ALBERT

Description: Introduction: Data on APCC´s effectiveness, safety and quality of life are relatively poor because of the rarity of patients with FVIII or FIX inhibitors, the small populations included in clinical trials and the relatively short follow-up available. The FEIBA-GO study was designed to capture long-term outcomes on effectiveness, safety and health-related quality of life (HR-QoL) in subjects receiving APCC in different settings in routine clinical practice. Primary objective is to describe the hemostatic effectiveness of APCC in different settings (prophylaxis and on demand, including patients on immune tolerance induction); most relevant secondary objectives aim at describing joint functionality outcomes, safety, HR-QoL, daily activity level, acute and chronic pain associated with hemophilia, as well as healthcare resources used. Methods: The study is a prospective, non-interventional, multicenter cohort study in patients with hemophilia A or B and high-responding inhibitors treated with APCC. A hundred subjects are targeted for enrollment; treatment regimens are at the discretion of the attending physicians in accordance with routine clinical practice, either on early, secondary or tertiary prophylaxis or on demand, including patients treated with APCC during immune tolerance induction. The observation period per subject will be 4 years. Results: As of June 1, 2016, 40 centres have been qualified in 14 countries and 16 centres have been initiated. 27 patients have been enrolled at 14 open sites in 7 countries. Demographic data are available for the 27 patients enrolled so far and are presented for the first time. All patients have severe hemophilia A: 23 are caucasian, 1 african (3 missing). At the enrolment, 18 of them were on prophylaxis and 6 treated on demand (3 missing). Overall median age is 19 years (min-max: 3-71), 17.5 years in patients on prophylaxis (min-max: 3-71) and 39.5 years in patients on demand (min-max: 22-65). Overall median inhibitor titer at enrolment was 8 BU (min-max: 1-2410), 8 BU for prophylaxis (min-max: 1-92) and 12 BU in patients on demand (min-max: 3-35). Nijmegen modified Bethesda assay was used in 18 centres, while 4 used non-modified Nijmegen Bethesda assay (5 missing). Six subjects (3 on prophylaxis, 2 on demand and 1 unknown) have been reported to have overall 13 target joints. Assessment for acute pain was performed in 12 patients and for chronic pain in 9 patients. Two of 12 patients assessed reported acute pain (both on demand). Two of the 9 patients in whom the assessment was performed reported chronic pain (treatment regimen missing). For one patient, information is not available and for another one it has been reported that pain assessment is not routine examination. Gilbert Score was assessed in 6 patients at screening. Discussion/Conclusion: This study will further enhance the information on long-term effectiveness, HR-QoL and safety of APCC across and beyond Europe in the real world on hemophilia A and B patients with high-responding inhibitors under a variety of prescribing regimens in routine clinical practice. Disclosures Cid: Baxalta Innovations GmbH, now part of Shire: Other: Investigator Clinical Studies. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Hermans:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies. Holme:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies. Negrier:LFB: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; SOBI: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Alnylam: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Rangarajan:Baxter: Research Funding; Grifols: Consultancy, Research Funding; Biogen: Consultancy; Pfizer: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Novo Nordisk: Research Funding; Biotest: Research Funding. Rocino:Baxalta, now part of Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Windyga:Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker's honorarium; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau. Gringeri:Shire: Employment, Equity Ownership. Crea:Shire: Employment, Equity Ownership.

Description: Introduction and Objectives: The use of bypassing agents have contributed to a better management of bleeding (prevention and treatment) of persons with haemophilia (PWH) and inhibitors. One of these, an activated prothrombin complex concentrate (APCC - FEIBA - FVIII inhibitor bypassing activity, Shire) became commercially available 40 years ago in 1975. While bypassing therapy has been proven effective, it introduced a potentially increased risk of treatment-associated thrombo-embolic events (TEEs). The small size of clinical trials and post-authorization surveillance studies in PWH with inhibitors limits the capability to ascertain risk factors for APCC-associated TEEs. The present review provides an overview of clinical details of all spontaneous and literature cases TEEs reported with the use of APCC in congenital haemophilia, documented in the Company's global safety database. Materials and Methods: The global safety database was reviewed for all spontaneous and literature adverse events reports of APCC received from 1975 through July 2016, addressing patient demographics, dosing regimens, confounding and risk factors deemed relevant for the development of TEEs in temporal association with APCC treatment. Results: More than 7 billion units of APCC (more than 2million infusions) were distributed during the review period. Overall 108 TEE have been reported in patients with different indications (congenital haemophilia, acquired haemophilia, anticoagulation reversal, etc.). Of these, 85 reports including one or more thromboembolic events were received for PWH (thereof 60 spontaneous reports), aged 0-73 years (mean 32, median 22). Of the 85 TEEs, 13 were reported as deep vein thrombosis and/or pulmonary embolism (median age: 11 years, min-max 3-22), 32 as myocardial infarction or stroke (median age: 41 years; min-max 8-73), 18 as disseminated intravascular coagulation (median age: 49; min-max: 0-71) and 22 as other events (median age: 30 years; min-max: 3-57). Of the 85 TEEs, 31 TEEs were reported with rFVIIa as a concomitant medication (7 DVT/PE, 9 MI/stroke, 9 DIC, 6 others). Conclusion: The reporting rate of TEEs associated with APCC remains comparable with data published earlier and confirms its long-time overall safety profile. Moreover, the majority of the TEEs occurred in the presence of additional/confounding risk factors such as underlying disease and concomitant medications. The review of clinical details of all TEEs reported in temporal association with the use of APCC is a valuable resource for the understanding and perhaps the prevention. Disclosures Crea: Shire: Employment, Equity Ownership. Novack:Shire: Employment, Equity Ownership. Reininger:Shire: Employment, Equity Ownership. Kennedy:Shire: Employment, Equity Ownership. Raff:Shire: Employment, Equity Ownership. Gringeri:Shire: Employment, Equity Ownership. Bajwa:Shire: Employment, Equity Ownership.

Description: BACKGROUND Ligneous Conjunctivitis (LC) is the most common clinical manifestation of type-1 plasminogen (PLG) deficiency, a very rare autosomal recessive disorder with an estimated prevalence of ~1.6/million. LC is a membranous conjunctivitis characterized by the formation of fibrin-rich, soft/hard pseudomembranes on tarsal conjunctivae, resulting in visual impairment/loss, and commonly presents in the first weeks/months of life, but may present in childhood or any age. PLG is the precursor of plasmin; absence of plasmin activity results in impaired fibrinolysis and formation of fibrin-rich membranes. LC affects bilateral eyes in up to 51% of cases, and corneal involvement, leading to blindness, occurs in 20-30% of cases. Although non-specific therapies have been reported to result in lesion improvement/resolution, only FFP administered topically or systemically, and topical/systemic plasminogen have demonstrated more consistent efficacy. Surgery is often performed for hard membrane removal; surgical intervention can trigger regrowth without adequate medical therapy. We report the long-term results of topical ocular administration from a PLG eye drop formulation [Kedrion Biopharma, CVP, Barga, Italy] for LC. METHODS A phase 2/3, 3-segment [Fig], open label, historically controlled, clinical trial (KB046) was initiated in May 2013 at three sites (1 US; 2 Italy). Segments 1 & 2 assessed the efficacy and safety of short-term PLG treatment in pseudomembrane regression/recurrence and prevention. Subjects with residual hard membranes at Segment 1 end underwent surgical removal. Patients completing Segment 2 without pseudomembranes continued to segment 3 for long-term safety continuation. Segment 3 is ongoing. Primary and secondary Efficacy Endpoints: a) Pseudomembrane recurrence prevention at end of Segment 2 and b) Regression of surface area of existing pseudomembranes at end of Segment 1 including Time (days) to pseudomembrane recurrence post-surgery or complete regression at end Segment 2. Regression and recurrence occurring during the trial were compared to the patients' prior treatments and surgical history. Safety Endpoints of segment 1/2 included overall safety, local tolerability, immunogenicity and viral safety. RESULTS Eleven patients (15 eyes) with pseudomembranes were enrolled in segment 1 and treated for 4 weeks with PLG drops. At Segment 1 end, four patients showed regression, proceeded to Segment 2, and treated with PLG drops for 8 weeks to prevent recurrence; seven patients had residual hard pseudomembranes and underwent surgical removal followed by 8 weeks with PLG. At Segment 2 end, 10 patients compliant per protocol without recurrence, transitioned to Segment 3. The primary endpoint of no pseudomembrane recurrence was 100% in all patients compliant with the treatment regimen at end Segment 2. Regression of surface area of existing pseudomembranes at end Segment 1 was achieved in 83.3% of affected eyes. Prior to trial enrollment, all patients experienced recurrences with prior historical therapies. Eleven patients were treated in segment 3 with 3 ongoing (as of July, 2020). Eight patients exited the study: one patient due to noncompliance, and two who developed systemic manifestations requiring other therapy. No other subjects have experienced new eye lesions. No major safety concerns arose during any the 3 Segments. Final data on immunogenicity will be available at the end of 2020. CONCLUSIONS Kedrion PLG eye drops were well tolerated and effective in recurrence prevention of pseudomembranes in patients with LC due to PLG deficiency who were compliant with the study protocol with long term follow-up now at 7 years (median: 74 months, range: 37-85 months); 3 subjects are still ongoing. Disclosures Caputo: Kedrion SpA: Research Funding. Suffredini:Kedrion SpA: Current Employment. Calcinai:Kedrion SpA: Current Employment. Crea:Kedrion SpA: Current Employment. Mathew:Kedrion SpA: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakar:Kedrion SpA: Research Funding; Prometic Biotherapeutics: Research Funding. Shapiro:Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kedrion Biopharma: Research Funding; Daiichi Sankyo: Research Funding; BioMarin: Research Funding; Novartis: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding; OPKO: Research Funding; Glover Blood Therapeutics: Research Funding; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; Sangamo: Research Funding. OffLabel Disclosure: Plasminogen eye drops, for treatment of Ligneous conjunctivitis due to Plasminogen Type I deficiency