Reduction of Anti-FIX Inhibitor Titers in a Hemophilia B Patient with Continuous Use of FEIBA.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4051-4051
Author(s):  
Hiroyoshi Watanabe ◽  
Tsutomu Watanabe ◽  
Toshihiro Onishi ◽  
Kazumi Okamura ◽  
Shoji Kagami ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
High Titer ◽  
Rare Event ◽  
Poor Response ◽  
Factor Ix ◽  
Hemophilia B ◽  
High Dose ◽  
Duration Of Treatment ◽  
On Demand ◽  
Inhibitor Titer

Abstract Background: Inhibitor formation is a severe complication of hemophilia B associated with poor response to factor replacement and uncontrolled bleeding, although an inhibitor formation in hemophilia B is a rare event compared to hemophilia A. Currently, immune tolerance is the only proven method for inhibitor eradication. However, immune tolerance induction in patients with hemophilia B is a rare occurrence. We report a case of a hemophilia B patient who had a reduction of inhibitor titer during continual use of FEIBA. Case report: Patient is an 11-year-old boy with severe FIX deficiency and high titer inhibitor (historical peak: 65 BU/mL) since age 3 years. Since inhibitor formation, the patient had received FEIBA or FVIIa on demand. FVIIa became therapeutically not effective in 1999 October, and bleeding frequency increased as he developed a target joint. In 1999 November, 2002 February, and 2004 September, he received high dose of FIX concentrate for neutralization of inhibitor and then cyclophosphamide for 8 weeks. We achieved only a transient effect in reducing the inhibitor titer. The inhibiter titer fluctuated between 20 and 60 BU/mL. Since 2005 January, subsequently, he had received FEIBA 1,000–2,000 IU per dose (30–50 units/kg) on demand. He needed FEIBA twice or thrice a week, and continued to receive this dose till now. The inhibitor titer was gradually getting lower after a transient rise up to 39 BU/mL on 2005 February. On 2006 February, the inhibitor titer became below 1.0 BU/mL, and finally undetectable on 2006 March, despite the longevity of the inhibitor (8 years). Factor IX recovery was normalized, and bleeding frequency dramatically decreased. Elimination of the inhibitor by the continued administration of FEIBA was observed. Anaphylactic reaction and the development of nephrotic syndrome were not seen. Conclusion: The continuing use of FEIBA safely and effectively might decrease the inhibitor titer and the frequency of bleeding episodes in hemophilia B patients. This case may provide us the optimization of the FEIBA dose, and duration of treatment for inducing tolerance by using FEIBA.

Novel Treatment Approaches in Combination with Rituximab for Immune Tolerance Induction in Severe Hemophilia B.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3975-3975 ◽  
Author(s):  
Amanda M. Brandow ◽  
Rowena C. Punzalan ◽  
Karen Stephany ◽  
Craig Helsell ◽  
Joan C. Gill
Keyword(s):  
Immune Tolerance ◽  
High Titer ◽  
Tolerance Induction ◽  
Factor Ix ◽  
Hemophilia B ◽  
High Dose ◽  
Subdural Hemorrhage ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Novel Approaches

Abstract Although only 4–5% of patients with severe Hemophilia B (HB) develop factor IX (FIX) antibodies that cause inactivation of transfused FIX concentrate (conc), about 1/3 of these are associated with life-threatening anaphylactic reactions; immune tolerance induction (ITI) with high-dose FIX conc is often unsuccessful. We present individualized novel approaches to ITI in 2 boys with severe HB and high-responding inhibitors. ELISA assays utilizing recombinant FIX (rFIX) to capture patient IgG followed by detection with subclass specific monoclonal antibodies were developed to evaluate the characteristics of the factor IX inhibitors before, during and following ITI. Patient 1, a 2 yo boy, presented with a subdural hemorrhage; his inhibitor titer was 14 BU. He was treated with recombinant VIIa (rVIIa), 200 mcg/kg followed by 100 mcg/kg q2 hours plus rFIX conc (BeneFix), 1000 U/kg prior to and post subdural hematoma evacuation; a continuous infusion, 40U/kg/hour rFIX conc was started. FIX:C was >100%, so rVIIa was discontinued and the rFIX infusion was continued to maintain FIX:C levels above 50%. Rituximab (375 mg/m2 q week x 4) was started. On the 6th day, he developed anamnesis; plasma FIX:C dropped to the 20% range in spite of increases in his rFIX conc drip to 68 u/kg/hour. Investigation of right leg edema revealed a large thrombus involving the popliteal, iliac and inferior vena cava with pulmonary embolism. In order to remove the inhibitor antibody and achieve plasma FIX levels that would allow safe anticoagulation with heparin, plasmapheresis with an immunoadsorption Protein A sepharose column (Fresenius) was undertaken. FIX:C levels were unexpectedly lower immediately following each cycle. Investigation of FIX: Ag and anti-FIX IgG, IgG1 and IgG4 by ELISA assays before and after each cycle revealed the presence of FIX: Ag and specific anti-FIX IgG in the column eluates. After the 5th cycle, increasing FIX:C levels allowed weaning of the rFIX conc; the thromboses completely resolved. The patient currently is on standard prophylactic doses of rFIX conc with expected recoveries with no evidence of inhibitor. Patient 2 was a 9 year old boy with a high responding anaphylactoid inhibitor; he had severe and frequent hemarthroses treated with rVIIa with variable success resulting in significant hemophilic arthropathy. He had previously received 2 courses of rituximab with recurrence of inhibitor 3 weeks post-therapy. Therefore, in order to suppress T-cell as well as B-cell immune responses, after desensitization with increasing infusions of rFIX conc, he was treated with cyclophosphamide (10 mg/kg IV on days 2, 3 and PO on days 4 and 5) a standard course of rituximab (375 mg/m2 on days 1, 8, 15, 22), IVIG (100 mg/kg on days 2–5) initially, and high dose rFIX conc, 100U/kg/day. He is now maintained on every-other monthly doses of rituximab and replacement doses of IVIG. As FIX levels rose during ITI, rFIX conc was weaned; eight months after initiation of ITI, he has expected recoveries of FIX: C on standard prophylactic doses of rFIX conc. Investigation of the nature of the patient’s inhibitors revealed that both patients had high titer IgG1 and IgG 4 anti-factor IX antibodies that disappeared after ITI. Unlike the persistence of non-inhibitory IgG4 factor VIII antibodies reported in some patients with hemophilia A, in these two patients, there was no detectable FIX-specific pan-IgG, IgG1 or IgG4 following ITI. We conclude that novel approaches to ITI can be successfully undertaken in severe HB patients with high titer factor IX inhibitors.

Oral Delivery of Bioencapsulated Factor IX Protects From Inhibitor Formation and Anaphylaxis in Protein Replacement Therapy for Hemophilia B.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 222-222 ◽  
Author(s):  
Roland W. Herzog ◽  
Dheeraj Verma ◽  
Babak Moghimi ◽  
Harminder D Singh ◽  
Paul A LoDuca ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Oral Delivery ◽  
Fusion Gene ◽  
High Titer ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Total Soluble Protein ◽  
Plant Materials ◽  
Furin Cleavage Site

Abstract Abstract 222 While the incidence of inhibitor formation against the infused coagulation factor is overall relatively low in factor IX-deficiency (1–4% of patients), 9–23% of patients with severe hemophilia B form inhibitors, which seriously complicates treatment. Factor IX (F.IX) inhibitors tend to be high titer and not effectively eliminated by immune tolerance induction protocols, and are often associated with serious anaphylactic reactions. Inhibitor formation and anaphylaxis is more typical for patients with F9 gene deletions or early stop codons. We sought to develop a novel approach to induction of antigen-specific immune tolerance that is safe, not based on immune suppression, and does not require knowledge of specific T cell epitopes. Chloroplast transgenic plants expressing human F.IX were generated. Because the plant cell provides bioencapsulation, the recombinant polypeptide is protected from acids and enzymes in the stomach and released in the gut. The hF.IX coding sequences were fused with the transmucosal carrier CTB. The fusion gene cassettes were expressed from the light-regulated psbA 5′ untranslated region/promoter in order to achieve hyper-expression. To prevent steric hindrance, a GPGP hinge was introduced between CTB and FIX. A furin cleavage site was also introduced in one of the constructs. Plasmid DNA was bombarded on nicotine-free tobacco leaves via a particle-mediated method using the gene gun, resulting in transgene integration into the chloroplast genome by homologous recombination. Transformed tissues were repeatedly cultured on selective media, and transplastomic plants were regenerated. Chloroplast transplastomic lines were examined by Southern blot analysis in order to confirm site-specific integration and to test for homoplasmic lines. Transplastomic lines of CTB-GPGP-hFIX (F1) and CTB-GPGP-Furin-hFIX (F2) had expression levels of up to 3.8% and 0.28% fusion protein, respectively, in the total soluble protein. Control and transplastomic plant materials (250 mg) were fed twice per week for 8 weeks by oral gavage to Hemophilia B mice, known to develop strong antibody responses against hF.IX (C3H/HeJ F9−/− mice with targeted F9 gene deletion). For the F2 material, this was equivalent to 2 μg of hF.IX per dose. After 4 weeks, animals received weekly infusions of hF.IX (Benefix) at 1 IU per dose for 4 weeks (1 IP followed by 3 IV doses). As expected, ≥80% of mice control groups had developed significant inhibitors at titers of 4–10 BU (average titers were 5.5 BU for wild-type material fed and 7 BU for unfed controls). In contrast, all F1 and F2 fed mice (n=15 and n=14, respectively) had undetectable or at most very low titer inhibitors (≤2 BU) and showed normal clearance of hF.IX. Some F2 fed mice (n=9) was subjected to 1 more month of weekly IV infusions of hF.IX. At the end of this experiment, inhibitor titers remained undetectable to low (< 3 BU) in 6/9 mice, while 3 mice had formed titers of 4–12 BU, in contrast to on average 80 BU in control mice. Importantly, a rise in inhibitor titers was not seen in another cohort, in which feeding was continued during subsequent treatment. Most importantly, 30–50% of control mice developed allergic reactions, went into respiratory arrest, and died instantly or shortly after the 4th and subsequent injections of hF.IX. This severe anaphylactic response was not observed for up to 12 hF.X injections in any F1/2-fed animals regardless of whether feeding was continued beyond 8 weeks. The underlying mechanism appears to involve a shift to non-inhibitory antibodies and shifts in immunoglobulin subclasses. In summary, repeated feeding of bioencapsulated hF.IX prevents inhibitor formation and life-threatening anaphylactic reactions. Disclosures: Daniell: Chlorogen Inc: Technical founder.

scholarly journals Immune Tolerance Induction for FIX Inhibitors Using Combined B and T Cell Immune Modulation Therapy in Severe Hemophilia B

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1193-1193 ◽  
Author(s):  
Yasmina L. Abajas ◽  
Paul Edward Monahan ◽  
Brenda Nielsen ◽  
Pia Petrini ◽  
Susanna Ranta ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Median Time ◽  
Immune Tolerance ◽  
Research Funding ◽  
Immune Modulation ◽  
Tolerance Induction ◽  
Factor Ix ◽  
Hemophilia B ◽  
Inhibitor Titer

Abstract Introduction Development of an inhibitor to Factor IX is a potentially life-threatening complication that occurs in 2-4% of severe hemophilia B patients. Attempt to eradicate these neutralizing alloantibodies with immune tolerance induction (ITI) regimens using prolonged repeated exposure to FIX fails to induce tolerance in ~70% of cases, and is limited by severe complications including FIX hypersensitivity and nephrotic syndrome. Cases of FIX ITI with immunosuppressive drugs have been reported infrequently. In light of increased understanding of the role of active T lymphocyte regulation of clotting factor-directed B lymphocyte-mediated humoral immunity, an approach combining immune modulating agents and frequent FIX infusions was reported by Beutel, et al (Haemostaseologie, 2009; 2014). We report a multi-institutional retrospective experience with combination immune modulation therapy (CIT), including B cell suppression with anti-CD20 monoclonal antibody Rituximab and T cell modulation using mycophenylate mofetil (MMF) with FIX ITI in 11 males with severe congenital hemophilia B. Methods The originally published regimen of Beutel, et al involves a 50 day course including FIX 100 IU/kg twice daily, rituximab 375 mg/m2 x 4 doses, mycophenolate (MMF) 300 mg/m2/dose daily, dexamethasone 6 mg/m2/dose pulses and IVIG 1 g/kg x 6 doses. Following individual Institutional Review Board approval, data on 11 patients was contributed by the INPH investigators and via outreach internationally and collected retrospectively using a uniform data collection form. Cases were included in the CIT series if the combination of FIX, rituximab and MMF was used. Approaches varied in the concomitant use of IVIG and pulse corticosteroids (dexamethasone or prednisone). Results CIT was the first immune tolerance therapy for 9/11 patients. Patients were 14-222 months of age at time of CIT, with a median time from inhibitor diagnosis to CIT 20 (range 0-207) months. Median historical peak inhibitor titer prior to initiation of CIT was 3.2 (range 1-42) BU/ml. Inhibitor titers at the initiation of CIT ranged from undetectable to 7 BU/ml. Eighty-onepercent of patients had a history of FIX hypersensitivity reaction. Prior to initiation of therapy, 27% of the patients underwent FIX desensitization during the initial course. The patients received FIX BID (9/11 patients) or QD (2/11 patients), 4 doses of rituximab 375 mg/m2, MMF for a minimum of 49 days (varying duration from 49-1247 days). IVIG was infused in 10/11 patients, with most receiving 3-7 doses during each course of CIT. 6/11 patients received between 2-10 courses of pulse corticosteroids during a CIT course. Each course of CIT achieved disappearance of the titer of FIX inhibitor at a median time of 1 month (range 1-41 months) Hypersensitivity reactions did not limit the courses of CIT, but did recur with inhibitor recurrence in 1 patient. Recurrence occurred in 6/11 patients at a median time of 11 months from time of CIT, in some cases soon after documented B cell recovery with a median inhibitor titer of 1.8 (range 0.7-7) BU/ml. In cases of recurrence, a negative inhibitor titer was achieved again in 1 patient by increasing FIX dose and in 4 patients who received additional courses of CIT. Repeat recurrence was seen in these patients following repeat CIT, although at low titer with a median of 1 BU/ml (range 1-4), allowing ongoing management with FIX in 3 of the 4. Overall, patients have had a median follow-up of 61 months following CIT, 9/11 patients are currently managed with factor IX for prophylaxis and bleeding, while 2/11 use bypassing agents. The most common complication was hospitalization for central venous catheter-related bacterial infection that occurred from < 1 to > 12 months after the use of rituximab in 3/11 patients. Nephrotic syndrome occurred in 3/11 patients. In each case, nephrotic syndrome responded to corticosteroids or re-initiation of CIT and FIX could be resumed. Conclusions FIX ITI with CIT targeting both B and T cells in hemophilia B is an effective means of achieving a negative inhibitor titer with tolerable safety in this series, allowing return to use of FIX for hemostasis and prophylaxis in most patients. Although recurrence is common and longer follow up is needed, when compared to the experience with using FIX alone, outcomes appear to be improved using CIT with FIX ITI as an initial approach. Disclosures Abajas: Bayer: Honoraria; CSL Limited: Honoraria. Allen:Shire: Employment, Equity Ownership. Oldenburg:Pfizer: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding.

scholarly journals Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-5-LBA-5
Author(s):  
Lynn Malec ◽  
An Van Damme ◽  
Anthony Chan ◽  
Mariya Spasova ◽  
Nisha Jain ◽  
...  
Keyword(s):  
Half Life ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
First Time ◽  
Inhibitor Titer ◽  
Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer &lt;0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR &gt;66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

scholarly journals Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1123-1123
Author(s):  
Teresa Ceglie ◽  
Berardino Pollio ◽  
Irene Ricca ◽  
Maria Messina ◽  
Claudia Linari ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Null Mutation ◽  
Severe Hemophilia ◽  
Factor Level ◽  
On Demand ◽  
Active Life ◽  
Genetic Assessment

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

Stable Factor IX Activity Following AAV-Mediated Gene Transfer in Patients with Severe Hemophilia B

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 752-752
Author(s):  
Andrew Davidoff ◽  
Edward GD Tuddenham ◽  
Savita Rangarajan ◽  
Cecilia Rosales ◽  
Jenny McIntosh ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Board Of Directors ◽  
Normal Values ◽  
Factor Ix ◽  
Hemophilia B ◽  
High Dose ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Short Course

Abstract Abstract 752 Introduction: We are conducting a phase I/II clinical trial of factor IX gene transfer for severe hemophilia B. In the trial we are using a serotype-8 pseudotyped self-complementary adeno-associated virus (scAAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco). We have previously reported the early safety and efficacy of our novel gene transfer approach in six patients with severe hemophilia B following a single peripheral vein infusion of one of three vector doses (low [2×1011 vector particles (vp)/kilogram weight (kg)], intermediate [6×1011 vp/kg], or high dose [2×1012 vp/kg]) (Nathwani et al, NEJM 365:2357–65, 2011). AAV-mediated expression of FIX at 1–6% of normal was established in all six participants with an initial follow-up of between 6–14 months following gene transfer. We now report longer follow-up of these participants, as well as data from two additional participants recently enrolled at the high dose level. Methods: We have now infused scAAV2/8-LP1-hFIXco in eight subjects with severe hemophilia B (FIX activity, <1% of normal values). Vector was administered without immunosuppressive therapy, and participants have now been followed for 3 months to 2½ years. FIX activity, serum transaminases, vector genomes in secretions/excretions, antibodies to FIX and AAV8, and AAV8 capsid-specific T-cells were monitored during the follow-up. Results: Each of the participants currently has AAV-mediated activity of FIX at 1 to 6% of normal levels. These levels have been stable in each during the follow-up period which is now greater than 1½ years for the first six participants. Five of the eight participants have discontinued FIX prophylaxis and remain free of spontaneous hemorrhage; in the other three, the interval between prophylactic injections has increased. None of the participants in the low or intermediate dose cohorts had evidence of transaminitis; each currently has FIX activity of 1–3% for over 1½ years. Of the four participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; two others had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these three participants received a short course of glucocorticoid therapy, which rapidly normalized their aminotransferase levels and maintained FIX levels in the range of 4 to 6% of normal values. The fourth participant has not had transaminitis three months after vector administration. Conclusions: This represents the first successful, long-term, gene therapy-mediated expression of a therapeutic protein from an AAV vector delivered to human liver. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. Larger numbers of patients followed for longer periods of time are necessary to fully define the benefits and risks and to optimize dosing. However, this gene therapy approach, even with its risk of mild, transient transaminitis, has the potential to convert the bleeding phenotype of patients with severe hemophilia B into a mild form of the disease or to reverse it entirely for a prolonged period of time following vector administration. (ClinicalTrials.gov number, NCT00979238). Disclosures: Chowdary: Novo Nordisk: Consultancy. High:Amsterdam Molecular Therapeutics: ; Baxter Healthcare: Consultancy; Biogen Idec: Consultancy; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees; Genzyme, Inc.: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: ; Sangamo Biosciences: ; Shire Pharmaceuticals: Consultancy.

French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

1998 ◽  
Vol 80 (11) ◽  
pp. 779-783 ◽  
Author(s):  
Y. Laurian ◽  
E. P. Satre ◽  
A. Borel Derlon ◽  
H. Chambost ◽  
P. Moreau ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Intron 22 Inversion ◽  
Median Period

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

RESULTS OF AN OPEN, PROSPECTIVE, MULTICENTER, NONCOMPARATIVE STUDY OF THE PHARMACOKINETICS, EFFICACY AND SAFETY OF NONACOG ALFA IN PATIENTS AGED 6–12 YEARS WITH SEVERE AND MODERATE HEMOPHILIA B

2020 ◽  
Vol 99 (6) ◽  
pp. 190-198
Author(s):  
T.A. Andreeva ◽  
◽  
V.V. Lebedev ◽  
V.V. Vdovin ◽  
M.A. Timofeeva ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Study Drug ◽  
Factor Ix ◽  
Hemophilia B ◽  
Efficacy And Safety ◽  
Open Label ◽  
Time Curve ◽  
Entire Study ◽  
On Demand ◽  
Bleeding Episodes

Providing hemophilia patients with blood coagulation preparations is one of the priority tasks of the national health care system. In 2011, the first recombinant factor IX was created in Russia (rFIX, nonacog alpha, Innonafactor, GENERIUM JSC), that was previously studied for pharmacokinetic (PK) parameters, efficacy and safety in adult patients and adolescents over 12 years of age with severe and moderate hemophilia B. Objective of this open-label, prospective, multicenter, noncomparative clinical study was to study PK, efficacy and safety of Innonafactor in 12 patients aged 6 to 12 years with severe and moderate forms of hemophilia B (FIX activity less than 2%). The study included periods of screening, studies of PK parameters and treatment within 26±1 weeks, but not less than 50 days of administration of the studied drug. Nonacog alfa was administered in the study of PK parameters at a dose of 75 IU/kg, once, for prophylactic treatment – at a dose of 45±10 IU/kg, 2 times a week with an interval of 72–96 h. 30 minutes after administration of the studied drug, FIX activity increased to 73,93±13,35%, with a gradual decrease to 5,88±1,97% 72 hours after administration. The area under the «concentration ‒ time» curve in the section 0–72 h (AUC0–72) and with exponential extrapolation to infinity (AUC00‒∞) was 1573,41±407,16%*h and 1808,74 ± 437,59%*h respectively. Biological half-life (T1/2) was 28,11±8,60 hours. During preventive treatment there were 19 hemorrhagic episodes, 14 (74%) bleedings were post-traumatic and 5 (26%) bleedings were spontaneous. Mean number of bleeding episodes over the entire observation period was 1,9±1,4. Mean number of episodes of spontaneous bleeding that occurred within 72 hours after Innonafactor administration in patients with bleeding was 2,5±2,1. During the entire study period, patients received 942,5 thousand IU of the drug Innonafactor, 890,5 thousand IU were administered for prophylaxis and 52 thousand IU to stop bleeding on demand. Mean single dose of Innonafactor for prophylactic treatment was 46,24±5,86 IU/kg, for on-demand treatment – 49±13,1 IU/kg. Of the 19 registered bleeding episodes, 14 (73.7%) episodes required the administration of the studied drug; 5 (26,3%) bleedings stopped on their own. To stop one episode of bleeding, an average of 2,3±2,3 administration of nonacog alfa was required. At the end of the study, the proportion of hemophilia B patients with residual FIX activity of 2% or more was 92%. During the study, 14 adverse events (AEs) were registered in 7 (58,3%) patients. All reported AEs were not study drug related and did not require study drug withdrawal. Thromboembolic complications and immunogenic reactions were not registered. Thus, the data obtained indicate efficacy and safety of Innafactor both for prophylactic treatment and for on-demand treatment of bleeding in patients aged 6 to 12 years with severe and moderate hemophilia B.

Prophylactic Use of rFVIIa in a Young Hemophilia A Patient with Factor VIII Inhibitor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4068-4068
Author(s):  
Annie Borel-Derlon ◽  
Mounia Slaoui ◽  
Philippe Gautier ◽  
Patricia Guillon
Keyword(s):  
Quality Of Life ◽  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Factor Viia ◽  
High Dose ◽  
Factor Viii Inhibitor ◽  
On Demand ◽  
Viii Inhibitor

Abstract The prevention of bleeding by prophylaxis regimen particularly for joint rehabilitation, could be considered a more effective treatment for hemophilia patients. In hemophiliacs with factor VIII inhibitor (F VIII inh) prophylaxis is not generally proposed because the bypassing agents for these patients may be less effective than F VIII concentrates. We report the regimen and results of a 6 months rFVIIa (Recombinant factor VIIa) prophylaxis, in a young hemophilia A patient (4 years old), with F VIII inh and immune tolerance induction (ITI) treatment and compared, with rFVIIa, the on demand treatment results for the 6 months prior to prophylaxis. After 2 years of a high dose regimen ITI, the FVIII inh titer was less than 50 BU and the immune tolerance treatment remains on going. Due to the development of a right knee target joint the rFVIIa prophylaxis was decided as an active rehabilitation approach to prevent the development of chronic arthropathy as well as to improve the quality of life of the child. During the 6 months period, prior to the initiation of rFVIIa prophylaxis 22 bleeds occurred i.e., 9 right knee hemarthrosis and 13 other joint bleedings and hematoma including elbow, wrist, ankle, foot, arm and chest. These bleeds were all treated with rFVIIa with a dose ranging from 100 to 200 μg/kg depending on the severity of the episodes and the duration of treatment ranged from 1 to 8 days. After 6 recurrent right knee hemarthrosis, a lavage of the joint was performed and prophylaxis with rFVIIa was subsequently initiated. A 120 μg/kg rFVIIa injection was performed 3 times a week concomitantly with the ITI treatment infusion and just before the physiotherapy course. During the 6 months of prophylaxis regimen we observed 9 bleeds with 3 major post traumatic bleedings which were treated by one 200 μg/kg/day rFVIIa injection which was resolved in one to three days. This prophylaxis treatment was effective for the arthropathy evolution and permitted the patient to return to school on a regular basis compared to the previous year. The total dose of on demand rFVIIa treatment used before prophylaxis was 458 mg/6 months. This amount decreased by 25% during the six months of prophylaxis with rFVIIa to reach 343 mg. The results of this significant observation led us to conclude that rFVIIa could be effectively used as prophylactic treatment in patients with FVIII inh and administered safely via a portacath device even in cases of high doses, as demonstrated in this young patient. This prevention approach resulted in a decrease of bleeding episodes, injections, and a significant improvement in the quality of life.

Hepatic Gene Transfer of Factor IX Reverses Inhibitors and Protects From Anaphylaxis in a Murine Hemophilia B Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 669-669 ◽  
Author(s):  
David Markusic ◽  
Roland W Herzog
Keyword(s):  
At Risk ◽  
Bone Marrow ◽  
Gene Transfer ◽  
Antibody Response ◽  
B Cell ◽  
Gene Deletion ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
High Dose

Abstract Abstract 669 Hemophilia B is a X-linked bleeding disorder caused by loss of coagulation factor IX (F.IX) function. Under current treatment protocols, approximately 2–4% of hemophilia B patients develop inhibitory antibodies to F.IX protein, and those with F.IX gene deletions are at risk for anaphylaxis. We work with a murine model for this pathogenic antibody response, namely C3H/HeJ hemophilia B (HB) mice with a F9 gene deletion. Anaphylactic reactions to intravenously administered F.IX protein are the result of a strong Th2-driven antibody response, comprised of IgG1 and IgE. Interestingly, we find that IgE levels correlate with the dose of recombinant F.IX protein. HB mice treated with weekly intravenous doses of 0.1 or 0.3 IU F.IX were free from allergic/anaphylactic reactions during the course of treatment (1 IP and 5 weekly IV injections of F.IX protein) and had very low to undetectable IgE against F.IX. In contrast, a dose of 1 IU induced IgE formation and caused fatal anaphylactic reactions after repeated administration. These results suggest that prophylaxis with lower F.IX doses may be recommended in individuals with F.IX gene deletion (Mice with missense or nonsense F.IX mutations did not show inhibitor formation or anaphylaxis at the high dose). In an attempt to reverse the response and desensitize the gene deletion HB animals, F.IX-treated mice with inhibitors, including those with detectable circulating IgE, received hepatic AAV8-F.IX gene transfer (1e11 vg/mouse). Within one month, these mice lost detectable IgG and IgE against F.IX and showed a level of correction of coagulation comparable to gene transfer in naive mice. Subsequent intravenous injections of 1 IU F.IX (weekly for 1 month) did not cause anaphylaxis, demonstrating successful desensitization. Control mice (no gene transfer) maintained their IgE levels during the course of the experiment. We are currently investigating if a lower AAV8 F.IX vector dose (1e10 vg) is similarly capable of reversing existing F.IX inhibitors/anaphylaxis. In order to determine the fate of F.IX antibody-secreting cells (ASC), we performed a B cell ELISPOT assay on bone marrow cells and splenocytes in F.IX immunized HB mice left untreated or treated with AAV8 F.IX vector. Control immunized mice showed predominantly ASC in the spleen with a few detected cells from bone marrow. ASC were nearly undetectable in vector-treated mice. These results suggest that AAV8 liver gene transfer not only suppresses F.IX-specific ASC, but may also prevent the re-activation of memory B cells. Experiments are ongoing to explore the role of induced regulatory T cells in modulating ASC. To characterize T cell responses against F.IX, we isolated splenocytes isolated from control immunized and vector treated mice, stimulated these cells in vitro with F.IX protein, and collected RNA for analysis with RT-PCR array. Control mice showed an upregulation of Th2 cytokines IL-4 and IL-13, which are known to induce B cell class switching to IgG1 and to IgE, corresponding to the observed antibody formation. Vector treated immunized mice did not show up regulation of any cytokines representative of Th1 or Th2 responses, indicating down-regulation of T help required for the antibody response. In summary, our data show that liver directed AAV8 F.IX gene transfer may not only induce tolerance to those at risk of developing inhibitors, but may offer an alternative treatment approach to expensive and long-term immune tolerance induction (ITI) protocols in those with existing pathogenic antibody responses. This concept may also apply to other genetic diseases, in which antibodies complicate protein replacement therapy. Disclosures: Herzog: Genzyme Corporation: Patents & Royalties.

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