What to know before switching a patient to a long-acting factor concentrate. PD Dr. med. Manuela Albisetti

Transcription

1 What to know before switching a patient to a long-acting factor concentrate PD Dr. med. Manuela Albisetti

2 Increased therapeutic options for haemophilia Irish Haemophilia Society

3 Available products Cell line Mechanism of half-life extention Pharmacokinetics Efficacy Safety Benefit for patients

4 Products, cell lines and mechanisms of half-life extention Product Cell line Mechanism of half-life extention Generic name rfviiifc HEK Efmoroctocog alfa Elocta rfixfc HEK Fusion protein Eftrenonacog alfa Alprolix rix-fp CHO Albutrepenonacog alfa Idelvion N8-GP CHO Turoctocog alfa BAY BHK Damoctocog alfa BAX 855 CHO PEGylation / Glyco-PEGylation Rurioctocog alfa Idynovi N9-GP CHO Nonacog beta CSL 627 CHO Single chain molecule Lonoctocog alfa Afstyla Human-cl rfviii HEK Human cell line expression Simoctocog alfa Nuwiq HEK: Human Embryonic Kidney CHO: Chinese Hamster Ovary BHK: Baby Hamster Kidney

5 Cell line The expression cell lines differ in the ability to perform human-like glycosylation N-glycan structures Biological activity The choice of expression system is crucial because non-human glycoforms adversely impact pharmacokinetics and may raise safety concerns Crit Rev Biotechnol, 2014; 34:

6 Cell line N-glycans differences between mammalian und human cell lines Cell line α-gal NeuGc α2,6-sa HEK Not found Not found Present CHO Not found Present Not found BHK Present Not found Not found α-gal: Galactose-α1,3-galactose immunogenic NeuGc: N-glycolylneuraminic acid immunogenic α2,6-sa: α2,6-linked sialid acid increased serum half-life Crit Rev Biotechnol, 2014; 34: Thromb Res 2013;131: 78-88

7 Cell line Degree of sulfation of Tyr 1680 influence the affinity to vwf HEK BHK CHO Fully sulfation y1680 Non-sulfated y1680 Non-sulfated y1680 Complete sulfation of y1680-containing peptides Incomplete sulfation of y1680-containing peptides 20% decreased sulfation = 5-fold decreased rfviii-vwf binding Thromb Res 2013; 131: 78-88

8 Fusion protein technology Fc-Fusion protein Albumin-Fusion protein Rescue endocytosed FVIII / FIX from intracellular degradation pathway through interaction with the neonatal Fc receptor J Thromb Haemost 2013 ;11: Thromb Res 2013;131 Suppl 2:S2-S6

9 PEGylation / Glyco-PEGylation PEGylation defines the modification of a protein by the linking of one or more polyethylene glycol (PEG) chains

10 PEGylation / Glyco-PEGylation PEGylated full length molecule Glyco-PEGylated B- domain deleted molecule FVIII Lysin binding site Reduced renal elimination through increased hydrodynamic volume Reduced receptor-mediated clearance and proteolytic degradration through increased size and steric effect Hamostaseologie 2012; 32 Suppl 1:S29-S38 Blood 2013; 121:

11 Single-chain molecule FVIII Truncated B-domain covalently links the heavy and light chains Stronger affinity to vwf Thromb Res 2015; 136:

12 Human cell line expression FVIII Combination of native physiological advantanges of plasma-derived FVIII with the recombinant technology Elimination of non-human glycans Fully sulfation at Tyr 1680 increased vwf-binding affinity and FVIII stability Protein Expr Purif 2015;115:

13 Pharmacokinetics and efficacy - References Mahlangu J et al. Blood 2014; 123: Young G et al. J Thromb Haemost 2015; 13: Giangrande P et al. Thromb Haemost 2017; 117: Reding MT et al, J Thromb Haemost 2017; 15: Konkle BA et al. Blood 2015; 126: Mullins ES et al. Haemophilia 2016; 1-9 Mahlangu J et al. Blood 2016; 128: Stasyshyn O et al. J Thromb Haemost 2017; epub Powell JS et al. NEJM 2013; 369: Fischer K et al. Lancet Haematol 2017; 4: e75-82 Young G et al. Thromb Res 2016; 141: Tiede A et al. Haemophilia 2017; 1-9 Kenet G et al. Thromb Haemost 2016; 116: Klukowska A et al. Haemophilia 2016; 22: Lissitchkov T et al. Haemophilia 2016;

14 Half-life extention of rfviii concentrates Half-life (hours)

15 Half-life extention of rfviii concentrates Half-life (hours)

16 Half-life extention of rfix concentrates Half-life (hours)

17 Half-life extention of rfix concentrates Half-life (hours)

18 Efficacy of rfviii in adults & children > 12 y Product Prophylactic dose (IU/kg 2x/week) ABR (median) Response (%) rfviiifc N8-GP BAY BAX CSL Human-cl rfviii ABR: annual bleeding rate Response: % of bleeding episodes controlled with 1 or 2 infusions

19 Efficacy of rfviii in children < 12 y Product Prophylactic dose (IU/kg 2x/week) ABR (median) Response (%) rfviiifc N8-GP BAY No published information BAX CSL Human-cl rfviii ABR: annual bleeding rate Response: % of bleeding episodes controlled with 1 or 2 infusions

20 Efficacy of rfix in adults & children > 12 y Product Prophylactic dose (IU/kg) Interval (q days) ABR (median) Response (%) rfixfc rixfp N9-GP ABR: annual bleeding rate Response: % of bleeding episodes controlled with 1 or 2 infusions

21 Efficacy of rfix in children < 12 y Product Prophylactic dose (IU/kg) Interval (q days) ABR (median) Response (%) rfixfc rixfp N9-GP ABR: annual bleeding rate Response: % of bleeding episodes controlled with 1 or 2 infusions

22 Safety Purification / Viral inactivation Immunogenicity Other possible safety issues

23 Purification / Viral inactivation Product Immunoaffinity chromatography Ion exchange chromatography Nanofiltration Solvent/detergent Size exclusion Ultrafiltration rfviiifc X X X X X X rfixfc X X X X X rix-fp X X X N8-GP X X X X X BAY No published information BAX 855 X X X X X N9-GP X X X X X CSL 627 X X X Human-cl rfviii X X X X X

24 Immunogenicity Inhibitor development PTPs Product Mechanism of half-life extention Inhibitor rfviiifc 0.0 Fc-fusion protein rfixfc 0.0 rix-fp Albumin-fusion protein 0.0 N8-GP 0.0 BAY PEGylation / Glyco-PEGylation BAX N9-GP 0.0 CSL 627 Single chain molecule 0.0 Human-cl rfviii Human cell line expression 0.0

25 Immunogenicity Inhibitor development PUPs Product Mechanism of half-life extention Inhibitor rfviiifc? Fc-fusion protein rfixfc? rix-fp Albumin-fusion protein? N8-GP? BAY ? PEGylation / Glyco-PEGylation BAX 855? N9-GP? CSL 627 Single chain molecule? Human-cl rfviii Human cell line expression

26 Immunogenicity Inhibitor development 66 PUPs Human-cl rfviii SIPPET rfviii pdfviii All inhibitors 20.8% High-titer 12.8% 44.5% 26.8% 28.4% 18.6% Only 2 PUPs developed inhibitor after 20 ED Haemophilia 2017; 23 (Suppl.2): 11-27

27 Other possible safety issues Accumulation of PEG in the organism leading to vacuolation of renal tubular endothelium reticuloendothelial system lung alveolar macrophages hepatic kupffer cells splenic histiocytes and macrophages bone marrow macrophages Production of anti-peg antibodies Accellerated clearance PEG-related activation of the complement system Anaphylaxis Toxicol Sci 1998; 42: Trans Res J Lab Clin Med 2007; 149: Expert Opin Drug Deliv 2012; 9: Adv Drug Deliv Rev 2011; 63:

28 Benefit for patients Decreased number of infusions Haemophilia B: 1x/week instead 2x/week - 50% Haemophilia A: 2-3x/week instead 3-4x/week - 30% Reduced need for central venous lines Haemophilia 2014; 20 (Suppl. 4)22:

29 Benefit for patients Higher trough levels Minimize number of infusions while maintaining trough levels 1% Higher dosing to achieve trough levels >>> 1% More frequent dosing to achieve trough levels >>> 1% Individualization of treatment (age / physical activity) Haemophilia 2016; 22:

30 Benefit for patients Infusion non essentially in the morning / during the weekend Families rushing to get kids at school and themselves to work Adolescents sleeping in the morning More flexibility with the time of injection Haemophilia 2014; 20 (Suppl. 4)22:

31 Benefit for patients Increased quality of life Increased adherence Improved outcome Haemophilia 2014; 20 (Suppl. 4)22:

32 Summary and conclusions Tremendous improvement of haemophilia treatment in the last 2 decades Several long-acting FVIII and FIX concentrates using different cell lines and technologies are available Pharmacokinetics have been improved Half-life FVIII: 1.5-fold Half-life FIX: > 4-fold

33 Summary and conclusions Optimal purification and viral inactivation No inhibitor development in PTP, both adults and children Decreased inhibitor development in PUPs with Human-cl rfviii Ongoing studies on PUPs will answer still open questions

34 Summary and conclusions Data from studies are promising Good (or better) efficacy with less infusions Individualized therapy Prolongation of injection interval Higher dosis or unchanged interval to increase trough levels Increased adherence Improved outcome

35 Thank you for your attention