Novità in tema di terapia delle emofilie Marco Marie3a - Modena marco.marie)a@unimore.it
Relazioni con sogge9 portatori di interessi commerciali in campo sanitario Ai sensi dell’art. 3.3 sul Confli3o di Interessi, pag. 17 del Regolamento Applica=vo dell’Accordo Stato-Regione del 5 novembre 2009, io so3oscri3o Do3. Marco Marie3a dichiaro che negli ul=mi due anni ho avuto i seguen= rappor= ricevendo compens individuali con soggeG portatori di interessi commerciali in campo sanitario: � Partecipazione ad Advisory Board per l’ Azienda Novo-Nordisk � Relazioni a congressi per la di3a Kedrion, Orphan, Novo-Nordisk, Werfen
Da dove veniamo? Che siamo? Dove andiamo? Paul Gauguin, 1897
Da dove veniamo? Che siamo? Dove andiamo? Paul Gauguin, 1897
Haemophilia treatment pre-1930 1940 1950 1960 1970 1980 1990 1970 ImmobilizaTon, ice, rest, analgesia Limited plasma-derived replacement material Plasma Mainly on-demand, in-hospital treatment Early crippling Whole blood Cryoprecipitate transfusion arthropathy Bleeding-related deaths: 47% (NL) Life expectancy: 59 yrs (Sweden) 25 yrs (Finland)
Haemophilia treatment pre-1930 1940 1950 1960 1970 1980 1990 2000 2010 ImmobilizaTon, Low-purity FVIII First ice, rest, analgesia concentrate recombinant FVIII product Heat-treated Newer high-purity FVIII recombinant Plasma Intermediate- concentrate FVIII products purity FVIII concentrate Whole blood transfusion Cryoprecipitate Darby et al, AIDS 2004
Haemophilia treatment 2000 Plasma-derived and recombinant concentrates largely available Diffusion of prophylaxis Home Treatment Minimal joint disease in pa=ents on prophylaxis Bleeding-related deaths: <10% (NL) Life expectancy: 71 yrs (Italy, NL)
All that glisters is not gold, Often have you heard that told William Shakespeare The Merchant of Venice All that is gold does not glitter, Not all those who wander are lost JRR Tolkien The Lord of the Rings
Current challenges for treatment of hemophilia � Venous access: intravenous route of administra=on � Infusion frequency: half-life FVIII ∼ 12 hrs, FIX ∼ 20 hrs � Inhibitors � Costs and availability of concentrates � Barrier to highly demanding regimens: � Prophylaxis � Immune tolerance inducTon � Major surgery
Da dove veniamo? Che siamo? Dove andiamo? Paul Gauguin, 1897
REVIEW ARTICLE disorders. J Thromb Haemost 2016; 14 : 2095 – 106. Advances in the treatment of bleeding disorders to 1% after dose Estimated time � 1 of 50 lU kg F. PEYVANDI,* † I. GARAGIOLA † and E. BIGUZZI* (days) 6.5 4.9 11.2 NA 5 4 22 14 ) � 1 kg Clearance � 1 (mL h 2.47 2.64 0.75 1.4 1.4 0.7 3.2 2 (minimum – maximum) 18.4 (13.7 – 28.1) 18.8 (14.3 – 24.5) 82.1 (71.4 – 94.5) 19 (11.6 – 27.3) Mean t 1/2 (h) 93 (85 – 111) 14.3 – 16.0 91.57 14.5 Site-directed glycoPEGylation Site-specific glycoPEGylation Site-specific PEGylation (60- Controlled PEGylation (2 9 20-kDa PEG) Single-chain rFVIII (40-kDa PEG) (40-kDa PEG) Albumin fusion kDa PEG) Technology Fc fusion Fc fusion Table 1 New therapeutic agents for hemophilia A and B Alprolix (rFIX – Fc) Idelvion (rFIX-FP) rVIII-SingleChain Eloctate; Elocta (rFVIII – Fc) BAY94-9027 (BAX855) Adynovate (CSL627) Product N8-GP N9-GP Hemophilia A Hemophilia B Deficiency
REVIEW ARTICLE disorders. J Thromb Haemost 2016; 14 : 2095 – 106. Advances in the treatment of bleeding disorders F. PEYVANDI,* † I. GARAGIOLA † and E. BIGUZZI* Table 2 Dose and frequency of treatment for the control of acute bleeding in patients with hemophilia A and B [16,20,29] Dose (IU kg � 1 ) Frequency of dosing (h) Type of bleeding rFVIII standard rFVIII EHL rFVIII standard rFVIII EHL Minor/moderate 20 – 30 20 – 30 12 – 24 24 – 48 Major (life-threatening hemorrhages) 40 – 50 40 – 50 8 – 24 12 – 24 Dose (IU kg � 1 ) Frequency of dosing (h) Type of bleeding rFIX standard rFIX EHL rFIX standard rFIX EHL Minor/moderate 40 – 60 30 – 60 12 – 24 48 Major (life-threatening hemorrhages) 60 – 80 80 – 100 12 to 24 24 for the first 3 days, and then every 48 EHL, extended half-life; rFIX, recombinant factor IX; rFVIII, recombinant factor VIII.
REVIEW ARTICLE disorders. J Thromb Haemost 2016; 14 : 2095 – 106. Advances in the treatment of bleeding disorders F. PEYVANDI,* † I. GARAGIOLA † and E. BIGUZZI* Table 3 Dose and frequency for standard and extended half-life Table 4 Dose and frequency for standard and extended half-life (EHL) products in the management of hemophilia A patients under- (EHL) products in the management of hemophilia B patients under- going minor and major surgical procedures going minor and major surgery procedures Duration Duration Dose Frequency of therapy Dose Frequency of therapy (IU kg � 1 ) (IU kg � 1 ) (h) (days) References (h) (days) rFIX standard product rFVIII standard product Minor 50 – 80 Every 24 l [29] Minor 25 – 40 Every 12 – 24 1 – 3 Major Major Preoperative 60 – 80 A single-dose injection [29] Preoperative 40 – 50 A single-dose injection Postoperative 40 – 60 Every 8 – 24 7 [29] FIX EHL Postoperative 30 – 40 Every 8 – 24 1 – 7 Minor 50 – 80 A single injection may be sufficient. FVIII EHL Repeat as needed after 24 – 48 h Minor 62.50* Every 24 l Major Major Preoperative 84.16* A single-dose injection [32] Preoperative 58.3 † A single-dose injection 80 A single-dose injection [35] 87 † A single-dose injection [37] and Postoperative 49.12 – 64.61* 24 – 48 1 – 14 [32] intraoperative 40 24 – 96 13 [35] 58.8 ‡ Every 24 7 51 24 – 72 14 [37]
A J H A J H UPDATES IN CLINICAL TRIALS FOR HEMATOLOGICAL DISEASES AJH Educational Material 2017 Clinical trials update: Innovations in hemophilia therapy Jan Hartmann 1 and Stacy E. Croteau 2 * � EHL factor concentrates build on the familiar management strategies of conven=onal factor concentrates � The challenges of frequent IV infusions, pa=ent adherence, and inhibitor risk remain. � The degree to which the addi=on of these various moie=es increase, decrease, or have a neutral effect on immunogenicity remains under inves=ga=on. Am. J. Hematol. 91:1252–1260, 2016. Published online: 26 August 2016 in Wiley
A J H A J H UPDATES IN CLINICAL TRIALS FOR HEMATOLOGICAL DISEASES AJH Educational Material 2017 Clinical trials update: Innovations in hemophilia therapy Jan Hartmann 1 and Stacy E. Croteau 2 * � Interes=ngly, uptake of these products in the immediate postlicensure period has been modest � EHL products have accentuated the variability of pa=ent half-life. � The real-world impact of EHL products on health- related quality of life and health economics are also under inves=ga=on Am. J. Hematol. 91:1252–1260, 2016. Published online: 26 August 2016 in Wiley
Da dove veniamo? Che siamo? Dove andiamo? Paul Gauguin, 1897
Why is hemophilia an excellent target for gene therapy � Single gene disorder � Small absolute amounts of cloGng factors in normal plasma (fVIII 50 ng/ml, fIX 5 µ g/ml) � 1/10 of these values sufficient for normal hemostasis � Biologically ac=ve factors can be produced in a wide variety of cells � Large animal models are available (hemophilic dogs)
A J H A J H UPDATES IN CLINICAL TRIALS FOR HEMATOLOGICAL DISEASES AJH Educational Material 2017 Clinical trials update: Innovations in hemophilia therapy Jan Hartmann 1 and Stacy E. Croteau 2 * Am. J. Hematol. 91:1252–1260, 2016. Published online: 26 August 2016 in Wiley
A J H A J H UPDATES IN CLINICAL TRIALS FOR HEMATOLOGICAL DISEASES AJH Educational Material 2017 Clinical trials update: Innovations in hemophilia therapy Jan Hartmann 1 and Stacy E. Croteau 2 * � Cell-based approach to gene therapy for hemophilia uses Len=viral vectors and several cell types : liver sinusoidal endothelial cells, stem cells derived from bone marrow, blood-outgrowth endothelial cells, and endothelial progenitor cells � It requires cytoabla=ve agents to create a niche for hematopoie=c stem cells transduced ex vivo → harm? � Trials only in in murine models of HA with inhibitors � Use of platelet-specific promoters enables expression of FVIII within the α -granules of platelets → delivery at the site of hemosta=c need Am. J. Hematol. 91:1252–1260, 2016. Published online: 26 August 2016 in Wiley
Buscar el levante por el poniente… Cristoforo Colombo
A J H A J H UPDATES IN CLINICAL TRIALS FOR HEMATOLOGICAL DISEASES AJH Educational Material 2017 Clinical trials update: Innovations in hemophilia therapy Jan Hartmann 1 and Stacy E. Croteau 2 * Nonfactor Replacement Strategies: “DisrupTve Therapies” Emicizumab � Concizumab � APC-specific serpin � FVIII-specific human (CAR) T-regulatory cells Am. J. Hematol. 91:1252–1260, 2016. Published online: 26 August 2016 in Wiley
● a humanized bispecific an=body to factor IXa (FIXa) and factor X (FX), termed hBS23 ● restores factor =vity in model � ACE910 (emicizumab) is a bispecific Ab to FIXa and FX that (hBS23 ) mimics the cofactor func=on of FVIII � In non-human primate model: prolonged half-life and high subcutaneous bioavailability (Lillicrap et al Nat Med 2012;18:1460-61)
● a humanized bispecific an=body to factor IXa (FIXa) and factor X (FX), termed hBS23 ● restores factor =vity in model (hBS23 ) subcutaneous emicizumab once weekly (Lillicrap et al Nat Med 2012;18:1460-61)
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