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Hemophilia A ameliorated in mice by CRISPR-based in vivo genome editing of human Factor VIII

https://www.nature.com/articles/s41598-019-53198-y

https://www.ncbi.nlm.nih.gov/pubmed/31727959?dopt=Abstract

Related Articles

Hemophilia A ameliorated in mice by CRISPR-based in vivo genome editing of human Factor VIII.

Sci Rep. 2019 Nov 14;9(1):16838

Authors: Chen H, Shi M, Gilam A, Zheng Q, Zhang Y, Afrikanova I, Li J, Gluzman Z, Jiang R, Kong LJ, Chen-Tsai RY

Abstract

Hemophilia A is a monogenic disease with a blood clotting factor VIII (FVIII) deficiency caused by mutation in the factor VIII (F8) gene. Current and emerging treatments such as FVIII protein injection and gene therapies via AAV-delivered F8 transgene in an episome are costly and nonpermanent. Here, we describe a CRISPR/Cas9-based in vivo genome editing method, combined with non-homologous end joining, enabling permanent chromosomal integration of a modified human B domain deleted-F8 (BDD-F8) at the albumin (Alb) locus in liver cells. To test the approach in mice, C57BL/6 mice received tail vein injections of two vectors, AAV8-SaCas9-gRNA, targeting Alb intron 13, and AAV8-BDD-F8. This resulted in BDD-F8 insertion at the Alb locus and FVIII protein expression in the liver of vector-, but not vehicle-, treated mice. Using this approach in hemophilic mice, BDD-F8 was expressed in liver cells as functional human FVIII, leading to increased plasma levels of FVIII and restoration of blood clotting properties in a dose-dependent manor for at least 7 months, with no detectable liver toxicity or meaningful off-target effects. Based on these findings, our BDD-F8 genome editing approach may offer an efficacious, long-term and safe treatment for patients with hemophilia A.

PMID: 31727959 [PubMed – in process]

Mesenchymal stem cells as carrier of the therapeutic agent in the gene therapy of blood disorders

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.29324

https://www.ncbi.nlm.nih.gov/pubmed/31691976?dopt=Abstract

Related Articles

Mesenchymal stem cells as carrier of the therapeutic agent in the gene therapy of blood disorders.

J Cell Physiol. 2019 Nov 06;:

Authors: Shomali N, Gharibi T, Vahedi G, Mohammed RN, Mohammadi H, Salimifard S, Marofi F

Abstract

Nonhematopoietic stem cells as a delivery platform of therapeutic useful genes have attracted widespread attention in recent years, owing to gained a long lifespan, easy separation, high proliferation, and high transfection capacity. Mesenchymal stem/stromal cells (MSCs) are the choice of the cells for gene and cell therapy due to high self-renewal capacity, high migration rate to the site of the tumor, and with immune suppressive and anti-inflammatory properties. Hence, it has a high potential of safety genetic modification of MSCs for antitumor gene expression and has paved the way for the clinical application of these cells to target the therapy of cancers and other diseases. The aim of gene therapy is targeted treatment of cancers and diseases through recovery, change, or enhancement cell performance to the sustained secretion of useful therapeutic proteins and induction expression of the functional gene in intended tissue. Recent developments in the vectors designing leading to the increase and durability of expression and improvement of the safety of the vectors that overcome a lot of problems, such as durability of expression and the host immune response. Nowadays, gene therapy approach is used by MSCs as a delivery vehicle in the preclinical and the clinical trials for the secretion of erythropoietin, recombinant antibodies, coagulation factors, cytokines, as well as angiogenic inhibitors in many blood disorders like anemia, hemophilia, and malignancies. In this study, we critically discuss the status of gene therapy by MSCs as a delivery vehicle for the treatment of blood disorders. Finally, the results of clinical trial studies are assessed, highlighting promising advantages of this emerging technology in the clinical setting.

PMID: 31691976 [PubMed – as supplied by publisher]

Tissue Factor-Negative Cell-Derived Microparticles Play a Distinctive Role in Hemostasis

https://www.ncbi.nlm.nih.gov/pubmed/31195421?dopt=Abstract

Tissue Factor-Negative Cell-Derived Microparticles Play a Distinctive Role in Hemostasis: A Viewpoint Review.

Semin Thromb Hemost. 2019 Jun 13;:

Authors: Horstman LL, McCauley RF, Jy W, Ahn YS

Abstract

Circulating cell-derived microparticles (MPs) exhibit procoagulant activity and have been investigated for a possible role in some human pathologies. However, their potential role in hemostasis has been neglected and often denied. This review brings to attention a specific body of direct clinical evidence supporting an important but distinctive role of MPs in hemostasis. Evidence for a role of MPs in hemostasis includes: (1) two congenital bleeding disorders attributed to impaired release of MPs; (2) two recent studies of trauma patients relating naturally elevated endogenous MPs at admission to reduced transfusion requirements and better outcomes; (3) a study of coronary surgery patients showing that elevated MP before surgery reduces transfusion requirements during surgery; and (4) a clinical study of patients with immune thrombocytopenia demonstrating that those with high circulating MP have reduced bleeding compared to patients with similar platelet counts but lower MP levels. Mechanisms involving potentiating the contact factor pathway are thought to play a key role and are probably synergistic with polyphosphate released from activated platelets at sites of endothelial injury. Hemostatic defect of patients with deficient MP-mediated coagulation resembles deficiency of FXI (hemophilia C), distinct from hemophilia A or B, so can be termed type C hemostasis. A better understanding of this proposed hemostatic pathway may lead to improved methods for controlling excessive bleeding in surgery, trauma, and other clinical settings.

PMID: 31195421 [PubMed – as supplied by publisher]

Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Previously Untreated Patients With Haemophilia B

https://clinicaltrials.gov/ct2/show/NCT02141074?type=Intr&cond=hemophilia&lupd_s=05%2F23%2F2019&lupd_d=14

Conditions :   Congenital Bleeding Disorder;   Haemophilia B

Intervention :   Drug: nonacog beta pegol

Sponsor :   Novo Nordisk A/S

Recruiting

Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Previously Untreated Patients With Haemophilia B

NCT02141074

Mon, 19 May 2014 12:00:00 EDT

Last Update Posted: 06/06/19 07:30AM

Fitusiran Prophylaxis in Male Pediatric Subjects Aged 1 to Less Than 12 Years With Hemophilia A or B

https://clinicaltrials.gov/ct2/show/NCT03974113?type=Intr&cond=hemophilia&lupd_s=05%2F21%2F2019&lupd_d=14

Condition :   Hemophilia

Intervention :   Drug: Fitusiran

Sponsor :   Genzyme, a Sanofi Company

Not yet recruiting

Fitusiran Prophylaxis in Male Pediatric Subjects Aged 1 to Less Than 12 Years With Hemophilia A or B

NCT03974113

Tue, 04 Jun 2019 12:00:00 EDT

Last Update Posted: 06/04/19 06:53AM

Limitations of prophylactic treatment in patients with hemophilia

https://www.ncbi.nlm.nih.gov/pubmed/31157677?dopt=Abstract

Limitations of prophylactic treatment in patients with hemophilia.

Blood Coagul Fibrinolysis. 2019 May 30;:

Authors: López Fernández MF

Abstract

: Prophylaxis with factor VIII concentrates is the cornerstone of treatment for severe hemophilia A. In children, early onset of primary and secondary prophylaxis is the gold standard in most of countries with adequate financial resources. In adults, it is reasonable to continue the prophylactic treatment initiated during childhood to preserve joint functionality. Adults with advanced hemophilic arthropathy can also benefit from tertiary prophylaxis, showing reductions in bleeding episodes, target joints and missed days from work. The long-term evolution of hemophilic patients usually depends on how successfully prophylaxis can prevent bleeding in both children and adults. For prophylaxis to be efficient it is essential to consider the resources available (factor concentrate use and trough levels) and the patient’s bleeding phenotype and clinical situation (levels of activity required, presence of chronic synovitis and arthropathy), and to define the annual number of bleeds (particularly into joints) acceptable for each patient.

PMID: 31157677 [PubMed – as supplied by publisher]

Lentiviral FVIII Gene Therapy for Hemophilia A [YUVA-GT-F801]

https://clinicaltrials.gov/ct2/show/NCT03217032?type=Intr&cond=hemophilia&lupd_s=05%2F09%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Biological: YUVA-GT-F801

Sponsor :   Shenzhen Geno-Immune Medical Institute

Not yet recruiting

Lentiviral FVIII Gene Therapy

NCT03217032

Thu, 13 Jul 2017 12:00:00 EDT

Last Update Posted: 05/23/19 07:43AM

The central role of thrombin in bleeding disorders

https://www.ncbi.nlm.nih.gov/pubmed/31164248?dopt=Abstract

https://www.sciencedirect.com/science/article/pii/S0268960X18300973?via%3Dihub

Related Articles

The central role of thrombin in bleeding disorders.

Blood Rev. 2019 May 22;:

Authors: Negrier C, Shima M, Hoffman M

Abstract

Maintaining normal hemostasis relies on a regulated system of procoagulant and anticoagulant pathways, and disruption of these processes leads to the loss of hemostatic control, with the potential for excessive bleeding or thrombosis. Evaluation of bleeding disorders has conventionally been achieved by laboratory assays that measure the activity of individual coagulation factors. While such assays have proven effective for detecting abnormalities of the coagulation system and aiding diagnosis, inherent limitations prevent them from capturing a complete picture of hemostatic function. An improved understanding of thrombin activity and its central role in hemostasis and bleeding disorders has led to the clinical development of global assays that are more physiologically relevant than traditional assays; furthermore, these global assays are able to monitor responses to therapy. In this review, we provide an overview of the role of thrombin in hemostasis, and describe the clinical benefits of thrombin monitoring in patients with bleeding disorders. Moreover, we discuss recent advances in thrombin-targeting therapeutic strategies that aim to correct thrombin deficiency and prevent bleeding in patients with hemophilia and other rare bleeding disorders.

PMID: 31164248 [PubMed – as supplied by publisher]

A Trial Evaluating the Efficacy and Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients With Inhibitors

https://clinicaltrials.gov/ct2/show/NCT03196284?type=Intr&cond=hemophilia&lupd_s=05%2F08%2F2019&lupd_d=14

Conditions :   Congenital Bleeding Disorder;   Haemophilia A With Inhibitors;   Haemophilia B With Inhibitors

Interventions :   Drug: Concizumab;   Drug: Eptacog alfa

Sponsor :   Novo Nordisk A/S

Active, not recruiting

A Trial Evaluating the Efficacy and Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients With Inhibitors

NCT03196284

Thu, 22 Jun 2017 12:00:00 EDT

Last Update Posted: 05/22/19 07:39AM

A Trial Evaluating Efficacy and Safety of Prophylactic Administration of Concizumab in Patients With Severe Haemophilia A Without Inhibitors

https://clinicaltrials.gov/ct2/show/NCT03196297?type=Intr&cond=hemophilia&lupd_s=05%2F08%2F2019&lupd_d=14

Conditions :   Haemostasis;   Haemophilia A

Interventions :   Drug: Concizumab;   Drug: Turoctocog alfa

Sponsor :   Novo Nordisk A/S

Active, not recruiting

A Trial Evaluating Efficacy and Safety of Prophylactic Administration of Concizumab in Patients With Severe Haemophilia A Without Inhibitors

NCT03196297

Thu, 22 Jun 2017 12:00:00 EDT

Last Update Posted: 05/22/19 07:39AM

Gene Therapy: Paving New Roads in the Treatment of Hemophilia

https://www.ncbi.nlm.nih.gov/pubmed/31096314?dopt=Abstract

Gene Therapy: Paving New Roads in the Treatment of Hemophilia.

Semin Thromb Hemost. 2019 May 16;:

Authors: Yamaguti-Hayakawa GG, Ozelo MC

Abstract

Hemophilia is a monogenic disease with robust clinicolaboratory correlations of severity. These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy. The road from animal models to human clinical studies has heralded significant successes, but major issues concerning a previous immunity against adeno-associated virus and transgene optimization remain to be fully resolved. Despite significant advances in gene therapy application, many questions remain pertaining to its use in specific populations such as those with factor inhibitors, those with underlying liver disease, and pediatric patients. Here, the authors provide an update on viral vector and transgene improvements, review the results of recently published gene therapy clinical trials for hemophilia, and discuss the main challenges facing investigators in the field.

PMID: 31096314 [PubMed – as supplied by publisher]

A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors

https://clinicaltrials.gov/ct2/show/NCT03417245?type=Intr&cond=hemophilia&lupd_s=05%2F01%2F2019&lupd_d=14

Conditions :   Hemophilia A;   Hemophilia B

Interventions :   Drug: fitusiran;   Drug: factor VIII or factor IX

Sponsor :   Genzyme, a Sanofi Company

Recruiting

A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors

NCT03417245

Wed, 31 Jan 2018 12:00:00 EST

Last Update Posted: 05/15/19 07:45AM

Study Investigating a PEGylated Recombinant Factor VIII (BAX 855) for Hemophilia A (PROLONG-ATE Study) [Completed]

https://clinicaltrials.gov/ct2/show/NCT01736475?type=Intr&cond=hemophilia&lupd_s=04%2F30%2F2019&lupd_d=14

Condition :   Hemophilia A

Interventions :   Biological: Antihemophilic Factor (Recombinant) – Plasma/Albumin Free Method;   Biological: PEGylated Recombinant Factor VIII

Sponsor :   Baxalta now part of Shire

Completed

Study Investigating a PEGylated Recombinant Factor VIII (BAX 855) for Hemophilia A (PROLONG-ATE Study)

NCT01736475

Thu, 29 Nov 2012 12:00:00 EST

Last Update Posted: 05/14/19 06:46AM

uniQure Announces New Preclinical Data in Hemophilia A [AMT-180] in Oral Presentations at the 22nd ASGCT Annual Meeting

https://www.globenewswire.com/news-release/2019/05/02/1815127/0/en/uniQure-Announces-New-Preclinical-Data-in-Hemophilia-A-and-Fabry-Disease-in-Oral-Presentations-at-the-22nd-ASGCT-Annual-Meeting.html

uniQure Announces New Preclinical Data in Hemophilia A and Fabry Disease in Oral Presentations at the 22nd ASGCT Annual Meeting

“proof-of-concept of AMT-180 demonstrated in hemophilia A mouse model”

Clinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors

https://clinicaltrials.gov/ct2/show/NCT03935334?type=Intr&cond=hemophilia&lupd_s=04%2F18%2F2019&lupd_d=14

Condition :   Hemophilia A or B With Inhibitor

Interventions :   Biological: Biosimilar eptacog alfa, activated (AryoSeven);   Biological: Eptacog alfa, activated (Novoseven)

Sponsor :   AryoGen Pharmed Co.

Recruiting

Clinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors

NCT03935334

Thu, 02 May 2019 12:00:00 EDT

Last Update Posted: 05/02/19 07:49AM

Current and Emerging Biologics for the Treatment of Hemophilia

https://www.tandfonline.com/doi/abs/10.1080/14712598.2019.1614163?journalCode=iebt20

https://www.ncbi.nlm.nih.gov/pubmed/31039049?dopt=Abstract

Current and Emerging Biologics for the Treatment of Hemophilia.

Expert Opin Biol Ther. 2019 Apr 30;:

Authors: Castaman G, Linari S

Abstract

INTRODUCTION: The development of new biologic agents able to restore thrombin generation has become the focus of innovation in hemophilia management. There is growing interest in the proposal of novel, non-replacement therapy with alternative mechanisms of action and route of administration, hoping to solve still unmet needs in treatment of hemophilic patients with or without inhibitors. Areas covered: The review describes the new molecules, in particular the bi-specific antibody mimicking the coagulation function of FVIII and/or those which work by inhibiting the natural anticoagulants, their mechanism of action and the results of ongoing clinical trials. Expert opinion: Exciting results in enhancing the protection against bleeding and improving quality of life are emerging from clinical trials. However, these molecules with their mechanisms of action also open new problems. Treatment of bleeding and management of surgery in subjects with a rebalanced hemostasis may be difficult, especially for the lack of laboratory tests perfectly reflecting the in vivo coagulation status. A careful surveillance is required to evaluate the risk of thrombotic complication in patients with rebalanced hemostasis, in addition to understand whether these new products offer the same protection on joints as regular prophylaxis with the missing clotting factors.

PMID: 31039049 [PubMed – as supplied by publisher]

Study to evaluate safety, immunogenicity and hemostatic efficacy of PEGylated Recombinant Factor VIII (BAX 855) in previously untreated patients with severe hemophilia A

https://clinicaltrials.gov/ct2/show/NCT02615691?type=Intr&cond=hemophilia&lupd_s=04%2F11%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Biological: PEGylated Recombinant Factor VIII

Sponsor :   Baxalta now part of Shire

Recruiting

BAX 855 Previously Untreated Patient (PUP)

NCT02615691

Thu, 26 Nov 2015 12:00:00 EST

Last Update Posted: 04/25/19 07:35AM

Long-term Safety and Efficacy Study of SPK-9001 in Individuals With Hemophilia B

https://clinicaltrials.gov/ct2/show/NCT03307980?type=Intr&cond=hemophilia&lupd_s=04%2F10%2F2019&lupd_d=14

Condition :   Hemophilia B

Intervention :   Biological: SPK-9001

Sponsor :   Pfizer

Recruiting

Long-term Safety and Efficacy Study of SPK-9001 in Individuals With Hemophilia B

NCT03307980

Thu, 12 Oct 2017 12:00:00 EDT

Last Update Posted: 04/24/19 07:45AM

Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A

https://clinicaltrials.gov/ct2/show/NCT03818763?type=Intr&cond=hemophilia&lupd_s=04%2F09%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Biological: Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII

Sponsor :   Parameswaran Hari

Not yet recruiting

Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A

NCT03818763

Mon, 28 Jan 2019 12:00:00 EST

Last Update Posted: 04/23/19 08:32AM

Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A

https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30054-7/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31003963?dopt=Abstract

Related Articles

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 Apr 16;:

Authors: Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, Key NS, Portron A, Schmitt C, Podolak-Dawidziak M, Selak Bienz N, Hermans C, Campinha-Bacote A, Kiialainen A, Peerlinck K, Levy GG, Jiménez-Yuste V

Abstract

BACKGROUND: Emicizumab, a subcutaneously administered, humanised, bispecific, monoclonal antibody, is approved to treat people with haemophilia A of all ages with and without coagulation factor VIII (FVIII) inhibitors. HAVEN 4 assessed emicizumab prophylaxis administered as one dose every 4 weeks in adults and adolescents with haemophilia A, regardless of FVIII inhibitor status.

METHODS: In this phase 3, multicentre, open-label, two-stage study, patients aged 12 years and older with severe congenital haemophilia A (<1% of normal FVIII activity in blood) or haemophilia A with FVIII inhibitors, undergoing treatment with either FVIII concentrates or bypassing agents were recruited from three sites in Japan and Spain for a run-in cohort, and from 17 sites in Australia, Belgium, Japan, Poland, Spain, and the USA for a subsequent expansion cohort. Participants in the run-in and expansion cohorts were given emicizumab subcutaneously 6 mg/kg every 4 weeks for 24 weeks or more; for patients in the expansion cohort this regimen was preceded by four loading doses of 3 mg/kg once weekly. In the run-in cohort, we assessed pharmacokinetics after single and multiple (every 4 weeks) subcutaneous administration of 6 mg/kg emicizumab and safety. In the expansion cohort, the efficacy endpoint was efficacy of prophylactic emicizumab in maintaining adequate bleed prevention, assessed in all patients who received at least one dose of emicizumab and reported as annualised bleed rates for treated bleeds, all bleeds (treated and untreated), treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds. Safety was assessed in all participants given emicizumab. This study is registered with ClinicalTrials.gov, number NCT03020160, and is ongoing. FINDINGS: Between Jan 30, 2017, and Feb 27, 2017, seven patients were enrolled into the initial run-in cohort, which confirmed the expected pharmacokinetic profile and safety of the regimen based on model-based simulations, providing sufficient evidence for opening of the expansion cohort (n=41), which was recruited and enrolled between May 24, 2017, and June 30, 2017. The annualised rate of treated bleeds was 2·4 (95% CI 1·4-4·3). 23 (56·1%; 95% CI 39·7-71·5) of 41 reported no treated bleeds and 37 (90%; 76·9-97·3) reported zero to three treated bleeds. The annualised bleed rate was 4·5 (95% CI 3·1-6·6) for all bleeds, 0·6 (0·3-1·5), for treated spontaneous bleeds, 1·7 (0·8-3·7) for treated joint bleeds, and 1·0 (0·3-3·3) for treated target joint bleeds. The most frequent treatment-related adverse event was injection-site reaction (nine [22%] of 41 patients). We observed no thrombotic events or development of de-novo antidrug antibodies with neutralising potential or FVIII inhibitors. INTERPRETATION: Emicizumab given once every 4 weeks showed clinically meaningful bleed control while being well tolerated. This regimen could improve patient care by decreasing treatment burden and increasing adherence to effective prophylaxis, potentially decreasing the development of secondary complications for people with haemophilia A. FUNDING: F Hoffmann-La Roche and Chugai Pharmaceutical. PMID: 31003963 [PubMed - as supplied by publisher]

CRISPR/Cas9-mediated in vivo gene targeting corrects hemostasis in mice

http://www.bloodjournal.org/content/early/2019/04/10/blood.2019000790?sso-checked=true

https://www.ncbi.nlm.nih.gov/pubmed/30975639?dopt=Abstract

Related Articles

CRISPR/Cas9-mediated in vivo gene targeting corrects hemostasis in newborn and adult factor IX knockout mice.

Blood. 2019 Apr 11;:

Authors: Wang L, Yang Y, Breton CA, White J, Zhang J, Che Y, Saveliev A, McMenamin D, He Z, Latshaw C, Li M, Wilson JM

Abstract

Many genetic diseases, including hemophilia, require long-term therapeutic effects. Despite the initial success of liver-directed adeno-associated virus (AAV) gene therapy for hemophilia in clinical trials, long-term, sustained therapeutic effects have yet to be seen. One explanation of the gradual decline of efficacy over time is that the non-integrating AAV vector genome could be lost during cell division during hepatocyte turnover, albeit at a slow pace in adults. Readministering the same vector is challenging due to the AAV neutralizing antibodies elicited by the initial treatment. Here, we investigated the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated homology-directed gene targeting for sustained treatment of hemophilia B. We developed a donor vector containing a promoter-less, partial human factor IX (FIX) cDNA carrying the hyperactive FIX Padua mutation. A single injection of dual AAV vectors in newborn and adult FIX-knockout (FIX-KO) mice led to stable expression of FIX at or above the normal levels for eight months. Eight weeks after the vector treatment, we subjected a subgroup of newborn and adult treated FIX-KO mice to a two-third partial hepatectomy; all of these animals survived the procedure without any complications or interventions. FIX levels persisted at similar levels for 24 weeks after partial hepatectomy, indicating stable genomic targeting. Our results lend support for the use of a CRISPR/Cas9 approach to achieve lifelong expression of therapeutic proteins.

PMID: 30975639 [PubMed – as supplied by publisher]

Gene Therapy Study in Severe Haemophilia A Patients With Antibodies Against AAV5

https://clinicaltrials.gov/ct2/show/NCT03520712?type=Intr&cond=hemophilia&lupd_s=03%2F25%2F2019&lupd_d=14

Conditions :   Haemophilia A;   Gene Therapy;   Clotting Disorders;   Blood Disorder

Intervention :   Biological: Valoctocogene Roxaparvovec

Sponsor :   BioMarin Pharmaceutical

Enrolling by invitation

Gene Therapy Study in Severe Haemophilia A Patients With Antibodies Against AAV5

NCT03520712

Thu, 10 May 2018 12:00:00 EDT

Last Update Posted: 04/08/19 08:25AM

A Study to Evaluate Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Participants With Inhibitors Undergoing the First ITI Treatment (verITI-8 Study)

https://clinicaltrials.gov/ct2/show/NCT03093480?type=Intr&cond=hemophilia&lupd_s=03%2F20%2F2019&lupd_d=14

Condition :   Hemophilia A With Inhibitors

Intervention :   Biological: rFVIIIFc

Sponsors :   Bioverativ Therapeutics Inc.;   Swedish Orphan Biovitrum

Recruiting

A Study to Evaluate Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Participants With Inhibitors Undergoing the First ITI Treatment (verITI-8 Study)

NCT03093480

Tue, 28 Mar 2017 12:00:00 EDT

Last Update Posted: 04/03/19 07:43AM

Study to Determine the Safety and Efficacy of rFIXFc in Untreated Males With Severe Hemophilia B

https://clinicaltrials.gov/ct2/show/NCT02234310?type=Intr&cond=hemophilia&lupd_s=03%2F20%2F2019&lupd_d=14

Condition :   Hemophilia B

Intervention :   Biological: rFIXFc

Sponsors :   Bioverativ Therapeutics Inc.;   Swedish Orphan Biovitrum

Active, not recruiting

Study to Determine the Safety and Efficacy of rFIXFc in Untreated Males With Severe Hemophilia B

NCT02234310

Tue, 09 Sep 2014 12:00:00 EDT

Last Update Posted: 04/03/19 07:43AM

Evaluation of Safety Following Immune Tolerance Induction Treatment With Turoctocog Alfa in Patients With Haemophilia A Following Inhibitor Development in NN7170-4213 Trial

https://clinicaltrials.gov/ct2/show/NCT03588741?type=Intr&cond=hemophilia&lupd_s=03%2F18%2F2019&lupd_d=14

Condition :   Haemophilia A

Intervention :   Drug: Turoctocog alfa

Sponsor :   Novo Nordisk A/S

Active, not recruiting

Evaluation of Safety Following Immune Tolerance Induction Treatment With Turoctocog Alfa in Patients With Haemophilia A Following Inhibitor Development in NN7170-4213 Trial

NCT03588741

Tue, 17 Jul 2018 12:00:00 EDT

Last Update Posted: 04/01/19 08:54AM

Hemophilia in a Changing Treatment Landscape

https://www.sciencedirect.com/science/article/pii/S0889858819300231?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31030810?dopt=Abstract

Related Articles

Hemophilia in a Changing Treatment Landscape.

Hematol Oncol Clin North Am. 2019 Jun;33(3):409-423

Authors: Pelland-Marcotte MC, Carcao MD

Abstract

The mainstay of hemophilia management has been the regular, prophylactic infusion of missing coagulation factors VIII/IX. This approach is limited by the need for frequent intravenous infusions, high cost, limited availability, and the development of inhibitory antibodies to factors VIII/IX. Numerous recent breakthroughs are addressing many of these limitations. These include the development of extended half-life factors that require less frequent infusions and the development of various novel agents that can be given subcutaneously and infrequently, including FVIII-mimetic antibody and downregulators of natural anticoagulants. Finally, gene therapy is set to offer patients a possibility for a cure.

PMID: 31030810 [PubMed – in process]

Hemophilia Inhibitor Prevention and Eradication Clinical Trials (INHIBIT) Platform

https://clinicaltrials.gov/ct2/show/NCT02196207?type=Intr&cond=hemophilia&lupd_s=03%2F12%2F2019&lupd_d=14

Condition :   Severe Hemophilia A

Interventions :   Drug: rFVIIIFc;   Drug: rFVIII;   Drug: Emicizumab;   Drug: “Winner”: rFVIIIFc or rFVIII;   Drug: Eloctate and Emicizumab;   Drug: Eloctate

Sponsor :   Margaret Ragni

Not yet recruiting

Hemophilia Inhibitor Prevention and Eradication Clinical Trials (INHIBIT) Platform

NCT02196207

Mon, 21 Jul 2014 12:00:00 EDT

Last Update Posted: 03/26/19 09:35AM

Trial of AAV5-hFIX in Severe or Moderately Severe Hemophilia B

https://clinicaltrials.gov/ct2/show/NCT02396342?type=Intr&cond=hemophilia&lupd_s=03%2F12%2F2019&lupd_d=14

Condition :   Hemophilia B

Intervention :   Genetic: AAV5-hFIX

Sponsor :   UniQure Biopharma B.V.

Active, not recruiting

Trial of AAV5-hFIX in Severe or Moderately Severe Hemophilia B

NCT02396342

Tue, 24 Mar 2015 12:00:00 EDT

Last Update Posted: 03/26/19 09:35AM

Long-term Safety and Efficacy Study of Fitusiran in Patients With Hemophilia A or B, With or Without Inhibitory Antibodies to Factor VIII or IX

https://clinicaltrials.gov/ct2/show/NCT03754790?type=Intr&cond=hemophilia&lupd_s=02%2F27%2F2019&lupd_d=14

Condition :   Hemophilia

Intervention :   Drug: Fitusiran

Sponsor :   Genzyme, a Sanofi Company

Recruiting

Long-term Safety and Efficacy Study of Fitusiran in Patients With Hemophilia A or B, With or Without Inhibitory Antibodies to Factor VIII or IX

NCT03754790

Tue, 27 Nov 2018 12:00:00 EST

Last Update Posted: 03/13/19 10:19AM

A Gene Therapy (SPK-9001) Study in Subjects with Hemophilia B

https://clinicaltrials.gov/ct2/show/NCT02484092?type=Intr&cond=hemophilia&lupd_s=03%2F08%2F2019&lupd_d=14

Condition :   Hemophilia B

Intervention :   Biological: SPK-9001

Sponsor :   Pfizer

Active, not recruiting

A Gene Therapy Study for Hemophilia B

NCT02484092

Mon, 29 Jun 2015 12:00:00 EDT

A Phase 1/2, Open-Label, Non-Randomized, Dose-Escalation Study of SPK-9001 in Subjects with Hemophilia B

Last Update Posted: 03/22/19 09:19AM

A Research Study Looking at How a Factor VIII Medicine Called Turoctocog Alfa Pegol (N8-GP) Works in People With Haemophilia A

https://clinicaltrials.gov/ct2/show/NCT03528551?type=Intr&cond=hemophilia&lupd_s=03%2F08%2F2019&lupd_d=14

Conditions :   Congenital Bleeding Disorder;   Haemophilia A

Intervention :   Drug: Turoctocog alfa pegol

Sponsor :   Novo Nordisk A/S

Enrolling by invitation

A Research Study Looking at How a Factor VIII Medicine Called Turoctocog Alfa Pegol (N8-GP) Works in People With Haemophilia A

NCT03528551

Fri, 18 May 2018 12:00:00 EDT

Last Update Posted: 03/22/19 09:19AM

Safety and Efficacy of BAY94-9027 in Previously Treated Male Children With Haemophilia A

https://clinicaltrials.gov/ct2/show/NCT01775618?type=Intr&cond=hemophilia&lupd_s=03%2F04%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Biological: BAY94-9027

Sponsor :   Bayer

Active, not recruiting

Safety and Efficacy of BAY94-9027 in Previously Treated Male Children With Haemophilia A

NCT01775618

Fri, 25 Jan 2013 12:00:00 EST

Last Update Posted: 03/18/19 10:44AM

A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A

https://clinicaltrials.gov/ct2/show/NCT01580293?type=Intr&cond=hemophilia&lupd_s=03%2F01%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Biological: BAY94-9027

Sponsor :   Bayer

Active, not recruiting

A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A

NCT01580293

Thu, 19 Apr 2012 12:00:00 EDT

Last Update Posted: 03/15/19 11:40AM

HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients

https://clinicaltrials.gov/ct2/show/NCT03569891?type=Intr&cond=hemophilia&lupd_s=02%2F28%2F2019&lupd_d=14

Condition :   Hemophilia B

Intervention :   Genetic: AAV5-hFIXco-Padua

Sponsor :   UniQure Biopharma B.V.

Recruiting

HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients

NCT03569891

Tue, 26 Jun 2018 12:00:00 EDT

Last Update Posted: 03/14/19 09:49AM

FEIBA Reconstitution Volume Reduction and Faster Infusion Study (FEIBA STAR)

https://clinicaltrials.gov/ct2/show/NCT02764489?type=Intr&cond=hemophilia&lupd_s=02%2F27%2F2019&lupd_d=14

Condition :   Hemophilia A or B With Inhibitors

Intervention :   Biological: FEIBA

Sponsors :   Baxalta now part of Shire;   Baxalta Innovations GmbH, now part of Shire

Recruiting

FEIBA Reconstitution Volume Reduction and Faster Infusion Study (FEIBA STAR)

NCT02764489

Fri, 06 May 2016 12:00:00 EDT

Last Update Posted: 03/13/19 10:19AM

Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors

https://clinicaltrials.gov/ct2/show/NCT03734588?type=Intr&cond=hemophilia&lupd_s=02%2F27%2F2019&lupd_d=14

Conditions :   Adeno-Associated Virus (AAV);   Blood Coagulation Disorder;   Blood Coagulation Disorders, Inherited;   Coagulation Protein Disorders;   Factor VIII (FVIII);   Factor VIII (FVIII) Deficiency;   Factor VIII (FVIII) Gene;   Factor VIII (FVIII) Protein;   Genetic Diseases, Inborn;   Genetic Diseases, X-Linked;   Gene Therapy;   Gene Transfer;   Hematologic Diseases;   Hemorrhagic Disorders;   Recombinant;   Vector;   Inhibitors

Intervention :   Genetic: SPK-8016

Sponsor :   Spark Therapeutics

Recruiting

Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors

NCT03734588

Thu, 08 Nov 2018 12:00:00 EST

Last Update Posted: 03/13/19 10:19AM

Human-cl-rhFVIII in Previously Untreated Patients

https://clinicaltrials.gov/ct2/show/NCT01712438?type=Intr&cond=hemophilia&lupd_s=02%2F27%2F2019&lupd_d=14

Condition :   Severe Hemophilia A

Intervention :   Biological: Human cl rhFVIII

Sponsor :   Octapharma

Active, not recruiting

Human-cl-rhFVIII in Previously Untreated Patients

NCT01712438

Tue, 23 Oct 2012 12:00:00 EDT

Last Update Posted: 03/13/19 10:19AM

A Gene Transfer Study for Hemophilia A

https://clinicaltrials.gov/ct2/show/NCT03003533?type=Intr&cond=hemophilia&lupd_s=02%2F27%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Genetic: SPK-8011

Sponsor :   Spark Therapeutics

Recruiting

A Gene Transfer Study for Hemophilia A

NCT03003533

Wed, 28 Dec 2016 12:00:00 EST

Last Update Posted: 03/13/19 10:19AM

FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice

https://www.ncbi.nlm.nih.gov/pubmed/30862611?dopt=Abstract

http://www.bloodadvances.org/content/3/5/825?sso-checked=true

Related Articles

FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice.

Blood Adv. 2019 Mar 12;3(5):825-838

Authors: Merlin S, Famà R, Borroni E, Zanolini D, Bruscaggin V, Zucchelli S, Follenzi A

Abstract

Here we describe a successful gene therapy approach for hemophilia A (HA), using the natural F8 promoter (pF8) to direct gene replacement to factor VIII (FVIII)-secreting cells. The promoter sequence and the regulatory elements involved in the modulation of F8 expression are still poorly characterized and biased by the historical assumption that FVIII expression is mainly in hepatocytes. Bioinformatic analyses have highlighted an underestimated complexity in gene expression at this locus, suggesting an activation of pF8 in more cell types than those previously expected. C57Bl/6 mice injected with a lentiviral vector expressing green fluorescent protein (GFP) under the pF8 (lentiviral vector [LV].pF8.GFP) confirm the predominant GFP expression in liver sinusoidal endothelial cells, with a few positive cells detectable also in hematopoietic organs. Therapeutic gene delivery (LV.pF8.FVIII) in hemophilic C57/Bl6 and 129-Bl6 mice successfully corrected the bleeding phenotype, rescuing up to 25% FVIII activity, using a codon-optimized FVIII, with sustained activity for the duration of the experiment (1 year) without inhibitor formation. Of note, LV.pF8.FVIII delivery in FVIII-immunized HA mice resulted in the complete reversion of the inhibitor titer with the recovery of therapeutic FVIII activity. Depletion of regulatory T cells (Tregs) in LV-treated mice allowed the formation of anti-FVIII antibodies, indicating a role for Tregs in immune tolerance induction. The significant blood loss reduction observed in all LV.pF8.FVIII-treated mice 1 year after injection confirmed the achievement of a long-term phenotypic correction. Altogether, our results highlight the potency of pF8-driven transgene expression to correct the bleeding phenotype in HA, as well as potentially in other diseases in which an endothelial-specific expression is required.

PMID: 30862611 [PubMed – in process]

Multiple Escalating Dose Study of BAY1093884 in Adults With Hemophilia A or B With or Without Inhibitors

https://clinicaltrials.gov/ct2/show/NCT03597022?type=Intr&cond=hemophilia&lupd_s=02%2F26%2F2019&lupd_d=14

Condition :   Hemophilia A and B

Intervention :   Drug: BAY1093884

Sponsor :   Bayer

Recruiting

Multiple Escalating Dose Study of BAY1093884 in Adults With Hemophilia A or B With or Without Inhibitors

NCT03597022

Tue, 24 Jul 2018 12:00:00 EDT

Last Update Posted: 03/12/19 09:58AM

Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants

https://clinicaltrials.gov/ct2/show/NCT03315455?type=Intr&cond=hemophilia&lupd_s=02%2F25%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Drug: Emicizumab

Sponsor :   Hoffmann-La Roche

Active, not recruiting

Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants

NCT03315455

Fri, 20 Oct 2017 12:00:00 EDT

Last Update Posted: 03/11/19 10:08AM

A Study to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors

https://clinicaltrials.gov/ct2/show/NCT03191799?type=Intr&cond=hemophilia&lupd_s=02%2F22%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Drug: Emicizumab

Sponsor :   Hoffmann-La Roche

Active, not recruiting

A Study to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors

NCT03191799

Mon, 19 Jun 2017 12:00:00 EDT

Last Update Posted: 03/08/19 11:54AM

Critical Evaluation of Strategies for the Production of Blood Coagulation Factors in Plant-Based Systems – “Significant progress has been achieved in oral delivery of bioencapsulated FVIII and FIX to induce immune tolerance in murine models of hemophilia A and B”

https://www.frontiersin.org/articles/10.3389/fpls.2019.00261/full

https://www.ncbi.nlm.nih.gov/pubmed/30899272?dopt=Abstract

Related Articles

Critical Evaluation of Strategies for the Production of Blood Coagulation Factors in Plant-Based Systems.

Front Plant Sci. 2019;10:261

Authors: Top O, Geisen U, Decker EL, Reski R

Abstract

The use of plants as production platforms for pharmaceutical proteins has been on the rise for the past two decades. The first marketed plant-made pharmaceutical, taliglucerase alfa against Gaucher’s disease produced in carrot cells by Pfizer/Protalix Biotherapeutics, was approved by the US Food and Drug Administration (FDA) in 2012. The advantages of plant systems are low cost and highly scalable biomass production compared to the fermentation systems, safety compared with other expression systems, as plant-based systems do not produce endotoxins, and the ability to perform complex eukaryotic post-translational modifications, e.g., N-glycosylation that can be further engineered to achieve humanized N-glycan structures. Although bleeding disorders affect only a small portion of the world population, costs of clotting factor concentrates impose a high financial burden on patients and healthcare systems. The majority of patients, ∼75% in the case of hemophilia, have no access to an adequate treatment. The necessity of large-scale and less expensive production of human blood coagulation factors, particularly factors associated with rare bleeding disorders, may be an important area for plant-based systems, as coagulation factors do not fit into the industry-favored production models. In this review, we explore previous studies on recombinant production of coagulation Factor II, VIII, IX, and XIII in different plant species. Production of bioactive FII and FIX in plants was not achieved yet due to complex post-translational modifications, including vitamin K-dependent γ-carboxylation and propeptide removal. Although plant-made FVIII and FXIII showed specific activities, there are no follow-up studies like pre-clinical/clinical trials. Significant progress has been achieved in oral delivery of bioencapsulated FVIII and FIX to induce immune tolerance in murine models of hemophilia A and B, resp. Potential strategies to overcome bottlenecks in the production systems are also addressed in this review.

PMID: 30899272 [PubMed]

GC starts Phase 1 trials of MG1113, an anti-TFPI antibody treatment for hemophilia

http://www.koreabiomed.com/news/articleView.html?idxno=5237

GC starts P1 trials of hemophilia treatment

GC said Thursday that it has administered the first dose of MG1113, a hemophilia treatment, to a patient participating in phase 1 clinical trial for the drug.

The company plans to evaluate the safety of MG1113 in 49 healthy adults and hemophilia patients at two hospitals — Severance Hospital and Korea University Anam Hospital.

Compared to conventional methods of injecting insufficient blood coagulation factors, MG1113 is a therapeutic agent made of antibodies that activate coagulation factors.

 

Factor VIII Gene Therapy Study in Patients With Hemophilia A

https://clinicaltrials.gov/ct2/show/NCT03588299?type=Intr&cond=hemophilia&lupd_s=02%2F20%2F2019&lupd_d=14

Condition :   Hemophilia A

Intervention :   Drug: BAY2599023 (DTX201)

Sponsors :   Bayer;   Ultragenyx Pharmaceutical Inc

Recruiting

Factor VIII Gene Therapy Study in Patients With Hemophilia A

NCT03588299

Tue, 17 Jul 2018 12:00:00 EDT

Last Update Posted: 03/06/19 06:39PM

Reprogrammed CD4+ T Cells That Express FoxP3+ Control Inhibitory Antibody Formation in Hemophilia A Mice

https://www.frontiersin.org/articles/10.3389/fimmu.2019.00274/full

https://www.ncbi.nlm.nih.gov/pubmed/30842776?dopt=Abstract

Related Articles

Reprogrammed CD4+ T Cells That Express FoxP3+ Control Inhibitory Antibody Formation in Hemophilia A Mice.

Front Immunol. 2019;10:274

Authors: Herzog RW, Kuteyeva V, Saboungi R, Terhorst C, Biswas M

Abstract

Coagulation Factor VIII (FVIII) replacement therapy in hemophilia A patients is complicated by the development of inhibitory antibodies, which often render the treatment ineffective. Previous studies demonstrated a strong correlation between induction of regulatory T cells (Treg) and tolerance to the therapeutic protein. We, therefore, set out to evaluate whether the adoptive transfer of FVIII-specific CD4+ Treg cells prevents inhibitor response to FVIII protein therapy. To this end, we first retrovirally transduced FoxP3+ into FVIII-specific CD4+ cells, which resulted in cells that stably express FoxP3, are phenotypically similar to peripherally induced Tregs and are antigen specific suppressors, as judged by in vitro assays. Upon transfer of the FVIII-specific CD4+ FoxP3+ cells into hemophilia A mice, development of inhibitory antibodies in response to administering FVIII protein was completely suppressed. Suppression was extended for 2 months, even after transferred cells were no longer detectable in the secondary lymphoid organs of recipient animals. Upon co-transfer of FoxP3+-transduced cells with the B cell depleting anti-CD20 into mice with pre-existing inhibitory antibodies to FVIII, the escalation of inhibitory antibody titers in response to subsequent FVIII protein therapy was dramatically reduced. We conclude that reprogramed FoxP3 expressing cells are capable of inducing the in vivo conversion of endogenous FVIII peripheral Tregs, which results in sustained suppression of FVIII inhibitors caused by replacement therapy in recipient hemophilia A animals.

PMID: 30842776 [PubMed – in process]

Gene therapy for blood diseases

https://www.sciencedirect.com/science/article/abs/pii/S0958166918302088?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30599357

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data

https://www.ncbi.nlm.nih.gov/pubmed/30408848?dopt=Abstract

Related Articles

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data.

Haemophilia. 2019 Jan;25(1):60-66

Authors: Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jiménez-Yuste V, Harder Delff P, Chowdary P

Abstract

INTRODUCTION: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential.

AIM: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy.

METHODS: Free TFPI predictions were generated using an estimated concizumab-free TFPI exposure-response (Emax ) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations.

RESULTS: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re-established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab-free TFPI and concizumab-TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once-daily dosing would minimize within-patient concizumab PK variability.

CONCLUSION: Concizumab phase 2 trials will target an exposure ≥100 ng/mL, with a once-daily regimen.

PMID: 30408848 [PubMed – indexed for MEDLINE]

Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics

https://www.ncbi.nlm.nih.gov/pubmed/30887008?dopt=Abstract

Related Articles

Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics.

Hemasphere. 2018 Oct;2(5):e144

Authors: DiMichele DM

Abstract

The unprecedented emergence of novel therapeutics for both hemophilia A and B during the last half decade has been accompanied by the promise of even more extraordinary progress in ameliorative and curative strategies for both disorders. Paradoxically, the speed of innovation has created new dilemmas for persons with hemophilia and their physicians with respect to optimizing individual choices from the expanding menu of standard and novel therapies and approaches to symptom or risk reduction, and ultimately, to normalizing the hemophilia phenotype. Among the most disruptive new approaches, challenges remain in the form of the adverse reactions that have been observed with nonfactor therapies, as well as in the uncertain long-term safety profile of potentially curative gene therapy. Together, these challenges have generated uncertainty as to how to adopt novel therapies and treatment strategies across a diverse patient population, creating speed bumps on the hemophilia innovation highway. It is from this perspective that this article discusses the current state of gene therapy and bleeding prophylaxis for hemophilia A and B, as well as prevention and treatment of the factor VIII inhibitor phenotype in hemophilia A. It further posits that these speed bumps may provide important clues to the mechanistic understanding of both symptom manifestation and resilience within the hemophilia phenotype, as well as opportunities to reconsider and reconfigure the current paradigms for symptom prediction and individualized therapeutic decision making.

PMID: 30887008 [PubMed]

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