Journal of Multiple Sclerosis

A Retrospective Study of Utilization of Repository Corticotropin Injection (HP Acthar Gel) as Pretreatment for Alemtuzumab Infusion

Christen Kutz^{* *}Correspondence: Christen Kutz, Colorado Springs Neurological Associates, 2312 N. Nevada Avenue, Colorado Springs, CO 80907, USA, Tel: (719) 473-3272, Fax: (719) 389-1192, Email:

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Introduction

Alemtuzumab (Lemtrada®; Sanofi Genzyme, Cambridge, MA) is a highly effective, humanized, monoclonal antibody treatment approved for Relapsing- Remitting Multiple Sclerosis (RRMS) [1]. Alemtuzumab is administered as two courses, on 5 consecutive days at treatment initiation and 3 consecutive days 12 months later. It acts by binding CD52, a cell surface protein expressed at high levels by T and B lymphocytes, causing their lysis and rapid depletion, followed by cellular repopulation [2]. This mechanism of action is associated with an acute cytokine release syndrome, leading to Infusion-Associated Reactions (IARs) [3]. In phase 3 trials and their extension study (NCT00530348; NCT00548405; NCT00050778), IARs were the most common adverse events associated with alemtuzumab, occurring in 90% of patients [4-7]. IARs were mostly mild to moderate and primarily manifested as headache, rash, pyrexia, urticaria, or nausea. IAR incidence declined after the first course (Course 1: 84.7%, Course 2: 68.6%, Course 3: 64.6%, and Course 4: 62.8%); incidence of serious IARs was ≤ 2% with each course [8]. Prophylactic corticosteroids were given to patients in the clinical trials to minimize IARs [4,6], and such pretreatment is now recommended in the product label [1]. However, many patients have a contraindication or intolerance for corticosteroids.

Repository corticotropin injection (RCI; H.P. Acthar Gel, Mallinckrodt Pharmaceuticals Inc; Bedminister, NJ, USA) has historically been used in the clinic in MS patients as an alternative to corticosteroids for treatment of MS relapses [9,10]. It is a purified preparation of adrenocorticotropic hormone that is slowly absorbed into the bloodstream when injected intramuscularly or subcutaneously [11], and stimulates endogenous steroid release from the adrenal gland [9]. In recent years, RCI has been used off-label as alemtuzumab pre-infusion medication in patients for whom corticosteroid use is not feasible. This study investigated real-world clinical experience with RCI to alleviate the risk of alemtuzumab-associated IARs in patients with MS.

Methods

This was a retrospective survey study of patients in the United States who were administered RCI prior to alemtuzumab infusion. The primary objectives of the study were to identify patient characteristics that necessitate alternatives to corticosteroids, and to investigate the efficacy of RCI in reducing IARs with alemtuzumab. The secondary objectives were to describe demographics of real-world MS patients treated with alemtuzumab, identify additional pretreatment medications used in the clinic, and identify differences in pretreatment practices during the first course of alemtuzumab compared with the second course.

Data were collected using an electronic questionnaire completed by qualified healthcare providers who prescribed RCI to alleviate the risk of alemtuzumab-associated reactions. The questionnaire was sent via e-mail to 300 MS-specific health care providers, and included questions pertaining to patient disease characteristics, demographics, experience with RCI, concomitant pretreatment medications, IARs, and RCI-associated adverse events. De-identified data from the questionnaires were returned to the study investigator and analyzed using descriptive statistics. Catholic Health Initiatives Institute for Research and Innovation Institutional Review Board (CHIRB) reviewed and approved this study on June 18, 2018.

Results

Patients

A total of 206 questionnaires was returned to the study investigator. Of these, 175 questionnaires (1 per patient) were complete and used for the analysis; 23 questionnaires included information on alemtuzumab Courses 1 and 2, and the remainder included information on Course 1 only. Patients were predominantly Caucasian (62%), but the proportions of black (21%) and Hispanic (15%) patients was higher than in clinical trials [4,6]. Forty percent of patients had progressive forms of MS. Prior disease-modifying therapies (DMTs) included glatiramer acetate, interferon preparations, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and others (Table 1).

Table 1. Baseline characteristics and prior disease modifying therapies (DMTs)

RCI Use

The most common reason for using RCI prior to alemtuzumab infusion was a history of steroid intolerance; this reason was more frequent with Course 2 than with Course 1 (Figure 1). Comorbidities also precluded corticosteroid use during Course 1 (20%) and Course 2 (27%). Although information on the nature of the comorbidities was not systematically collected, diabetes and steroid-induced psychosis were commonly noted by respondents.

Figure 1: Reasons for RCI administration in lieu of corticosteroids prior to alemtuzumab

Most healthcare providers reported administering RCI one day prior to alemtuzumab Course 1 (61%) and Course 2 (76%) infusions; most others began RCI on the same day as the first alemtuzumab infusion. RCI was primarily administered subcutaneously (Course 1: 91%; Course 2: 82%), at a dose of 80 units (range 60–120 units), for 1 to 5 days in most patients (Table 2). In addition to RCI, the most frequent pretreatment medications prior to Course 1 were ranitidine (22%), acetaminophen (21%), and diphenhydramine (20%) (Table 2). Interestingly, intravenous methylprednisolone was given in addition to RCI in 5% of patients. Higher percentages of patients received pretreatment medications with Course 2 than with Course 1 (Table 2).

Table 2. RCI use and other concomitant pretreatment medications prior to alemtuzumab infusion

RCI Efficacy

Patients receiving Course 1 (56%) and Course 2 (61%) infusion reported having no alemtuzumab IARs following treatment with RCI (Table 3). The most commonly reported IARs were headache, fatigue, nausea, dizziness, weakness, and rash. Paresthesia’s and itching were reported in 6% of patients. Other less common events (<5%) observed in this category included trouble breathing, irregular heartbeats, swelling in mouth or throat, and other side effects.

Table 3. Infusion-associated reactions

RCI Safety

Most patients had no adverse events related to RCI as assessed by the reporting health care provider (Course 1: 72% and Course 2: 91%). The most common adverse events included insomnia and gastrointestinal discomfort. Fluid retention, elevated blood pressure, and altered glucose tolerance was observed in ≤ 5% of patients with each infusion course (Figure 2).

Figure 2: Adverse events associated with RCI use

Discussion

In this retrospective survey study, the reported incidences of IARs (Course 1: 44%; Course 2: 39%) in patients pretreated with RCI was lower than those reported in the CARE-MS studies (Course 1: 85%; Course 2: 69%) [8], in which patients were pretreated with intravenous corticosteroids. As in the CAREMS studies, the incidence of IARs decreased after the first course. However, in the present study, use of antihistamines and antipyretics was more common during Course 2 compared with Course 1, which may contribute to the lower frequency of IARs with Course 2. Data on the use of antihistamines and antipyretics in the CARE-MS studies are unfortunately not available for comparison. The types of IARs reported in this study were similar to those observed in the CARE-MS studies [3], such as headache, fatigue, nausea, dizziness, weakness, and rash. Taken together, these results suggest that RCI is as effective in reducing the risk of alemtuzumab IARs as intravenous corticosteroids.

For some patients, corticosteroids are not feasible, necessitating an alternative pretreatment option. In this study, healthcare providers most often reported opting for RCI instead of corticosteroids due to a history of corticosteroid intolerance, followed by comorbidity and history of poor response to corticosteroids. The RCI premedication dosage healthcare providers prescribed to their patients was similar to the dosage used in the treatment of MS exacerbations (80 units) [9,12,13], although the 100-unit dose was also frequently used. RCI was most commonly given on 5 days for each alemtuzumab treatment course, which would have exceeded the number of infusion days for Course 2 (3 days). The preferred route of RCI administration in this study was subcutaneous, as prior studies have demonstrated that the intramuscular route of administration was associated with more injection site pain compared with subcutaneous administration [10].

RCI has been associated with fewer adverse events than high doses of corticosteroids in certain clinical disorders [14,15]. In this study, 72% of patients had no RCI-associated adverse events during Course 1 infusion; this percentage increased to 91% during Course 2. The adverse events reported in this study are consistent with known side effects of RCI [11]. The most frequently reported adverse events were insomnia and gastrointestinal discomfort. Medications addressing gastrointestinal disorders, such as ranitidine and famotidine, were used by a higher percentage of patients during Course 2 than Course 1, which may explain the drop in gastrointestinal adverse event incidence during Course 2 infusion. Overall, survey respondents reported a low incidence of adverse events attributable to RCI.

In addition to informing healthcare providers on the use of RCI as a pretreatment for alemtuzumab infusion, the data from this study provide a snapshot of the patient population that is receiving alemtuzumab treatment in the United States. The percentage of patients with progressive forms of MS was considerable (40%), although the label indicates the drug for relapsing forms. Pivotal trials have been restricted to patients with relapsing-remitting MS [4,6], and efficacy has not been demonstrated in progressive MS patients [16]. However, this observation may indicate that clinicians perceive a potential benefit of alemtuzumab in progressive patients. A second observation from patient characteristic data in this study is the high proportion of black patients (21%) receiving alemtuzumab treatment, compared with the phase 3 trials, in which >90% of participants were white [4,6]. Patients in the present study are more representative of the US MS population, which has been reported to be 24% black [17]. This observation strengthens the applicability of the present data to real-world populations, and further highlights the previously documented underrepresentation of minority populations in clinical trials [18].

Conclusion and Limitations

There are several limitations in this study, aside from its retrospective design. First, the number of questionnaires collected for patients who received RCI treatment during Course 2 infusion (n=23) was much smaller than those collected for Course 1 infusion (n=175). Second, there were no control arms to separate the effects of alemtuzumab infusion, RCI pretreatment, and pretreatment with other medications. Furthermore, there is a possibility that concomitant medications or long-term effects of prior DMTs may have affected both the alemtuzumab IAR profile and the RCI adverse event profile. Prospective, controlled studies evaluating RCI for IAR management are warranted.

In summary, RCI treatment prior to alemtuzumab infusion was a welltolerated and safe alternative to corticosteroids in a real-world population with MS. Alemtuzumab-associated IARs were reduced with RCI treatment compared with clinical trial data. These findings can aid healthcare providers in premedication decision-making for patients with MS undergoing alemtuzumab treatment, for whom corticosteroid pretreatment is not feasible.

Practice Points

• Repository corticotropin injection is an effective, well-tolerated alternative premedication for infusion-associated reactions during alemtuzumab treatment

• Healthcare providers use repository corticotropin injection in patients with a history of steroid intolerance, poor response to steroids, contraindication, or comorbidities

• No adverse events attributable to repository corticotropin injection were reported in the majority of patients (72%), when used as pretreatment for alemtuzumab infusion

Acknowledgments

The author would like to thank survey respondents for their participation in the study. Medical writing assistance was provided by Noopur Mandrekar, PhD, and Valerie P. Zediak, PhD, of Eloquent Scientific Solutions.

Financial Disclosures

Author has been a consultant for Sanofi Genzyme, Biogen, EMD Serono, Teva, Mallinckrodt, and Novartis.

Funding/Support

This study and medical writing assistance were funded by a research grant from Sanofi. The author collected and analyzed the study data and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Previous Presentation

These data were previously presented as a poster at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 11−13, 2019, Stockholm, Sweden.

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