1 / 51

Switching between coagulation factors and Immunogenicity

Switching between coagulation factors and Immunogenicity. Peyman Eshghi Prof. of Pediatric Hematology &Oncology Pediatric Congenital Hematologic Disorders Research Center Mofid Children Hospital Shahid Beheshti University of Medical sciences Tehran,12-10-1397.

nagel
Télécharger la présentation

Switching between coagulation factors and Immunogenicity

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Switching between coagulation factors and Immunogenicity Peyman Eshghi Prof. of Pediatric Hematology &Oncology Pediatric Congenital Hematologic Disorders Research Center Mofid Children Hospital Shahid Beheshti University of Medical sciences Tehran,12-10-1397

  2. What is recombinant CFCs and their classification? • Why recombinant therapy in haemophilia? • What is the risk of inhibitor development with recombinant products? • How should we switch from pdFC to rFC?

  3. Truncated B domain Full length FVIII HC (1–740) B domain (741–1648) LC (1649–2332) • B domain does not seem to have any function with respect to FVIII clotting activity3 1 372 740 1648 2020 2173 2332 C2 C2 C1 C1 A2 A2 B A1 A1 A3 A3 a2 a2 a1 a1 a3 a3 1637 750 Truncated B domain 1 372 741–750 1638–1648 2020 2173 2332 B HC (1–740) LC (1649–2332) HC, heavy chain; LC, light chain Thim L et al. Haemophilia 2010;16:349‒59 Ezban M et al. Euro J Haematol 2014;93:369‒76 Toole JJ et al. Proc Natl Acad Sci 1986;83:5939‒42

  4. Extensive purification process to yield a homogeneous product • Developed to obtain a highly purified product and to minimize risk of viral contamination 3 2 5 1 • Anion-exchange chromatography • Separates molecules by their charge • Gel filtration • Utilizes size to remove FVIII multimersand other contaminants to yield a highly homogeneous product • Immunoaffinity chromatography • Selects intact molecules • Detergent inactivation • Helps inactivate and eliminate enveloped viruses • Also serves to concentrate the product 4 • Nanofiltration4 • 20-nm double filter has been shown to remove small nonenvelopedviruses based on size exclusion WFH guidelines: gold standard in viral safety

  5. Approved rFVIII products turoctocog alfa BDD rFVIII (CHO) Eloctate BDD rFVIII fused to Fc (HEK) ReFacto AF BDD rFVIII (CHO) Advate Full Length rFVIII (CHO) Recombinate (CHO) Full Length rFVIII Kogenate-FS Full Length rFVIII (BHK) Xyntha BDD rFVIII (CHO) Nuwiq BDD rFVIII (HEK)

  6. What is recombinant CFCs and their classification? • Why recombinant therapy in haemophilia? • What is the risk of inhibitor development with recombinant products? • How should we switch from pdFC to rFC?

  7. Why recombinant therapy in haemophilia? • Global shortage of safe Plasma compared to increased CF request and consumption regardless of strict donor selection,PCR,NATtest,etc. • Safety with regard to blood-borne pathogens:non-enveloped viruses (eg, B19V and PARV4),perions,etc • Purity :minimize non clotting-factor protein exposure • Scalability and reproducibility of the manufacturing process • Allows for molecular engineering to create improvements • Longer acting, fewer infusions • Many protraction principles theoretically mitigate immunogenicity • Alternative routes of administration

  8. Ongoing concerns for contamination of factor concentrate • HCV and HIV transmission successfully reduced, but safety concerns remain1 : • Plasma-derived products may contain infectious non-enveloped viruses (eg, B19V and PARV4)2,3 : • Not all inactivated by heat methods1 • Not affected by solvent/detergent procedures1 • Available viral-inactivation methods unable to inactivate prions1 • Modern manufacturing processes may reduce contamination but transmission risk remains3,4 • Ongoing vigilance and monitoring of both people with haemophilia and clotting factor products essential5 Srivastava A et al. Haemophilia. 2013;19(1):1-47. Wu CG et al. Transfusion. 2005;45(6):1003-1010. Fryer JF et al. Vox Sang. 2007;93(4):341-347. Schneider B et al. Haemophilia. 2008;14(5):978-986. Norja P et al. Br J Haematol. 2012;159(4):385-393. 1.

  9. Increasing product purity and viral safety results in lower manufacturing yields and higher costs

  10. What is recombinant CFCs and their classification? • Why recombinant therapy in haemophilia? • What is the risk of inhibitor development with recombinant products? • How should we switch from pdFC to rFC?

  11. Risk factors for inhibitor development • Plasma-derived • Recombinant • Severity of haemophilia • F8 gene mutation • Family history of inhibitors • black ethnic origin • Polymorphisms of immune-response genes (IL-10, CTLA4, TNFA, and FCGR) Type of concentrate Patient-related Danger signals Inhibitor Intensity of treatment • Bacterial/viralinfection • Vaccination • Surgery • Antenatalexposure to maternal FVIII • Age at treatment onset • Treatment regimen • Dosage • Frequency • Prophylacticvs on-demand

  12. UNTIL THE YEAR 2016 AND SIPPET: MULTIPLE OBSERVATIONAL STUDIES • Contradictory outcomes of studies and systematic reviews • Different designs • Heterogenous population (MTPs) • Postmarketing studies not including high-risk children

  13. 2004

  14. Studies of treatment-associated inhibitor risk Risk of inhibitor development does not vary with FVIII concentrate used • CANAL Study (Gouw, 2007)1 • Recombinant FVIII (rFVIII) products not associated with higher risk of inhibitor development than plasma-derived (PD) products • RODIN Study (Gouw, 2013)2 • Risk of inhibitor development with PD products similar to rFVIII products Exposure days: 24-hour period during which a dose of concentrate has been administered Gouw et al. Blood 2007; 109(11):4693–4697 Gouw et al. New England Journal of Medicine 2013;368:231–239 SIPPET Project. 2013. Available at: www.sippet.org

  15. RODIN Study Global Medical Affairs Dialogue Meeting

  16. Study Overview Objectives • To assess whether the type of FVIII product (recombinant vs. plasma-derived) and switching among products were associated with inhibitor development Methods & Materials • Observational ,multicenter, prospective , non-controlled, non-randomized study • Consecutive, previously untreated patients (N=574) with severe haemophilia A • Data collected on all clotting-factor administration ≤75 exposure days or until the development of inhibitory antibodies Gouw SC et al. N Engl J Med. 2013; 368:231–9. Factor VIII Products and Inhibitor Development in Severe Haemophilia A

  17. Methods: Assessment of Incidence/Risk Assessment of Incidence/Risk Switching Among Products • Risk was assessed in children who were receiving a plasma-derived and then switched to a recombinant product Plasma-derived vs. recombinant • No vWF • <0.01 IU vWF/IU FVIII • ≥0.01 IU vWF/IU FVIII von Willebrand factor (vWF)* Product types • Plasma-derived • 1st, full-length • 2nd, B-domain-deleted • 2nd full-length • 3rd, full-length *Kogenate (Bayer Healthcare) and Refactor AF (Pfizer) were not evaluated due to small number of patients on therapy Gouw SC et al. N Engl J Med. 2013; 368:231–9. Presentation title

  18. Patient characteristics *Median age listed in years Gouw SC et al. N Engl J Med. 2013; 368:231–9. Presentation title

  19. Risk of Inhibitor Development (1) * Number of exposure days **NA denotes not applicable Gouw SC et al. N Engl J Med. 2013; 368:231–9. Factor VIII Products and Inhibitor Development in Severe Haemophilia A

  20. Risk of Inhibitor Development (2) * Number of exposure days **NA denotes not applicable Gouw SC et al. N Engl J Med. 2013; 368:231–9. Factor VIII Products and Inhibitor Development in Severe Haemophilia A

  21. Adjusted Relative Risk (95% CI) 3rd Full Adjusted Relative Risk of Inhibitor Development 3 Risk of Inhibitor Development Plasma-derived and recombinant products carried a similar risk Second-generation were associated with a significantly higher risk than third-generation full-length products 2 ● ● • Findings are in line with CANAL study2 ● ● ● ● ● 1 1st Full 2nd Full All Recombinant Plasma-Derived All Plasma-Derived 2nd B-Domain-Deleted N=574 Gouw SC et al. N Engl J Med. 2013; 368:231–9. Factor VIII Products and Inhibitor Development in Severe Haemophilia A

  22. Take-home messages from the RODIN study • Recombinant and plasma-derived FVIII products conferred similar risks of inhibitor development • B-domain modified products were not associated with increased risk of inhibitor development • Switching among products was not associated with risk of inhibitor development 2,3 Gouw SC et al. N Engl J Med. 2013; 368:231–9. Iorio A et al. Blood. 2012; 120:720–7. Hay C. Presented at WFH Congress Paris, 10 July 2012.

  23. The SIPPET study • The first investigator-initiated, international, multicenter, prospective, controlled, randomized, open-label clinical trial on inhibitor frequency in 303 PUPs from42 hemophilia centres in 14 countries when exposed to plasma-derived FVIII products with von Willebrand factor or to recombinant FVIII products

  24. SIPPET results • Incidence of inhibitors: 37.3% in rFVIII vs23.2% in pd-FVIII All High-titre HR:Hazard Ratio

  25. 1. Results are not country-driven • Majority of patients from India (33%), Egypt (31%) and Iran (12%) • Fewer patients from developed countries eg US (7%) and EU (6%) • A sensitive analysis looking at HR results every time that a given country is left out shows no change

  26. 2. Results are not recombinant product-driven • Compares two types/classes of products, not two specific products 84% of patients assigned to rFVIII received 1st and 2nd generation products and 16% received available 3rd generation at that time (did not include turoctocogalfa; Eloctate and Nuwiq) • A sensitive analysis looking at HR results every time that a given recombinant product is left out shows no change

  27. Timing and severity of inhibitor development:a SIPPET subanalysis • The highest rate of inhibitor development is in the first 10 EDs with a rate for rFVIII that started earlier, lasted longer and peaked higher ALL INHIBITORS HIGH-TITRE INHIBITORS (Peyvandi et al. J ThrombHaemost 2017, doi: 10.1111/jth.13888)

  28. Genetic risk stratification:a SIPPET subanalysis • Patients were classified at: • High risk when they carried a null mutation • Low risk when they carried another o no causative variant Rosendaal FR et al. Blood 2017; 130:1757-1759

  29. Genetic risk stratification:Kaplan-Meier survival curves • Low risk for patients with low genetic risk and treated with pdFVIII • Intermediate risk for patients with a high genetic risk and treated with pdFVIII • High risk for patients treated with rFVIIIregardless their genetic profile Rosendaal FR et al. Blood 2017; 130:1757-1759

  30. Take home message from SIPPET study: • Previous Untreated Patients (PUP) treated with rFVIII have higher risk to develop inhibitors than those treated with pdFVIII containing VWF • It occurs mostly before 30 Eds • The highest rate of inhibitor development is in the first 10 EDs with a rate for rFVIII that started earlier, lasted longer and peaked higher • It happened with all classes of rFVIIIs which were available and used in the study • Has not warned against rFVIII usage or switching in PTP • These findings lead to better understand the mechanisms of the immunogenicity of various FVIII preparations

  31. Misunderstandings from both groups of studies RODIN & CANAL SIPPET Do not use recombinent CFS IN CHILDREN DO NOT SWITCH from pdFVIII to rFVIII Do starting rFVIII in lOW RISK instead of HIGH RISK PUPs (regarding to their mutations or family history of inhibitor) • There is NO RISK to start rFVIII in PUPs • Switching from pdFVIII to rFVIII is safe in ANY CLINICAL CONDITIONS (surgery, intensive treatment , post-ITI, etc)

  32. In MCCCH (our ceneter in TEHRAN) • 68 patient with hemophilia(PWH) less than 15 Y old on regular prophylaxis: • 48 /68 are on rFVIII: • 9/48 were PUPs who were enrolled in SIPPET • 37/48 switched from pdFVIII to rFVIII • 20/68 are on pdFVIII Iranaian Society of Thrombosis & Hemostasis wrote an official letter to MOH to resolve misunderstandings from the study and guide how to satate switching from pdFVIII to rFVIII AND IT IS APPLIED IN IRAN

  33. What is recombinant CFCs and their classification? • Why recombinant therapy in haemophilia? • What is the risk of inhibitor development with recombinant products? • How should we switch from pdFC to rFC?

  34. Rationale for switching Product-specific considerations • Improved safety (real or perceived)1,2 • Less risk of infection1,2 • Less inhibitor risk1 • Fewer side-effects (e.g. allergic reactions)1,2 • Newer generation of product1,2 • Volume of final product3 • Mixing and administration device1,2 • Storage advantage1,2 • Longer half-life1,2 Other considerations • Price1,2 • National contracting1,2 • Shortage or termination of product supply3 • Patient/family preference1,2 • Participation in a clinical trial/research study1,2 “It is extremely rare, if not impossible, for adult [people with haemophilia] in most countries worldwide to have used the same concentrate throughout their lives”1 Iorio et al. Blood 2012;120(4):720-727 Santagostino E, et al. Eur J Haematol 2015;94(4):284-9

  35. Common treatment switches Plasma-derived product Recombinant product Recombinant product Recombinant product* *Including extended half-life products Santagostino E, et al. Eur J Haematol 2015;94(4):284-9

  36. Overview of rFVIII product switches: national switches Cohort studies show a generally low incidence of new inhibitors when unselected groups are switched to new products.

  37. Overview of rFVIII product switches: national switches Cohort studies show a generally low incidence of new inhibitors when unselected groups are switched to new products. *Out of a total of 339 patients with 2 years follow up; **In subjects completing the full surveillance protocol of 24 monthsAHCDC, Association of Hemophilia Clinic Directors of Canada; pdFVIII, plasma-derived factor VIII1. Giles AR et al. Transfusion Science 1998; 19(2): 139–148; 2. Santagostino E, et al. Eur J Haematol 2015;94(4):284-9; 3. Rubinger M et al. Haemophilia 2008;14:281–286;

  38. Inhibitor incidence in an Italian cohort study Low incidence of inhibitor development following switching to rFVIII PTP, previously treated patient; rFVIII, recombinant FVIIIGringeri A et al. Brit J Haematology 2004; 126:398–404

  39. Investigating perceived barriers to switching: HCPs • Modified* DELPHI process in 2011 aimed to reach consensus on statements/topics relating to product switching (N=12) ED, exposure days; HCP, healthcare professional; *Structured group communication involving a kick-off face-to-face meeting presenting the topic followed by multiple sequential rounds of question and answer sessions Matino D, et al. Haemophilia 2014;20:200–206

  40. Consideration on inhibitor development with switching FCs Recommendation for switching FCs Apply in PTPs DO NOT switch when patients have: Intensive treatment Surgery Simultaneous infection or inflammation process Family history of inhibitor previous history of inhibitors • usually occur in the first 50 EDs (PUP) • Intensive treatment/surgery may influence • Simultaneous infection or inflammation process may trigger • Patients with family history of inhibitors may have higher risk • Patients with a previous history of inhibitors may be at risk of inhibitor recurrence • Including those with successful ITI

  41. Guidelines and expert opinion • Physicians should discuss different FVIII products with patients before the need for switching arises • Monitor switched patients for inhibitor development1 • Test for inhibitors: • Before switching2,3 • At regular intervals after switching2,3 • After intensive treatment/surgery2 • Physicians are obliged to prospectively monitor safety and efficacy of new products4 • All switching patients should be enrolled into registry studies3 • Srivastava et al. Haemophilia 2013 Jan;19(1):e1-47 • Santagostino E, et al. Eur J Haematol 2015;94(4):284-9 • Iorio et al. Blood 2012; 120: 720-727 • Keeling et al. Haemophilia 2008;14:671–684

More Related