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Disclosures Hemophilia Treatment: ▫ There are no relevant financial interests to disclose for Factors to Consider myself or my spouse/partner from within the last 12 months.

PJ Barker, PharmD, BCPPS Clinical Coordinator St. Jude Children’s Research Hospital

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Objectives Hemophilia

Hemophilia A Hemophilia B • Discuss standard half life and extended half life • Factor VIII (FVIII) Deficiency • Factor IX (FIX) Deficiency factor treatment options for patients with • 80% of cases • 20% of cases hemophilia • Describe emicizumab-kxwh role in therapy for Hemophilia A

MedlinePlus, National Library of Medicine.

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Complications and Classification Factor fVIII fIX Concentrates Severity Mild Moderate Severe

Bypassing Agents rfVIIa aPCC Activated prothrombin Baseline Factor (BPA) Factor 7 activated complex concentrate Level (% of 6-30% 1-5% <1 % normal) Tranexamic Aminocaproic Antifibrinolytics acid acid Major Minor No Bleeding Trauma Trauma Trauma Emicizumab- • Life threatening bleeds • Inhibitors (factor antibodies) Desmopressin kxwh • Joint damage and • Viral Transmission TreatmentOptions Immobility

Srivastava A. Hemophilia. 2020.

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Treatment Approaches Prophylactic Therapy • Primary Prophylaxis Mild ▫ Initiation of preventative therapy before onset of joint Episodic Treatment disease, second clinically relevant bleed, and 3 years of Moderate age • Secondary Prophylaxis ▫ Initiation of preventative therapy after two or more joint bleeds but before disease and typically > 3 years of age Prophylaxis Episodic • Tertiary Prophylaxis Severe (ppx) Treatment ▫ Initiation of preventative therapy after onset joint disease

Manco-Johnson,et al. NEJM. 2007; Strisava A. Hemophilia. 2020 7 8

Recombinant Factor Concentrates Factor Concentrates • First Generation • Standard Half-Life (SHL) ▫ Animal and/or human ▫ FVIII: ~12hr proteins in final ▫ FIX: ~18-24hr formulation • Extended Half-Life (EHL) • Second Generation ▫ FVIII: 1.4-1.6x half-life SHL ▫ Animal and/or human ▫ FIX: 3-5x half-life SHL proteins in culture  Recovery and medium but not final extravascular distribution formulation differ from SHL FIX and • Third Generation between EHL FIX ▫ No animal and/or human concentrates proteins in medium or MASAC #263. NHF. 2020; Srivastava A. Hemophilia. 2020. final formulation MASAC #263. NHF. 2020

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Third Generation FVIII Concentrates Third Generation FIX Concentrates

• Efmoroctocog alfa • Octocog alfa (Advate®; Eftrenonacog alfa (Eloctate®) Kovaltry®) Nonacog alfa (Alprolix®) • Damoctocog alfa pegol • Simoctocog alfa (Benefix®)

(Jivi®) (Nuwiq®) Albutrepenonacog HalfLife Standard

Standard HalfLife Standard Trenonacog alfa • Life Half ended • Ruiroctocog alfa pegol Turoctocog alfa alfa (Idelvion®) (Ixinity®)

(NovoEight®) Ext

Extended Half Half Life Extended (Adynovate®) • Moroctocog alfa Nonacog beta pegol Nonacog gamma • Turoctocog alfa pegol (Rebinyn®) (Esperoct®) (Xyntha®) (Rixubis®) • Lonoctocog alfa (Afstyla®)

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Factor Concentrate Prophylaxis Dosing for Prophylaxis Conventional/ Fixed Dosing Tailored Approach SHL FVIII Monday Wednesday Friday • Standard dosing • Pharmacokinetic Approach approaching that utilizes ▫ Typically targets maintaining SHL factor trough >1-5% ▫ High dose ▫ Limited sampling strategy EHL FVIII Tuesday Friday  Achieves lowest annual with Bayesian analysis joint bleeding rate (AJBR) ▫ Extended sampling strategy  Essentially ensures ~11 samples patients always have • Clinical Factors Approach SHL FIX Tuesday Friday measurable factor ▫ Bleeding phenotype ▫ Intermediate dose ▫ Physical activity  Reduces AJBR ~90% ▫ Low dose EHL FIX Tuesday Tuesday  Reduces AJBR ~80%

Srivastava A. Hemophilia. 2020.

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Pharmacokinetic Modeling RL is a 14yo male with severe hemophilia A. He has previously refused factor prophylaxis, but recent developed multiple joint • Pharmaceutical • WAPPS-Hemo© bleeds. The family and patient would like to begin a prophylactic Manufacturers ▫ Endorsed by World Federation factor concentrate regimen that allows for the least amount of ▫ myPKFiT® of Hemophilia infusions. What regimen do you recommend? ▫ Hemotik® ▫ Bayesian approach A. Efmoroctocog alfa (Eloctate®) 50 units/kg IV twice weekly, with follow-up pharmacokinetic studies • PK Platforms ▫ FREE ▫ ADAPT® ▫ Worldwide product with B. Albutrepenonacog alfa (Idelvion®) 50 units/kg IV once weekly, with follow- up pharmacokinetic studies ▫ WinNonlin® wide variety of factor concentrates (SHL and EHL) C. Fixed dose Octocog alfa (Advate®) 25 units/kg twice weekly ▫ www.wapps-hemo.org

D. Fixed dose Eftrenonacog alfa (Alprolix®) 50 units/kg IV once monthly

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Emicizumab-kxwh • FDA approved for prophylaxis in adults and pediatric patients with Hemophilia A • Subcutaneous injection ▫ Loading dose 3 mg/kg weekly x 4 weeks ▫ Maintenance dose: Alternative to Infusions?  1.5 mg/kg weekly  3 mg/kg every 2 weeks  6 mg/kg every 4 weeks • Most common side effect injection site reaction, headache, arthralgia • Boxed warning for thromboembolism/thrombotic microangiopathy (TMA) when used in combination with aPCCs

Knight T. Thera Adv in Hem. 2018 17 18

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Emicizumab Significantly Reduces Annual Emicizumab Significantly Reduces ABR for Bleeding Rate for Inhibitor Patients Pediatric Inhibitor Patients

Study Population Primary Objective Outcome Study End Points Outcome

Inhibitor Patients ABR and bleeding Intraindividual comparison to BPA Inhibitor Patients Difference annual ABR- 89% decrease between H H Age 1-15y reduction compared to showed 99% reduction [97.4- 12y+ bleeding rate (ABR) group A and B (p<0.001) A A prior BPA treatment; 99.4] in ABR (n=15) V Receiving BPA for health QOL V Treated with A: Emicizumab ppx A: 2.9 [1.7-5.0] episodic/ppx A: ABR 0.3 [0.17-0.5], 77% ABR=0 bypassing agent (BPA) B: Episodic treatment B: 23.3 [12.3-43.9] E E treatment A: Emicizumab ppx B: ABR 0.2 [0.03-1.72] for episodic therapy with BPA C: Lowered ABR by 79% (p N once weekly C: ABR 2.2 [0.69-6.81] N or ppx + episodic C: Previous ppx pts <0.001) than previous BPA for N=88 (85 <12y) B: Emicizumab ppx therapy changed to emicizumab ppx therapy 2 every 2 weeks AE: 2 patients developed 1 C: Emicizumab ppx antibodies, 1 lost efficacy N=109 TMA (N=3) and thrombosis every 4 weeks (N=1)treated with aPCC + Emicizumab dosing 3 mg/kg subQ weekly x 4 weeks, then (A) 1.5 mg/kg subQ weekly; (B)3 mg/kg subq every 2 weeks; (C) emicizumab 6 mg/kg every 4 weeks Emicizumab dosing 3 mg/kg subQ weekly x 4 weeks, then 1.5 mg/kg subQ weekly Oldenburg J, et al. NEJM, 2017. Young G. et al, Blood. 2019 19 20

Emicizumab Significantly Reduces ABR for Emicizumab Treatment Plan Non-Inhibitor Patients

Study Primary Objective Outcome Prophylaxis Episodic = Non-inhibitor Difference ABR, 96% and 97% (p<0.001) reduction Severe HemA Emicizumab treatment H Patients treated bleeds ABR treated bleeds for A and B A 12y+ between groups compared to C V Receiving ppx or A: Once weekly dosing A: 1.5 [0.9-2.5] • Episodic Treatment Options: E episodic fVIII B: q2week dosing B: 1.3 [0.8-2.3] ▫ N C: No ppx C: 38.2 [22.9-63.8] rFVIIa (inhibitor patients) N=152 D: previous on ppx D: 68% lower ABR (p<0.001) ▫ SHL or EHL rFVIII with fVIII, once weekly ▫ Antifibrinolytics in addition to factor 3 No major AE related to emicizumab concentrates Emicizumab 3mg/kg subQ once week x 4 weeks; 1.5mg/kg weekly or 3mg/kg every other week ▫ Avoid aPCC due to risk of thrombosis and TMA

Mahlangu J. et al. NEJM. 2018. 21 22

RC is a 5yoM (25kg) with high titer inhibitor. He has a target Coagulation Labs for Emicizumab Patients joint of right elbow and family would like to switch from bypassing agent prophylaxis to emicizumab. They desire a • Emicizumab interferes with the following test regimen that minimizes injections but provides best ▫ Acvated Clong Time (ACT) prevention of bleeds. What do you recommend? ▫ Activated partial thomboplastin time (aPTT) ▫ aPTT based clong factor assays Emicizumab 3 mg/kg weekly x 4 weeks, 3 mg/kg every 2 weeks; rfVIIa (Novoseven RT®) 90 mcg/kg prn bleeding episodes  Bethesda units  Intrinsic pathway clong based assays Emicizumab 3 mg/kg every 2 weeks; rfVIIa (Sevenfact®) 90 mcg/kg prn bleeding • Unaffected Assays episode ▫ Bovine chromogenic Bethesda assay Emicizumab 3 mg/kg weekly x 4 weeks, 1.5 mg/kg every week; aPCC (FEIBA®) 50 ▫ One stage PT based single factor assays units/kg q8h prn bleeding episode ▫ Chromogenic based single factor assays  For fVIII, must be bovine based Emicizumab 3 mg/kg weekly x 4 weeks, 3 mg/kg every 2 weeks; Efmoroctocog alfa (Eloctate®) 50 units/kg prn severe bleeding episode

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On the Horizon Hemophilia Treatment

• National and international guidelines do not give • Non-factor therapies: preference to emicizumab vs factor concentrates for ▫ Concizumab the prophylactic treatment of Hemophilia A ▫ Fiturisan • When utilizing factor concentrate for prophylaxis ▫ Anti-TFPI monoclonal antibody patients should be targeted to a trough of >1% • Gene Therapy • Emicizumab is only approved for prophylaxis and patients must be provided with an episodic treatment option • Patient’s lifestyle and preference should be Mannucci. Haematologica.2020 considered when choosing a treatment plan

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References Hemophilia Treatment: • National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2020 Aug 17. [Illustration] X- Linked Recessive; [cited 2020 Sep 24]; Available from: https://ghr.nlm.nih.gov/primer/inheritance/inheritancepatterns • Franchini M and Mannucci PM. The History of Hemophilia. Semin Thromb Hemost. 2014; 40:571-76. • Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Factors to Consider Severe Hemophilia. NEJM. 2007. 357(6):535-544. • Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines to for the Management of Hemophilia, 3rd Edition. Hemophilia. 2020 Aug3. • MASAC Recommendations Concerning Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders. National Hemophilia Foundation. 2020: 263. Available from: https://www.hemophilia.org/Researchers-Healthcare- Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendations-Concerning- Products-Licensed-for-the-Treatment-of-Hemophilia-and-Other-Bleeding-Disorders • WAPPS-Hemo, McMaster University. 2020. www.wapps-hemo.org. • Knight T. and Callaghan MU. The Role of Emicizumab, a Bispecific Factor Ixa and Factor X-directed antibody, for the Prevention of PJ Barker, PharmD, BCPPS Bleeding Episodes in Patients with Hemophilia A. Therapeutic Advances in Hematology. 2018; 9(10):319-334. • Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in Hemophilia A with Inhibitors. NEJM. 2017; 377(9):809-18. Clinical Coordinator • Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019; 134(24):2127-38. St. Jude Children’s Research Hospital • Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. NEJM 2018: 379(9):811-22. • Pipe SW, Shima M, Lehle M, et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A(HAVEN 4): a multicentre, open-label, non randomised phase 3 study. Lancet Haematol. 2019; 6(6):e295-305. • Mannuncci PM. Hemophilia therapy:the future has begun. Haematologica. 2020; 105(3):545-53.

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