Nouveaut

1
Nouveautés dans le traitement des
microangiopathies thrombotiques Place de
leculizumab

• Chantal LoiratService de Néphrologie
  Pédiatrique,
• Hôpital Robert Debré, Paris

CREUF,Chartres, 2 Octobre 2014
2
The various forms of TMAs according to etiology
/ pathophysiology

• HUS with coexisting disease / condition
• Bone marrow transplantation
• Solid organ transplantation
• Malignancy/ cancer chemotherapy
• Autoimmune disease (SLE, antiphospholipids
  syndrome, scleroderma, dermatomyositis)
• Drugs (calcineurin inhibitors, sirolimus and
  anti-VEGF agents)
• Malignant hypertension
• HIV infection
• Cocaïne

• Infection-induced HUS
• S pneumoniae
• STEC

HELLP syndrome
Thrombotic thrombocytopenic purpura ADAMTS13 lt 10
Cbl-C deficiency-HUS
TMA
Alternative complement pathway dysregulation-HUS
Anti-FH antibodies
Mutations in CFH, CFI, MCP, C3, CFB, THBD
Congenital ADAMTS13 deficiency
Anti-ADAMTS13 antibodies
HUS with DGKE mutation
Unexplained HUS
Including pregnancy- HUS
3
Treatment of aHUS up to 2009Pre-eculizumab era

• Plasma exchange (PE)or plasma infusion (PI)

4
Poor prognosis in aHUS patients in the
pre-eculizumab era

• Mortality higher in children than in adults
• High risk of rapid progression to end stage renal
  disease at all ages but higher in adults than in
  children

100
French cohort, 214 patients
80
Mortality 8 in children, 2 in adults
60
Overall renal survival ()
40
20
plt0.0001
0
0
5
10
15
20
Years
39 of children and 80 of adults received PE/PI
at first episode
Number of aHUS patients at risk
Paediatric onset
89
34
17
13
6
Adult onset
125
18
7
2
0
Fremeaux-Bacchi et al. Clin J Am Soc Nephrol 2013
5
Eculizumab blocks terminal complement
Complement cascade2,3
Eculizumab

• Eculizumab binds with high affinity to C51,2

C3
C3a
Proximal

• Terminal complement C5a and C5b-9 formation
  blocked1,2

C3b

• Proximal functions of complement remain intact1,2
• Weak anaphylatoxin2,4
• Immune complex clearance2
• Microbial opsonisation2

C5
C5a
Terminal
C5b-9
C5b
Eculizumab Prescribing Information. Alexion
Pharmaceuticvals, Inc. 20131. Eculizumab
Summary of Product Characteristics. Alexion
Europe SAS, 2012 2. Rother RP et al. Nat
Biotechnol 2007251256643. Walport MJ. N Engl
J Med 2001344105866 4. Figueroa JE, Densen P.
Clin Microbiol Rev 1991435995
6
Efficacy of eculizumab in aHUS 180 patients (124
adults, 56 children)100 treated within
protocols, 80 outside of protocols

• aHUS in native kidneys, n124
• Post-transplant recurrence, n43
• Prophylaxis of post-transplant recurrence, n13

7
Data from case reports

• Patients treated with eculizumab outside of
  protocols

8
Eculizumab to treat aHUS in native kidneys in
adult patients
Historical controls treated by PE (between 2004
and 2008) had a pooreroutcome compared to
patients treated with eculizumab since 2009
French cohort
Features at presentation
Kidney disease outcome
80
p0.04
PE
Controls(n41) Eculizumab (n18) p
Female sex 28 (68) 13 (72) 0.8
Age, years 34 (18?85) 27 (19?53) 0.4
Complement gene mutations 28 (68) 13 (72) 0.2
Haemodialysis 29 (71) 12 (63) 0.8
Platelet countgt150 ? 109/L 6/36 (17) 4 (21) 0.6
Plasma exchange 24/38 (63) 15 (83) 0.1
Eculizumab
63
p0.02
60
Percentage of patients
46
40
25
17
20
0
ESRD within3 months of HUS
ESRD at1 year
Fakhouri F et al. Am J Kidney Dis 2014
9
Eculizumab efficacy to rescue renal function
the earlier, the better !
Median duration from HUS onset and eculizumab
initiation 6 days (160)
eGFR at last follow-up 9.5 months (422)
Bars PE treatment duration
Eculizumab ongoing at 3 m
Patient
At eculizumab initiation
At last follow-up
2
-

3

10
12

Haemodialysis
47
16
1

15

Median Screatinine (non-dialysed patients)
µmol/L (range)
251 (145655)
89 (55340)
-
11

18

19
9

4
-
7

14


8
Patients who received eculizumab within 6 days
of onset (n10) tended to have lower Screatinine
at last follow-up compared to those treated after
6 days of onset (n9) (p0.5)
5


16

13

17

6
10
0
20
30
40
50
60
90
Time after aHUS onset (days)
Fakhouri et al. Am J Kidney Dis 2014
10
Eculizumab was successful to treat aHUS on native
kidneys in 19 children, including 14 who failed
to improve under PE/PI Median age 1.5 years (11
days -11 y) ( 1 year in 9) Complement mutation
identified 15/18 (83) PE/PI resistant 12,
dependent 21st line Eculizumab 5
Median duration from current HUS onset to eculizumab initiation (range) 19 days (lt1- 225)
Hematological remission under eculizumab 19 (100)
Dialysis required at baseline, n () Dialysis required at last follow-up, n () 13 (68) 1 (6)
Median Screatinine, µmol/L (range) At baseline (6 non-dialysed patients) At last follow-up (18 non-dialysed patients) 99 (20-264) 43 (20-90)
Screatinine lt50 µmol/L at last follow-up, n () (18 non-dialysed patients) 13 (72)
Median follow-up, months ( range) 13 (2.5-42)
Zuber et al, Nat Rev Nephrol 2012 (pooled
analysis of 7 cases reported in 2009-2012)
Vilalta et al, Pediatr Nephrol 2012 Cayci et
al, Pediatr Nephrol 2012 Giordano et al,
Pediatrics 2012 Besbas et al, Pediatr Nephrol
2012 Gulleroglu et al, Pediatr Nephrol 2013
Malina et al, Pediatrics 2013 Gilbert et al,
Pediatr Nephrol 2013 Vaisbich et al, J Bras
Nefrol 2013 Hu et al, Pediatr Nephrol 2013
Christmann et al, Pediatrics 2014 Michaux et al,
Pediatr Nephrol 2014
11
Eculizumab for extra-renal manifestations of
thrombotic microangiopathy
12
Eculizumab rescues distal ischaemic
manifestations of aHUS

• Malina et al. Pediatrics 2013
• 2-month-old child
• ESRD, multiple relapses despite plasma infusions
• C3 gain of function mutation
• At 9 months, acute ischaemia of feet and hands,
  resistant to PE
• Eculizumab ? immediate reversal of distal
  ischaemia
• Follow-up 22 months, remission

• Ariceta et al. AJKD 2012
• 28-day-old child, 3.6 kg
• No mutation
• Leg skin necrosis, intestinal perforation
• Eculizumab ? remission within 3 days
• Recovery of skin lesions and renal function
• Follow-up 18 months,Screatinine 23 µmol/L,
  remission

13
Ulcerative-necrotic skin lesions in aHUS
Recovery under eculizumab
Before eculizumab
After eculizumab

• 19-year-old man (no mutation)
• On dialysis
• Skin lesions for 10 months thrombocytopenia
• Skin biopsy TMA lesions
• Recovery after one dose of eculizumab

• 19-year-old man (factor H mutation)
• Functioning kidney graft under PE/PI
• Skin lesions for several months
• ? Switch from PE to eculizumab
• Improvement of skin lesions after first dose
• with further complete reversal

Ardissino G et al. Am J Kidney Dis 2013
14
Eculizumab appears efficient to rescue
CNS involvement in aHUS
9 case reports (PE resistant 7 1st line
eculizumab2)
Author Age (years) Neurological manifestations MRI Time to eculizumab initiation (days) Outcome
Pu2013 85 Seizures, mental disturbances ND 18 Improvement over 2 weeks Full recovery
Salem 2012 66 Seizures, mental disturbances, coma Focal lesions 3 Awoke and verbal after 8 weeks Nearly complete recovery
Beye2013 64 Status epilepticus, focal defects, nystagmus, confusion Normal CTS 9 Improvement within 24 hours Full recovery
Ohanian 2011 50 Seizures, unresponsiveness Right parietal infarction 3 Improvement after 1 week Full recovery
Chaudhary 2014 20 Seizures, lethargy ND 42 Slow initial improvement (subtherapeutic doses) Full recovery after dose increase
Gulleroglu 2013 11 Seizures, visual loss, confusion Bilateral occipital and posterior parietal hyperdensities/oedema 2 Improvement after 4 days Full recovery after 1 month
Gulleroglu2013 6 Seizures, visual loss Bilateral occipital and posterior parietal hyperdensities lt1 Normal vision within 24 hours Full recovery after 5 weeks
Diamante Chiodini 2014 8 Confusion, delirium Persistant psychocognitive impairment under PE/PI Multifocal hypersignals 20 Full recovery within 2 weeks
Hu 2013 1.7 Seizures, hemiparesis, lethargy, unresponsiveness Subtle bilateral anomalies lt1 Improvement over 3 weeks Full recovery with residual weakness of right thumb/index
15
Eculizumab appears efficient to rescue ischemic
cardiomyopathy in aHUS
Author Age (yrs) Cardiac manifestations Response to PE Time to eculizumab initiation (days) Outcome
Vilalta 2012 1.5 Day 60 under PE Dilated cardiomyopathy Cardiorespiratory arrest Resistance to PE 80 Improvement of cardiac function over 6 days. Subsequent full recovery.
Hu 2013 1.6 Day 0 Dilated cardiomyopathy EF 30 Cardiovascular instability, hypotension First line eculizumab lt 12 hours Recovery over 9 days
Diamante Chiodini 2014 8 Day 20 under PE Dilated cardiomyopathy EF 37 Repolarization anomalies High troponine level Resistance to daily PE plasma intolerance 37 Normalization of LV volume and function over 2 weeks
16
Eculizumab in aHUSProspective trials in adult /
adolescent patients under prior plasmatherapy

• Results at 26 and 64 weeksLegendre CM et al. N
  Engl J Med 2013
• Results at 2 yearsGreenbaum L et al. ASH
  Atlanta, USA 811 Dec 2012. Abstract and Poster
  2084Legendre CM et al. WCN Hong Kong 31 May4
  Jun 2013. Abstract and Poster MO065

17
Prospective trials of eculizumab
C08-002 17 patients with progressing TMA (4
PE/PI in the week prior to screening)
C08-003 20 patients with a long duration of
aHUSand chronic kidney disease under long-term
PE/PI
All patients offered to continue into long-term
extension study86 (32/37) continued eculizumab
treatment, median duration 100 weeks (002) and
114 weeks (003)
C08-002 no OP C08-0038-week OP
1200 mg every 2 weeks through 26 weeks
900 mg/week
Wk 1
Wk 5
Plasma exchange/infusion removed
OP, observation period
18
Prospective trials Patients baseline
characteristics
C08-002 Progressing TMA (N17) C08-003 Long disease duration (N20)
Median age, years (range) 28 (1768) 28 (1363)
Identified complement mutations or anti-CFH Ab, 76 70
Prior kidney transplant, 41 40
Median time from onset of current aHUS manifestation to screening, months (range) 0.8 (0.2-3.7) 8.6 (1.2-45.0)
Median platelet count, x109/L (range) 118 (62-161) 218 (105-421)
Mean baseline eGFR, mL/min/1.73 m2 (SD) 22.9 (14.5) 30.8 (19.0)
Dialysis at baseline, 35 10
Median number of PE/PI 7 days prior to first eculizumab dose (range) 6 (0-7) 1.5 (1-3)
One patient had no PE/PI 7 days prior to
eculizumab due to severe allergic reaction after
2 sessions
19
Patients with progressing TMA under
PE/PI Hematologic normalization after the switch
to eculizumab
C08-002

• Significant increase in platelet count as early
  as day 7 (p0.027)
• 53 of patients with abnormal platelet count at
  baseline had normal platelet count at day 7

Mean increase 73x109/L plt0.001

• Median delay before 1st normal value
• Platelets (150X109/L) 7days (1-218)
• LDH 14 days (0-56)

20
C08-002
Patients with progressing TMA under PE/PI
Eculizumab allowed rapid improvement in eGFR,
thatwas sustained under ongoing treatment over 2
years
plt0.001

• Mean increase in eGFR
• from baseline,
• mL/min/1.73m2 (SD)
• Week 26 33.1 (33.3) p0.001
• Week 100 36.6 (29.8) p0.006

pNS
plt0.001
p0.03
Slope
1
2
3

• Mean eGFR, mL/min/1.73 m2 (SD)
• Baseline 22.9 (14.5)
• Week 26 55.9 (40.2)
• Week 100 55.8 (30.0)

eGFR mean change from baseline
4/5 patients (80) eliminated the need for
dialysis and remained dialysis free through week
100 ?At median 100 weeks, only 2/17 patients
(12) on dialysis
One patient started dialysis at week 64
(baseline eGFR 19 mL/min/1.73m2 )
Patients
5
5
6
17
17
16
15
15
15
15
15
15
15
13
15
15
14
13
12
11
12
11
13
12
13
13
12
9
12
12
10
9
9
9
Shorter time from clinical manifestation
predicted greater eGFR gain (p0.009)
21
Patients with long duration of aHUS Eculizumab
allowed rapid improvement in eGFR, that was
sustained under ongoing treatment over 2 years
C08-003
p0.007
pNS
p0.001
pNS

• Mean increase in eGFRfrom baseline,mL/min/1.73
  m2 (95 CI)
• Week 26 6.1 (3.38.8) p0.0001
• Week 104 7.2 (0.7613.6) plt0.05

Slope
1
2
3

• Mean eGFR,
• mL/min/1.73 m2 (SD)
• Baseline 30.8 (18.9)
• Week 104 40.1 (17.5)

2 patients on dialysis at baseline remained
on dialysis at week 104 (10). No patient not on
dialysis at baseline initiated dialysis
Shorter time from clinical manifestation
predicted greater eGFR gain (plt0.0001)
21
22
C08-002 and C08-003 Conclusions
These data suggest early switch to eculizumab or
eculizumab as first line therapy may be warranted
to offer patients the best chance of full
recovery of renal function
23
The new prospective trials in pediatric and adult
patients with aHUS,with or without prior
plasmatherapy

• Presented at Am Soc Nephrol, Atlanta USA 59 Nov
  2013
• Paediatric trial Greenbaum L et al. Abstract
  5579 and Poster SA-PO849
• Adult trial Fakhouri F et al. Abstract 5593 and
  Presentation FR-OR057

24
Early/first line eculizumab initiation as adopted
by pediatricians may offer the best chance of
full renal recovery
C10-003, children, n22 Median delay before
eculizumab 6 d (lt1 d4.3 m) 12/22 (55) without
prior PE Mean eGFR at baseline 3330 mL/min/1.73
m2
C10-004, adults, n41 Median delay before
eculizumab 15 d (lt1 d19.2 m) 6/41 (15) without
prior PE Mean eGFR at baseline 1712
mL/min/1.73m2
eGFR mean increase at week 27 64 mL/min/1.73m2
eGFR mean increase at week 26 29.3 mL/min/1.73m2

• 11/22 (50) on dialysis at baseline
• 9/11(82) discontinued dialysis
• 0/11 not on dialysis at baseline initiated
  dialysis
• 2/22 (9) on dialysis at 6 months

• 24/41 (58) on dialysis at baseline
• 20/24 (83) discontinued dialysis
• 4/17 (24) not on dialysis at baseline initiated
  dialysis(2 short course)
• 6/41 (15) on dialysis at 6 months

25
In practice

• Proposals from
• 1. The French Study Group for aHUS and C3G (Zuber
  et al, Nat Rev Nephrol 2012)
• Coordinated by V Fremeaux-Bacchi, F Fakhouri, J
  Zuber and C Loirat
• Working group M Buchler, S Burtey, D Chauveau, Y
  Delmas,
• G Deschenes, A Garnier, A Karras, B Knebelmann, Y
  Lebranchu,
• B Legallicier, C Legendre, M Lequintrec, B
  Moulin, P Niaudet,
• C Pouteil-Noble, F Provot, B Ranchin, E Rondeau
• 2. HUS International (Loirat et al, Pediatr
  Nephrol 2014, in press)

26
Is it necessary to know whether the patient with
a first episode of aHUS has a complement anomaly
andwhich one it is before starting eculizumab?
NO

• Eculizumab is efficacious and thus can be
  administered to patients with aHUS and
• Any type of complement mutation
• No mutation identified (However, uncertain
  efficacy in patients with DGKE mutation)

• However
• Obtain anti-factor H antibody results rapidly
• Genetic screening is recommended for further
  decisions

27
First episode of aHUSWhich first-line treatment?
PE or eculizumab?
In children ? Eculizumab first-line, within 24
hours, to avoid PE/central catheter
In adults

• Diagnosis of aHUS needs confirmation
• (e.g. eliminate cancer, TTP)
• ? PE first
• ? Switch to eculizumab if
• plasma resistance
• relapse at PE tapering or cessation

• Diagnosis of aHUS unequivocal
• (e.g. familial history, relapse of HUS,
  post-transplant recurrence)
• Eculizumab first-line, within 24 hours

Definition of plasma resistance no constant
upward trend of platelet count ( particularly if
still lt 150x109/l) or no constant downward trend
of LDH (particularly if still gtULN) or no
significant decrease of Screatinine (at a minimum
25 decrease) after 5 daily PE
28
Conclusion

• Eculizumab offers aHUS patients the best chance
  of sustained remission and full rescue of renal
  function if started early
• Prospective studies are now required to
  establish whether treatment withdrawal is safe,
  in whom and when.

29
(No Transcript)
30
Prevention of meningococcal infections
Risk of invasive meningococcal infection in PNH
patients under eculizumab 0.5/year /100 patients
One aHUS patient out of approximately 65 outside
of protocoles and 2 patients out of 100 within
trials had invasive meningococcal infection
(favourable outcome).

• Anti-meningococcal vaccine mandatory
• Quadrivalent conjugate vaccines (anti-A, C, W,
  Y) (Menveo (2y) or Nimenrix (1y)) should be
  used
• Anti-B vaccine available in France since Dec 11,
  2013 and recommended.
• However, further data on its clinical efficacy
  and duration of protection are still pending.
• The bactericidal activity of immune response
  after vaccination is uncertain in patients with
  complement deficiency and/or receiving eculizumab
  and/or immunosuppressive therapy. This justifies
  immediate antibioprophylaxis allowing prompt
  initiation of eculizumab.

• Repeated information to the patient, his family
  and family doctor
• Information card

• Continuous antibioprophylaxis obligatory in some
  countries (France, UK)
• Oral methyl penicillin (full dose, twice daily)
• To our opinion, should be recommended for children

Struijik et al, AJT 2013 Fakhouri et al,
ASN, Nov 5-10 2013, FR-OR057, Atlanta
31
Complications of plasma exchanges in children
with aHUS 71 children from 11 European countries
and North America with aHUS between 1 July 2009
to 31 Dec 2010 Audit of the 2009 Guidelines for
initial therapy of aHUS (Ariceta et al, Pediatr
Nephrol 2009)

• Central venous catheters n 51
• 17 complications in 16 children (31)
• Infection n 8, thrombosis n3, limb ischemia
  n1,
• haemorrhage n 2, chylothorax n 1.
• Plasma hypersensitivity n8, leading to
  withdrawal of therapy in 1

Johnson S et al, for the European Paediatric
Study Group for HUS, Pediatr Nephrol 2014
32
Eculizumab treatmentWhich duration?
33
Outcome after eculizumab discontinuation in 20
patients
Age (y) Complement anomaly Eculizumab treatment duration until withdrawal Relapse of HUS after eculizumab withdrawal Delay between eculizumab withdrawal and relapse (m) Screatinine at relapse (µmol/l) Screatinine at last f-up (µmol/l) F-up after eculizumab withdrawal or re-initiation (m)
20 (PP) CFH 9 m Yes 6 Normal ? 451 (3 weeks dialysis ) ND (off dialysis) ND
26 (PP) CFH CFI 18 m No NA NA 70 18
4.3 CFH 5.5 m Yes 1.5 71 ? 248 71 25
37.7 CFH 14 m Yes 0.9 124?203 115 10
11 CFI 2 w No NA NA 48 11
52.7 CFI 1.5 m No NA NA 88.5 22
34.8 CFI 11.5 m No NA NA 221 10
2.6 CFI 5.5 m No NA NA 35 15.5
6 MCP 5 w No NA NA Normal 9
22 MCP 8 w No NA NA 84 11
5.4 MCP 0.5 m No NA NA 44 13.5
49 Anti-CFH 8 w No NA NA 88.5 10
19.1 Anti-CFH 5.5 m No NA NA 106 14.5
13.3 Anti-CFH 2.5 m No NA NA 53 8.5
10.9 Anti-CFH (high titer) 0.4 m Yes 1 62 ?301 53 5
85 None 3m No NA NA Normal 12
64 ND 13 w No NA NA 60 6
32 (PP) None 6 m No NA NA 88.5 12
20 None 9 m No NA NA 70.8 9
1.3 None 13.5 m No NA NA 26 6.5
Cayci 2012 Beye 2013 Canigral 2013 Carr 2013
Delmas 2013 Pu 2013 Fakhouri 2014 Ardissino
2014 Chaudhary 2014
34
The specific subgroup of anti- factor H antibody-
associated aHUS

• First described in 2005 3 cases in children1
• Approximately 200 cases reported currently2-4,
  mainly in childhood
• Frequency 6-10 (up to 25) of aHUS in European
  children, 50 in Indian children

All patients (n 45) mean 9 years (8 months 52 years)
Children (n 38) 9 years (8 months 14 years)
Adults (n7) 41 years (28 - 52 years)
Ref 2
Number of cases
1 Dragon-Durey et al, JASN 2005 2 Dragon-Durey et
al JASN 2010 3 Hofer et al, CJASN 2013 4 Sinha et
al, KI 2013
Age at onset (Years)
35
Anti-CFH antibody-associated HUSBenefit from
early PE immunosuppression with subsequent
maintenance immunosuppression guided by anti-CFH
antibodies titer
92
Maintenance IS
87
Combined PEIS
76
69
71
P 0.010
Plt0.0001
46
41
No maintenance IS
33
No combined therapy
Probability of renal survival with respect to
induction combined therapy with plasma exchanges
and immunosuppression
Probability of relapse free survival with respect
to maintenance immunosuppression
Renal survival free of adverse outcome alive
with eGFR 30 ml/min/1.73m2
Sinha et al, KI 2013
36
New prospective trials in paediatric and adult
patients Haematologic normalisation in most
patients
22 children C10-003
41 adults C10-004
95
82
98
88
(95 CI 77100)
(95 CI 6095)
(95 CI 88100)
(95 CI 7496)
Median days to endpoint (range) 7 (180) 55 (1153)
8 (084) 55 (2146)
Haematologic normalisation platelet count 150 x
109/L and LDH ULN for at least 2 consecutive
measurements over 4 weeks
37
Clinical characteristics at first episode
according to ageFrench cohort
Children (n89) Adults (n125)
Trigerring event 47 33
Diarrhea 39 15
Upper respiratory tract infection 8 1
Pregnancy (post-partum ) 19 of women
Complete triad Platelets gt 150G/L Hbgt10g/dl 74 15 6 83 16 11
CNS involvement 16 8
Dialysis required 59 81
Fremeaux-Bacchi et al, CJASN 2013
38
The late 2000s Recommended schedule for PE/PI
for aHUS at presentation and during the first
month

• PE with plasma for restitution (or PI if PE not
  possible) within 24 hours of onset
• Daily for at least 5 days and until normalisation
  of platelet count and LDH, and improvement of
  renal function
• Then five sessions per week during 2 weeks
  followed by three sessionsper week for 2 weeks
• Followed by empirical treatment schedule
  (modality and interval)per patient

Ariceta G et al. for the European Pediatric Study
Group for HUS. Pediatr Nephrol 2009 Taylor CM et
al. for the Renal Association, the British
Committee for Standards in Hematology and the
British Transplantation Society. Br J Hematol 2010
39
Eculizumab was well tolerated up to 2-year update
C08-002 (N17)
C08-003 (N20)
Event Patients () Worst severity
Serious Adverse Events
Hypertension 1 (6) Severe
Accelerated hypertension 2 (12) Moderate
Asymptomatic bacteriuria 1 (6) Mild
Adverse Events
Leukopenia 2 (12) Mild
Nausea 2 (12) Mild
Vomiting 3 (18) Mild
Asthenia 1 (6) Moderate
Dermatitis 1 (6) Mild
Diarrhea 1 (6) Mild
Erythema 1 (6) Moderate
Fatigue 1 (6) Moderate
Headache 1 (6) Mild
Hematocrit decreased 1 (6) Mild
Hematuria 1 (6) Mild
Hemoglobin decreased 1 (6) Mild
Herpes zoster 1 (6) Mild
Impetigo 1 (6) Moderate
Pyrexia 1 (6) Mild
Tremor 1 (6) Moderate
Urinary tract infection 1 (6) Mild
Vertigo 1 (6) Mild
Event Patients () Worst severity
Serious Adverse Events
Peritonitis 1 (5) Severe
Influenza 1 (5) Severe
Venous sclerosis at infusion site 2 (10) Severe
Adverse Events
Headache 3 (15) Moderate (1 pt)
Lymphopenia 2 (10) Moderate (1 pt)
Leukopenia 2 (10) Mild
Cough or productive cough 2 (10) Mild
Abnormal blood clotting 1 (5) Mild
Anemia 1 (5) Moderate
Deafness bilateral 1 (5) Moderate
Extravasation 1 (5) Moderate
Chest discomfort 1 (5) Mild
BK infection 1 (5) Mild
Nasopharyngitis 1 (5) Mild
Nasal congestion 1 (5) Mild
Rhinorrhea 1 (5) Moderate
Pharyngolaryngeal pain 1 (5) Moderate
Alopecia 1 (5) Mild
Pruritus 1 (5) Mild
Hypotension 1 (5) Moderate
Q fever 1 (5) Moderate
Menorrhagia 1 (5) Mild

• No infection-related serious adverse events and
  no meningococcal infections
• Treatment-related adverse events remained steady
  or declined in the 2-year study period
• One death deemed unrelated to study drug was
  reported in C08-003 during the study period

40
The risk of meningococcal infection in patients
with terminal complement factors deficiency or
blockade

• Immunity against Neisseria meningitis is mainly
  mediated by the lytic terminal
• complement complex C5b-9
• Walport MJ, NEJM 2001  The risk of
  meningococcal disease for a person with a
  complement deficiency can be calculated to be
  0.5 percent per year. This is a relative risk of
  5000, as compared with persons without a
  complement deficiency  .
• Invasive meningococcal infection in PNH patients
  under eculizumab
• 0.5 / year / 100 patients (Hillmen et al, 2013)
• Invasive meningococcal infection in aHUS
  patients under eculizumab
• 1 patient out of 80 treated outside of trials
  (Struijk 2013) and 2 patients out of 100 within
  trials (Fakhouri, ASN 2013) (favourable outcome).
  

41
Prevention of meningococcal infections

• Obligatory anti-meningococcal vaccine
  antibioprophylaxis for 2 weeks
• Conjugate tetravalent vaccines protect against
  serogroups A, C, W135 and Y, not against
  serogroup B
• Anti-B vaccine now available (since Dec 11, 2013
  in France) must be associated

• Education/information to the patient, his family
  and family doctor
• Information card

• Continuous antibioprophylaxis obligatory in some
  countries (France, UK)
• Oral methyl penicillin (full dose, twice daily)
• To our opinion, should be recommended for children

42
Early initiation of eculizumab as adopted in
children seems to offer the best chance of renal
function full recovery
C10-003, Children, N22 Median delay before
eculizumab 6d (lt1d-4.3m) 12/22 (55) without
prior PE Mean eGFR at baseline 3330
ml/min/1.73 m2
C10-004, Adults, N41 Median delay before
eculizumab 15d (lt1d-19.2m) 6/41 (15) without
prior PE Mean eGFR at baseline 1712
ml/min/1.73m2
eGFR mean Increase at Week 27 64 ml/min/1.73m2
eGFR mean Increase at Week 26 29.3 ml/min/1.73m2
11/22 (50) on dialysis at baseline 9/11(82)
discontinued dialysis 0 not on dialysis at
baseline initiated dialysis 2/22 (9) on
dialysis at 6 months
24/41 (58) on dialysis at baseline 20/24 (83)
discontinued dialysis 4/17not dialysed at
baseline initiated dialysis (short course in 2)
6/41 (15) on dialysis at 6 months
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The new prospective trials in pediatric and adult
patients Hematologic normalization in most
patients
C10-003
22 Children C10-003
41 Adults C10-004
(95 CI 77-100 )
21/22
18/22
14/22
8 (084) 55 (2-146)
Median days to endpoint (range) 7 (1-80) 55 (1-153) 60.0 (7.0153.0)
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Hematologic normalization platelet count
150x109/l and LDH ULN for at least 2
consecutive measurements over 4 weeks
44
Conclusion

• Eculizumab offers aHUS patients the chance of
  sustained remission and full rescue of renal
  function if started early
• Lets make the best use of this revolution
  through
• registries
• treatment duration studies

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C10-003 and C10-004Conclusions
C10-003

• The results of the two current studies support
  the recommendation of eculizumab as first line
  treatment in pediatric patients and also in
  adults once unequivocal diagnosis of aHUS is
  made.

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