Updated Follow-up of the Alta Study, a Phase 1/2, Open Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 Gene Therapy in Adult Patients with Severe Hemophilia A

Konkle, Barbara A.; Stine, Kimo C.; Visweshwar, Nathan; Harrington, Thomas J.; Leavitt, Andrew D.; Giermasz, Adam; Arkin, Steven; Russo, G.; Snyder, Ashley; Woolfson, Adrian; Rouy, Didier

doi:10.1182/blood-2019-122143

Cited by 19 publications

(17 citation statements)

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“…Assaydiscrepancies involving higher OS than CS values have also been identified for other AAV-based gene therapies in HA when using BDD-FVIII 35 and in hemophilia B when using FIX-Padua (FIX R338L ). 36 The Padua mutation increases the specific activity of FIX, and thus kinetic issues related to an accelerated onset of the clotting reaction in the OS assay may play a role for FIX-Padua as well.…”

Section: Discussionmentioning

confidence: 99%

Activity of transgene-produced B-domain–deleted factor VIII in human plasma following AAV5 gene therapy

Rosén¹,

Tiefenbacher

Robinson

et al. 2020

Blood

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Adeno-associated virus (AAV)-based gene therapies can restore endogenous factor VIII (FVIII) expression in hemophilia A (HA). AAV vectors typically utilize a B-domain deleted FVIII transgene, such as human FVIII-SQ in valoctocogene roxaparvovec (AAV5-FVIII-SQ). Surprisingly, the activity of transgene-produced FVIII-SQ was between 1.3 and 2.0 times higher in one-stage clot (OS) than chromogenic-substrate (CS) assays, while recombinant FVIII-SQ products have lower OS than CS activity. Transgene-produced and recombinant FVIII-SQ showed comparable specific activity (IU/mg) in the CS assay, demonstrating that the diverging activities arise in the OS assay. Higher OS activity for transgene-produced FVIII-SQ was observed across various assays kits and clinical laboratories, suggesting intrinsic molecular features as a potential root cause. Further experiments in two participants showed that transgene-produced FVIII-SQ accelerated early factor Xa and thrombin formation, which may explain the higher OS activity based on a kinetic bias between OS and CS assay readout times. Despite the faster onset of coagulation, global thrombin levels were unaffected. A correlation with joint bleeds suggested that both OS and CS assay remained clinically meaningful to distinguish hemophilic from non-hemophilic FVIII activity levels. During clinical development, the CS activity was chosen as a surrogate endpoint to conservatively assess hemostatic efficacy and enable comparison with recombinant FVIII-SQ products. Relevant trials are registered on Clinicaltrials.gov (NCT02576795 and NCT03370913).

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Section: Discussionmentioning

confidence: 99%

Activity of transgene-produced B-domain–deleted factor VIII in human plasma following AAV5 gene therapy

Rosén¹,

Tiefenbacher

Robinson

et al. 2020

Blood

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“…Sangamo Therapeutics (SB-525) announced results of their ongoing phase 1/2 trial in 8 patients with severe hemophilia A treated in 4 dose cohorts (9e11, 2e12, 1e13, and 3e13 vg/kg; n 5 2 per cohort. 36 At 6 weeks postinfusion, the 2 patients at the highest tested dose (3e13 vg/kg) reached between 94% and 140% of normal levels. One of the 2 patients treated at the 3e13-vg/kg dose level had ALT elevation requiring a tapering course of oral corticosteroids.…”

Section: Aav Vectors and Gene Therapy For Hemophilia Amentioning

confidence: 91%

Gene therapy for hemophilia

Nathwani

2019

Hematology

105

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Gene therapy offers the potential for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX (FIX) following transfer of a functional gene to replace the hemophilic patient’s own defective gene. The hemophilias are ideally suited for gene therapy because a small increment in blood factor levels (≥5% of normal) is associated with significant amelioration of bleeding phenotype in severely affected patients. In 2011, the St. Jude/UCL phase 1/2 trial was the first to provide clear evidence of a stable dose-dependent increase in FIX levels in patients with severe hemophilia B following a single administration of adeno-associated viral (AAV) vectors. Transgenic FIX expression has remained stable at ∼5% of normal in the high-dose cohort over a 7-year follow-up period, resulting in a substantial reduction in spontaneous bleeding and FIX protein usage without toxicity. This study has been followed by unparalleled advances in gene therapy for hemophilia A and B, leading to clotting factor activity approaching normal or near-normal levels associated with a “zero bleed rates” in previously severely affected patients following a single administration of AAV vectors. Thus, AAV gene therapies are likely to alter the treatment paradigm for hemophilia A and B. This review explores recent progress and the remaining limitations that need to be overcome for wider availability of this novel treatment of inherited bleeding disorders.

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“…No alanine aminotransferase elevation was observed in the three cohort of patients treated with low or intermediate dose of vector. While in the high dose cohort, three patients experienced a transient liver enzymes elevation managed a course of steroid, but none were associated with a loss of FVIII activity (55). Preliminary data has been reported from the phase 1/2 clinical trials in haemophilia A, in which one patient with severe haemophilia A received a dose of 6x10 11 and the subsequent two patients received a dose of 2x10 12 vg/kg of AAV8-HLP-hFVIII-V3 vector (University College London).…”

Section: Haemophilia a Clinical Trailsmentioning

confidence: 97%

State of the art on clinical trials of gene therapy in haemophilia

Garagiola¹,

Peyvandi²

2020

Pharm Adv

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Haemophilia A and B are rare inherited bleeding disorders, caused by deficiency or dysfunction .of the coagulation factors(F) VIII (haemophilia A) or IX (haemophilia B) which have an essential role in the coagulation cascade. These dysfunctions cause a defect in clot formation and consequent bleeding diathesis. The main therapeutic strategy is the venous infusion of either plasma-derived or recombinant products. Treatment is given in response to an acute bleeding episode (on-demand) or as prophylaxis by infusion 2-3 times per week to prevent haemorrhages. Nowadays, the introduction of new extended half-life products has transformed the concept of haemophilia replacement therapy by reducing the frequency of injections, achieving a higher trough level and improving patients' quality of life. Furthermore, a substantial change has happened with the availability of the bispecific antibody. Haemophilia A patients with and without inhibitors can be subcutaneously treated reducing significantly the interval between injections once a week or every two weeks. In the last few years, clinical trials in both haemophilia A and B hve shown efficacy and durability of transgene expression. Phase 1/2 studies have shown that a single intravenous infusion allows to reach a normal level in patients with haemophilia A and B. Long-term follow-up for gene therapy in haemophilia B showed that the infusion of a single dose of vector resulted in a therapeutic FIX activity level after 10 years. These levels of FVIII and FIX expression allow to patients to leave the prophylactic regimen and to reduce the bleeding events to zero. This article mentions the state of the art of gene therapy studies for haemophilia A and B, including data on efficacy and any side effects observed until now.

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Updated Follow-up of the Alta Study, a Phase 1/2, Open Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 Gene Therapy in Adult Patients with Severe Hemophilia A

Cited by 19 publications

References 0 publications

Activity of transgene-produced B-domain–deleted factor VIII in human plasma following AAV5 gene therapy

Activity of transgene-produced B-domain–deleted factor VIII in human plasma following AAV5 gene therapy

Gene therapy for hemophilia

State of the art on clinical trials of gene therapy in haemophilia

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