Les traitements des hémophiles: histoire et perspectives

Transcription

1 Les traitements des hémophiles: histoire et perspectives Pr Claude Négrier Centre national de référence de l hémophilie Hôpital Edouard Herriot Université Claude Bernard Lyon 1 claude.negrier@chu-lyon.fr

2 Coagulation

3 FVIII - FIX interaction in the coagulation cascade FIX FXII HMWK PK FXIIa FT FVII FXI FXIa FVIIIa FIXa FT FVIIa FVIII Ca 2+ + PL - FX Ca 2+ + PL - FIX FX FXIII FV FVa FXa Stable polymeric Fibrin FXIIIa Instable polymeric Fibrin monomeric Fibrin Ca 2+ + PL - FIIa FII Fibrinogen Tenase complex

4 JMH 2013 Histoire de la prise en charge des patients Etat des lieux des prochains traitements : les produits anti-hémophiliques à demi-vie longue La thérapie génique : guérir demain?

5 Effet du PIB et des CTH sur l espérance de vie des patients en fonction du produit intérieur Ratio des patients <$2,000 <$2,000 + CTH PIB par habitant <13 ans >19 ans La survie et le passage à l âge adulte augmentent 5 fois si le PIB du pays est supérieur à US$ 2,000 et s il y a un accès à un CTH

6 Effet de l utilisation de concentré de FVIII sur la survie des patients La courbe représente la prévalence (survie) des hémophiles en fonction de la quantité de FVIII utilisé par habitant L impact le plus important est retrouvé entre 0,1 et 2 U par habitant

7 Espérance de vie chez les patients atteints d hémophilie Life expectancy (years) Larsson. Br J Haematol 1985;59:

8 Evolution of FVIII / FIX concentrates Subfraction I-O Low purity pdfviii concentrates Intermediatepurity concentrates rfviii Modified rfix and rfviii Cryoprecipitates High-purity concentrates rfix Late 1950s Mid 1960s Early 1970s Late 1970s Early 1980s Mid 1980s Late 1980s Early 1990s Late 1990s Early 2000s Plasma fractionation Donor / plasma screening for HBV Heat treatment of pdfviii Heat-treated concentrates widely available Immunoaffinity, S / D, ion exchange HIV / HCV screening Qualification of donors, inventory hold, NAT, nanofiltration rfviii: Recombinant FVIII; rfix: Recombinant FIX; pdfviii: Plasma derived FVIII; HBV: Hepatitis B virus; HCV: Hepatitis C virus; S / D: Solvent detergent; NAT: Nucleic acid testing Key NS, Negrier C. Lancet 2007;370:439 48

9 Plasma Fractionation (example) FROZEN PLASMA CRYOPRECIPITATION CRYOSUPERNATANT ETHANOL PRECIPITATION ALBUMIN DEAE SEPHADEX IV Ig IM Ig FIX FVII Protein C PCC Thrombin Antithrombin CRYO RESUSPENSION PREPURIFICATION SD TREATMENT ION EXCHANGE CHROMATOGRAPHY Fibrinogen vwf FVIII

10 Recombinant FVIII/FIX production Vector FVIII/FIXcDNA Mammalian cell (CHO, BHK,HEK) ER GRP94 GRP78 CalX CalR Golgi vesicle

11 Percentage alive Survival in men in the United Kingdom with hemophilia who were not infected with HIV and in the general male population of the United Kingdom in % 96% 89% 92% 88% 68% 59% 50 49% 25 0 Severe Mod / mild All UK males 23% Age (years) Darby SC. et al. Blood 2007;110:

12 Consequences of Joint Bleeding

13 Advanced haemophilic arthropathy

14 Advantages of prophylaxis Decreased to absent bleeding Minimise school/ job absences Minimal to reduced joint damage Prophylaxis Normalise family and social life Greater activities/ sports participation

15 Disadvantages of prophylaxis Cost Prophylaxis Port-a-cath complications Non-compliance

16 Histoire de la prise en charge des patients Etat des lieux des prochains traitements : les produits anti-hémophiliques à demi-vie longue La thérapie génique : guérir demain?

17 Bio-engineering of improved molecules Improvement of production levels with potential lower cost Improvement of pharmacokinetics Improvement of haemostatic potential Alteration of FVIII antigenicity Alternative approaches to improve clot formation/stability

18 Potential impacts On prophylaxis On on-demand treatment On surgery On laboratory monitoring On immunogenicity/iti

19 Half-life improvement Products with improved half-life will be beneficial to patients Less frequent injections (from 3 per week prophylaxis to once per week) Improved compliance May facilitate prophylaxis Numerous technologies to extend half-life of proteins Chemical modification Genetic modification Fusion with carrier proteins (Fc fusion, albumin)

20 FIX (U/dL) Summary profiles comparing N9-GP to previous FIX: normalised to 50 U/kg N9-GP pdfix rfix Time (days) No ethnic differences were observed between the PK profiles Negrier C et al. Blood 2011;118: Negrier C et al. Blood 2011;118:

21 Monte Carlo simulation for rfixfc doses to achieve a trough of 1 IU/dL or 3 IU/dL Shapiro A D et al. Blood 2012;119:

22 Mean plasma FVIII activity PK profiles for low-dose and high-dose cohorts Powell J S et al. Blood 2012;119:

23 Potential impacts On prophylaxis On on-demand treatment On surgery On laboratory monitoring On immunogenicity/iti

24 Summary of number of on-demand rfix infusions required for resolution of 997 hemorrhages N=54 patients 1505 infusions 94.1% excellent or good response Shapiro AD et al. Blood 2005;105:

25 Potential impacts On prophylaxis On on-demand treatment On surgery On laboratory monitoring On immunogenicity/iti

26 Potential impacts On prophylaxis On on-demand treatment On surgery On laboratory monitoring On immunogenicity/iti

27 Peters RT et al., JTH 2013

28 Potential impacts On prophylaxis On on-demand treatment On surgery On laboratory monitoring On immunogenicity/iti

29 JMH 2013 Histoire de la prise en charge des patients Etat des lieux des prochains traitements : les produits anti-hémophiliques à demi-vie longue La thérapie génique : guérir demain?

30 Gene therapy in haemophilia: In vivo approach Haemophilia patient Route of administration Intravenous infusion of the vector Direct injection of vector into somatic tissue, e.g. skeletal muscle vector (viral or nonviral) Herzog RW, Hagstrom JN. Am J Pharmacogenomics. 2001;1:

31 FIX activity after peripheral-vein infusion of the AAV vector Nathwani AC et al. N Engl J Med 2011;365:

32 Gene therapy in haemophilia: Remaining questions What is the correct vector? What is/are the correct target cell(s)? What is the correct dose and timing of administration? Who are the most appropriate patients: children, adults, previously treated, previously untreated? What are the effects of long-term use? What is the best way to handle inhibitor formation? How can gene therapy complement other therapies?

33 Barriers to participation in clinical trials Could be protocol-related, patient-related, or physician-related The most common reasons cited as barriers included: concerns with the trial setting dislike of randomisation general discomfort with the research process complexity and stringency of the protocol presence of a placebo or no-treatment group potential side-effects being unaware of trial opportunities idea that clinical trials are not appropriate for serious diseases fear that trial involvement would have a negative effect on the relationship with their physician physician's attitudes towards the trial

34 Annual Clinical Trial Applications (CTA) and Average Annual Growth Rates (AAGR) for the period 2001 to 2009 Hartmann Trials 2012;13:53

35 Clinical trials in haemophilia Peculiarities due to rare disease status Require multicenter, multinational clinical trials Become more demanding due to regulatory issues More objective assessments of clinical efficacy Necessitate specific organisation within the haemophilia center (physicians, nurses, CRAs ) Require patients participation and understanding of the rules (minimisation of the risk of deviation or violation). The biggest barrier to completing studies is the shortage of people who accept to take part Globally, it is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work)

36 Conclusion Significant improvements of recombinant technology in the last 20 years After the progressive elimination of human and animal-derived raw-materials, more subtle modifications should improve upon nature Various approaches undertaken (PK, clotting activity, antigenicity, organic compounds with clotting activity, gene therapy ) Rebalancing the coagulation system by inhibiting the inhibitors of coagulation could represent a valuable option. Stand-alone therapy (prophylaxis?) or adjunctive treatment (increase in thrombin generation to achieve hemostasis more efficiently?) More individualised therapeutic regimens Still 70% of the haemophilia population has no access to treatment; transgenic molecules produced in livestock? Gene therapy is still on the horizon Increase in convenience of treatment cannot be obtained without extensive preclinical testing in appropriate models Cautious examination of potential side-effects (long-term PEG exposure, immune response ) Barriers to participation in clinical trials should not be neglected