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Multiple Sclerosis (Houndmills,... Dec 2018Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments.
BACKGROUND
Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments.
OBJECTIVE
Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE.
METHODS
Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the overall population and subgroups defined by baseline demographic/disease characteristics.
RESULTS
Daclizumab beta significantly reduced risk of 24-week CDP (hazard ratio (HR), 0.73; 95% confidence interval (95% CI), 0.55-0.98), risk of 24-week sustained MSFCS progression (HR, 0.80; 95% CI, 0.67-0.95), and odds of clinically meaningful worsening in MSIS-29 PHYS (odds ratio, 0.76; 95% CI, 0.60-0.95) versus IM interferon beta-1a. Point estimates showed trends favoring daclizumab beta over IM interferon beta-1a across several patient subgroups for all three outcome measures.
CONCLUSION
Daclizumab beta showed consistent benefit versus IM interferon beta-1a across measures assessing patient disability/function and across a range of clinical baseline characteristics in patients with relapsing-remitting MS.
Topics: Adult; Antibodies, Monoclonal, Humanized; Daclizumab; Disease Progression; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Interferon beta-1a; Male; Middle Aged; Multiple Sclerosis; Treatment Outcome
PubMed: 28984179
DOI: 10.1177/1352458517735190 -
Neurotherapeutics : the Journal of the... Oct 2017Patient-reported outcomes (PROs) are playing an increasing role in multiple sclerosis (MS) research and practice, and are essential for understanding the effects that MS... (Review)
Review
Patient-reported outcomes (PROs) are playing an increasing role in multiple sclerosis (MS) research and practice, and are essential for understanding the effects that MS and MS treatments have on patients' lives. PROs are captured directly from patients and include symptoms, function, health status, and health-related quality of life. In this article, we review different categories (e.g., generic, targeted, preference-based) of PRO measures and considerations in selecting a measure. The PROs included in MS clinical research have evolved over time, as have the measures used to assess them. We describe findings from recent MS clinical trials that included PROs when evaluating Food and Drug Administration-approved disease-modifying therapies (e.g., daclizumab, teriflunomide). Variation in the measures used in these trials makes it difficult to draw any conclusions from the data. We therefore suggest a standardized approach to PRO assessment in MS research and describe 2 generic, National Institutes of Health-supported measurement systems [Neuro-QoL and the Patient-Reported Outcomes Measurement Information System (PROMIS)] that would facilitate such an approach. The use of PROs in MS care and research is expanding beyond clinical trials, as is demonstrated by examples from comparative effectiveness and other patient-centered research. The importance of PRO assessment is expected to continue to grow in the future.
Topics: Clinical Trials as Topic; Endpoint Determination; Humans; Multiple Sclerosis; Patient Reported Outcome Measures; Quality of Life; Treatment Outcome
PubMed: 28913785
DOI: 10.1007/s13311-017-0571-6 -
Neurotherapeutics : the Journal of the... Oct 2017Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects... (Review)
Review
Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects via multiple mechanisms, including reduction of IL-2-mediated lymphocyte activation and upregulation of CD56-bright natural killer cells. Intravenous daclizumab (Zenapax™) was initially approved for prevention of rejection in renal transplant. In subsequent early testing, followed by larger-scale phase II and phase III trials, both intravenous and subcutaneous daclizumab have demonstrated clinical efficacy in the treatment of multiple sclerosis. The subcutaneous daclizumab prepared by high-yield process was utilized in the advanced phase II and phase III trials (SELECT and DECIDE). High-yield process daclizumab is now approved by the US Food and Drug Administration for relapsing-remitting multiple sclerosis, and is now formally termed daclizumab beta (DAC-beta; Zinbryta™). In this review, the early development of anti-IL-2 receptor alpha monoclonal antibodies and the properties of IL-2 and its receptor are discussed, and diverse mechanisms of action for daclizumab are presented. Results of the CHOICE, SELECT, and DECIDE clinical trials are discussed in detail. Adverse events observed in clinical trials included cutaneous reactions, liver enzyme elevations, infections, and autoimmune phenomena. DAC-beta is a monthly, patient-administered subcutaneous injection that requires enrollment in a safety monitoring (REMS) program for monthly liver function testing. Prescribers should be aware of the potential adverse events, as early recognition and management is important, particularly in cutaneous and hepatic reactions. Continued clinical experience with DAC-beta, including observations from the REMS program, will define its place in the armamentarium of immunotherapeutics for relapsing-remitting multiple sclerosis.
Topics: Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-2; Multiple Sclerosis; Receptors, Interleukin-2; Treatment Outcome
PubMed: 28707278
DOI: 10.1007/s13311-017-0553-8 -
Annals of Clinical and Translational... Jul 2017It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of...
OBJECTIVE
It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.
METHODS
Forty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open-label clinical trials. MRI contrast-enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease.
RESULTS
Rapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant ( < 0.0001) decreases in CSF levels of T-cell activation marker CD27 and IgG index. Interleukin 2 (IL-2) CSF levels increased from baseline levels during treatment, consistent with reduced IL-2 consumption by T cells, as a consequence of daclizumab's saturation of high-affinity IL-2 receptors. CSF levels of IL-12p40, chitinase-3-like protein-1 (CHI3L1), chemokine C-X-C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression.
INTERPRETATION
These observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.
PubMed: 28695148
DOI: 10.1002/acn3.427 -
Brain Sciences Jul 2017The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a... (Review)
Review
The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumb, ocrelizumab, alentuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS.
PubMed: 28686222
DOI: 10.3390/brainsci7070078 -
Annals of Surgery Sep 2017Determine the impact of cytolytic versus IL-2 receptor antibody (IL-2RA) induction on acute rejection, graft loss and death in African-American (AA) kidney transplant... (Comparative Study)
Comparative Study
OBJECTIVE
Determine the impact of cytolytic versus IL-2 receptor antibody (IL-2RA) induction on acute rejection, graft loss and death in African-American (AA) kidney transplant (KTX) recipients.
BACKGROUND
AAs are underrepresented in clinical trials in transplantation; thus, there is controversy regarding the optimal choice of perioperative antibody induction in KTX to improve outcomes.
METHODS
National cohort study using US transplant registry data from January 1, 2000 to December 31, 2009 in adult solitary AA KTX recipients, with at least 5 years of follow-up. Multivariable logistic and Cox regression were utilized to assess the outcomes of acute rejection, graft loss, and mortality, with interaction terms to assess effect modification.
RESULTS
Twenty-five thousand eighty-four adult AAs receiving solitary KTX were included, 16,927 (67.5%) received cytolytic induction and 8157 (32.5%) received IL-2RA induction. After adjustment for recipient sociodemographics, donor, and transplant characteristics, the use of cytolytic induction therapy reduced the risk of acute rejection by 32% (OR 0.68, 0.62-0.75), graft loss by 9% (HR 0.91, 0.86-0.97), and death by 12% (HR 0.88, 0.83-0.94). There were a number of significant effect modifiers, including public insurance, panel reactive antibody, delayed graft function, and steroid withdrawal; in these groups, cytolytic induction substantially improved clinical outcomes.
CONCLUSIONS
These data demonstrate that cytolytic induction therapy, as compared with IL-2RA, reduces the risk of rejection, graft loss, and death in adult AA KTX recipients, particularly in those who are sensitized, receive public insurance, develop delayed graft function, or undergo steroid withdrawal.
Topics: Adolescent; Adult; Black or African American; Aged; Aged, 80 and over; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Daclizumab; Female; Follow-Up Studies; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation; Logistic Models; Male; Middle Aged; Muromonab-CD3; Proportional Hazards Models; Recombinant Fusion Proteins; Registries; Retrospective Studies; Treatment Outcome; United States; Young Adult
PubMed: 28654544
DOI: 10.1097/SLA.0000000000002366 -
International Journal of MS Care 2017For patients with relapsing-remitting multiple sclerosis (RRMS) undergoing continuous immunomodulatory therapy, understanding whether vaccinations can be performed...
Immune Response to Seasonal Influenza Vaccine in Patients with Relapsing-Remitting Multiple Sclerosis Receiving Long-term Daclizumab Beta: A Prospective, Open-Label, Single-Arm Study.
BACKGROUND
For patients with relapsing-remitting multiple sclerosis (RRMS) undergoing continuous immunomodulatory therapy, understanding whether vaccinations can be performed safely and effectively is important. We tested the immune response to inactivated seasonal influenza vaccine during long-term daclizumab beta treatment.
METHODS
In this prospective, open-label, single-arm extension SELECTED study, an optional vaccine substudy was performed on patients with RRMS who had already received daclizumab beta for 1 to 2 years in previous studies. Patients were administered the seasonal vaccine as a single intramuscular dose containing three inactivated influenza virus strains: A/California/7/2009 (A/H1N1), A/Texas/50/2012 (A/H3N2), and B/Massachusetts/2/2012 (B). Endpoints included proportion of patients achieving seroprotection, proportion of patients who seroconverted, geometric mean titer ratio before and after vaccination, and adverse events reported during 28-day follow-up.
RESULTS
Ninety patients received the influenza vaccine (mean previous daclizumab beta exposure, 49.6 doses). Seroprotection (anti-hemagglutination immunoglobulin G titer ≥40) was detected in 92% (95% confidence interval [CI], 85%-97%) of patients for A/H1N1, 91% (83%-96%) for A/H3N2, and 67% (56%-76%) for B. The proportion of patients who seroconverted was 69% (95% CI, 58%-78%) for A/H1N1, 69% (58%-78%) for A/H3N2, and 44% (34%-55%) for B. The anti-hemagglutination immunoglobulin geometric mean titer ratio was 7.7 for A/H1N1, 9.0 for A/H3N2, and 4.3 for B. There were no significant adverse events considered related to vaccination during 28-day follow-up.
CONCLUSIONS
Patients with RRMS receiving long-term daclizumab beta treatment mounted an immune response to the seasonal influenza vaccine at levels considered to confer protection. No major or new safety issues were identified.
PubMed: 28603462
DOI: 10.7224/1537-2073.2016-026