New directions to develop therapies for people with hemophilia

Figures & data

Table 1. Depicting Plasma derived products and their characteristics [36]

Plasma derived	FDA approval	Prophylaxis Dose	Treatment dose (Major trauma or surgery)	Half-life (hours)	Viral Attenuation Method	Other characteristics
Factor VIII
Hemofil M (Baxter)	1966	20–40 IU/dL plasma	80–100 IU/dL plasma	15	Solvent and detergent and Nanofiltration	Ultrahigh Purity
Koate (previously called Koate DVI) (Kedrion Biopharma)	1974	15 units per kg	80–100 units per kg	16	Solvent and detergent and Polyethylene glycol (PEG) precipitation/depth filtration	High Purity
Factor IX
AlphaNine SD (Grifols Biologicals)	1996	25–40 IU/kg two times weekly or 15–30 IU/kg two times weekly	30–50 IU/kg - Repeat dose every 12 hours as needed for 3–5 days	18	Solvent and detergent	High Purity
Mononine (CSL Behring)	1992	up to 20–30 IU/kg repeat in 24 hours if necessary	up to 75 IU/kg	23	Immunoaffinity chromatography	High Purity

Table 2. Depicting Recombinant products and their characteristics [36]

Recombinant	FDA approval	Prophylaxis Dose	Treatment dose (Major trauma or surgery)	Half-life (hours)	Viral Attenuation Method	Other characteristics
Factor VIII
Octocog alpha, Recombinate (Baxter Healthcare Corporation and Wyeth BioPharma)	1992	None	60–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	15	Immunoaffinity chromatography	First Generation
Kogenate FS (Bayer)	1993	25 units per kg of body weight three times per week.	25 units per kg of body weight three times per week.	11–15	Solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography and monoclonal antibody immunoaffinity chromatography	Second Generation
Octocog alpha,Advate (Takeda)	2003	20 to 40 International Units of Factor every other day (3 to 4 times weekly)	30–60 International Units/kg (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	9–12	Immunoaffinity chromatography includes a dedicated, viral inactivation solvent-detergent treatment step	Third Generation.
Xyntha (Pfizer)	2008	30 IU/kg administered 3 times weekly.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	8–11	Affinity chromatography includes a solvent-detergent viral inactivation step and a virus-retaining nanofiltration step.	Third Generation.
Turoctocog alpha, Novoeight (Novo Nordisk)	2013	20–50 IU/kg three times per week.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	8–12	Nanometer filtration with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Third Generation.
Simoctocog alfa, Nuwiq (Octapharma)	2015	20 to 40 IU per kg of body weight every other day	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	12–17	Nanometer filtration with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Fourth Generation
Octocog alpha, Kovaltry (Bayer)	2016	20 to 40 IU per kg of body weight two or three times per week.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	12–14	Nanometer filtration with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Third Generation.
Factor IX
BeneFIX (Pfizer)	1997	100 IU/kg once weekly	20–100 IU/dL	16–19	Four-step chromatography purification	Genetically engineered Chinese Hamster Ovary (CHO)
Rixubis (Baxter)	2013	60 to 80 IU/kg twice weekly for patients <12 years of age 40 to 60 IU/kg twice weekly for patients ≥12 years of age.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	23–26	Chromatography purification with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Genetically engineered Chinese Hamster Ovary (CHO)
Ixinity (Aptevo)	2021	40 to 70 IU/kg twice weekly	50–80 IU/dL	24	Four-step chromatography purification	Genetically engineered Chinese Hamster Ovary (CHO)

Table 3. Depicting EHL factor products and their characteristics [36]

EHL	FDA approval	Prophylaxis Dose	Treatment dose (Major trauma or surgery)	Half-life (hours)	Viral Attenuation Method	Other characteristics
Factor VIII
Eloctate (Sanofi Genzyme)	2014	50 IU/kg administered every 4 days.	25–50 IU per kg (Every 8 to 24 hours for major surgery)	19 1.5-fold longer than rFVIII (Advate)	Nanofiltration along with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Recombinant protein consisting of a B-domain deleted analogue of human Coagulation Factor VIII covalently linked to the human immunoglobulin G1 (IgG1) Fc domain
Adynovate (rurioctocog alpha pegol, BAX 855, Takeda)	2015	55 IU per kg body weight two times per week for < 12 years of age with a maximum of 70 IU/kg 40–50 IU/ kg twice weekly in adults and adolescents for 12 years and older.	30–60 IU per kg (Every 8 to 24 hours for major surgery)	18 1.3–1.5 fold longer than rFVIII (Advate)	Chromatography column along with viral inactivation solvent-detergent treatment step	Recombinant full-length human coagulation factor VIII covalently conjugated with one or more molecules of polyethylene glycol
Jivi (BAY 94–9027, Bayer)	2018	45–60 IU/kg every 5 days	15–50 IU per kg (Every 8 to 24 hours for major surgery)	18 1.4–1.5-fold longer than rFVIII (Kogenate-FS)	Chromatography and ultrafiltration	Conjugation of recombinant B-domain deleted human coagulation Factor VIII to 60-kDa branched PEG molecule
Esperoct (turoctocog alfa pegol; N8-GP, Novo Nordisk)	2019	50 IU/kg every 4 days.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	22 1.6 fold longer than rFVIII (Novoeight)	Two step: detergent (Triton X-100) treatment for inactivation of enveloped viruses, and nano- filtration for removal of enveloped and non-enveloped viruses.	40-kDa PEG molecule is conjugated to the O-glycan moiety of the B domain using an enzymatic reaction to produce a glycopegylated FVIII.
Factor IX
Alprolix (Efrenonacog alfa, Bioverativ)	2014	60 IU/kg once weekly for < 12 years of age 50 IU/kg once weekly, or 100 IU/kg once every 10 days for > 12 years of age	20–100 IU/dL	54–90 3 to 5 fold longer than SHL-rFIX	Two step: detergent treatment for inactivation of viruses, and nano- filtration for removal of viruses.	Human coagulation Factor IX sequence covalently linked to the Fc domain of human immunoglobulin G1 (IgG1).
Idelvion (albutrepenonacog alfa, CSL Behring)	2016	25–40 IU per kg every 7 days. Once well controlled, 14-day interval at 50–75 IU per kg for < 12 years of age 40–55 IU per kg every 7 days for > 12 years of age.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	102 5.6 fold longer than SHL-rFIX	Virus inactivation by solvent/detergent treatment and virus removal by filtration.	Genetic fusion of recombinant albumin to recombinant coagulation Factor IX.
Rebinyn (nonacog beta pegol [N9-GP], Novo Nordisk	2017	Not indicated	40–80 IU/dL	93 5 fold longer than SHL-rFIX	Two step: detergent treatment for inactivation of viruses, and nano- filtration for removal of viruses	40 kDa PEG group is selectively attached to specific -N-linked glycans in the rFIX activation peptide, with mono-PEGylated rFIX

US Food and Drug Administration [internet]. https://www.fda.gov/vaccines-blood-biologics/approved-blood-products (cited 2022 Sep 15).

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