I nuovi concentrati di fattori della coagulazione a lunga emivita nel trattamento del paziente emofilico. Maria Elisa Mancuso

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1 I nuovi concentrati di fattori della coagulazione a lunga emivita nel trattamento del paziente emofilico Maria Elisa Mancuso Centro Emofilia e Trombosi Angelo Bianchi Bonomi Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milano Giornate Ematologiche Vicentine VII edizione Palazzo Bonin Longare, -12 ottobre 16

2 B-LONG: Phase 3 Study of rfixfc in PTPs SCREENING Current regimen On demand Prophylaxis or on demand 18 On demand ( IU/kg as required) 1 - Weekly (5 IU/kg to start, PK driven dosing) 2 - Tailored ( IU/kg qd to start, PK driven interval) Peri-operative treatment (Surgical study) Median annualised bleeding rate patients (> 12 yrs) t 1/2 : ~ 82 hours; IVR:.92 Target trough: 1-3% or higher In the tailored arm 54% of patients were treated every 14 days No inhibitors were detected (55 pts with > 5 EDs) No cases of anaphylactic reactions or thromboembolic events were reported (n=27) Once weekly (n=63) Tailored (n=29) Powell et al NEJM 13; 369:

3 A-LONG: Phase 3 Study of rfviiifc in PTPs SCREENING Current regimen On demand Prophylaxis or on demand 33.6 On demand ( 5 IU/kg as required) Weekly (65 IU/kg) Tailored (25-65 IU/kg every 3-5 days) Peri-operative treatment (Surgical study) 165 patients (> 12 yrs) Median annualised bleeding rate t 1/2 : 19. hours; IVR: 2.2 Target trough: 1-3% or higher In the tailored arm the median weekly dose was 78 IU/kg 3% of subjects achieved a 5-day dosing interval No inhibitors were detected (1 pts with > 5 EDs) 9 major procedures in 9 pts (n=23) Once weekly (n=24) Tailored (n=118) Mahlangu J et al Blood 14; 123:

4 Post-hoc analysis on bleeding rates Shapiro AD et al JTH 14; 12:

5 Paradigm 2: Phase 3 study of N9- GP for 28 weeks (n=15) Screening Prophylaxis: IU/kg 1xw for 52 weeks (n=3) Prophylaxis: 4 IU/kg 1xw for 52 weeks (n=29) Blinded randomisation Median annualised bleed rate t 1/2 : 93 hours Overall success rate for treatment of bleeds: 92.4% (excellent or good) Bleeds were treated with a single dose of 4 IU/kg 91.7% of bleeds successfully treated with a single dose No inhibitory antibodies to N9-GP No safety issues (n=15) Prophylaxis IU/kg (n=3) Prophylaxis 4 IU/kg (n=29) Collins P et al Blood 14; 124: 388-6

6 Pathfinder 2: Phase 3 Study of N8-GP SCREENING On demand (n=11) Prophylaxis (5 IU/kg every 4 days) (n=175) 4 Median annualised bleed rate t 1/2 : 18.4 hours One patient developed anti-fviii inhibitors Inhibitor development in line with expectations in PTPs (1 inhibitor) Mean trough level: 8% (n=11) Prophylaxis (n=175) ClinicalTrials.gov identifier: NCT14818 Company announcement 19 march 14

7 Prolong9-FP: Phase 3 study of rix-fp Current regimen 26 weeks > 26 weeks SCREENING Prophylaxis On demand rix-fp PK 14 days 7-day On demand 14-day -day 7-day 7-day Median annualised bleeding rate patients (> 12 yrs) t 1/2 : 2 hours; IVR: 1.27 No inhibitors were detected No cases of anaphylactic reactions or thromboembolic events were reported Mean trough: IU/dL (4 IU/kg/w) Mean trough: 12 IU/dL (75 IU/kg/eow) (n=19) 7-day (n=4) -day (n=7) 14-day (n=21) Santagostino E et al Blood 16; 127:

PROTECT-VIII: Phase 2/3 Study of BAY 94-927 in PTPs Screening therapy individual dosage (n=) 2 or more breakthrough bleeds: 2x/wk 25 IU/kg (n 1) 2x/wk 3 4 IU/kg (n ) No or 1 breakthrough bleeds: 23.

8 PROTECT-VIII: Phase 2/3 Study of BAY in PTPs Screening therapy individual dosage (n=) 2 or more breakthrough bleeds: 2x/wk 25 IU/kg (n 1) 2x/wk 3 4 IU/kg (n ) No or 1 breakthrough bleeds: 23.4 Randomization Every 5 days Every 7 days 45 6 IU/kg (n 4) 6 IU/kg (n 4) Median annualised bleed rate t 1/2 : 18.7 hours Treatment tailored to individual bleeding tendency Mean dose every 5 days: 45 IU/kg Mean dose every 7 days: 57 IU/kg (n=) Every 5 days (n=43) Every 7 days (n=43) ClinicalTrials.gov identifier: NCT158293

9 PROLONG-ATE: Phase 2/3 Study of BAX 855 SCREENING 4 Current regimen Prophylaxis or on demand 41.5 PK assessment Assigned per patient s previous treatment regimen On demand (n=17) Prophylaxis ( IU/kg 2x/wk) (n=9*) *21 were previously on demand Median annualised bleed rate Full-lenght rfviii covalently bound to a branched kda PEG moiety (random PEGylation) 6% of PEG localized on the B-domain Target trough: > 1% t 1/2 : 15 hours No inhibitor development (n=17) Prophylaxis (n=1) Konkle B et al Blood 15; 126: 78-85

10 rfviii a singola catena (CSL Behring) Aumentata stabilità della molecola dovuta a: Legame covalente tra catena leggera e catena pesante Espresso come FVIII a singola catena Maggiore integrità e stabilità molecolare dopo la ricostituzione La forma della singola catena si traduce in una maggiore affinità di legame con il vwf rispetto ad altri tipi di molecole di FVIII (potenziale effetto sull immunogenicità) rfviii standard rviii a singola catena Schulte. Thromb Res 13;131(Suppl 2):S2 6 Zollner et al. Thromb Res 13;132:28 7

11 Il ruolo del livello basale Nel passato livelli mantenuti tra 1 e 3% erano considerati sufficienti 1 Per proteggere le articolazioni dagli emartri sono necessari livelli più alti 2 Il rischio di emorragie intercorrenti è proporzionale al tempo in cui i livelli basali sono inferiori all 1% 3 1 Ahlberg A. Acta Orthop Scand 1965; 77 (Suppl): Collins P et al. JTH 9; 7: Den Uijl IE et al. Haemophilia 11; 17:

12 Concentrati ad emivita modificata Cambiamenti attesi riguardo ai regimi di profilassi Prodotti standard (n di infusioni/anno) Prodotti ad emivita modificata (n di infusioni/anno) Emofilia A Emofilia B

13 A new era for haemophilia? Prophylaxis is the cornerstone of hemophilia therapy Primary in children without inhibitors is able to prevent overt joint damage Secondary is useful to improve quality of life and functioning in adult patients New long-acting products may facilitate feasibility and improve adherence to treatment regimens due to fewer injections New long-acting products may provide a better protection due to higher factor levels attained and maintained longer

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