Conflito de Interesse - IWEVENTOS

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.

Inibidor de complemento na HPN:

passado, presente e futuro

Phillip Scheinberg

Hospital A Beneficência Portuguesa

São Paulo

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


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


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


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


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

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

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)

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

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


Hemolysis

Cytopenia

Aplastic Anemia

PNH

Bone Marrow Failure and PNH

Normal

Aplastic

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”!?

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)

Ricklin et al,

Blood 2015

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

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

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

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

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

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

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

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


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


19 26

5 7 9 11 13

11

3

Q8W

Q8W

Screening up

to 4 weeks

Extension period

2 years

https://clinicaltrials.gov/ct2/show/NCT03056040

Normalização de LDH

Blood 133: 530, 2019

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


C1q

C1rC1s

C2 C4

C4b2a

C3

MBL

MASPs

C3bBbC3(H2O)Bb

C3

hydrolysis

fB fI

P

(tick-over)

Immune


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


C1q

C1rC1s

C2 C4

C4b2a

C3

MBL

MASPs

C3bBbC3(H2O)Bb

C3

hydrolysis

fB fI

P

(tick-over)

Immune


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

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

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


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

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

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

38

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

41

Other compstatin analogs (Apellis Pharmaceuticals)

Plans for Phase III just announced (different indications)

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”

Centro Oncológico BP

Beneficência Portuguesa Hospital BP Mirante

[email protected]

Documents

Conflito de Interesse - IWEVENTOS