Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data

Alemtuzumab; Product surveillance; Risk assessmentAlemtuzumab; Vigilancia de productos; Evaluación de riesgosAlemtuzumab; Vigilància de productes; Avaluació de riscosDoes preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The CAMMS223 and CARE-MS studies, and their extensions, were supported by Sanofi and Bayer Healthcare Pharmaceuticals. Editorial and writing assistance was supported by Sanofi

Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years

Alemtuzumab; Efficacy; SafetyAlemtuzumab; Eficacia; SeguridadAlemtuzumab; Eficàcia; SeguretatBackground Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]). Methods Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years). Results Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22–0.24 vs. 0.38–0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%–92% vs. 62%–88%; achievement of 6-month confirmed disability improvement [CDI]: 20%–31% vs. 13%–25%), increased proportions free of MRI disease activity (70%–86% vs. 42%–63% per year), and slowed brain volume loss (BVL; –0.45% to –0.87% vs. –0.50% to –1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%–2.2% vs. >45 years: 8.1%) and deaths (0%–1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts. Conclusions Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.The study was supported by Sanofi and Bayer HealthCare Pharmaceuticals

Toward Precision Phenotyping of Multiple Sclerosis

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS.</p

FLAIR (3T) and GRE phase (7T) images of a patient with active relapsing-remitting MS.

<p>FLAIR images show numerous white matter MS lesions of which 2 are magnified (inset, red arrows). Phase imaging at 7T phase/GRE reveals a hypointense ring corresponding with one lesion on FLAIR. The other lesion is not visible on 7T GRE (inset, arrows).</p

Iron and myelin uptake in human monocyte-derived macrophages (MDMs).

<p>Non-polarized M0, M1- and M2-polarized macrophages were stained for neutral lipids (oil red-O) and iron (Perls). In untreated cultures, macrophages did not contain iron or significant amounts of lipids [a–c]. In macrophages exposed to FeCl₃ (10 µM; 10 hrs), Perls' staining showed polarization-dependent iron uptake [d–f]. Exposure of iron-rich macrophages to purified human myelin (30 µg/ml; 24 hrs) lead to depletion of iron from myelin-phagocytosing macrophages in all polarization states [g–i]. Presence of iron within macrophages was closely mirrored by macrophage expression of ferritin: macrophages without iron-load express little ferritin [aa–cc], while iron loading leads to increased expression of ferritin [dd–ff], particularly in M1 macrophages [ee]. Addition of myelin to iron-rich macrophages resulted in substantial reduction of ferritin in all polarization states [gg–ii]. In macrophages exposed first to myelin [j–l] and subsequently to iron, iron accumulation was significantly reduced compared to that in naive macrophages [m–o]. When M1 macrophages were incubated with myelin in the presence of the receptor-associated protein (GST-RAP), which binds to the presumed receptor for myelin ingestion, LRP-1, and inhibits interaction with other ligands, myelin ingestion was prevented [p]. Blockade of myelin ingestion in M1 macrophages with GST-RAP and subsequent exposure to FeCl₃ led to unimpeded iron uptake [q]. In contrast to myelin, internalization of fluorescent polystyrene microspheres by M1 macrophages did not prevent subsequent iron uptake [r].</p

Patient demographics.

<p>Patient demographics.</p

Iron uptake enhances M1 polarization.

<p>A. Human MDMs were seeded in 48 well dishes at cell density of 2×10⁶ cells/ml and polarized according to protocol. Various concentrations of FeCl₃ (0–100 µM) were added to the differentially polarized macrophages. Where indicated, cells were pre-incubated with human myelin (30 µg/ml) for 24 hrs before addition of FeCl₃. After 10 hrs, cell-free supernatants were collected and TNF-α and IL-10 concentrations were measured by ELISA. Iron uptake increased secretion of TNF-α in M1-polarized but not in M0 and M2-polarized macrophages and reduced IL-10 in M2-polarized macrophages. Cytokine secretion did not change in myelin-laden macrophages after exposure to iron. Results are expressed as means ± SEM from three separate experiments. *p<0.05; **p<0.01; ***p<0.005 by Student's t test. B. For measurement of reactive oxygen species (ROS), cells were loaded with 30 µM of oxidant-sensitive DCF-DA dye after exposure to iron and fluorescent emission was measured at 540 nm. The experiment was performed in triplicates and repeated three times. The data are expressed as change in fluorescence/8×10⁴ cells (± SEM). Iron uptake increased generation of ROS secretion in non-phagocytosing macrophages in all polarization states, most prominently in M1 polarization. Myelin-laden macrophages did not respond to iron exposure. *p<0.05; **p<0.005 by Student's t test. C. To visualize ROS generation, macrophages seeded on coverslips were incubated with 30 µM FeCl₃ for 2 hrs and subsequently loaded with 30 µM of DCF-DA. Images were acquired at timed intervals (representative images at 10 min are shown). The results recapitulate ROS quantification in (B): ROS was increased in iron-laden MDMs [d–f] compared to naïve [a–c] or myelin-laden MDMs [g–i]. In contrast, labeling for the M2 polarization marker CD206, revealed decreased expression of CD206 in macrophages exposed to iron [dd–ff] and increased expression in myelin-laden macrophages [gg–ii].</p

Efficacy, safety, and cost-effectiveness of glatiramer acetate in the treatment of relapsing–remitting multiple sclerosis

The current Multiple Sclerosis (MS) therapeutic landscape is rapidly growing. Glatiramer acetate (GA) remains unique given its non-immunosuppressive mechanism of action as well as its superior long-term safety and sustained efficacy data. In this review, we discuss proposed mechanisms of action of GA. Then we review efficacy data for reduction of relapses and slowing disability as well as long term safety data. Finally we discuss possible future directions of this unique polymer in the treatment of MS