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New highlights from NEJM 2017

New highlights from NEJM 2017
Presented by Anchalee Senavonge, MD.
September1, 2017

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New highlights from NEJM 2017

  1. 1. Anchalee Senavonge. MD. 1 September 2017 Division of Allergy & Immunology Department of Pediatrics, Faculty of Medicine Chulalongkorn University
  2. 2. Publish 22 June 2017 Publish 30 June 2017 ZONDA trial
  3. 3. Asthma phenotype Sally E Wenzel et al. Nature Medicine. May 2012. Vol 18 No 5.
  4. 4. J.B. Bice et al. / Ann Allergy Asthma Immunol 112 (2014) 108e115.
  5. 5. GINA 2017 • “Add-on anti-IgE (omalizumab): patients aged ≥6 years with moderate or severe allergic asthma that is uncontrolled on Step 4 (Evidence A)” • “Add-on anti-IL-5 treatment (SC mepolizumab, IV reslizumab): patients aged ≥12 years with severe eosinophilic asthma that is uncontrolled on Step 4 treatment (Evidence B)” Pavord ID et al.DREAM study. Lancet 2012;380:651-9 Castro M et al. Lancet Respir Med 2015;3:355-66.
  6. 6. Anti IL-5 1. Mepolizumab (Nucala, GSK) : humanized IgG1 mAb against IL-5 2. Reslizumab (Cinqair,Teva) : humanized IgG4 mAb against IL-5 3. Benralizumab (Astra) : humanized Ab targeting the alpha-chain of IL-5 receptor
  7. 7. Benralizumab • A humanized, afucosylated IgG1 monoclonal antibody • engineered to eliminate fucose sugars from the oligosaccharides in the Fc region • directed against the alpha subunit of the IL-5 receptor • Mechanism: induces direct, rapid, nearly complete depletion of eosinophils by means of NK cell–mediated Ab-dependent cellular cytotoxic effects N Engl J Med 2017;376:2448-58
  8. 8. G Pelaia et al. Role of biologics in severe eosinophilic asthma. Ther Clin Risk Manag 2016:12: 1075-1082 Anti IL-5 vs Anti-IL5R
  9. 9. Tan LD et al. Benralizumab: a unique IL-5 inhibitor for severe asthma. J Asthma Allergy 2016 Apr 4;9:71-81 Benralizumab targets the effector cells themselves that are circulating and lung- tissue/resident tissue eosinophils and basophils Mepolizumab and Reslizumab act by neutralizing the effects and block the activation of eosinophils by IL-5
  10. 10. Before ZONDA trial… SIROCCO CALIMA Bleecker ER, et al.Lancet; October 2016; 388: 2115–27 FitzGerald JM et al. Lancet; October 2016; 388: 2128–41
  11. 11. • Randomized, double-blind, parallel-group, placebo- controlled phase 3 study at 374 sites in 17 countries • P: 1,205 severe uncontrolled asthmatics (age 12-75 years) • diagnosis of asthma for at least 1 year and at least 2 exacerbations while on high-dosage ICS plus LABA in previous year Bleecker ER, et al.Lancet 2016; 388: 2115–27 SIROCCO
  12. 12. SIROCCO Intervention • Randomly assigned (1:1:1) 1. Benralizumab 30 mg SC q 4 weeks 2. Benralizumab 30 mg SC q 4 weeks for 3 doses then q 8 weeks 3. Placebo For 48 weeks - stratified patients (2:1) for eosinophil counts of >=300/μL and <300/μL Outcome • Primary endpoint: annual exacerbation rate ratio “add-on effect” • Secondary endpoint: prebronchodilator FEV 1 and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells/µL Bleecker ER, et al.Lancet 2016; 388: 2115–27
  13. 13. Bleecker ER, et al.Lancet 2016; 388: 2115–27 51%45% Primary endpoint exacerbation
  14. 14. Bleecker ER, et al.Lancet 2016; 388: 2115–27 Secondary Endpoint FEV1
  15. 15. Bleecker ER, et al.Lancet 2016; 388: 2115–27
  16. 16. SIROCCO study conclusion • The study confirmed the efficacy and safety of benralizumab for severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA (additional option) • Clinical efficacy related to baseline blood eosinophil counts, similar in mepolizumab and reslizumab studies • Q8W dosage was efficacious: potential to lower disease burden and reduce costs Bleecker ER, et al.Lancet 2016; 388: 2115–27
  17. 17. CALIMA • Randomized, double-blind, parallel-group, placebo- controlled phase 3 study at 303 sites in 11 countries • P: 1,306 severe uncontrolled asthmatics (age 12-75 yr) • by medium-dosage to high-dosage ICS plus LABA and a history of two or more exacerbations in the previous year FitzGerald JM et al. Lancet 2016; 388: 2128–41
  18. 18. Intervention • Randomly assigned (1:1:1) 1. Benralizumab 30 mg SC q 4 weeks 2. Benralizumab 30 mg SC q 4 weeks for 3 doses then q 8 weeks 3. Placebo For 56 weeks - stratified patients (2:1) for eosinophil counts of >=300/μL and <300/μL Outcome • Primary endpoint: annual rate ratio of asthma exacerbations for patients receiving high-dosage ICS+ LABA with baseline blood eosinophils ≥300/μL • Secondary endpoint: pre-bronchodilator FEV1 and total asthma symptom score for patients receiving high-dosage ICS+ LABA with baseline blood eosinophils ≥300/μL FitzGerald JM et al. Lancet 2016; 388: 2128–41 CALIMA
  19. 19. Primary outcome Exacerbation FitzGerald JM et al. Lancet 2016; 388: 2128–41 36% 28%
  20. 20. FitzGerald JM et al. Lancet 2016; 388: 2128–41 Secondary Endpoint FEV1
  21. 21. • The study showed that 56 weeks of add-on therapy with benralizumab 30 mg Q4W and Q8W significantly reduced the annual rate of asthma exacerbations by up to 36% for patients with severe asthma and elevated blood eosinophils • Confirm and support SIROCCO study, but efficacy less than SIROCCO- possible regional heterogeneity CALIMA study conclusion FitzGerald JM et al. Lancet 2016; 388: 2128–41
  22. 22. FitzGerald JM et al. Lancet;Oct 2016; 388: 2128–41Bleecker ER, et al.Lancet; Oct 2016; 388: 2115–27
  23. 23. ZONDA trial Assessed the effect of benralizumab on the steroid sparing effect In adult patients who had severe asthma with persistent blood eosinophilia despite high-dose ICS+LABAs and oral glucocorticoids
  24. 24. Inclusion criteria • 369 patients, age 18-75 years • Severe asthma treated with • medium to high-dose ICS (>250 mcg fluticasone DPI) and LABA ≥ 12 months • high-dose ICS (>500 mcg fluticasone DPI) and LABA therapy for ≥ 6 months • Blood eosinophil> 150 cells/ul • Receiving oral glucocorticoid (GC) therapy for ≥ 6 continuous months (equivalent to 7.5 to 40 mg/day of prednisolone) P Nair et al. N Engl J Med 2017;376:2448-58
  25. 25. Exclusion criteria • Significant asthma exacerbation requiring systemic GC, or ↑ dose of oral GC • History of life-threatening asthma • Asthma control reached at an oral GC dose of ≤5 mg/day • Use Omalizumab, on immunotherapy P Nair et al. N Engl J Med 2017;376:2448-58
  26. 26. Intervention Randomly assigned (1:1:1) 1. Benralizumab 30 mg SC q 4 weeks 2. Benralizumab 30 mg SC q 4 weeks for 3 doses then q 8 weeks 3. Placebo For 28 weeks • stratified according to eosinophil count (150 -300, ≥300 cells/ul) P Nair et al. N Engl J Med 2017;376:2448-58
  27. 27. P Nair et al. N Engl J Med 2017;376:2448-58
  28. 28. P Nair et al. N Engl J Med 2017;376:2448-58
  29. 29. Assessment • Asthma exacerbation defined as • temporary increase in systemic GC dose for at least 3 days to • an emergency department visit • ACQ score • Blood and induced sputum for the analysis of eosinophils P Nair et al. N Engl J Med 2017;376:2448-58
  30. 30. Endpoints • Primary : percentage change in oral GC dose from baseline to week 28 • Secondary: • percentages of patients who had a reduction in the average daily oral GC dose of ≥ 25%, ≥ 50%, or 100% (discontinuation) • percentage of patients with an average final oral GC dose of ≤ 5.0 mg/day P Nair et al. N Engl J Med 2017;376:2448-58
  31. 31. Primary Outcome Mean reduction 75% from baseline Vs Placebo 25% Odd ratio 4 times P Nair et al. N Engl J Med 2017;376:2448-58
  32. 32. P Nair et al. N Engl J Med 2017;376:2448-58
  33. 33. Secondary outcome 50% in Benralizumab group stop OCS Reduce OCS ≤5.0 mg/day Odd ratio =3 P Nair et al. N Engl J Med 2017;376:2448-58
  34. 34. Benralizumab was associated with a longer time to the first exacerbation Every 4 weeks: hazard ratio = 0.39; (95% CI 0.22 to 0.66) Every 8 weeks: hazard ratio = 0.32; (95% CI, 0.17 to 0.57) P Nair et al. N Engl J Med 2017;376:2448-58
  35. 35. Secondary outcome: Annual asthma exacerbation rate • Placebo = 1.83 • Benralizumab Q4W= 0.83 • 55% lower than placebo • benralizumab Q8W=0.54 • 70% lower than placebo P Nair et al. N Engl J Med 2017;376:2448-58
  36. 36. P Nair et al. N Engl J Med 2017;376:2448-58 At week 20, higher than placebo by 256 ml (Q4W), 222 ml (Q8W) By 28 weeks, no longer significant difference Secondary outcome: FEV1
  37. 37. Side effects Nasopharyngitis 17% Worsening asthma 13% Bronchitis 10% P Nair et al. N Engl J Med 2017;376:2448-58
  38. 38. ZONDA trial conclusion • Benralizumab significantly reduced the oral GC dose, while asthma control was maintained, in patients who had severe asthma an elevated blood eosinophil count • The likelihood was more than 4 times • One half the patients who were receiving benralizumab stopped oral GC therapy completely • Targeting of the alpha subunit of the IL-5 receptor has potential advantages over existing anti–IL-5 therapies P Nair et al. N Engl J Med 2017;376:2448-58
  39. 39. Limitation • Not address long-term efficacy and safety • 20% not respond to Benralizumab- unclear why • Perhaps the presence of blood eosinophilia may not identify the eosinophil as a key effector cell in some patients P Nair et al. N Engl J Med 2017;376:2448-58
  40. 40. Muraro et al. J Allergy Clin Immunol 2016;137:1347-58.
  41. 41. 30 June 2017 O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  42. 42. What is CD55 • “Decay accelerating factor” (DAF) • One of complement regulatory proteins • A globular glycoprotein anchored to the cell membrane by glycosylphosphatidylinositol (GPI) Middleton textbook 8th edition
  43. 43. What is CD55? Middleton textbook 8th edition
  44. 44. Amanda Kirchner Piccoli et al. Rev Bras Reumatol 2011;51(5):497-510 CD55 inhibits formation of new C3 and C5 convertases and accelerate the degradation of these pre-formed enzymes
  45. 45. Monogenic IBD diseases • At least 64 genes identified in early-onset or very- early-onset inflammatory bowel disease • Mutations affect intestinal epithelial barrier, phagocytosis processes, immune regulation, and inflammation O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  46. 46. • loss-of-function variant in PLVAP (encoding plasmalemma vesicle associated protein) • biallelic loss-of-function variants in CCBE1 or FAT4 (Hennekam syndrome) • Previous studies: CD55 deficiency associated with PLE O Zen et al. NEJM 2017 Jul 6;377(1):52-61. Monogenic IBD diseases
  47. 47. Uhlig et al. Gastroenterology Nov 2014. Vol. 147, No. 5
  48. 48. Method • 11 patients from 8 consanguineous families with unaffected parents (AR pattern) • Moroccan, Syrian, or Turkish • Age 3-23 years • Diagnosis of early-onset protein-losing enteropathy • primary intestinal lymphangiectasia, edema due to hypo-proteinemia, malabsorption, bowel inflammation, recurrent infections, angiopathic thromboembolic disease • Whole-exome sequencing was performed • Evaluate the function of CD55 in patients' cells O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  49. 49. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  50. 50. Results • identified 5 distinct homozygous, novel, loss-of- function CD55 variants mutations in 9 patients O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  51. 51. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  52. 52. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  53. 53. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  54. 54. O Zen et al. NEJM 2017 Jul 6;377(1):52-61. Loss of CD55 and Increased complement deposition Panel B shows the pooled analysis of C3d staining with or without IgG1 precoating with an anti-CD28 antibody to activate the classical pathway Panel A shows pooled analyses of C3d staining on T cells obtained from healthy controls and from five patients with CD55 deficiency. The middle lines of the I bars indicate mean values, and the I bars ±1 SD
  55. 55. Excessive Production of Inflammatory Cytokines by CD55-Deficient T Cells • Cd55−/− mice producing more interferon-γ and less interleukin-10 • TNF and interferon-γ induced procoagulatory decreases in thrombomodulin and increases in tissue factor • Thus instigate the severe thrombophilia • CD55 can convey a costimulatory signal for T-cell activation and production of IL-10, inhibitory cytokine to intestinal inflammation O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  56. 56. O Zen et al. NEJM 2017 Jul 6;377(1):52-61. CHAPLE CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy
  57. 57. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  58. 58. In Vitro Inhibition of Complement by Eculizumab Formulation Eculizumab is a humanized monoclonal antibody that was derived from the murine antihuman C5 antibody m5G1.1. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  59. 59. Potential treatment • “Eculizumab” • suppressed C5a production on patients' cells • warrants further investigation as a potential treatment of the CHAPLE syndrome O Zen et al. NEJM 2017 Jul 6;377(1):52-61.
  60. 60. Eculizumab • recombinant, fully humanized hybrid IgG2/IgG4 monoclonal antibody directed against human complement component C5 • derived from the murine antihuman C5 antibody m5G1.1 • Role: atypical HUS, C3 glomerulopathies, PNH Zuber, J. et al. Nat. Rev. Nephrol. 8, 643–657 (2012)
  61. 61. Zuber, J. et al. Nat. Rev. Nephrol. 8, 643–657 (2012)
  62. 62. Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. N Engl J Med. July 2017. Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. Loss of CD55 in eculizumab-responsive protein-losing enteropathy. N Engl J Med 2017;377:87-9. DOI: 10.1056/NEJMc1707173
  63. 63. • Off-label compassionate therapy initially obtained for 2.5-year-old boy (V-7) in a critical deteriorating condition (Cheyne–Stokes respiration, hypotension, hypothermia, acidosis) • Following therapeutic success, compassionate care approval a 10-year-old girl (V-3) and a 20-year-old man (IV-11) Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. N Engl J Med. July 2017.
  64. 64. Results • The positive effect within 12 hours • V-7 stabilized and a reduction in bowel movements, discharged after 17 days of treatment. His albumin and protein normalized within a month and remain stable. • V-3: hospitalized with severe hypoalbuminemia, significant ascites and bowel obstruction • After 1st dose, an alleviation of abdominal pain, taken off analgesics, enable corrective intestinal resection surgery in 2 months • IV-11: constant uncontrolled diarrhea • After 1st dose, reduction in frequency and consistency of bowel movements, albumin and total protein normalized in 2 weeks Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. N Engl J Med. July 2017.
  65. 65. Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. N Engl J Med. July 2017.
  66. 66. Conclusion • Although the exact mechanism that causes intestinal protein loss is currently unclear • The response to eculizumab in these patients suggests that high levels of MAC, possibly precipitating intestinal-tissue damage are involved Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. N Engl J Med. July 2017.
  67. 67. Take home messages • Currently, biologic personalized medicine is widely studied. • New anti-IL5 alpha receptor, Benralizumab, showed efficacy in decrease asthma exacerbation and steroid-sparing effect. • Patients 12 years or older with moderate to severe asthma and blood eosinophil more than 300 mm3/ul are likely to benefit from Benralizumab. • Protein-losing enteropathy can be monogenic diseases. CD55, a complement regulator protein, defect can cause inflammatory bowel and PLE. • CD55 deficiency have shown relation to hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE syndrome). • Identification the CD55 deficiency is clinical significant due to the possible treatment with Eculizumab.

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