Conflito de Interesse - IWEVENTOS
Transcript of Conflito de Interesse - IWEVENTOS
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Conflito de Interesse
De acordo com a resolução do Conselho Federal de Medicina nº 1595/2000 e Resolução da Diretoria Colegiada da ANVISA nº 96/2008, eu declaro que:
• Pesquisa Clínica – Como investigador: Novartis
• Apresentações científicas – Como palestrante: Novartis, Amgen, Roche, Alexion, Janssen, Pfizer
• Atividades de Consultoria – Como membro de Advisory Boards: Novartis, Abbvie, Roche, Alexion, Janssen, Pfizer
Declaro não ter ações em bolsa de valores das empresas supracitadas.
Meus pré-requisitos para participar destas atividades são o intercâmbio científico, a autonomia do pensamento científico, independência de opinião e liberdade de expressão, aspectos estes respeitados pela Takeda.
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Inibidor de complemento na HPN:
passado, presente e futuro
Phillip Scheinberg
Hospital A Beneficência Portuguesa
São Paulo
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THE COMPLEMENT CASCADE REGULATION IN PNH
C3b
C3
+C3b
C5
convertase
Classical
pathway
Lectin
pathway
Alternative
pathway
Physiological
C3 tick-over
CD55 CD55
Amplification
loop
PNH RBCs
C3b
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THE COMPLEMENT CASCADE REGULATION IN PNH
C3b
C3
+ C5b
C5
C3b
C5
convertase
PNH RBCs
Classical
pathway
Lectin
pathway
Alternative
pathway
C6MAC
Physiological
C3 tick-over
C7 C8 C9
CD55 CD55 CD59
Amplification
loop
C3b
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THE COMPLEMENT CASCADE REGULATION IN PNH
C3b
C3
+ C5b
C5
C3b
C5
convertase
PNH RBCs
Classical
pathway
Lectin
pathway
Alternative
pathway
C6MAC
Physiological
C3 tick-over
C7 C8 C9
CD55 CD55 CD59
Amplification
loop
C3b MAC
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THE COMPLEMENT CASCADE REGULATION IN PNH
C3b
C3
+ C5b
C5
C3b
C5
convertase
PNH RBCs
Classical
pathway
Lectin
pathway
Alternative
pathway
C6MAC
Physiological
C3 tick-over
C7 C8 C9
CD55 CD55 CD59
Amplification
loop
C3b
MAC-mediated intravascular hemolysis
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THE COMPLEMENT CASCADE REGULATION IN PNH
C3b
C3
+
C5
C3b
C5
convertase
Classical
pathway
Lectin
pathway
Alternative
pathway
Physiological
C3 tick-over
C5b
C6MACC7 C8 C9
CD55 CD55
Amplification
loop
Eculizumab
Risitano et al, Blood 2009
MAC-mediated intravascular hemolysisPNH RBCs
C3b
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EFFECT OF ECULIZUMAB ON HEMOLYSISLactate dehydrogenase (LDH) and transfusion independency
Time, Weeks
Lacta
te D
eh
yd
rog
en
ase (
U/L
)
0
500
1000
1500
2000
2500
3000
0 10 20 30 40 50
TRIUMPH – Placebo/extension
TRIUMPH – SOLIRIS/extension
SHEPHERD – SOLIRIS
Study Week
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Pa
tien
ts A
vo
idin
g T
ran
sfu
sio
n (
%)
0
10
20
30
40
50
60
70
80
90
100
P < 0.000001
Eculizumab
Placebo
51%
0%
44% reduction in
PRBC units
transfused
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0
2
4
6
8
10
12
14
16
Pre-Eculizumab Treatment Eculizumab Treatment
Th
rom
bo
sis
Ev
en
t R
ate
(TE
pe
r 1
00
pt-
ye
ars
)
92% reduction in event rate with eculizumab
(n=195) (n=195)
39 events 3 events
P = 0.0001
Hillmen et al.,
Blood 2007
Normalized by
time of
observation
(pre and post)
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Long-term effect of eculizumab treatment in PNHA retrospective comparison (Loschi et al, AJH 2016)
PNH patients with indication to
eculizumab (clinically meaningful
hemolysis and/or thrombosis)
– Eculizumab: n=123 (>2005)
– Non-eculizumab: n=191
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Hematological response
Hgb ≥1136.6%
8 ≤ Hgb < 1143.9%
≤50%12.2%
>50%7.3%
THE CLINICAL RESPONSE TO ECULIZUMAB
• Normal or almost-normal LDH level in all patients
• Persistent reticulocytosis in almost all patients
n= 41
Risitano et al, Blood 2009
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Hemolysis
Cytopenia
Aplastic Anemia
PNH
Bone Marrow Failure and PNH
Normal
Aplastic
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Hemoglobinuria}
–8731––38119AST
29171687697––7842624LDH
3310933332-310Urine
2101312111091-80Days
Eculizumab Eculizumab
“BREAKTHROUGH” hemolysis during eculizumab treatmentPharmakokinetic breakthrough
… but in patient’s chart it has been written “possible pharmakodinamic breakthrough”!?
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Polymorphisms of C5 at Arg 885
– Single heterozygous missence (p.Arg885His) mutation (generating a
new ApaLI restriction site) found in 11 out 11 Japanese PNH patients
lacking any response to eculizumab (n=345; 3,3%)
– also found in healthy Japanese population (allelic frequence 3,5%)
The mutation affected the
binding to eculizumab
– A similar mutation (p.Arg885Cys)
was found in a non-responder
from Argentina (Asian ancestry)
Genetics of response to eculizumab in PNH: C5Rare C5 mutation may result in resistance (Nishimura et al, NEJM 2014)
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Ricklin et al,
Blood 2015
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Unmet clinical needs in anti-complement therapy
1. Rare intrinsic (genetic) resistance
2. Suboptimal hematological benefit
• Underlying bone marrow failure
• Breakthrough (pharmacokinetic and
pharmacodynamics)
• C3-mediated extravascular hemolysis
3. Patient perspective: i.v. therapy, bi-monthly infusion,
(hospitalization)
4. Limited access (worldwide) and costs
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Classical pathway Lectin pathway Alternative pathway
C1q
C1rC1s
C2 C4
C4b2a
C3
MBL
MASPs
C3bBbC3(H2O)Bb
C3
hydrolysis
fB fI
P
(tick-over)
Immune
complexes Bacterial LPS
and membranes
C4b2aC3b C3bBbC3b
C6
MAC
C7
C8
C9
C3 convertases
C5 convertases
Lytic complex
C3b
C3a
C5 C5b
C5a
Novel anti-C5 agents:
• Other mAbs: ALXN1210,
SKY59, REGN3918, LFG316,
Mubodina (Adienne)
• Small peptides (e.g.,
RA101348)
• Coversin
• Aptamers
• siRNAs
Amplification
loop
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Chugai-RocheRO7112689 / SKY59 / RO/CH7092230 / RG6107
▪ Humanized anti-C5 “recycling” mAb. Based on Chugai’s Sequential Monoclonal
Antibody Recycling Technology – Immunoglobulin (SMART-Ig) platformDescription
▪ Phase 1/2 global PNH study (naïve and switch patients) underwayPhase
▪ IV and SC initially weekly (regimen may be modified based on data from Part 2 of
the study)
Dosing &
RoA
▪ Chugai is conducting a 3 part adaptive phase 1 /2 trial in NHV followed by PNH
patients in 9 disclosed countries. Trial includes IV and SC (@170mg/ml
concentration) and use of placebo comparator
– Part 1: Phase 1 SAD in healthy adult males
– Part 2: Naïve transfusion dependent PNH patients and patients with C5
polymorphism
– Part 3: Stable PNH patients adequately controlled on eculizumab
– Per Eudra website, the trial represents first in human administration
▪ Trial endpoints include:
– Safety (% patients with dose limiting events, AEs, SAEs, terminal complement
activity, ADAs);
– Clinical efficacy measures (LDH, free Hgb, FACIT-fatigue, HRQoL, # PRBC
transfusions etc);
– PK / PD (Cmax, Tmax, AUC, T1/2, bioavailability, C5 levels, etc.)
▪ n: between 39-74 (different public sites describe different patient numbers)
Ongoing
clinical
development
NCT03157635; EudraCT 2016-002128-10
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RA pharmaRA 101495
Company website; Company IPO prospectus;
NCT03030183; NCT03078582; Eudra CT 2016-003522-16
▪ Synthetic 15-amino acid macrocyclic peptide C5 inhibitor
▪ Binds to C5 at a site that also blocks C6 binding to C5b, preventing MAC
formation even if C5 cleaves
Description
▪ 2 Phase 2 open label studies underway
▪ Testing daily SC - loading dose 0.3mg/kg; 0.1mg/kg/d (week 1); opportunity to
up-titrate maintenance dose to up to 0.3mg/kg/d in weeks 2-12 using a 40mg/ml
solution
Dosing &
RoA
▪ RA Pharma is conducting two Phase 2 studies:
– Study 1 (ex-US): Cohort A Naïve PNH subjects with LDH≥2xULN; Cohort B
PNH patients on eculizumab therapy for at least 6 months prior to screening
– Study 2 (US only): Patients with inadequate response to eculizumab defined
as having received eculizumab for at least 6 months plus a documented LDH
level ≥ 1.5 x ULN and/or the presence of a known C5 mutation conferring
resistance to eculizumab
▪ Trial endpoints include:
– Change from baseline in LDH (primary endpoint), total bilirubin, total
hemoglobin, free hemoglobin, haptoglobin, reticulocytes, and hemoglobinuria
▪ n: 20 patients in study 1 (Cohort A ~12; Cohort B~8); 8 patients in Study 2
Ongoing
clinical
development
Phase
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ALNYLAMALN-CC5
Company website and statements;
NCT02352493
▪ GalNAc-siRNA conjugate interfering with production of C5 protein; targets
hepatocytes via the Asialoglycoprotein Receptor
▪ Recruits RNA-Induced Silencing Complex (RISC) for catalytic (as opposed to
stoichiometric) mRNA silencing
Description
▪ PNH patients from Phase 1b (Part C) open label study are still being followed
▪ Subcutaneous administration
▪ Alnylam’s prior statements suggest quarterly 600mg ‘CC5 + 300 or 600mg Q4W
eculizumab in PNH
Dosing &
RoA
▪ 3 part Phase 1 study active – all subjects enrolled:
– Part A: Single ascending dose in healthy subjects
– Part B: Multiple ascending dose in healthy subjects
– Part C (Phase 1b): 6 PNH patients recruited. Data presented at EHA and
ASH 2016. Company statements suggest these patients continue to be
followed
▪ Part C endpoints include:
– Primary – Safety and tolerability
– Secondary – PK, C5, LDH, complement activity
▪ n: 6 PNH patients, 3 naïve to eculizumab therapy, 2 patients previously stable
on 900mg Q2W eculizumab, 1 patient previously on 1200mg Q2W eculizumab
Ongoing
clinical
development
Phase
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AKARICoversin
Company website and statements;
ASH 2014 & EHA 2017
▪ Small (16 kDa) protein of the lipocalin family with anti-complement activity
isolated from the tick of Ornithodoros moubata
▪ Binds to human C5 and prevents its cleavage by C5 convertases
▪ In vitro effect in preventing hemolysis of PNH erythrocytes, but:
– Inhibition doesn’t seem complete
– No expected effect on C3 decoration
▪ Immunogenicity (evolutionary distant protein)?
Description
▪ Phase I in HV
▪ Phase I/II in PNH (untreated)
▪ Subcutaneous administration, dailyDosing &
RoA
▪ Phase II in PNH
– N=5 screened (4 on treatment)
– 60 mg loading dose followed by 23.5 mg BID, then QID
– PD: CH50 fully inhibited
– Hematological response, with LDH reduction (< 2x ULN)
– One patient with R885 H/C C5 polymorphism
▪ Phase III in PNH announced (poor responders and/or untreated)
Ongoing
clinical
development
Phase
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ALEXIONALXN1210
ALXN1210 Innovative Engineering Immediate, complete, sustained
reduction of free C5 activity ≥99% – High affinity Anti-C5 monoclonal
antibody
– Derived from eculizumab through
targeted engineering designed to:
Enhance Fc receptor recycling
Increase half-life
Maintain favorable safety and
tolerability profile
Clinical development– Phase I and Phase II completed
– Two phase III trials in PNH
ongoing
PNH 301: untreated patients
PNH 302: patients on ecu, with
stable response
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ALXN1210 Phase 3 PNH Switch Study:Trial Design (Ravulizumab)
15aALXN1210 dosage: loading dose = 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, 3000 mg for patients weighing ≥ 100 kg; maintenance dose=3000 mg for
patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, 3600 mg for patients weighing ≥ 100 kg. bSoliris maintenance dose=900 mg.
NCT03056040. Clinical Trial.gov website. https://clinicaltrials.gov/ct2/show/NCT03056040
Provided April 26, 2018, as part of an oral presentation and is qualified by such, contains forward-looking statements, actual results may vary materially; Alexion disclaims any duty to update.
Randomized treatment period
26 weeks
Primary Objective: Assess non-inferiority of ALXN1210 compared to Soliris® in patients with PNH who are clinically stable after having
been treated with Soliris® for at least the past 6 months
Primary Endpoint: Hemolysis as directly measured by percentage change in LDH levels from Baseline to Day 183.
Patients who meet eligibility criteria
and on Soliris® for≥ 6 months
N=195
Stratification Randomization
1:1 Soliris® maintenance doseb
Day 1 and every 2 weeks
ALXN1210maintenance dosea
Day 197 and every 8 weeks
ALXN1210loading dosea
Day 183
15 17 19 21 23 25
ALXN1210 loading dosea Day 1
3
Continue ALXN1210 maintenance doseEvery 8 weeks
aALXN1210 maintenance dosea
Day 15 and every 8 weeks
19 26
5 7 9 11 13
11
3
Q8W
Q8W
Screening up
to 4 weeks
Extension period
2 years
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Normalização de LDH
Blood 133: 530, 2019
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The perfect complement inhibitor for PNH
1. As safe as first-generation inhibitors (eculizumab)
2. Similar control of intravascular hemolysis, as
compared with eculizumab
3. Possible effect on C3-mediated extravascular
hemolysis
4. Effective in rare genotypes?
5. Possibly better in terms of patients compliance
(administration route, frequency): no hospitalization?
6. Cost: a cheap treatment for everybody, worldwide
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Classical pathway Lectin pathway Alternative pathway
C1q
C1rC1s
C2 C4
C4b2a
C3
MBL
MASPs
C3bBbC3(H2O)Bb
C3
hydrolysis
fB fI
P
(tick-over)
Immune
complexes Bacterial LPS
and membranes
C4b2aC3b C3bBbC3b
C6
MAC
C7
C8
C9
C3 convertases
C5 convertases
Lytic complex
C3b
C3a
C5 C5b
C5a
Proximal complement
inhibitors (alternative pathway-
specific):
• Factor B (fB) inhibitors
• Factor D (fD) inhibitors
• Properdin (P) inhibitors
• Factor H (fH)-based protein
(e.g., TT30)
• Complement Receptor 1
(CR1)-based proteins**: may also modulate other
complement pathways
Amplification
loop
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Classical pathway Lectin pathway Alternative pathway
C1q
C1rC1s
C2 C4
C4b2a
C3
MBL
MASPs
C3bBbC3(H2O)Bb
C3
hydrolysis
fB fI
P
(tick-over)
Immune
complexes Bacterial LPS
and membranes
C4b2aC3b C3bBbC3b
C6
MAC
C7
C8
C9
C3 convertases
C5 convertases
Lytic complex
C3b
C3a
C5 C5b
C5a
Broad C3 inhibitors:
• Compstatin and derivativesAmplification
loop
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COMPSTATINA Peptide Drug to Block Complement at the C3 Level
Qu et al., 2012, Immunobiology
4V9H3,000 nM
4(1MeW)10 nM
Cp400.5 nM
1996 2006 2012
AMD [Phase II]POT-4 [Potentia/Alcon]
AMD, PNH, Sepsis,Hemodialysis, …
C3b
C5
C5aMAC
C4
C2
FD
FB
C3a C3b C3d
C1 MBL Fic P
Compsta n
iC3b
C3
P1:1 (molar) binding
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Effect of compstatin analogs on hemolysis of PNH RBCsDose-dependent inhibition
PNH RBC hemolysis:Cp40 (AMY-101) and PEG-Cp40 (AMY-105)
0
10
20
30
40
50
60
70
80
90
100
0,1 1 10 100
Concentration (uM)
% o
f ly
sis
ob
serv
ed
in
aN
HS
CP30
AMY-101
AMY-105
Risitano et al, Blood 2014
C3-FITC
Erythrocytes in
acidified serum
+ Cp40 10 uM
CD
59
-PE
CD
59
-PE
Erythrocytes in
acidified serum
+ PEG-Cp40 10 uM
Both Cp40 and its PEGylated derivative completely
abolish hemolysis of PNH erythrocytes in vitro
Cp40 and PEG-Cp40 completely prevent C3 fragment
deposition on PNH RBCs incubated in aNHS
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Other compstatin analogs (Apellis Pharmaceuticals)
• APL-1 and APL-2: PEGylated derivatives of the first-generation
compstatin (POT-4)
• In vitro, efficacy comparable to that of novel derivatives
• Complete inhibition of lysis
• Complete prevention of C3 deposition
• Clinical translation ongoing (with APL-2):
• Phase I in healthy volunteers
• Phase Ib in PNH patients already on eculizumab
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PADDOCK (interim): APL-2 shows potential to reach normal LDH levels
as monotherapy in treatment in naïve PNH patients – 270 mg/day
0
2600
2400
2200
2000
1800
1600
1400
1200
1000
800
600
400
20019 18 19 17 15 15 15 14 12 11
1 15 29 43 57 71 85 99 113 127 141 155 169
LD
H(U
/L)
Day
• Reductions in LDH were rapid following initiation of APL-2 therapy, with 95% of
subjects achieving an LDH in the normal range by day 29
• Reductions in LDH have been sustained and durable, with mean
LDH maintained within the normal range at all timepoints beyond day
29
Decrease in LDH
normal
• All 19 subjects responded rapidly after initiating APL-2 therapy, and by day
29 mean baseline Hb increased from 8.0 g/dL to 10.8 g/dL
• Increases in Hb were sustained and durable as represented by a mean Hb of
12.2 g/dL at day 85
5
7
9
11
13
15
17
19
1 15 29 43 57 71 85 99 113 127 141 155 169
Day
Hem
og
lob
in(g
/dL
)
Increase in Hemoglobin
normal
19 18 19 17 15 15 15 14 12 11n n
Interim data as reported Dec 2, 2018
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PHAROAH: APL-2 add-on to Soliris® - all four patients
successfully transitioned to APL-2 monotherapy
Eculizumab
Monotherapyi
APL-2 +
Eculizumabii
APL-2
Monotherapyiii
Hemoglobin (g/dL) * 8.9 11.9 11.4
Annual Transfusions (avg.) 6.0 0 0
LDH (ULN) * 1.0x 0.8x 0.9x
Reticulocytes (ULN)* 2.7x 1.2x 0.8x
Patient Years (Total) NA 5.9 Years 1.9 Years
Multiple of Eculizumab Label Dose
(900mg x 2wk.)1.6x 1.0x -
*Average last available reading for all four patients on each dosing regimen(i) last reading during eculizumab monotherapy prior to co-treatment with APL-2
(ii) last reading during co-treatment and prior to APL-2 monotherapy
(iii) last reading while on APL-2 monotherapy
Interim data as reported Sept 4, 2018
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Other compstatin analogs (Apellis Pharmaceuticals)
Plans for Phase III just announced (different indications)
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Second generation complement inhibitors for PNHTake home messages
1. Alternative anti-C5 agents (or terminal complement inhibitors) may
result in limited benefit Possible improvement of treatment compliance: administration route and
intervals (reduced/abolished hospitalization?)
Reduced costs?
Likely no clinical benefit over eculizumab (except for C5 mutations)
2. Second-generation inhibitors must target early complement activation C3-mediated extravascular hemolysis is the main unmet clinical need in
PNH
i. C3 inhibitors: compstatin
Optimal strategy for PNH, due to deranged regulation along all the three
pathways
Initial data in PNH very encouraging (mostly add-on therapy)
Subcutaneous availability, but need of s.c. INFUSIONS
ii. Alternative pathway inhibitors: anti-FB and anti-FD
Preliminary data in PNH (anti-FD only) very promising (add-on therapy)
Orally available
short half-life; risk concerning “missing doses”