants, the mean age was 45.7 years (standard deviation [SD], 8.35), 138 (66%) were women, and 184 (89%) were White. In RADIUS‐P, the distribution was nrSPMS (52%) and PPMS (48%), the mean age was 52.6 years (SD, 7.04), 59 (48%) were women, and 111 (90%) were White. Most participants in RADIUS‐R (79%) and RADIUS‐P (76%) were on DMT at baseline, most commonly ocrelizumab (RADIUS‐R, 102 [49%]; RADIUS‐P, 79 [64%]) (Table S4). The distributions of baseline EDSS scores by treatment arm in the 2 trials are summarized in Table S5.
TABLE 1.
Demographics and Baseline Characteristics of the mITT Population
| Parameter | RADIUS‐R | RADIUS‐P | ||||
|---|---|---|---|---|---|---|
| Placebo | Elezanumab | Elezanumab | Placebo | Elezanumab | Elezanumab | |
| 400mg | 1800mg | 400mg | 1800mg | |||
| (N = 70) | (N = 69) | (N = 69) | (N = 43) | (N = 40) | (N = 40) | |
| Sex, female, n (%) | 46 (66) | 45 (65) | 47 (68) | 24 (56) | 14 (35) | 21 (53) |
| Race, White, n (%) | 60 (86) | 62 (90) | 62 (91) | 42 (98) | 32 (80) | 37 (93) |
| Ethnicity, Hispanic/Latino, n (%) | 10 (14) | 4 (6) | 6 (9) | 2 (5) | 0 (0) | 3 (8) |
| Age, years, mean (SD) | 46 (7) | 47 (9) | 44 (9) | 52 (7) | 53 (8) | 54 (7) |
| BMI, kg/m2, mean (SD) | 28 (6) | 28 (6) | 27 (6) | 29 (6) | 27 (5) | 27 (6) |
| Type of MS, n (%) | ||||||
| RRMS | 66 (94) | 67 (97) | 66 (96) | N/A | N/A | N/A |
| rSPMS | 4 (6) | 2 (3) | 3 (4) | N/A | N/A | N/A |
| nrSPMS | N/A | N/A | N/A | 24 (56) | 19 (48) | 21 (53) |
| PPMS | N/A | N/A | N/A | 19 (44) | 21 (53) | 19 (48) |
| Months since first onset of symptoms | ||||||
| Mean (SD) | 187 (93) | 190 (112) | 147 (100) | 170 (112) | 186 (120) | 202 (111) |
| Months since relapse, mean (SD) | 53 (49) | 56 (52) | 43 (37) | 80 (56) | 103 (96) | 118 (96) |
| EDSS, mean (SD) | 4 (2) | 4 (2) | 4 (1) | 5 (1) | 5 (1) | 5 (1) |
| Baseline MS immunomodulator DMT, a n (%) | ||||||
| Any | 53 (76) | 56 (81) | 56 (81) | 33 (77) | 29 (73) | 31 (78) |
BMI = body mass index; DMT = disease modifying therapy; EDSS = Expanded Disability Status Scale; mITT = modified intent‐to‐treat; MS = multiple sclerosis; N = number of participants in the treatment group; n = number of participants in the individual parameter; N/A = not applicable; nrSPMS = non‐relapsing secondary progressive multiple sclerosis; PPMS = primary progressive multiple sclerosis; RRMS = relapsing remitting multiple sclerosis; rSPMS = relapsing secondary progressive multiple sclerosis; SD = standard deviation.
Baseline MS immunomodulator DMT use defined as use on the first dose date.
Based on prespecified criteria for clinically meaningful improvement (an effect size ≥0.3), neither study met the primary efficacy endpoint (Table 2). The ORS was similar between groups throughout the double‐blind treatment period in RADIUS‐R and RADIUS‐P (Fig 2, Table 2). Overall negative ORS values indicate worsening, whereas overall positive ORS values indicate improvement (Fig S2).
TABLE 2.
Primary and Selected Secondary Endpoints in the mITT Population
| mITT population | RADIUS‐R | RADIUS‐P | ||||
|---|---|---|---|---|---|---|
| Placebo | Elezanumab 400mg | Elezanumab 1800mg | Placebo | Elezanumab 400mg | Elezanumab 1800mg | |
| (N = 70) | (N = 69) | (N = 69) | (N = 43) | (N = 40) | (N = 40) | |
| Primary endpoint | ||||||
| ORS at week 52, n | 59 | 61 | 55 | 36 | 31 | 34 |
| Median (min, max) a | 0 (−3, 3) | 0 (−3, 3) | 0 (−1, 2) | −1 (−3, 1) | −1 (−3, 1) | −0.5 (−3, 2) |
| LS mean (SE) b | 0.04 (0.17) | −0.2 (0.2) | −0.2 (0.2) | −0.7 (0.2) | −0.8 (0.2) | −0.6 (0.2) |
| Difference from placebo (95% CI) b | −0.2 (−0.6 to 0.2) | −0.2 (−0.6 to 0.2) | 0.0 (−0.5 to 0.5) | 0.1 (−0.4 to 0.6) | ||
| Effect size (95% CI) b | −0.2 (−0.5 to 0.2) | −0.2 (−0.6 to 0.1) | 0.0 (−0.5 to 0.5) | 0.1 (−0.4 to 0.6) | ||
| Selected secondary endpoints | ||||||
| ORS at week 12, n | 63 | 65 | 68 | 38 | 35 | 34 |
| Median (min, max) a | 0 (−2, 3) | 0 (−2, 2) | 0 (−1, 2) | 0 (−2, 0) | 0 (−2, 2) | 0 (−2, 1) |
| LS mean (SE) b | 0.1 (0.2) | −0.1 (0.2) | 0.1 (0.2) | −0.5 (0.1) | 0.0 (0.1) | −0.2 (0.1) |
| Difference from placebo (95% CI) b | −0.1 (−0.4 to 0.2) | 0.1 (−0.2 to 0.3) | 0.5 (0.1–0.8) | 0.3 (−0.1 to 0.6) | ||
| Effect size (95% CI) b | −0.1 (−0.5 to 0.2) | 0.1 (−0.3 to 0.4) | 0.6 (0.1–1.1) | 0.4 (−0.1 to 0.9) | ||
| ORS at week 24, n | 60 | 57 | 59 | 36 | 28 | 31 |
| Median (min, max) a | 0 (−4, 2) | 0 (−3, 2) | 0 (−2, 2) | 0 (−2, 1) | 0 (−4, 2) | 0 (−3, 1) |
| LS mean (SE) b | 0.0 (0.2) | −0.1 (0.2) | −0.1 (0.2) | −0.3 (0.2) | −0.3 (0.2) | −0.5 (0.2) |
| Difference from placebo (95% CI) b | −0.1 (−0.2 to 0.2) | 0.0 (−0.4 to 0.3) | 0.0 (−0.5 to 0.5) | −0.3 (−0.8 to 0.3) | ||
| Effect size (95% CI) b | −0.1 (−0.5 to 0.3) | 0.0 (−0.4 to 0.3) | 0.0 (−0.5 to 0.5) | −0.3 (−0.8 to 0.2) | ||
| ORS at week 36, n | 55 | 58 | 51 | 35 | 26 | 30 |
| Median (min, max) a | 0 (−3, 3) | 0 (−3, 3) | 0 (−2, 2) | 0 (−3, 1) | 0 (−3, 2) | −1 (−2, 1) |
| LS mean (SE) b | 0.1 (0.2) | −0.1 (0.2) | −0.2 (0.2) | −0.5 (0.2) | −0.5 (0.2) | −0.5 (0.2) |
| Difference from placebo (95% CI) b | −0.2 (−0.6 to 0.2) | −0.3 (−0.7 to 0.1) | 0.0 (−0.5 to 0.4) | −0.1 (−0.5 to 0.4) | ||
| Effect size (95% CI) b | −0.2 (−0.5 to 0.2) | −0.3 (−0.6 to 0.1) | 0.0 (−0.5 to 0.5) | −0.1 (−0.6 to 0.4) | ||
Data are LS mean (SE) or LS mean difference from placebo (95% CI) based on MMRM (unless indicated) in the mITT population.
9HPT = 9‐hole peg test‐dominant hand; 9HPT‐ND = 9‐hole peg test‐non‐dominant hand; CI = confidence interval; EDSS = expanded disability status scale; LS = least squares; max = maximum; min = minimum; mITT = modified intent‐to‐treat; MMRM = mixed‐effect model for repeated measures; MS = multiple sclerosis; N = number of participants in the treatment group; n = number of participants in the individual parameter; nrSPMS = non‐relapsing secondary progressive MS; ORS = Overall Response Score; PPMS = primary progressive MS; RRMS = relapsing remitting MS; rSPMS = relapsing secondary progressive MS; SD = standard deviation; SE = standard error; T25FW = timed 25‐foot walk.
Based on the as observed mITT population.
MMRM model includes fixed effects of treatment group, visits, baseline MS immunomodulator use (yes/no), MS type (RRMS/rSPMS or PPMS/nrSPMS in RADIUS‐R/RADIUS‐P, respectively), treatment by visit interaction, and covariates of baseline EDSS, T25FW, 9HPT‐D, 9HPT‐ND with an unstructured variance–covariance matrix. Effect size is the (LS mean elezanumab – LS mean placebo)/pooled SD.
FIGURE 2.
ORS in the mITT population. LS mean ORS in the mITT population based on MMRM in (A) RADIUS‐R and (B) RADIUS‐P. Error bars are 95% confidence intervals. The ORS was scored relative to baseline at each assessment and summed for a possible range of −4 (worsening in all components) to +4 (improvements in all components). LS = least squares; mITT = modified intent‐to‐treat; MMRM = mixed‐effect model for repeated measures; ORS = Overall Response Score. [Color figure can be viewed at www.annalsofneurology.org]
In RADIUS‐R, the least squares (LS) mean difference from placebo in ORS at week 52 was −0.2 (95% confidence interval [CI]: −0.6 to 0.2) with an effect size of −0.2 (95% CI: −0.5 to 0.2) for elezanumab 400mg, and was −0.2 (95% CI: −0.6 to 0.2) with effect size of −0.2 (95% CI: −0.6 to 0.1) for elezanumab 1800mg. In RADIUS‐P, the LS mean difference from placebo in ORS at week 52 was 0.0 (95% CI: −0.5 to 0.5) with an effect size of 0.0 (95% CI: −0.5 to 0.5) for elezanumab 400mg, and was 0.1 (95% CI: −0.4 to 0.6) with an effect size of 0.1 (95% CI: −0.4 to 0.6) for elezanumab 1800mg. Treatment benefits of elezanumab were not seen across any predefined subgroup (Fig 3).
FIGURE 3.
Overall Response Score by subgroups. Subgroup analysis of the primary endpoint (Overall Response Score at week 52) in the modified intent‐to‐treat population based on MMRM. Placebo versus elezanumab (A) 400mg and (B) 1800mg in RADIUS‐R and placebo versus elezanumab (C) 400mg and (D) 1800mg in RADIUS‐P. There is some imbalance in the numbers of participants by median EDSS because of the small number of study participants in each trial that were randomized to 3 treatment groups. aThe background immunotherapy subgroup included those taking any of the MS immunotherapies (not just ocrelizumab) outlined in the inclusion criteria for RADIUS‐R and RADIUS‐P at baseline. CI = confidence interval; EDSS = expanded disability status scale; LS = least squares; MMRM = mixed‐effect model for repeated measures; MS = multiple sclerosis; PPMS = primary progressive MS; rSPMS = relapsing secondary progressive MS.
In RADIUS‐R, 18 of 70 (26%) participants in the placebo group, 20 of 69 (29%) in the elezanumab 400‐mg group, and 13 of 69 (19%) in the elezanumab 1800‐mg group had improvement on at least 1 component of the EDSS+ at week 52 (Table S6). The difference from placebo in EDSS+ response rate was 3.3% (95% CI: −11.5 to 18.1) for elezanumab 400mg and − 6.9% (95% CI: −20.7 to 6.9) for elezanumab 1800mg.
In RADIUS‐R, neither the 400‐mg nor the 1800‐mg elezanumab groups demonstrated a positive response to elezanumab at week 52 based on the 9HPT (Table S7). A numerical improvement in the T25FW was seen in the elezanumab 1800‐mg group, in which the LS mean difference compared with placebo was −1.1 (95% CI: −3.8 to 1.6) with an effect size of 0.2 (95% CI: −0.2 to 0.6).
In RADIUS‐P, the proportion of participants with disability improvement in EDSS+ at week 52 was numerically higher in the elezanumab‐treated groups (elezanumab 400mg, 7/40 [18%]; elezanumab 1800mg, 9/40 [23%]) compared with placebo (3/43 [7%]) (Table S6). The difference from placebo in EDSS+ response rate was 10.5% (95% CI: −3.5 to 24.6) for elezanumab 400mg and 15.5% (95% CI: 0.5–30.5) for elezanumab 1800mg.
Based on change from baseline at week 52, there was limited evidence of improvement in 9HPT values with elezanumab versus placebo in RADIUS‐P (Table S7). For 9HPT‐D, the LS mean difference from placebo was −5.8 (95% CI: −15.6 to 4.1) for elezanumab 1800mg; there was no improvement for elezanumab 400mg. For 9HPT‐ND, the LS mean difference from placebo was −7.7 (95% CI: −19.9 to 4.4) for elezanumab 400mg; there was no improvement for elezanumab 1800mg. No improvements were seen in T25FW in RADIUS‐P for either elezanumab group.
In RADIUS‐R or RADIUS‐P, no change was observed in the SDMT, LCVA, and MFIS‐5 assessments in the mITT population or a pre‐specified subpopulation with baseline deficits (Table S7). The clinician‐reported outcome assessment, the MSIOA, did not suggest an impact on patients' activities of daily living (Table S7).
Exploratory MRI measures, including changes in whole‐brain or T2 lesion volumes, MTR, and FA from DTI, did not find a beneficial effect of elezanumab treatment across doses or MS populations (Table S8). Consistent with gradual disease progression, T2 lesion enlargement and brain atrophy occurred over the course of both studies. New lesion formation occurred in some participants, as might be expected because most participants were treated with DMTs (Table S8).
Because of the COVID‐19 pandemic, several participants missed study drug infusions. A sensitivity analysis of the primary endpoint was performed using a subset of the population who received at least 6 infusions and missed no consecutive infusions before the participant's final dose. Results were comparable with those in the minimal missed infusion analysis subgroup (Table S9).
Wearable biosensors provided 7‐day continuous waking‐hour actigraphy data during real‐world activity. Compliance for each individual week was high (≥89%) across both studies (Table S10). Moving steps declined from baseline to week 52 across all groups in RADIUS‐R and RADIUS‐P (Table S8). In RADIUS‐R, the decline in LS mean (standard error [SE]) moving steps from baseline to week 52 was numerically greater in both elezanumab treatment groups (elezanumab 400mg, −37.9 [18.4]; elezanumab 1800mg, −50.3 [18.2]) versus placebo (−33.0 [17.7]) (Table S7). In RADIUS‐P, the decline in LS mean (SE) moving steps from baseline to week 52 was numerically less in both elezanumab groups (elezanumab 400mg, −25.5 [15.1]; elezanumab 1800mg, −16.0 [13.8]) versus placebo (−34.2 [14.7]).
In RADIUS‐R, treatment‐emergent adverse events (TEAEs) were reported in 63 of 70 (90%) participants in the placebo group, 57 of 69 (83%) in the elezanumab 400‐mg group, and 64 of 69 (93%) in the elezanumab 1800‐mg group (Table 3). In RADIUS‐P, TEAEs were reported in 40 of 43 (93%) participants in the placebo group, 33 of 40 (83%) in the elezanumab 400‐mg group, and 34 of 40 (85%) in the elezanumab 1800‐mg group (Table 4). Overall, the incidence of TEAEs leading to study drug discontinuation was low, occurring in RADIUS‐R in 1 (1%) participant in the placebo group and 4 (6%) in the elezanumab 1800‐mg group, and occurring in RADIUS‐P in 1 (3%) participant in the elezanumab 400‐mg group. The most common adverse events (≥10%) in the total elezanumab‐treated population in RADIUS‐R were falls, urinary tract infections (UTIs), and headaches (Table S11); and in RADIUS‐P, the most common adverse events were UTIs, falls, fatigue, infusion‐related reactions, headaches, and muscular weakness (Table S12). The incidence of serious adverse events was low, occurring in RADIUS‐R in 6 (9%), 7 (10%), and 4 (6%) participants in the placebo, elezanumab 400‐mg, and elezanumab 1800‐mg groups, respectively, and in RADIUS‐P, serious adverse events occurred in 2 (5%), 5 (13%), and 3 (8%) participants in the placebo, elezanumab 400‐mg, and elezanumab 1800‐mg groups, respectively. Treatment‐emergent serious adverse events occurring in >1% of participants in any treatment group are shown in Tables S13 and S14. One death (1%) occurred in RADIUS‐R in the placebo group and 2 in RADIUS‐P (placebo, 1 [2%]; elezanumab 400mg, 1 [3%]). In the safety analysis sets of both trials, the incidence of confirmed MS relapse was comparable across groups (RADIUS‐R, n/N [%]: placebo, 4/70 [6%]; elezanumab 400mg, 4/69 [6%]; elezanumab 1800mg, 4/69 [6%]; RADIUS‐P: placebo, 1/43 [2%]; elezanumab 400mg, 1/40 [3%]; elezanumab 1800mg, 1/40 [3%]).
TABLE 3.
TEAEs Occurring in the RADIUS‐R Safety Population
| Incidence, n (%) | Placebo | Elezanumab | Elezanumab | Total |
|---|---|---|---|---|
| 400mg | 1800mg | Elezanumab | ||
| (N = 70) | (N = 69) | (N = 69) | (N = 138) | |
| Any TEAE | 63 (90) | 57 (83) | 64 (93) | 121 (88) |
| Any TEAE considered related to study treatment a | 24 (34) | 20 (29) | 29 (42) | 49 (36) |
| Any severe TEAE | 7 (10) | 7 (10) | 2 (3) | 9 (7) |
| Any serious TEAE b | 6 (9) | 7 (10) | 4 (6) | 11 (8) |
| Any TEAE leading to discontinuation of study drug | 1 (1) | 0 (0) | 4 (6) | 4 (3) |
| Any adverse events of special interest | ||||
| Infusion reactions c | 23 (33) | 17 (25) | 22 (32) | 39 (28) |
| Any TEAE leading to death d | 1 (1) | 0 (0) | 0 (0) | 0 (0) |
N = number of participants in the treatment group; n = number of participants in the individual parameter; TEAE = treatment‐emergent adverse event.
As assessed by investigator.
Note that an individual patient may have experienced more than 1 serious adverse event.
Infusion reaction includes hypersensitivity, angioedema, anaphylactic reaction, drug‐induced rash, and injection site reaction.
A 39‐year‐old woman experienced a fatal pulmonary embolism on day 193 (post‐treatment [placebo] day 22). The investigator assessed the event as having no reasonable possibility of relationship to study drug.
TABLE 4.
TEAEs Occurring in the RADIUS‐P Safety Population
| Incidence, n (%) | Placebo | Elezanumab | Elezanumab | Total |
|---|---|---|---|---|
| 400mg | 1800mg | Elezanumab | ||
| (N = 43) | (N = 40) | (N = 40) | (N = 80) | |
| Any TEAE | 40 (93) | 33 (83) | 34 (85) | 67 (84) |
| Any TEAE considered related to study treatment a | 17 (40) | 14 (35) | 15 (38) | 29 (36) |
| Any severe TEAE | 4 (9) | 6 (15) | 2 (5) | 8 (10) |
| Any serious TEAE | 2 (5) | 5 (13) | 3 (8) | 8 (10) |
| Any TEAE leading to discontinuation of study drug | 0 (0) | 1 (3) | 0 (0) | 1 (1) |
| Any adverse events of special interest | ||||
| Infusion reactions b | 14 (33) | 12 (30) | 13 (33) | 25 (31) |
| Any TEAE leading to deaths | 1 c (2) | 1 d (3) | 0 (0) | 1 (1) |
N = number of participants in the treatment group; n = number of participants in the individual parameter; TEAE = treatment‐emergent adverse event.
As assessed by investigator.
Infusion reaction includes hypersensitivity, angioedema, anaphylactic reaction, drug‐induced rash, and injection site reaction.
A 60‐year‐old placebo‐treated man experienced an unexplained death on day 450 (post‐treatment day 116). The investigator deemed the death to be unrelated to the study drug.
A 61‐year‐old man in the elezanumab 400‐mg group experienced fatal respiratory failure on day 470 (post‐treatment day 129), unrelated to the study drug.
Exploratory biomarkers NfL and GFAP were measured in plasma samples. In RADIUS‐R and RADIUS‐P, NfL and GFAP levels did not appreciably change over the 52‐week treatment period in participants receiving placebo, elezanumab 400mg, or elezanumab 1800mg, as indicated by the week 52/baseline ratio for both MS populations staying near 1.0 (Figs S3A,C and S4A,C). Elezanumab did not substantially reduce NfL or GFAP levels in participants receiving no other DMTs, in participants receiving ocrelizumab, or in participants receiving other DMTs (Figs S3B,D and S4B,D). However, the relatively small sample sizes in some subgroups require cautious interpretation.
Elezanumab serum concentration over time profiles following intravenous dosing of 400mg or 1800mg elezanumab every 4 weeks were similar across RADIUS‐R and RADIUS‐P, with participants achieving steady‐state levels by weeks 24 to 36 (Fig S5).
Discussion
The development of DMTs revolutionized MS treatment. However, millions of patients have residual deficits from long‐standing disease, and current therapies are unlikely to halt disease progression across the spectrum of MS. Neurorestorative therapies that repair demyelinated axons are urgently needed. Although elezanumab was well tolerated, neither dose improved physical function nor reversed disability across the MS subtypes. Despite some phase 2 trials showing positive remyelinating drug treatment effects in relapsing MS patients (with MTR when lesions were assessed based on their anatomic locations 18 or with visual evoked potential [VEP] latency improvement in eyes using a baseline threshold of VEP impairment 18 , 19 ), our negative signal‐seeking phase 2 study findings are consistent with clinical trials that investigated other remyelinating and neurorestorative agents. 16 , 20
The RADIUS studies incorporated novel design features that may benefit future MS clinical trials. Several endpoints and analyses were performed to prioritize detecting improvement in neurologic function rather than focusing on disability progression or relapses. First, the primary endpoint ORS 16 was a multicomponent endpoint encompassing measures of ambulatory function (T25FW), manual dexterity (9HPT), and EDSS. Composite endpoints incorporating scores from multiple measures were more sensitive than individual components alone, thereby allowing for a smaller sample size for a chronic disease. 17 , 21
Cognitive processing speed (SDMT) and low contrast visual acuity (LCVA) were also assessed and could be incorporated into future composite measures to detect neurologic improvement. In terms of additional innovations, a battery of neurorestorative biomarkers was used, including MRI markers related to axonal density/integrity (DTI) and myelin density (MTR), damage‐associated serum biomarkers, such as NfL and GFAP, and home‐utilized actigraphy biosensors. Inclusion of these outcomes enabled investigation of elezanumab's potential neurorestorative effects from multiple angles to assess consistency of a possible therapeutic effect. This design feature may inform future neurorestoration clinical trials in MS.
Elezanumab treatment was not associated with reductions in NfL or GFAP, regardless of background therapy. In patients with active MS, NfL levels are associated primarily with inflammatory disease activity, and DMTs may decrease NfL levels in patients with MS via their anti‐inflammatory effects. Given that participants were selected to not be actively relapsing and that most were treated with DMTs, a neuroprotective effect of elezanumab on NfL may not have been detectable in this population. It should be noted that study participants were on a heterogeneous background of DMT therapies, with some on no DMT therapy. Therefore, although participants receiving ocrelizumab (the most frequent DMT, accounting for 42–63% across the elezanumab treatment groups) (Table S4) did not differ from other DMT subgroups in terms of biomarker effects (Figs S3 and S4), it is possible that longer and larger studies could detect biomarker differences across DMT subtypes.
The studies were limited by the relatively short duration of the treatment period. It is conceivable that longer‐term therapy could yield benefits. In addition, RADIUS‐R and RADIUS‐P were hypothesis‐generating phase 2 clinical trials and were not designed to detect whether elezanumab might slow disability progression. When disability improvement response rate on the EDSS+ was assessed, some sparse‐data bias in the odds ratios was observed for the T25FW, 9HPT‐D, and 9HPT‐ND individual components of the EDSS+ in the RADIUS‐P study. Given the small overall sample size, it is not surprising that sparse data bias was observed. The number of patients in the RADIUS‐P trial who showed disability improvement in the individual components of T25FW, 9HPT‐D, and 9HPT‐ND ranged from n = 0–4 (Table S6). In RADIUS‐P at week 52, the proportion of participants with EDSS+ (and EDSS) improvement was numerically higher in a dose‐dependent manner, and moving steps declined less in the elezanumab‐treated groups compared with placebo. This observation underscores the potential for misattribution of a therapeutic effect had the study used only EDSS as an endpoint in progressive MS.
Another limitation of the present studies is that target engagement of elezanumab was not investigated. Although CSF biomarkers (such as soluble RGMa, elezanumab, and interleukin‐10) were assessed in the phase 1 clinical trials, CSF was not obtained in the RADIUS program and, therefore, target engagement and a dose‐dependent effect on CSF biomarkers are unknown. Last, the field of MS clinical trial research lacks a “gold standard” measure for functional restoration in MS.
Another method to study improvement in function is to target individual participant deficits and establish individual thresholds for efficacy per study participant based on each individual's deficit. Clinical endpoints are generally more interpretable by the MS community. Imaging correlates of improvements in function have yet to be developed, but might include modalities such as DTI, MTR, or functional MRI. Similarly, biomarkers that correlate with repair processes are unknown. These trials did not assess neurophysiology, and improvements in evoked potential latencies might occur with restorative treatment.
Beyond issues of study duration and methodology, there are several explanations as to why elezanumab did not lead to clinical improvement in these studies. RGMa inhibition may not promote remyelination and axonal regrowth after the initial insult and subsequent healing period has subsided. In addition, if RGMa inhibition cannot promote neurorestoration without the endogenous repair processes, this raises the possibility that elezanumab therapy may be best suited for the days, weeks, and months following demyelination, rather than after years or decades.
The maximum soluble RGMa reduction observed in phase 1b CSF was approximately 40%. 14 Although human equivalent doses promoted repair in acute animal models, it is possible that a greater magnitude of reduction is required in humans. The role of membrane‐bound RGMa and its required reduction for benefit also remains unknown.
Like other clinical trials ongoing at the time, the emergence of the COVID‐19 pandemic led to disruptions and necessary trial adjustments. All efforts were made to protect participant safety and study integrity. Protocol adjustments are detailed in Table S2.
Some preclinical studies (including those with elezanumab) assess treatment effects either during or shortly after nervous system injury. In contrast, participants in the RADIUS clinical trials had deficits resulting from lesions that were years to decades old. It is possible that elezanumab administration in closer proximity to a traumatic, inflammatory, or degenerative insult could prove beneficial. Consistent with this hypothesis, ongoing elezanumab trials in acute ischemic stroke (NCT04309474) and acute traumatic spinal cord injury (NCT04295538) are using an early administration time window.
Author Contributions
B.A.C.C., M.G., K.P., B.S., and A.Z. contributed to the conception and design of the study; B.A.C.C., M.S.F., M.G., K.P., B.S., A.W., and A.Z. contributed to the acquisition and analysis of data; B.A.C.C., M.S.F., M.G., K.P., B.S., A.W., and A.Z. contributed to drafting the text or preparing the figures.
Potential Conflicts of Interest
B.A.C.C. and M.S.F. have nothing to report. M.G. and A.Z. disclose former employment and holdings of stock and/or stock options with AbbVie, which manufactures a drug used in the study. K.P. and B.S. disclose employment and stock and/or stock options with AbbVie, which manufactures a drug used in the study. A.W. discloses research support and compensation as an advisor from AbbVie, which manufactures a drug used in the study.
Supporting information
Data S1. Supporting Informtion.
Acknowledgements
We and AbbVie thank: all study investigators and the participants who participated in these clinical trials; Dr English and Dr Thrower; H. Kalluri, M. Szapacs, and J. Mollon for analysis and interpretation of the data. AbbVie (North Chicago, IL) funded the study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. M.R. Distasi, PhD and P.E. Collins, PhD of AbbVie Inc. provided medical writing support, and A.T. Hadsell of AbbVie Inc. and E.J. Farrar, PhD of JB Ashtin provided editorial support during the development of this publication, all funded by AbbVie Inc.
Data Availability
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial‐level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, statistical analysis plan, and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvieclinicaltrials.com/hcp/data-sharing/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Informtion.
Data Availability Statement
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial‐level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, statistical analysis plan, and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvieclinicaltrials.com/hcp/data-sharing/.