Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Background The development of inhibitors to exogenous factor VIII (FVIII) is a serious treatment complication in patients with hemophilia A. Immune tolerance induction (ITI) is the only proven method for the eradication of FVIII inhibitors. This prospective, multicenter, open-label, phase 3 study (NCT02615691) is being conducted to determine the safety, immunogenicity, and efficacy of the extended half-life (EHL) recombinant FVIII rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in previously untreated patients (PUPs) with severe hemophilia A. The data presented here aims to evaluate the efficacy and safety of ITI therapy with rurioctocog alfa pegol in patients who developed FVIII inhibitors. Methods Eligible patients were ˂6 years of age with severe hemophilia A (FVIII <1%) and <3 exposure days (ED) to rurioctocog alfa pegol, octocog alfa, or plasma transfusion at any time prior to screening. Patients with detectable FVIII inhibitory antibodies at screening or a history of FVIII inhibitors prior to screening (≥0.6 Bethesda units [BU]) were excluded from the study. Patients received intravenous rurioctocog alfa pegol as prophylaxis (25-50 IU/kg, up to 80 IU/kg ≥1 × weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). Patients who developed a high-titer FVIII inhibitor (>5.0 BU) or low-titer FVIII inhibitor (≥0.6 BU to ≤ 5.0 BU) plus poorly controlled bleeding despite increased FVIII doses and/or bypassing agents, were eligible for ITI therapy. Dosing for ITI therapy ranged between 50 IU/kg 3 × weekly (low dose) and 100-200 IU/kg daily (high dose) at investigator discretion. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing confirmed inhibitors to rurioctocog alfa pegol or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. The primary endpoint of this study was the success rate of ITI with rurioctocog alfa pegol. Success was defined as an inhibitor titer persistently <0.6 BU, FVIII incremental recovery (IR) ≥66% of baseline following 84- to 96-hour wash-out, and FVIII half-life ≥6 hours (dependent on protocol version). Secondary endpoints included the rates of partial success and failure of ITI, and annualized bleeding rate (ABR) during ITI. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) were recorded for patients treated with ITI. Informed consent and ethics approval were obtained. Results As of the data cut-off, 59 (73.8%) of 80 enrolled patients had received ≥1 dose of rurioctocog alfa pegol; 18 patients did not meet the eligibility criteria (screen failures) and 4 discontinued prior to treatment. 10 patients developed an inhibitor to rurioctocog alfa pegol (high titer: n=5; low titer: n=5), of these, 6 patients were enrolled to receive ITI and only 5 of these (83.3%) actually received ≥1 dose of rurioctocog alfa pegol for the treatment of FVIII inhibitors (low dose: n=3; high dose: n=2). Of these 5 patients, 1 completed high-dose ITI therapy and this was successful (based on negative inhibitor titer and IR ≥66% of baseline). The remaining 4 patients were continuing in the study at the time of the data cut-off. Of the 5 patients who received ≥1 dose of ITI, 4 (80.0%) had a total of 17 AEs, 3 (60.0%) experienced 8 SAEs, and 1 experienced a treatment-related SAE of FVIII inhibition. It is important to note that the onset date of FVIII inhibitor development in this patient occurred prior to initiation of ITI. One patient experienced 2 catheter-related AEs, both of which resolved, and no patients experienced thrombotic AEs, study procedure-related AEs, or AEs leading to discontinuation of treatment. Discussion This is the first prospective study of the EHL recombinant FVIII rurioctocog alfa pegol for the treatment of PUPs with severe hemophilia A. These preliminary results demonstrate that rurioctocog alfa pegol has a safety profile consistent with previous studies. In addition, these interim data suggest that using a high-dose regimen for ITI therapy is potentially efficacious in PUPs who have developed FVIII inhibitors, although only 1 patient had completed ITI at the time of this interim analysis. Disclosures Sidonio: Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Guardian Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biomarin: Consultancy. Thompson: Global Blood Therapeutics: Current equity holder in publicly-traded company; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Peyvandi: Bioverativ: Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Spark: Honoraria; Takeda: Honoraria; Roche: Honoraria; Grifols: Honoraria. Yeoh: Grifols: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Lam: Takeda: Consultancy, Honoraria; Roche: Honoraria; Bayer: Honoraria; Pfizer: Consultancy, Honoraria. Maggiore: IQVIA: Current Employment. Engl: Takeda: Current equity holder in publicly-traded company; Baxalta Innovations GmbH, a Takeda company: Current Employment. Allen: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.: Current Employment. Tangada: Takeda Development Center Americas, Inc: Current Employment; Takeda: Current equity holder in publicly-traded company.

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Background Management of severe hemophilia A includes on-demand treatment or prophylaxis with replacement factor VIII (FVIII) concentrate. FVIII inhibitors can develop following exposure to exogenous FVIII in approximately 30% of previously untreated patients (PUPs), typically in the first 50 exposure days (EDs), with serious complications. This is the first study evaluating the safety, immunogenicity, and hemostatic efficacy of rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA), an extended half-life (EHL) recombinant FVIII, in PUPs with severe hemophilia A. Methods This prospective, open-label, multi-center, phase 3 study (NCT02615691) was conducted in patients ˂6 years of age with severe hemophilia A (FVIII <1%). Patients were previously untreated, or had <3 EDs to rurioctocog alfa pegol, octocog alfa, or plasma transfusion at any time prior to screening. Patients with detectable FVIII inhibitory antibodies at screening or a history of FVIII inhibitory antibodies prior to screening (≥0.6 Bethesda units) were not eligible. Patients received intravenous rurioctocog alfa pegol as prophylaxis (25-50 IU/kg, up to 80 IU/kg ≥1 × weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). Prophylaxis was started before 3 years of age or after a maximum of 2 joint bleeds, whichever occurred first. The primary endpoint was the incidence of FVIII inhibitor development. Secondary endpoints included safety and efficacy (annualized bleeding rate [ABR] and hemostatic efficacy). This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing an inhibitor to FVIII or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. Demographic and baseline characteristics were summarized using continuous and categorical data. The incidence of FVIII inhibitor development was calculated using the Clopper Pearson exact 95% CI computed for the proportion of patients who developed FVIII inhibitors during the study. ABR was analyzed by point and interval estimates derived from a negative binomial model with treatment regimen as a covariate. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) was recorded for all patients receiving rurioctocog alfa pegol. Informed consent and ethics approval were obtained. Results As of the data cut-off, 59 (73.8%) of 80 enrolled patients had received ≥1 dose of rurioctocog alfa pegol; 18 patients (screen failures) did not meet the eligibility criteria and 4 discontinued prior to treatment. 54 patients received prophylaxis and 35 received on-demand treatment at any time during the study period. The mean (SD) patient age at baseline was 11.8 (8.2) months. The number of patients with 0 EDs prior to screening was 36 (61.0%), with 9 (15.3%) patients having 1 ED and 14 (23.7%) having 2 EDs. Overall, 32 patients had a family history of hemophilia A. A large deletion, intron 1 or intron 22 inversion, or substitution nonsense hemophilia gene mutation was present in 29 (49.2%) patients and 21 (35.6%) had either a small deletion, small duplication, or substitution missense gene mutation. Of the 52 patients who qualified for this interim analysis, 10 developed an inhibitory antibody to rurioctocog alfa pegol during the study; the incidence of inhibitor development was 0.192 (95% CI, 0.096-0.325) (10/52). Rurioctocog alfa pegol exposure data and ABRs for patients receiving prophylaxis or on-demand treatment are presented in Table 1. At bleed resolution, hemostatic efficacy was rated by patients as "excellent" for 88/269 bleeds (32.7%) and "good" for 73/269 bleeds (27.1%). Overall, 52 (88.1%) patients receiving rurioctocog alfa pegol experienced a total of 283 AEs, and 13 patients experienced 14 rurioctocog alfa pegol-related AEs (including 10 SAEs). SAEs occurred in 24 patients, 10 of whom experienced 10 treatment-related SAEs of FVIII inhibitor development. Discussion This is the first prospective study of the EHL recombinant FVIII rurioctocog alfa pegol for the treatment of PUPs with severe hemophilia A. These preliminary results demonstrate a relatively low inhibitor rate compared with other EHL recombinant FVIII products and a safety and efficacy profile consistent with that previously observed for rurioctocog alfa pegol in the treatment of bleeding episodes in patients with hemophilia A. Figure 1 Figure 1. Disclosures Sidonio: Guardian Therapeutics: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biomarin: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst: Consultancy. Peyvandi: Takeda: Honoraria; Spark: Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Honoraria; Bioverativ: Honoraria; Grifols: Honoraria. Stasyshyn: Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding; Shire: Consultancy; Grifols: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Antmen: Takeda: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy. Yeoh: Takeda: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Grifols: Honoraria. Maggiore: IQVIA: Current Employment. Engl: Baxalta Innovations GmbH, a Takeda company: Current Employment; Takeda: Current equity holder in publicly-traded company. Allen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Tangada: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc: Current Employment.

Congenital hemophilia A with low activity of factor XII: a case report and literature review

Background Congenital hemophilia A is a recessive inherited hemorrhagic disorder. According to the activity of functional coagulation factors, the severity of hemophilia A is divided into three levels: mild, moderate and severe. The first bleeding episode in severe and moderate congenital hemophilia A occurs mostly in early childhood and mainly involves soft tissue and joint bleeds. At present, there are limited reports on severe congenital hemophilia A with low factor XII (FXII) activity during the neonatal period. Case presentation A 13-day-old neonate was admitted to the hospital with hematoma near the joints of both upper arms. Coagulation tests showed he had low activity of factor VIII (FVIII) and FXII. He was diagnosed with congenital hemophilia A and treated with human coagulation factor VIII (recombinant FVIII). Although the hematoma became smaller, FVIII activity was only increased to a certain extent and FXII activity decreased gradually. Unfortunately, the child responded poorly to recombinant human coagulation factor VIII and his guardian rejected prophylactic inhibitors and genetic testing and refused further treatment. Three months later, the child developed intracranial hemorrhage (ICH) due to low FVIII activity. Conclusions In hemophilia A, the presence of FVIII inhibitors, drug concentration and testing are three important aspects that must be considered when FVIII activity does not reach the desired level. Early positive disease treatment and prophylaxis can decrease the frequency of bleeding and improve quality of life. We recommend that pregnant women with a family history of hemophilia A undergo early prenatal and neonatal genetic testing.

Transperitoneal hernioplasty in a patient with severe hemophilia A on preventive treatment with emicizumab

Performance of surgical interventions in patients with severe hemophilia A on emicizumab requires the development of a protocol for the perioperative period management. Objective. To present the first experience of laparoscopic hernioplasty, hemostatic therapy and laboratory monitoring in a patient with severe hemophilia A on emicizumab. A transperitoneal hernioplasty was performed in a 31-year-old patient with severe hemophilia A on emicizumab. The patient received hemostatic therapy with recombinant FVIII for 5 days. Laboratory parameters (detection of FVIII via chromogenic and clotting methods, thromboelastography, determination of aPTT and FVII inhibitor titer) were monitored for 8 days. For a complete postoperative hemostasis, a significantly smaller amount of FVIII concentrate was required due to the lower frequency of administrations compared to similar surgical interventions in patients with severe hemophilia A who did not receive prophylactic therapy with emicizumab. According to thromboelastrography data, not a single episode of hypercoagulation was recorded. Emicizumab monotherapy can maintain adequate hemostasis during surgical procedures associated with a potentially low risk of perioperative bleeding in patients with hemophilia A. In other situations, the use of standard doses of FVIII concentrate concomitantly with emicizumab makes it possible to control hemostasis during postoperative period without the risk of thrombotic complications. The patient has signed a consent to the use of information, including photos, for research purposes and in publications.

Induction of Tolerance to Therapeutic Proteins With Antigen-Processing Independent T Cell Epitopes: Controlling Immune Responses to Biologics

The immune response to exogenous proteins can overcome the therapeutic benefits of immunotherapies and hamper the treatment of protein replacement therapies. One clear example of this is haemophilia A resulting from deleterious mutations in the FVIII gene. Replacement with serum derived or recombinant FVIII protein can cause anti-drug antibodies in 20-50% of individuals treated. The resulting inhibitor antibodies override the benefit of treatment and, at best, make life unpredictable for those treated. The only way to overcome the inhibitor issue is to reinstate immunological tolerance to the administered protein. Here we compare the various approaches that have been tested and focus on the use of antigen-processing independent T cell epitopes (apitopes) for tolerance induction. Apitopes are readily designed from any protein whether this is derived from a clotting factor, enzyme replacement therapy, gene therapy or therapeutic antibody.

Development of neutralizing antibodies in application of various concentrates of blood coagulation factor VIII in the treatment of hemophilia A

Серьезным осложнением, связанным с лечением гемофилии А, является развитие ингибиторов. В последние годы был проведён ряд исследований, посвящённых данной проблеме: RODIN, INSIGHT, FranceCoag, SIPPET и NuProtect. В данном обзоре суммируются основные результаты этих исследований. Согласно результатам рандомизированного исследования SIPPET, препараты плазматического фактора свертывания крови VIII (FVIII) обладают меньшей иммуногенностью, чем препараты рекомбинантного FVIII, синтезированного из клеточной линии китайских хомячков, что следует учитывать при выборе стратегии лечения. Согласно результатам исследования NuProtect, опубликованным в 2019 г., концентрат рекомбинантного FVIII, полученный из клеточной линии человека, демонстрирует профиль иммуногенности, сходный с таковым у препаратов плазматического FVIII. У ранее нелеченых пациентов с ненулевыми мутациями при применении симоктоког альфа не наблюдалось образования ингибиторов, также как и в случае применения препаратов плазматического FVIII в исследовании SIPPET. Inhibitor development is a serious complication associated with hemophilia A therapy. A number of studies have been carried out of this issue — RODIN, INSIGHT, FranceCoag, SIPPET, and NuProtect. This review summarizes the main results of these studies. According to the results of the SIPPET randomized trial, plasma-derived coagulation factor VIII (FVIII) products are less immunogenic than recombinant FVIII products synthesized from a Chinese hamster cell line; this fact should be taken into account in choosing a treatment strategy. According to the results of NuProtect study published in 2019, the concentrate of human cell line-derived recombinant FVIII demonstrates immunogenicity profi le similar to the one in plasma-derived FVIII products. Previously untreated patients with non-zero mutations receiving simoctocog alfa did not show development of inhibitors as well as in case of administration of plasma-derived FVIII products in SIPPET study.