Results from a multicenter, randomized, double‐blind, placebo‐controlled study of repository corticotropin injection for multiple sclerosis relapse that did not adequately respond to corticosteroids

Abstract Introduction About 20%–35% of multiple sclerosis (MS) patients fail to respond to high‐dose corticosteroids during a relapse. Repository corticotropin injection (RCI, Acthar® Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and pituitary peptides that has anti‐inflammatory and immunomodulatory effects. Aims The study objective was to determine the efficacy and safety of RCI in patients with MS relapse that inadequately responded to corticosteroids. This was a multicenter, double‐blind, placebo‐controlled study. Nonresponders to high‐dose corticosteroids were randomized to receive RCI (80 U) or placebo daily for 14 days. Assessments included improvements on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale (MSIS‐29), Clinical Global Impression of Improvement (CGI‐I), and adverse events (AEs). Results Eighteen patients received RCI, and 17 received placebo. A greater proportion of EDSS responders was observed in the RCI group at Day 7, 21, and 42 compared with the placebo group. Qualitative CGI‐I showed that more patients receiving RCI were much improved or very much improved than with placebo. No meaningful differences were observed between treatment groups for MSIS‐29. No serious AEs or deaths were reported. Conclusion RCI is safe and effective for MS relapse patients who do not respond to high‐dose corticosteroids.


| INTRODUC TI ON
Relapsing-remitting multiple sclerosis (RRMS) is a complex disease affecting the central nervous system with several pathophysiological mechanisms such as inflammation, demyelination, axonal damage, and repair. 1 Relapses are considered to be a hallmark of RRMS, which is the most common form of multiple sclerosis (MS). 2 In clinical trials, a relapse is normally defined as a minimum symptom period of 24-48 h accompanied by changes in functional measures. 2 MS relapses often result in significant functional impairments and decreased quality of life. 2,3 A relapse is usually followed by a period of remission, but incomplete recovery and residual symptoms can persist, leading to worsening disability. 2,4 Common triggers for relapses include infection and stress. 2,4 Relapses may reflect new demyelination or reactivation of previous demyelinated lesions in the central nervous system. 2 Disease-modifying therapies are highly effective, but relapses still occur and require treatment to prevent persistent residual symptoms and disability. 2,5 The standard of care therapy for relapses is high-dose corticosteroids. 2,6 However, it is estimated that 20%-35% of patients with MS do not respond to high-dose corticosteroids, 2 so alternative therapies are needed for these patients with  6 MC2R is expressed in adrenocortical cells and upon activation stimulates the production of endogenous cortisol. 6 Synthetic ACTH 1-24 has its highest activity at MC2R, while RCI has its lowest full agonistic activity at MC2R. 8 Consistent with their MC2R activity profiles, studies in animals and in healthy human subjects have demonstrated much lower endogenous cortisol production with RCI than with synthetic ACTH 1-24 depot. 8,11 This suggests that RCI primarily functions through direct modulation of immune cells, rather than through endogenous cortisol production from the adrenal cortex. 8 RCI has been shown to be immunomodulatory because it inhibits B-cell proliferation, antibody production, and inflammatory cytokine production from T cells and macrophages. 10,12,13 The objective of this clinical trial was to determine the efficacy and safety of RCI for treatment of relapses in patients with RRMS that failed to respond to high-dose corticosteroids.

| Study design
This was a multicenter, randomized, double-blind, placebo-controlled study to estimate the response rate and examine the safety of RCI in patients with RRMS who had inadequate responses to high-dose intravenous methylprednisolone (IVMP), oral prednisone, or oral methylprednisolone. The study was conducted across 31 centers in the United States of America from 2017 to 2020, in accordance with the principles and requirements of the Declaration of Helsinki, Good Clinical Practices, and clinical trial registration (ClinicalTrials. gov identifier NCT03126760). All participating patients provided written informed consent prior to enrollment in the study.

| Study population
Patients with RRMS who experienced a relapse with onset ≤42 days prior to the baseline visit and received 3 to 5 days (given over a period of up to 7 days) of treatment with high-dose IVMP (1000 mg /day), oral prednisone (1250 mg per day [QD]), or oral methylprednisolone (1000 mg QD) within 28 days of the onset of relapse symptoms were eligible to participate in the study. All patients had no prior use of RCI. A screening visit took place in the initial 28 days of the 42 days screening period, and patients were assessed with the Expanded Disability Index Scale (EDSS)/Function Systems Score (FSS) prior to treatment with IVMP, oral prednisone, or oral methylprednisolone. At 14 ± 1 days following the initiation of high-dose corticosteroids, patients were reassessed with EDSS/FSS and were defined as nonresponders (eligible for inclusion) if they did not improve by at least 1 point in one or more functions of the FSS. Other key inclusion criteria were being adult males or nonpregnant females with a diagnosis of RRMS, as well as having an EDSS score of 2.0-6.5 at the baseline visit and Hemoglobin A1C (HbA1c) ≤6.5% at screening.
Patients were ineligible if they had known contraindications to RCI or known sensitivity to ACTH preparations or to porcine protein products. Patients were excluded if they only had sensory, bowel/ bladder, and/or cognitive symptoms of MS associated with the most recent relapse. Those who were receiving any disease-modifying treatments must have been on a stable dose(s) for 30 days prior to the baseline visit and plan to remain on that dose(s) throughout the study. Patients were excluded from the clinical trial if they were treated with daclizumab or any immunosuppressants in the 6 months prior to the screening visit or throughout the study.

| Interventions and assessment schedule
Eligible patients were randomized according to a computergenerated allocation scheme to receive either RCI 1 mL (80 U) or placebo 1 mL QD for 14 consecutive days. Treatment response was evaluated using EDSS and other measures up to 42 days after study drug dosing. Patients participated in the study for up to 13 weeks, including a screening period of up to 42 days and an active treatment period of 14 days, and follow-up visits occurred at 21 ± 2 days and 42 ± 2 days after the start of study drug administration. The study design and treatments are summarized in Figure 1.

| Efficacy assessments
The primary objective of this study was to determine the EDSS response rate with 90% confidence intervals (CIs) at Day 42 for each treatment group. Other assessments included mean scores and 90%

| Safety outcomes
At the screening visit, both prior and current medical conditions were recorded, as well as the last date of the menstrual period in female patients. Prior to administration of the drug, all women of childbearing age must have had a negative pregnancy test. Physical examinations, clinical laboratory tests, pregnancy testing, medical history, weight, and vital signs were monitored at screening and throughout the study. Adverse events (AEs) were recorded and followed by the investigator until the AE had resolved or stabilized, with the first assessment made at the screening visit after treatment with corticosteroids and before treatment with RCI. Adverse events of special interest (AESIs) were elevated blood pressure, hyperglycemia, and AEs considered possibly, probably, or definitely related to study drug treatment of greater than moderate intensity or any infection/ infestation as defined by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class as being greater than moderate intensity and Hy's Law cases. Treatment-emergent adverse events (TEAEs) were defined as AEs that started or worsened on or after the first dose of the study drug. Treatment-related AEs were those TEAEs that were considered possibly related or related to the test drug.

| Patient selection, demographics, and characteristics
From the screening of 107 RRMS patients, there were 72 total screen failures; 25 responded to high-dose steroid therapy, while the remaining 47 did not respond to high-dose steroid therapy, but failed screening due to other criteria such as laboratory abnormalities (ie, HbA1c elevation, anemia, or aspartate aminotransferase/alanine aminotransferase elevation poststeroids). Specific steroid use was not captured in these patients; however, based on randomized patient data, it can be assumed that approximately 35 (75%) of these patients did not respond to IVMP and 12 (25%) did not respond to oral prednisone.
A total of 35 patients were randomized, with 18 patients assigned to the RCI arm and 17 patients to the placebo arm ( Figure 1).
One patient from the RCI group withdrew after 8 treatments because of TEAEs of edema and pain. However, the patient returned to complete the final visit.
Baseline demographics and patient characteristics are summarized in

| Efficacy
The primary objective of the study was met, with more EDSS re-  (Figure 3). There was no meaningful difference in the mean CGI-I scores between treatment groups (data not shown). Patient-reported outcomes (PROs) for quality of life also did not show meaningful differences between the RCI and placebo groups (data not shown).

| Safety
AEs recorded after corticosteroid treatment but prior to RCI initiation are presented in Table S1. After RCI initiation, the incidence of TEAEs throughout the study was similar between RCI and placebo groups (   included those with potentially more severe relapse than would be commonly seen in a normal treatment environment. In addition, patients received different (intravenous or oral steroid) treatments, and the relatively small number of patients prevents any generalization regarding the incidence of responders.
The findings in this clinical trial are supported by the results of a recent real-world registry study of the use of RCI for the treatment of MS relapse. 7 The MS relapse registry reported efficacy and safety outcomes in 125 patients with acute MS relapse treated with RCI over 24 months. 7 In the current study, there were more EDSS responders at Days 7, 21, and 42 after RCI initiation, which is consistent with the findings in the MS relapse registry. 7 In the MS relapse registry study, RCI showed improvements in MSIS-29 and CGI-I scores at 2 and 6 months compared to baseline. 7 In the current study, both RCI and placebo groups showed improvements in the MSIS-29 and CGI-I scores compared to baseline, but there were no substantial differences between treatment groups. The duration of the current study was only 42 days, so it is possible that greater differences between treatment groups in MSIS-29 and CGI-I scores may have been seen if the study were longer.
This study confirmed the safety of RCI, as most TEAEs were mild in severity and occurred at similar frequencies to the placebo group. The MS relapse registry study reported that only 28% of RCItreated patients experienced AEs, which is comparatively lower than the 77.8% who experienced TEAEs in the RCI group in the current study. In a large double-blind randomized clinical trial (N = 259) for RCI use in rheumatoid arthritis, 3.9% of patients had hyperglycemia or hypertension, suggesting that the incidence of these AEs was relatively low in this population. 15 AESIs defined for the current study included hyperglycemia and hypertension, but no patients experienced these specific events.
This randomized clinical trial demonstrated that RCI is effective in patients with RRMS that did not adequately respond to high-dose corticosteroids, which suggests that the mechanism of action of RCI is distinct from that of corticosteroids. 8,10,11 Although RCI does induce endogenous cortisol production from the adrenal cortex, recent studies in healthy human subjects suggest that these cortisol levels are relatively low following biweekly dosing. 11  suggesting that RCI has a unique anti-inflammatory mechanism of action.

ACK N OWLED G M ENTS
Professional writing and editorial support were provided by Genzyme.

AUTH O R CO NTR I B UTI O N S
All authors contributed to the conception or design of the study, analyzed or interpreted data, and contributed to the writing of the manuscript.

E TH I C A L S TATEM ENT
The study was conducted across 31 centers in the United States of America from 2017 to 2020, in accordance with the principles and requirements of the Declaration of Helsinki, Good Clinical Practices, and clinical trial registration (ClinicalTrials.gov identifier NCT03126760). All participating patients provided written informed consent prior to enrollment in the study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets generated during and/or analyzed during the current study are not publicly available. Individual patient data may be requested if allowed per informed consent and appropriately anonymized.