BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A.

Adult Dose-Response Relationship, Drug Factor VIII / antagonists & inhibitors Half-Life Hemophilia A / drug therapy Humans Injections, Intravenous Male Middle Aged Molecular Structure Recombinant Fusion Proteins / administration & dosage Young Adult

Journal

The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562

Informations de publication

Date de publication:
10 09 2020
Historique:
entrez: 9 9 2020
pubmed: 10 9 2020
medline: 9 10 2020
Statut: ppublish

Résumé

Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).

Sections du résumé

BACKGROUND
Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001.
METHODS
In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed.
RESULTS
No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments.
CONCLUSIONS
In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).

Identifiants

DOI: 10.1056/NEJMoa2002699 PMID: 32905674
pubmed: 32905674
doi: 10.1056/NEJMoa2002699
doi:

Substances chimiques

BIVV001 0
Recombinant Fusion Proteins 0
Factor VIII 9001-27-8

Banques de données

ClinicalTrials.gov
['NCT03205163']

Types de publication

Clinical Trial, Phase I Clinical Trial, Phase II Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1018-1027

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Massachusetts Medical Society.

Auteurs

Barbara A Konkle (BA)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Amy D Shapiro (AD)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Doris V Quon (DV)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Janice M Staber (JM)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Roshni Kulkarni (R)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Margaret V Ragni (MV)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Ekta S Chhabra (ES)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Stacey Poloskey (S)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Kara Rice (K)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Suresh Katragadda (S)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Joachim Fruebis (J)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

Craig C Benson (CC)

From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) - both in Waltham, MA.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Facteurs biologiques › Facteurs de la coagulation sanguine › Facteur VIII › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Phénomènes physiques › Temps › Période › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Troubles héréditaires de la coagulation sanguine › Hémophilie A › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Voies d'administration de substances chimiques et des médicaments › Injections › Injections veineuses › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines recombinantes › Protéines de fusion recombinantes › BIVV001 Fusion Protein as Factor VIII...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Jeune adulte › BIVV001 Fusion Protein as Factor VIII...