scholarly journals Etranacogene dezaparvovec for hemophilia B gene therapy

2021 ◽  
Vol 2 ◽  
pp. 263300402110588
Author(s):  
Courtney D. Thornburg
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Continuous Production ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Plain Language ◽  
Long Term Follow Up

The treatment landscape for hemophilia has been rapidly changing with introduction of novel therapies. Gene therapy for hemophilia is a promising therapeutic option for sustained endogenous factor production to mitigate the need for prophylactic treatment to prevent spontaneous and traumatic bleeding. Etranacogene dezaparvovec is an investigational factor IX (FIX) gene transfer product that utilizes the adeno-associated virus (AAV) 5 vector with a liver-specific promoter and a hyperactive FIX transgene. Here, the development of etranacogene dezaparvovec and available efficacy and safety data from clinical trials are reviewed. Overall, etranacogene dezaparvovec provides sustained FIX expression for more than 2 years and allows for a bleed and infusion-free life in the majority of patients. Safety, efficacy, and quality-of-life data will inform shared decision-making for patients who are considering gene therapy. Long-term follow-up regarding duration of expression and safety are crucial. Plain Language Summary Factor IX Padua gene therapy to boost clotting factor and prevent bleeding for people living with hemophilia B People living with hemophilia have low or missing clotting factor, which can lead to bleeding that is unexpected or caused by a traumatic event (such as a sports injury or surgery). There are two main types of hemophilia: clotting factor (F)VIII deficiency (known as hemophilia A) and FIX deficiency (known as hemophilia B). People living with the severe or moderately severe forms of hemophilia (clotting factor levels below 3% of normal) need regular treatment, typically by infusions into the vein, to stop or prevent bleeding and damage to their joints. Gene therapy is currently being investigated as a new treatment option that introduces a working copy of the clotting factor gene to the liver. Following treatment, clotting factor is produced by the liver. Etranacogene dezaparvovec [Et-ra-na-co-gene dez-a-par-vo-vec] is a form of gene therapy for people living with hemophilia B. This form of gene therapy includes a modified form of FIX (FIX Padua) which produces high levels of FIX activity compared with normal FIX. It is being tested to see whether individuals will have low rates of bleeding and not need to treat themselves with clotting factor. In the clinical trials, participants with FIX levels below 2% (of normal) receive a single gene therapy infusion. The results of the trials have so far shown that patients given etranacogene dezaparvovec have continuous production of FIX, whereby they have reported much less bleeding and factor treatment. Questions relating to the safety of the gene therapy and how long it works will hopefully be answered through long-term follow-up of the patients once the trials are completed.

scholarly journals Factor IX Expression within the Normal Range Prevents Spontaneous Bleeds Requiring Treatment Following FLT180a Gene Therapy in Patients with Severe Hemophilia B: Long-Term Follow-up Study of the B-Amaze Program

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3967-3967
Author(s):  
Pratima Chowdary ◽  
Susan Shapiro ◽  
Mike Makris ◽  
Gillian Evans ◽  
Sara Boyce ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Research Funding ◽  
Transgene Expression ◽  
Factor Ix ◽  
Hemophilia B ◽  
Normal Range ◽  
Follow Up Study ◽  
Long Term Follow Up

Abstract Introduction: FLT180a (verbrinacogene setparvovec) is an investigational, liver-directed AAV gene therapy for the treatment of patients with hemophilia B (HB). FLT180a consists of a novel, potent, engineered capsid (AAVS3) containing an expression cassette encoding a Factor IX (FIX) gain-of-function protein variant ('Padua'; FIX-R338L). The B-AMAZE study was designed to identify a dose of FLT180a that maintains FIX activity within the normal range (50-150%) and thereby protect patients with severe HB from spontaneous and traumatic bleeds. Methods: B-AMAZE was a multicentre, open-label Phase 1/2 clinical trial (NCT03369444; sponsored by UCL) that evaluated FLT180a dose levels using an escalating/descending adaptive design in patients with severe (FIX activity <1%) or moderately severe (FIX activity 1-2%) HB who were negative for AAVS3 neutralizing antibodies. A novel regimen of prophylactic corticosteroids with/without tacrolimus was implemented to mitigate the impact of vector-related transaminitis on FIX expression. Patients who completed the 26-week B-AMAZE study were eligible for the ongoing long-term follow-up study (NCT03641703; sponsored by Freeline). Results: Ten HB patients received a single dose of FLT180a. Four FLT180a doses ranging from 3.84e11 vg/kg to 1.28e12 vg/kg were assessed. As of the data cut-off date, all patients have been followed for ≥16 months. FLT180a demonstrated a favorable safety profile, without evidence of inhibitors against FIX, infusion-related or allergic reactions. The most common treatment-related adverse event was transient elevation in alanine aminotransferase. An event of AV fistula thrombosis occurred in a 67-year-old patient who received the highest dose of 1.28e12 vg/kg (total dose of 1.15e14 vg) and had supranormal FIX levels; this patient was treated with anticoagulants. While these FIX levels demonstrate the potency of our proprietary AAVS3 capsid, this dose will not be used in future hemophilia studies. At Week 26 after FLT180a administration, a dose-response relationship was observed with mean FIX activity of 45.0%, 35.5%, 141.5%, and 175.5% for 3.84e11, 6.4e11, 8.32e11, and 1.28e12 vg/kg doses, respectively (Table); FIX activity levels ≥50% were achieved in 7 of 8 patients treated with the three highest doses. One patient (Patient 4) who received 6.4e11 vg/kg lost transgene expression early due to transaminitis and resumed routine factor prophylaxis. The 8.32e11 vg/kg cohort received an extended immune management regimen (9-18 weeks) with prophylactic tacrolimus in addition to prednisolone to prevent breakthrough vector-related transaminitis. However, after cessation of the immune management regimen, transaminitis with concomitant reductions in FIX activity was observed in all patients in the 8.32e11 vg/kg cohort. The combination of prophylactic tacrolimus and prednisolone appeared to have suppressed immune-mediated transaminitis while administered, but recurrence of transaminitis developed soon after cessation. This unique and previously unreported observation suggests that the longer-duration prophylactic immune management regimen may have prevented tolerization to the vector because this was not observed in earlier cohorts where a brief course of tacrolimus was given reactively for breakthrough transaminitis. All patients (including the 8.32e11 vg/kg cohort) have achieved steady state. Patients in the earliest cohort who received the lowest dose (3.84e11 vg/kg) have shown stable FIX activity for >3 years. There were no spontaneous bleeds that required FIX supplementation in patients who maintained FIX activity above 50%; Patient 4 in the 6.4e11 vg/kg cohort experienced two bleeds (cause unknown) after he lost transgene expression, which were treated with exogenous FIX. One patient received exogenous FIX for treatment of a traumatic bleed, but his FIX activity level was 57% at the time of the event. Additional efficacy and safety results with >3.5 years of follow-up will be presented. Conclusions: B-AMAZE is the first HB gene therapy study to achieve normal levels of FIX activity using relatively low vector doses. Results suggest that a dose of 7.7e11 vg/kg, coupled with a short course of prophylactic immune management, has the potential to achieve durable FIX activity in the normal range (50-150%) and thereby prevent spontaneous bleeds and normalize hemostasis in the event of traumatic bleeds. Figure 1 Figure 1. Disclosures Chowdary: Sanofi: Honoraria; Roche: Honoraria; CSL Behring: Honoraria, Research Funding; Freeline: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; SOBI: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Chugai: Honoraria; Spark: Honoraria; Bayer: Honoraria, Research Funding. Shapiro: Roche: Honoraria; CSL Bering: Honoraria; Takeda: Honoraria, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Makris: Freeline: Consultancy. Dolan: Takeda: Speakers Bureau; Roche-Chugai: Speakers Bureau; Spark Therapeutics: Speakers Bureau; Octapharma: Speakers Bureau; CSL: Speakers Bureau; Biomarin: Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Pfizer: Research Funding. Tuddenham: Freeline: Consultancy, Current holder of individual stocks in a privately-held company. Long: Freeline: Current Employment. Krop: Freeline: Current Employment. Nathwani: Freeline: Current holder of individual stocks in a privately-held company, Other: Board of directors.

scholarly journals A Hemophilia Disorder Review: Gene Therapy for Hemophilia B Treatment using rAAV vectors

Bionatura ◽  
2019 ◽  
Vol 02 (Bionatura Conference Serie) ◽  
Author(s):  
Abad Gallardo Claudia Sofía ◽  
Merchán Muñoz Brian David
Keyword(s):  
Gene Therapy ◽  
Blood Clotting ◽  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Adeno Associated Virus ◽  
Long Term Effect ◽  
Blood Clotting Factor

Hemophilia is an X-linked recessive disorder characterized by the deficiency in one protein essential for blood coagulation. There are two main types of variants of this disease; hemophilia A (HA) which is related with blood clotting factor VIII (FVIII) deficiency and hemophilia B (HB) which is related with factor IX (FIX) deficiency. Nowadays, there are several options to treat this disorder, however, the most efficient is gene therapy since it has a long-term effect, and contrasts with traditional methods. This review is focused on hemophilia B treatment because FIX is a smaller protein than FVIII (<1kb), and thereby is easier to study. Within gene therapy, methods which use recombinant adeno-associated virus (rAAV) vectors are the best alternative to treat HB since they are safe and reliable. Moreover, rAAV vectors have the advantage of having a low inflammatory potential, a non-pathogenic status, plus the potential for long-term expression of the transferred gene. However, some patients showed an immune response to the capsids of the vectors before treatment. Hence, possible solutions were needed; one of them being the use of anti-antibodies. Finally, clinical trials results showed that under the use of the optimized codon hFIXco and serotype 8 the levels of expression were persistent, demonstrating the potential of gene therapy for hemophilia B treatment.

scholarly journals Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis

2021 ◽  
pp. 135245852110002
Author(s):  
Bruce AC Cree ◽  
Jeffrey A Cohen ◽  
Anthony T Reder ◽  
Davorka Tomic ◽  
Diego Silva ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Therapeutic Benefit ◽  
Disease Modifying Therapies ◽  
Long Term Follow Up ◽  
Post Hoc ◽  
Switch Group ◽  
Relevant Outcome

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years’ follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

scholarly journals Survival Differences in Clinical Trials With Long-Term Follow-Up

2016 ◽  
Vol 67 (5) ◽  
pp. 600
Author(s):  
William J. Kostis ◽  
Abel E. Moreyra ◽  
Javier Cabrera ◽  
John B. Kostis
Keyword(s):  
Clinical Trials ◽  
Long Term Follow Up ◽  
Survival Differences

Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2670-2676 ◽  
Author(s):  
Jane D. Mount ◽  
Roland W. Herzog ◽  
D. Michael Tillson ◽  
Susan A. Goodman ◽  
Nancy Robinson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Large Animal Model ◽  
Null Mutation ◽  
Large Animal ◽  
Adeno Associated Virus ◽  
Increased Risk

Abstract Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (FIX). Using adeno-associated virus (AAV)–mediated, liver-directed gene therapy, we achieved long-term (&gt; 17 months) substantial correction of canine hemophilia B in 3 of 4 animals, including 2 dogs with an FIX null mutation. This was accomplished with a comparatively low dose of 1 × 1012 vector genomes/kg. Canine FIX (cFIX) levels rose to 5% to 12% of normal, high enough to result in nearly complete phenotypic correction of the disease. Activated clotting times and whole blood clotting times were normalized, activated partial thromboplastin times were substantially reduced, and anti-cFIX was not detected. The fourth animal, also a null mutation dog, showed transient expression (4 weeks), but subsequently developed neutralizing anti-cFIX (inhibitor). Previous work in the canine null mutation model has invariably resulted in inhibitor formation following treatment by either gene or protein replacement therapies. This study demonstrates that hepatic AAV gene transfer can result in sustained therapeutic expression in a large animal model characterized by increased risk of a neutralizing anti-FIX response.

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