10 ani de contribu ie la cercetarea muticentric interna ional în

angioedemul ereditar

Dumitru MOLDOVAN

Noémi-Anna BARA

Enik MIHÁLY

Re eaua Român de Angioedem Ereditar

Conferin

ta Ziua B

olilor Ra

re 2017

Angioedemul ereditar (AEE)

• boal genetic rar , debilitant i cu poten ial letal

• cauzat de deficien a de C1-inhibitor esteraz (C1-INH)

Conferin

ta Ziua B

olilor Ra

re 2017

Prevalen a

• în lume: 1/10.000 - 1/50.000 de locuitori

• Europa: estimativ 10.000 - 50.000 persoane

• România: estimativ 400 – 2000 persoane

• centrul nostru: 92 pacien i confirma iCon

ferinta Z

iua Bolilo

r Rare 2

017

Manifest ri clinice

Episoade recurente de edem: - subcutanat localizat- al mucoasei c ilor respiratorii- al tubului gastrointestinal

•Edemul: spontan, nepruriginos, necompresibil, f urticarie

•durat : 3-5 zileCon

ferinta Z

iua Bolilo

r Rare 2

017

Manifest ri clinice

• 50% apar pân la vârsta de 10 ani,

• 35% între 10-20 ani i

• 15% peste vârsta de 20 aniConferin

ta Ziua B

olilor Ra

re 2017

Atacul periferic (cutanat)• cel mai frecvent, durere

Conferin

ta Ziua B

olilor Ra

re 2017

Atacul abdominal• durere colicativ , gre uri, v rs turi, diaree,

deshidratare• dureaz aproximativ 3 zile• frecvent interven ii chirurgicale inutile interpretate

ca abdomen acut chirurgical

Conferin

ta Ziua B

olilor Ra

re 2017

Atacul facial• cel mai deranjant• desfigurare temporar• 30% edem glotic i risc de

asfixiere

Conferin

ta Ziua B

olilor Ra

re 2017

Atacul laringian• cel mai periculos, 30% risc de deces• de obicei dup vîrsta de 11 ani, mai frecvent la 21-

40 ani• uneori progres rapid (deces în 20 min de la debut)• necesit tratament prompt

Conferin

ta Ziua B

olilor Ra

re 2017

Diagnostic

• Anamnez familial pozitiv în 75% din cazuri

• Simptome caracteristice

• Laborator: C1 esteraz protein i activitate, C4 (în tipurile 1 i 2 sc zute), examen genetic pentru tipul 3.

Conferin

ta Ziua B

olilor Ra

re 2017

Consensul tratamentului AEE• tratamentul atacului,• profilaxie de scurt durat i • profilaxie de lung durat

Conferin

ta Ziua B

olilor Ra

re 2017

Tratament disponbil în AEE

• plasm proasp t congelat (PPC)• androgenii atenua i (AA): Danazol, Stanozolol,

Oxandrolone • antifibrinolitice(AF): Acid tranexamic(AT), Acid

epsilon amino caproic (AEAC)• concentrat de C1-INH: derivat din plasm

(Berinert, Cinryze, Cetor) i recombinat (Ruconest)

• inhibitor de kallikrein : Ecallantide• antagonist de receptor de bradikinin : Icatibant

Conferin

ta Ziua B

olilor Ra

re 2017

BEHRING CE1145-3001A Randomized, double-blind, 3-arm, placebo-controlled trial to

evaluate human pasteurized C-1 esteraze inhibitor concentrate in subjects with congenital C1-INH deficiency and acute abdominal

or facial HAE attacks. (CE1145).

12 screened patients (*)4 enrolled patients: 3 abdominal and one facial attack(s)Ranked high en-roller (3rd outside US)

2006-2007

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

2007-2009

PHARMING 1304A randomized, placebo-controlled, double-blind Phase III study of the efficacy and safety of recombinant human C1 inhibitor for the treatment of acute attacks in patients with

hereditary angioedema

32 screened patients (*)DBPC 2 patients

OLE enrolled 14 patientsOLE treated attacks (safety) 86Patients with 26, 18 and 10 respectively attacks

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

2009

PHARMING C1-1207-2009 An Open-label exploratory Phase II study of the safety and Prophylactic Effect of a weekly 50 U/kg rC1INH

treatment in Asymptomatic patients with hereditary C1INH deficiency (HAE).(OPERA)

10 screened and treated patients (*)

Conferin

ta Ziua B

olilor Ra

re 2017

13 screened patients DBPC 5 patientsOLE 110 attacks treatment

2010-2011HGT-FIR-054 A Phase III Randomized Double-blind, Placebo-controlled Multicenter Study of Icatibant for Subcutaneous Injections in Patients with Acute Attacks of Hereditary Angioedema (HAE)

Conferin

ta Ziua B

olilor Ra

re 2017

2011-2013

PHARMING 1310A Phase III randomized, double-blind, placebocontrolled

study with an open-label extension evaluating the efficacy, safety and immunogenicity of recombinant human C1 inhibitor for the treatment of acute attacks of angioedema in patients with HAE

12 screened patients DBPC 9 patientsOLE 100 attacks treatment

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

Death and TaxesMeet Joe Black -- Brad Pitt and Anthony Hopkins

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

No action indicated (NAI)

September 9-13 2013

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

2012-2016

BEHRING CE1145-4001Prospective open-label uncontrolled multi-center postmarketing study to assess inhibitory antibody formation in subjects with congenital C1-INH deficiency and acute hereditary angioedema (HAE) attacks treated with Berinert®, a C1-esterase inhibitor

15 screened patients Enrolled 15 patients138 attacks treatment

Conferin

ta Ziua B

olilor Ra

re 2017

6. Pharming 1209

Safety of Ruconest in 2-13 year old HAE Patients 2 pacienti screenati

2011-2017

2 patients

PHARMING C 1209Open-label, phase II, single arm study to evaluate the safety,immunogenicity, pharmacokinetics and efficacy of recombinanthuman C1 inhibitor for the treatment of acute attacks in pediatricpatients with hereditary angioedema, from 2 up to and including 13years of age

Conferin

ta Ziua B

olilor Ra

re 2017

9.Pharming C1-3201.Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Period Crossover to Evaluate the Efficacy and Safety of Recombinant Human C1 Inhibitor in the Prophylaxis of Angioedema Attacks in Patients with Hereditary Angioedema (HAE).Pacienti screnati si randomizati 6

A Phase 3, Multicenter, Randomized, Single-blind, Dose-ranging, Crossover Study to Evaluate the

Safety and Efficacy of Intravenous Administration of CINRYZE® (C1 esterase inhibitor [human] for the

Prevention of Angioedema Attacks in Children 6 to 11 Years of age With Hereditary Angioedema

2015-2016

pacient

Conferin

ta Ziua B

olilor Ra

re 2017

Pharming C1-3201.Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Period Crossover to Evaluate the Efficacy and Safety of Recombinant Human C1 Inhibitor in the Prophylaxis of Angioedema Attacks in Patients with Hereditary Angioedema (HAE).

2014-2015

patients

Conferin

ta Ziua B

olilor Ra

re 2017

Shire ViroPharma, IncProtocol: SHP616-300

A huge THANK YOU shout-out goes to all investigators, study coordinators, study staff, and patients from Canada, Germany, Hungary, Israel, Romania, Spain and United States.

Congratulations to the high enrollers for the study:

Dr. Moldovan in Europe (8 Subjects)

Dr. Lumry in North America (7 Subjects),

Dr. Reshef in Middle East (6 Subjects

Conferin

ta Ziua B

olilor Ra

re 2017

În loc de concluzii

Conferin

ta Ziua B

olilor Ra

re 2017

Mul umiri

Conferin

ta Ziua B

olilor Ra

re 2017

Conferin

ta Ziua B

olilor Ra

re 2017

Our patients

Conferin

ta Ziua B

olilor Ra

re 2017

MUL UMESC

Conferin

ta Ziua B

olilor Ra

re 2017