Factor Replacement Products. Hem/Onc Fellows 2017

Transcription

1 Factor Replacement Products Hem/Onc Fellows 2017

2 Factor VIII concentrates: History and Current Issues Fresh Frozen Plasma Mid 1960 Cryoprecipitate from FFP 1970s Lyophilized concentrates from pooled plasma Mid 1980s to 1990s: dry heat treated no longer used exclusively solvent-detergent treatment Tri(n-Butyl) Phosphate (TNBP), with a detergent, such as polysorbate 80 or Triton-X-100, to inactivate lipid-enveloped viral contaminants (lipid-enveloped viruses include HIV, HBV, HCV). Pasteurization heated in aqueous solution with stabilizers Vaporization steam Monoclonal antibody purification immune affinity chromatography by monoclonal antibodies 1984: cloning of FVIII; screening of donors 1992: Recombinant Factor VIII 1997: Recombinant Factor IX 2014: Long-acting Factor VIII and IX

3 The Perfect Concentrate Safety (and purity?) Less immunogenic Longer-acting (increased half-life) Convenient Affordable

4 Safety and purity Heat-treated (long vs. short) Pasteurized (heated in aqueous solution) Solvent Detergent Monoclonal (immunoaffinity) Recombinant VIII (after cloning the gene in 1984) Hamster cell lines (baby hamster kidney (BHK) vs. chinese hamster ovary (CHO) cell lines

5 Generations and safety First generation Contains animal or human plasma-derived proteins in the culture cell medium and in the final formation Second generation Contains animal or human plasma-derived proteins in the culture medium but not in the final formation Third generation No animal or human plasma-derived proteins in the culture medium or final formation

6 Immunogenicity 20-30% Factor VIII patients develop neutralizing antibodies Type of mutation (null such as Intron 22-- vs. non-null mutation) Age at first exposure High dose, intensive treatment And product???

7 Product risks and inhibitors RODIN (Research of Determinants of Inhibitor) study Increased risk of inhibitor development with second generation products (BHK) cells (Kovaltry not tested) SIPPET ( Survey of Inhibitors in Plasma-Product Exposed Toddlers) Increased inhibitor development in rfviii than pdfviii Unfortunately stratification by genetic mutation doesn t identify those that can be safely treated with rfviii (lower risk mutations actually had greater risk difference)

8 Does VWF reduce the risk? i.e. Should our perfect product have VWF?

9 Without TRY 1699 Sulfation, FVIII is unable to form a complex with vwf (effect of thrombin is reduced in releasing FVIIIa)

10 Is the risk related to VWF? Does the FVIII-VWF complex have less efficient immunogenicity in the antigen presenting cell?

11 Does the cell line effect immunogenicity? All published data on products is with PTP but!

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13 NUWIQ PRELIMINARY DATA (AUGUST 2017) In total, positive anti-fviii inhibitor titers ( 0.6 BU) were detected in 13/66 (19.7%) patients; 8 (12.1%)were high-titer, and 5 (7.6%) were low-titer. Of the low-titer inhibitors, 4/5 (80%) were transient.6 The median (range) peak inhibitor titer was 66.9 (7 822) BU for high-titer and 2.3 ( ) BU for low-titer inhibitors.6

14 Does Fc Fusion decrease immunogenicity? Theoretical benefit: Would Fc fusion (and maybe albumin) decrease the immunogencity by antigen shielding (decreases uptake of FVIII by APCs) Dr. Ward: this only works when FVIII is multimerized so that it would only work in a clotting setting PUP study: no data reported yet

15 Factor VIII concentrates Generation Product FVIII Host Cell Line Half-life Product names Approved Plasma-derived FVIII only Full-length Pooled human plasma hours Hemofil-M Koate DVI Monarc-M Monoclate-P Plasmaderived/VWF FVIII/VWF complex Full-length Pooled human plasma 12/ Hours Alphanate HumateP Wilate First FVIII only Full-length CHO with albumin 14.6+/-4.9 Recombinate 1992 Second FVIII only Full length CHO with albumin in culture hours Helixate Kogenate 2000

16 Factor VIII concentrates: Third Generation Generation Product FVIII Host Cell line Half-life Product names Approved Third FVIII Full length CHO 12.0 Advate 2003 Third FVIII B-domain deleted CHO 11.2 Xyntha 2008 Third FVIII B-domain truncated CHO 11 Novoeight 2013 Third FVIII Full length BHK 13.4 Kovaltry 2016

17 Factor VIII concentrates: Third or Fourth Generation? Generation Product FVIII Host Cell Half-life Product Name Approved?? FVIII with increased VWF affinity Full length HEK 17.1 NuWiq 2015?? FVIII single chain Extended half life CHO 14.2 Afstyla 2016?? FVIII B domain deleted?? FVIII B domain deleted; Fc domain fusion protein CHO /-3.79 hours HEK /2.3 hours Adynovate 2016 Eloctate 2014

18 Factor IX Concentrates Plasma-derived Generation Product Host Cell Half-life Product Name Approval date Plasmaderived FIX Pooled Human Plasma 21 hours AlphaNine 1987? Plasmaderived FIX Pooled Human Plasma 22.6 hours Mononine 1992

19 Factor IX: Recombinant Generation Product Host Cell Half-life Product Name Approval date Third Full IX CHO 18.8+/ /- 7 hrs hrs Benefix Ixinity Rixubis 1998 (?); Third?? Full IX Peg EHL CHO hours Idelvion 2016 Fourth? Full IX; Fc fusion HEK hours Alprolix 2014

20 Extended half-life

21 Von Willebrand Factor Concentrates: Plasma-derived Generation Product Host Cell Half-life Ratio VWF:FVIII Product Name Approval date Plasmaderived VIII and VWF Pooled Human Plasma:SD / :1 Alphanate 1978; 2007 Plasmaderived VIII and VWF Pooled Human Plasma: Pasteurized 8.4 to 17.4 hours :1 Humate P 1986 Plasmaderived VIII and VWF Pooled human plasma:sd VWF:RCo: 15.8 ± 11 hours FVIII:C: 19.6 ± 6.9 hours 1:1 Wilate 2009

22 Von Willebrand Concentrates: Recombinant Generation Product Host Cell Half-life Product Name Approval date Third VWF CHO /- 4.9**Must have FVIII>40% or give FVIII VonVendi 2015