Ein rekombinanter humaner C1-inhibitor: Klinischer Überblick

Transcription

1 Ein rekmbinanter humaner C1-inhibitr: Klinischer Überblick B.M. Giannetti 23 Nvember 2011 Deutschen Gesellschaft für Angiödeme e.v. Univ. Hautklinik Mainz

2 Pharming Transgenic Technlgy Platfrm Select prtein Generate genetic cnstructs Develp funder/ mini-herd Purify prtein frm milk Frmulate prtein therapeutic 2

3 Rucnest is highly purified Nn-reduced SDS-PAGE analysis f rhc1inh and native C1INH Rucnest < 0.002% nn-prduct related impurities In lane 1: Rucnest In lane 2: pdc1inh Prteins, 100 ng/lane, were visualized by silver-staining. The migratin f the standard prtein markers is indicated n the left (10-3 x M r ). Data n File 3

4 rhc1inh activity similar t pdc1inh Similar affinity twards target prteins k n (M -1.s -1 ) C1s Factr XIa Factr XIIa Kallikrein rhc1inh a 6.1± 0.3 x ± 0.5 x ± 0.5 x ± 0.1 x 10 3 h-c1inh a 5.1± 0.3 x ± 0.2 x ± 0.4 x ± 0.3 x 10 3 Data generated at Pharming Technlgies B.V. The data are mean ± SD f three experiments. The values fr k ff were virtually zer. kn: secnd-rder rate cnstant f inhibitin EPAR Rucnest

5 rhc1inh 50 U/kg PK parameters Mean pharmackinetic parameters fllwing administratin f rhc1inh 50 U/kg t asymptmatic HAE patients Parameter Mean value ± SD (n=6) C max (U/mL) 1.36 ± C max abve baseline (U/mL) 1.18 ± T max (min) 18.3 ± 5.72 AUC abve baseline (U.min/mL) 218 ± 55.6 CL (ml/min) 22.8 ± 7.34 Half life (min) 93.7 ± 8.45 Vlume (L) 3.03 ± C baseline (U/mL) ±

6 rhc1inh PK prfile in asymptmatic HAE patients Restre levels t nrmal range Lwer limit f nrmal Level t prevent autactivatin Mdified graph frm M van Drn et al., J Allergy Clin Immunl 2005;116:

7 Functinal C1INH target levels N C4 cleavage at nrmal C1INH levels C. E. Hack et al., Allergy

8 rhc1inh Mechanism f Actin in HAE Insufficient (functinal) C1inh results in edema Treatment requires sufficient amunts f C1Inh activity 1 Unit = quantity in 1ml f nrmal plasma 2100U > nrmal quantity in 2l f plasma = 4 vials f Cinryze / Berinert C1inh binds t target prteases as a suicide inhibitr Once the cascade is switched ff, the edema is absrbed passively Dse is mre imprtant than half life 8

9 Weight (kg) Maximum Functinal C1INH (U/mL) Simulated C max by weight fr apprved dsing regimen C.Farrell et al, BJCP 2011 in Press

10 Rucnest Cntrlled Trials Overall VAS Scres ver time at the mst severe lcatin B. Zuraw, M. Cicardi et al., J Allergy Clin Immunl 2010;126:

11 Rucnest Cntrlled Trials Time t nset f relief B. Zuraw, M. Cicardi et al., J Allergy Clin Immunl 2010;126:

12 All C1INH cntrlled trials Placeb crrected dse respnse at 4 hurs Optimal efficacy achieved at 50 U/kg N further imprvement with 100 U/kg Dse is mre imprtant than half-life C. E. Hack et al., Allergy

13 Integrated safety findings Expsure Study Study ppulatin Subjects (n) Administratins (n) C1 1202/03 Symptmatic patients C RCT Symptmatic patients C OLE Symptmatic patients C RCT Symptmatic patients C OLE Symptmatic patients Subttal Symptmatic patients C Asymptmatic patients C Healthy Vlunteers C Asymptmatic patients Subttal All ppulatin Data n File 13

14 Integrated clinical safety findings Summary rhc1inh up t 100 U/kg was generally well tlerated, the AE prfile being similar t that f placeb N severe TEAEs were cnsidered t be prbable r definitely related t rhc1inh administratin N increase in the frequency f TEAEs upn repeated rhc1inh administratin 14

15 Integrated immunsafety Antibdies t C1INH N inductin f anti-c1inh antibdies N neutralizing antibdies Data n File 15

16 Integrated immunsafety Antibdies t HRIs Occasinal and transient antibdies t HRIs Nne assciated with clinical events Data n File 16

17 Integrated immunsafety IgE antibdies Rucnest is cntraindicated in patients with knwn r suspected rabbit allergy In Eurpe Rucnest is nly administered t patients wh tested negative fr rabbit epithelium (dander) antibdies, and re-testing is indicated nce yearly r every 10 treatments Subjects expsed t rhc1inh were tested fr the presence f preexisting IgE antibdies against rabbit epithelium N differences in pre- and pst expsure bld samples. N inductin bserved f IgE antibdies C. E. Hack et al, Pster IgE; EAACI 2010 Lndn, Allergy 2010 Jun; 65 Suppl 92:

18 Recmbinant C1INH Safety cnclusins 714 Rucnest expsures in 190 subjects N increase in adverse events with repeated expsures N evidence fr neutralizing antibdies t endgenus C1INH Cnfirmed anti-hri antibdies are spradic and transient, nt assciated with clinical events N inductin bserved f IgE antibdy Rucnest has an unremarkable safety prfile. Data n File 18

19 Cnclusins Rucnest is a nvel bitech alternative t plasma derived C1inh fr the treatment f HAE attacks Identical amin acid sequence Differences in glycsylatin prfile Highly purified Apprved at a higher dse (50U/kg) achieving ptimal efficacy Similar affinity t target prteases Functinal units are directly cmparable (1vial f Rucnest> 4 vials f plasma prduct) Dse is mre imprtant driver f efficacy than half-life N relapse Reassuring safety prfile N pharmaclgical AEs N inductin f allergies bserved N inductin f neutralizing antibdies Cntraindicated in pts with rabbit allergy 19