4. J.B. Bice et al. / Ann Allergy Asthma Immunol 112 (2014) 108e115.
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. 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. 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. 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. 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
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. 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. Bleecker ER, et al.Lancet 2016; 388: 2115–27
51%45% Primary
endpoint
exacerbation
14. Bleecker ER, et al.Lancet 2016; 388: 2115–27
Secondary
Endpoint
FEV1
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. 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. 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
20. FitzGerald JM et al. Lancet 2016; 388: 2128–41
Secondary
Endpoint
FEV1
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. FitzGerald JM et al. Lancet;Oct 2016; 388: 2128–41Bleecker ER, et al.Lancet; Oct 2016; 388: 2115–27
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. 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. 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. 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
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. 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. 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
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. 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. 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. 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
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. 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. Muraro et al. J Allergy Clin Immunol 2016;137:1347-58.
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
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. 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. • 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. Uhlig et al. Gastroenterology Nov 2014. Vol. 147, No. 5
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.
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.
55. 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
56. 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.
57. 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
59. 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.
60. 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.
61. 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)
62. Zuber, J. et al. Nat. Rev. Nephrol. 8, 643–657 (2012)
63. 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
64. • 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.
65. 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.
67. 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.
68. 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.