Treating breakthrough bleeds: A new approach

Transcription

1 Treating breakthrough bleeds: A new approach Using Bypassing Agents With HEMLIBRA Prophylaxis Indication HEMLIBRA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors. Important Safety Information Boxed WARNING: THROMBOTIC MICROANGIOPATHY and THROMBOEMBOLISM Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (apcc) was administered for 24 hours or more to patients receiving HEMLIBRA prophylaxis. Monitor for the development of thrombotic microangiopathy and thrombotic events if apcc is administered. Discontinue apcc and suspend dosing of HEMLIBRA if symptoms occur. For HCP audiences

2 As observed over 24 weeks (HAVEN 1) and 30 weeks (HAVEN 2) Sustained protection meant 0 treated bleeds for most patients 1 Significantly more patients with FVIII inhibitors had 0 bleeds * with HEMLIBRA vs no prophylaxis HAVEN 1: Adults and adolescents PATIENTS WHO HAD ZERO BLEEDS HEMLIBRA prophylaxis (n=35) No prophylaxis (n=18) % 63 VS 6 % 87% FEWER BLEEDS (95% CI: 72.3; 94.3), P< ABR 2.9 (95% CI: 1.7; 5.0) vs 23.3 (95% CI: 12.3; 43.9) HAVEN 2 interim analysis: Children 1 PATIENTS WHO HAD ZERO BLEEDS HEMLIBRA prophylaxis (n=59) 86 % ABR 0.3 (95% CI: 0.1; 0.5) 98% FEWER BLEEDS in the intra-patient analysis ABR 0.4 (95% CI: 0.2; 0.9) vs 19.8 (95% CI: 15.3; 25.7) with previous BPAs (n=18) Median ABR in HAVEN 1 was 0 (IQR: 0; 3.7) with HEMLIBRA prophylaxis vs 18.8 (IQR: 13.0; 35.1) with no prophylaxis Median ABR in HAVEN 2 was 0 (IQR: 0; 0) with HEMLIBRA prophylaxis 1 ABR=annualized bleed rate; FVIII=factor VIII; IQR=interquartile range. * Defined as bleeds treated with BPAs (standardized bleed definition adapted from the International Society on Thrombosis and Haemostasis [ISTH]). 2 Warnings and Precautions Thrombotic Microangiopathy (TMA) and Thromboembolism Associated With HEMLIBRA and apcc In clinical trials, TMA was reported in 1.6% of patients (3/189) and thrombotic events were reported in 1.1% of patients (2/189). In patients who received at least one dose of apcc, TMA was reported in 8.3% of patients (3/36) and thrombotic events were reported in 5.6% of patients (2/36). Patients with TMA presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13.

3 HEMLIBRA safety was evaluated in the largest clinical trial program of patients with FVIII inhibitors * Pivotal study protocol amendment following cases of TMA and thrombotic events At the start of HAVEN 1, BPA usage for breakthrough bleeds requiring treatment was based on the discretion of the investigator 2 Unexpected cases of TMA and thrombotic events prior to the HAVEN 1 data cutoff 2 Events occurred when on average a cumulative amount of >100 U/kg/24 hours of apcc was administered for 24 hours to patients receiving HEMLIBRA prophylaxis The study protocol was later amended to consider these risks when using BPAs during HEMLIBRA prophylaxis No TMA or thrombotic events were reported with HEMLIBRA prophylaxis in HAVEN 2 1 Results are based on an interim analysis at 30 weeks, and should be interpreted with caution due to the short observation time Advise patients and caregivers to discontinue prophylactic use of BPAs the day before starting HEMLIBRA BPA=bypassing agent. * Based on pooled data from a randomized trial (HAVEN 1), single-arm trial (HAVEN 2), and a dose-finding trial, in which a total of 189 male patients with hemophilia A received at least 1 dose of HEMLIBRA as routine prophylaxis. Ninety-four patients (50%) were adults (aged 18 years and older), 38 (20%) were adolescents (aged 12 to under 18 years), 55 (29%) were children (2 years to under 12 years), and 2 (1%) were infants (1 month to under 2 years). Seven of the 189 patients (4%) included in the safety population were patients without FVIII inhibitors from the dose-finding trial. Warnings and Precautions (continued) Thrombotic Microangiopathy (TMA) and Thromboembolism Associated With HEMLIBRA and apcc (continued) Consider the benefits and risks if apcc must be used in a patient receiving HEMLIBRA prophylaxis. Monitor for the development of TMA and/or thromboembolism when administering apcc. Immediately discontinue apcc and interrupt HEMLIBRA prophylaxis if clinical symptoms, imaging, or laboratory findings consistent with TMA and/or thromboembolism occur, and manage as clinically indicated. Consider the benefits and risks of resuming HEMLIBRA prophylaxis following complete resolution of TMA and/or thrombotic events on a case-by-case basis.

4 Clinical experience suggests that a drug interaction exists with HEMLIBRA and apcc In a pooled safety analysis of 189 HEMLIBRA patients 36 patients used apcc Reported incidence: TMA 8.3% (3/36); thrombotic events 5.6% (2/36) * 125 instances of apcc treatment with HEMLIBRA Average cumulative amount of apcc over 24 hours (U/kg/24 hours) apcc duration (hours) < >100 < treatment instances 1 thrombotic event > treatment instances 3 TMA cases 1 thrombotic event No events occurred when apcc was used for <24 hours 5 of the 13 treatment instances reported TMA and thrombotic events when using cumulative amounts of apcc averaging >100 U/kg/24 hours for 24 hours An instance of apcc treatment is defined as all doses of apcc received by a patient, for any reason, until there was a 36-hour treatment-free break. Synergistic thrombin generation has been shown with apcc in combination with HEMLIBRA in vitro and in vivo 2 apcc contains coagulation factors that can accumulate with multiple doses, and supplies substrates for HEMLIBRA that result in overcorrection of clotting 4 * Overall, TMA and thrombotic events were reported in 1.6% (3/189) and 1.1% (2/189) of patients, respectively. Warnings and Precautions (continued) Laboratory Coagulation Test Interference HEMLIBRA affects intrinsic pathway clotting-based laboratory tests, including activated clotting time (ACT), activated partial thromboplastin time (aptt), and all assays based on aptt, such as one-stage factor VIII (FVIII) activity. Intrinsic pathway clotting-based laboratory tests should not be used. Results affected by HEMLIBRA: aptt; Bethesda assays (clotting-based) for FVIII inhibitor titers; one-stage, aptt-based, single-factor assays; aptt-based Activated Protein C resistance (APC-R); ACT.

5 There is a possibility for hypercoagulability with rfviia with HEMLIBRA based on preclinical experiments In HAVEN 1 and HAVEN 2, no TMA or thrombotic events were observed with use of rfviia alone in patients taking HEMLIBRA 1, 2 Clinical experience was limited and of relatively short duration (median treatment exposure was 42 weeks for HAVEN 1 and 29 weeks for HAVEN 2), and cannot exclude the possibility of occurrence of events with rfviia when taking HEMLIBRA treatment instances in patients treated with rfviia in HAVEN 1 1 Treatment average <90 µg/kg/24 h µg/kg/24 h µg/kg/24 h >270 µg/kg/24 h % of treatment instances HEMLIBRA prophylaxis calls for a new way of using BPAs for treating breakthrough bleeds rfviia=recombinant factor VIIa. References: 1. Data on file. Genentech, Inc. 2. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9): , Supplement, and Protocol. 3. Uchida N, Sambe T, Yoneyama K, et al. A first-in-human phase 1 study of ACE910, a novel factor VIII mimetic bispecific antibody, in healthy subjects. Blood. 2016;127(13): National Hemophilia Foundation. MASAC update on the approval and availability of the new treatment: emicizumab (Hemlibra), for persons with hemophilia A with inhibitors to factor VIII: interim guidance on acute bleed management and use of laboratory assays. 2017; Kruse-Jarres R, Callaghan MU, Croteau SE, et al. Surgical experience in two multicenter, open-label phase 3 studies of emicizumab in persons with hemophilia A with inhibitors (HAVEN 1 and HAVEN 2) [abstract]. Presented at: ASH 59th Annual Meeting of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Most Common Adverse Reactions The most common adverse reactions (incidence 10%) are injection site reactions, headache, and arthralgia.

6 Retrospective review of BPA use during minor surgeries and procedures in HEMLIBRA clinical studies 5* Analysis of the use of additional BPAs for minor surgeries or procedures was not an objective of the 2 pivotal studies, and there is limited experience from the clinical trials Management of perioperative BPA treatment was determined based on the investigator s discretion 5 29 surgeries were conducted in 22 patients; 69% (20/29) were managed without prophylactic BPAs Of the 20 surgeries managed without prophylactic BPAs 5 14 (70%) did not result in a post-operative bleed 6 (30%) resulted in a post-operative bleed Of the 9 surgeries managed with prophylactic BPAs 5 8 (89%) did not result in a post-operative bleed 1 (11%) resulted in a post-operative bleed 2 of the 6 post-operative bleeds were treated with on-demand BPAs 1 tooth extraction resulted in a single treated post-operative bleed * Surgeries included 1 right knee arthroscopy, synovectomy, debridement of arthrofibrosis, and chondroplasty; 1 laparoscopic appendectomy; 9 central venous access device-related procedures; 6 tooth extractions; and 12 other minor surgical procedures. 3 surgeries resulting in post-operative bleeding were treated with rfviia. 8 surgeries were treated with rfviia and 1 surgery used a single dose of prophylactic apcc. Drug Interactions Clinical experience suggests that a drug interaction exists with HEMLIBRA and apcc. There is a possibility for hypercoagulability with activated recombinant factor VII (rfviia) or FVIII with HEMLIBRA based on preclinical experiments.

7 TMA and thrombotic events reported in HAVEN 1 Thrombotic microangiopathy (TMA) and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of apcc was administered for 24 hours to patients receiving HEMLIBRA prophylaxis 4 events fully resolved following apcc discontinuation and suspension of HEMLIBRA 1,2 2 TMA cases 1 2 thrombotic events 1,2 In the limited experience with these events, treatment included supportive care with or without hemodialysis/plasmapheresis Evidence of improvement was seen within 1 week Both patients recovered within 3 weeks, with 1 patient electing to resume HEMLIBRA without recurrence No thrombotic event required anticoagulation therapy Evidence of improvement was seen within 1 month Both patients fully recovered, with 1 patient electing to resume HEMLIBRA without recurrence Recovery from these events occurred in the continued presence of HEMLIBRA in plasma 2,3 Patients with TMA presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity 1 additional TMA case occurred after the data cutoff for the primary analysis 1 The patient passed away and the investigator determined the cause of death was unrelated to HEMLIBRA apcc=activated prothrombin complex concentrate. Based on data from HAVEN 1: a randomized, multicenter, open-label clinical trial of patients with hemophilia A with FVIII inhibitors aged 12 years and older (N=109, all males). The primary endpoint was reduction in treated bleeds over 24 weeks with prophylactic HEMLIBRA vs no prophylaxis. Based on data from HAVEN 2 (interim analysis): a single-arm, multicenter, open-label clinical study of patients with hemophilia A with FVIII inhibitors aged <12 years and years weighing <40 kg. HAVEN 2 outcomes are from an interim analysis. The interim efficacy analysis examined reduction in bleeds at 30 weeks. The interim intra-patient analysis evaluated ABR in patients switching to HEMLIBRA following previous prophylactic BPAs (n=15) or previous on-demand BPAs (n=3) at a median study duration of 59 weeks. Statistical significance will be conducted at final analysis. 1

8 A new approach to treating breakthrough bleeds when using concomitant BPAs Talk to patients and caregivers about how HEMLIBRA increases coagulation potential 1 PREPARE BEFORE ANY BLEEDS TREAT 2IN THE EVENT OF A BLEED 3MONITOR BEYOND THE BLEED Educate patients and caregivers to think differently Discuss which types of bleeds require BPAs while taking HEMLIBRA and the importance of seeking medical advice before treating these bleeds Describe the potential risks of TMA and thromboembolism if apcc is taken during HEMLIBRA prophylaxis Encourage patients to update emergency medical information and to inform all healthcare providers Assess the bleed and proceed with a plan Follow a protocol for when and how patients and caregivers should use BPAs during HEMLIBRA prophylaxis Ensure patients consult with you first when apcc doses >100 U/kg are required Discuss how to approach repeated dosing of any BPA Monitor for TMA and thromboembolism if using apcc * Ensure patients and caregivers know to seek medical treatment if they suspect these events Immediately discontinue apcc and suspend HEMLIBRA if these events occur, and manage as clinically indicated Consider the benefits and risks of resuming HEMLIBRA prophylaxis following complete resolution of TMA or thrombotic events on a case-by-case basis * Monitoring includes D-dimer, prothrombin fragment F1+2 (if available), platelet count, serum creatinine, LDH, and peripheral blood smear analysis for schistocytes. For patients who require multiple BPA doses, laboratory monitoring should be performed every hours thereafter until hours following the last BPA dose administered to treat a given bleed. 1 Pregnancy, Lactation, Females and Males of Reproductive Potential Women of childbearing potential should use contraception while receiving HEMLIBRA. HEMLIBRA should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus. Consider developmental/health benefits, clinical need and potential adverse effects on the breastfed child and mother. You may report side effects to the FDA at (800) FDA-1088 or You may also report side effects to Genentech at (888) FPO HEMLIBRA is a registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. The HEMLIBRA logo is a trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. The Genentech logo is a registered trademark of Genentech, Inc Genentech USA, Inc. All rights reserved. EMI/080317/0065(3) 05/18