Background:
Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk.
Objective:
To examine ITP ...incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials.
Methods:
CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion.
Results:
Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 2.0%; alemtuzumab 24 mg, 9 3.3%) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials.
Conclusion:
Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.
Background:
Alemtuzumab is administered as two annual courses for relapsing–remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.
Objective:
The objective ...was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).
Methods:
Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.
Results:
Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1–2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: −0.67% (CARE-MS I); −0.47% (CARE-MS II)) declined after Course 2 (Year 6: −0.24%; −0.13%).
Conclusion:
Early relapsers’ outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.
ClinicalTrials.gov registration numbers:
CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.
Introduction
Multiple sclerosis (MS) patients of African descent have increased risk for disease progression and may be less responsive to disease-modifying therapy.
Methods
Patients in the CARE-MS ...studies received alemtuzumab 12 mg/day initial alemtuzumab treatment (IAT); baseline: 5 days; 12 months later: 3 days or subcutaneous interferon beta-1a (SC IFNB-1a) 3 ×/week. Core study outcomes were compared between treatment groups. In the extension study CAMMS03409, SC IFNB-1a-treated patients switched to alemtuzumab delayed alemtuzumab treatment (DAT). Data from IAT and DAT arms were pooled to assess outcomes through 6 years post alemtuzumab initiation; IAT patients had an additional 2 years of follow-up in TOPAZ.
Results
Of 1200 CARE-MS patients, 43 (4%) were of African descent (35 IAT; 8 DAT) and received alemtuzumab in the 2-year core and/or 6-year extension; 29 (67%) remained on study at the time of analysis (24 IAT patients completed year 8 post alemtuzumab; 5 DAT patients completed year 6 post alemtuzumab). In year 2, annualized relapse rate (ARR; 0.09 versus 0.42), percentage of patients with improved Expanded Disability Status Scale (EDSS; 18% versus 11%), 6-month confirmed disability improvement (CDI; 28% versus 13%), no evidence of disease activity (55% versus 13%), and cumulative brain volume loss (BVL; − 0.55% versus − 1.32%) favored alemtuzumab versus SC IFNB-1a. Alemtuzumab remained efficacious at year 6 (pooled IAT/DAT) and at year 8 (IAT only) post alemtuzumab (ARR: 0.15 and 0.30; improved EDSS: 17% and 25%; CDI: 47% and 55%; BVL: − 1.14% and − 0.70%, respectively). No safety signals were unique to this population.
Conclusions
Alemtuzumab was efficacious in a small cohort of relapsing-remitting MS patients of African descent over 8 years. Safety was consistent with the overall CARE-MS population, although the small sample size may have prevented the detection of known low-frequency adverse events.
ClinicalTrials.gov Registration Numbers
CARE-MS I, II, extension, TOPAZ: NCT00530348, NCT00548405, NCT00930553, NCT02255656.
Funding
Sanofi (Cambridge, MA, USA) and Bayer HealthCare Pharmaceuticals (Leverkusen, Germany).
Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of ...inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis.
We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18–55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed.
Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean SD lesions per patient: placebo, 1·03 2·50; 5 mg, 1·39 3·20; 15 mg, 0·77 1·48; 30 mg, 0·76 3·31; 60 mg, 0·13 0·43; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one 3% of 33 in the 5 mg group; three 9% of 32 in the 15 mg group; one 3% of 33 in the 30 mg group; and four 13% of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred.
12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis.
Sanofi.
Background
In the phase 2 CAMMS223 trial (NCT00050778), alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over 3 years in treatment-naive patients ...with relapsing–remitting MS. Here, we assess efficacy and safety of alemtuzumab over 12 years in CAMMS223 patients who enrolled in the CAMMS03409 extension (NCT00930553), with available follow-up through the subsequent TOPAZ extension (NCT02255656).
Methods
In CAMMS223, patients received 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days); 22% received a third course. In the open-label, nonrandomized extensions, patients could receive as-needed additional alemtuzumab or other disease-modifying therapies.
Results
Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the CAMMS03409 extension; 33% received a total of 2 alemtuzumab courses, and 73% received no more than 3 courses through Year 12. Over 12 years, annualized relapse rate was 0.09, 71% of patients had stable or improved Expanded Disability Status Scale scores, and 69% were free of 6-month confirmed disability worsening. In Year 12, 73% of patients were free of MRI disease activity. Cumulatively throughout the extensions (Years 7–12), 34% of patients had no evidence of disease activity. Adverse event (AE) incidence declined through Year 12. Infusion-associated reactions peaked at first course and declined thereafter. Cumulative thyroid AE incidence was 50%; one immune thrombocytopenia event occurred, and there were no autoimmune nephropathy cases.
Conclusions
Alemtuzumab efficacy was maintained over 12 years in CAMMS223 patients, with 73% receiving no more than three courses. The safety profile in this cohort was consistent with other alemtuzumab clinical trials.
The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying ...therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs.
Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment.
Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0.024). Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001).
After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment.
ClinicalTrials.gov NCT01216072 .
Background The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable ...disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs. Methods Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment. Results Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0.024). Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001). Conclusions After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment. Trial registration ClinicalTrials.gov Keywords: 36-item Short-Form Health Survey (SF-36), Beck Depression Inventory-II (BDI-II), Clinical Global Impressions of Improvement (CGI-I), Fatigue Severity Scale (FSS), Fingolimod, FTY720, Multiple sclerosis, Treatment Satisfaction Questionnaire for Medication (TSQM)
Posthumanism in Art and Science is an anthology of indispensable statements and artworks featuring groundbreaking theorists as well as innovative, influential artists and curators. Their provocative ...and compelling works speak to the ongoing conceptual and political challenge of posthuman theories in a time of cultural and environmental crises.
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