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

1. Anchalee Senavonge. MD.
1 September 2017
Division of Allergy & Immunology
Department of Pediatrics, Faculty of Medicine
Chulalongkorn University

2. Publish 22 June 2017 Publish 30 June 2017
ZONDA trial

3. Asthma phenotype
Sally E Wenzel et al. Nature Medicine. May 2012. Vol 18 No 5.

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

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. • 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

15. Bleecker ER, et al.Lancet 2016; 388: 2115–27

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

19. Primary
outcome
Exacerbation
FitzGerald JM et al. Lancet 2016; 388: 2128–41
36% 28%

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

27. P Nair et al. N Engl J Med 2017;376:2448-58

28. 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

32. 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

37. Side effects
Nasopharyngitis 17%
Worsening asthma 13%
Bronchitis 10%
P Nair et al. N Engl J Med 2017;376:2448-58

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.

41. 30 June 2017
O Zen et al. NEJM 2017 Jul 6;377(1):52-61.

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. What is CD55?
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.

49. 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.

51. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.

52. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.

53. 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

58. O Zen et al. NEJM 2017 Jul 6;377(1):52-61.

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.

66. 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.