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International Society on Thrombosis and Haemostasis (ISTH)

The gene therapy FLT180a (Freeline Therapeutics) restored factor IX (FIX) production in patients with hemophilia B, according to new data from the phase 1/2 B-LIEVE trial (NCT05164471).

These data were presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress, July 9-13, in London, UK, by 

director, Hemostasis and Thrombosis Program, Children’s Hospital of Los Angeles and professor of Pediatrics, Keck School of Medicine, University of Southern California.

“The initial data show that FLT180a provides rapid and consistent elevations in FIX to normal levels, which can prevent bleeding and the need for regular FIX replacement in people with hemophilia B,” Pamela Foulds, MD, chief medical officer, Freeline, said in a statement.

“Emerging data suggest that while FIX expression was maintained at protective levels, a further refined immune management regimen may be required to avoid mild and transient transaminitis and to sustain FIX levels in the normal range. Potential adjustments in cohort two and forthcoming results from that cohort will help us interpret this further.”

Data from the 3 patients in cohort 1 treated with FLT180a were presented demonstrating a rapid increase of FIX to normal levels of 93, 92 and 80 IU/dL through days 77, 56 and 36, respectively, as of the data cut-off of May 23, 2022. 

Patients were all treated with 7.7e11 vg/kg and all stopped and did not have to resume FIX prophylaxis after treatment.

Reducing Treatment Burden in Hemophilia: Guy Young, MD

Overall, the adeno-associated virus vector S3 gene therapy and the prophylactic immune management regimen were well-tolerated. No serious adverse events (AEs) were observed, with most being mild and transient. These AEs were related to immune management and were consistent with the known profiles of corticosteroids and tacrolimus. No infusion reactions were observed, and there has been no evidence of FIX inhibitors.

Two patients have experienced a decrease in FIX expression along with a mild, transient increase in liver enzymes, although all patients’ levels have remained elevated above baseline and no patients have experienced bleeds or needed FIX therapy. Cohort 2 recently 

 in June 2022 and data so far seem similar to that of cohort 1. These patients received the same dose of FLT180a and prophylactic immune management regimen that were used in the first cohort based off data from the cohort and advice from the independent Data Monitoring Committee and Freeline hopes to confirm the dose for phase 3 trials.

“Our strategy is to advance gene therapy programs that have the potential to deliver best-in-class or first-in-class treatments,” Michael Parini, chief executive officer, Freeline added to the statement.

“While we continue to believe FLT180a has the potential to deliver a best-in-class gene therapy for people with hemophilia B, the availability of other treatment options and the need to prioritize our valuable resources dictate that we evaluate strategic options for FLT180a. These include, but are not limited to, seeking a partner that would enable the continuation of FLT180a through Phase 3 development.”


1. Young G, Chowdary P, Barton S, Yee D, Flight P, Ferrante F. Results from B-LIEVE, a Phase 1/2 Dose-Confirmation Study of FLT180a AAV Gene Therapy in Patients with Hemophilia B. Presented at: 2022 ISTH Congress, July 9-13, London, UK.
2. Positive initial clinical data from the B-LIEVE dose-confirmation trial for FLT180a in hemophilia B presented at the International Society on Thrombosis and Haemostasis Congress. July 10, 2022. https://www.globenewswire.com/news-release/2022/07/10/2476891/0/en/Positive-Initial-Clinical-Data-from-the-B-LIEVE-Dose-Confirmation-Trial-for-FLT180a-in-Hemophilia-B-Presented-at-the-International-Society-on-Thrombosis-and-Haemostasis-Congress.html

A second cohort has been dosed with 7.7e11 vg/kg to hopefully confirm the dose for phase 3 trials. 

Freeline Moves Closer to Identifying Hemophilia B Gene Therapy Dose 

 view dose frequency, durability, and effect on annual bleeding rate (ABR) as the most important factors when considering gene therapies and generally have a positive view of their experiences with gene therapies, according to findings presented at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Congress.

These insights into the real-world impact of gene therapies on people with hemophilia were presented in 2 abstracts at ISTH 2021 by Michelle Witkop, DNP, FNP-BC, chair, National Hemophilia Foundation Nursing Work Group,

 and Simon Fletcher, lead research nurse and PhD candidate, Oxford Haemophilia Centre.

“Gene therapy for haemophilia has the potential to change the life experience of individuals and their families. Few studies have sought to explore the impact of gene therapy on individuals and their families,” Fletcher and colleagues wrote.

In that study, Fletcher and colleagues uncovered 5 main themes of how gene therapies impacted the participants (N = 9, mean age, 43.1 years) who participated in semi-structured qualitative interviews along with 1 family member. Among the participants, 8 of whom had hemophilia A and 1 with hemophilia B, some experiences were positive, such as freedom and altruism, but others were negative, such as the adverse events of immunosuppression (which many participants reported being unprepared for), loss of factor expression, and loss of control.

Hemophilia Gene Therapy Registry Launched to Monitor Long-Term Outcomes

Altogether, most participants, of which mean time since gene therapy transfection was 1.89 years (range, 1-5), saw their participation in gene therapies positively but results from the study suggest more work needs to be done. Ongoing interviews hope to add to these data.

"[Gene therapy] freed [participants] from the personal burden of haemophilia and furthered treatment options for the wider haemophilia community... [but] psychosocial support needs to be integrated into gene therapy programmes to help participants and families process their experiences both positive and negative,” Fletcher and colleagues wrote.

In another abstract, Witkop and colleagues sought to assess preferences in selecting gene therapies among people with hemophilia in a discrete choice experiment (DCE). They conducted an online study of participants with severe or moderate hemophilia recruited from the National Hemophilia Foundation Community Voices in Research platform and other online patient panels that consisted of 14 choices between hypothetical pairs of treatment scenarios with varying attribute levels. These 6 attributes were developed based on literature review.

Altogether, the DCE had 183 participants with a mean age of 39.3 years (standard deviation [SD], 13.8), 120 with hemophilia A (HA) and 63 with hemophilia B (HB). Using random parameters logit models to estimate relative attribute importance (RAI), the investigators found that dose frequency and durability (RAI: HA, 23%; HB, 35%) and effect on overall ABR (RAI: HA, 32%; HB, 29%) were the most important attributes. These attributes were followed by uncertainty regarding short-term or long-term significant safety issues (RAI both 17%) and together, the 3 attributes made up 70% to 80% of the overall RAI.

Impact on activity of daily life/physical activity, transformative/mental health impact, and post treatment, possibility to undergo minor surgery without need for factor therapy made up the remaining 20-30% of RAI.

“Evidence of patient preferences for novel hemophilia treatment such as gene therapies is limited. Understanding which treatment attributes are important for people with hemophilia A and B will help to inform the value of gene therapy,” Witkop and colleagues wrote.

1. Fletcher S, Chaplin S, Holland M, Jenner K, Khair K. Exigency: The real-world impact of gene therapy on the lives of people with haemophilia and their families. An interim report. Presented at: ISTH 2021 Congress; July 17-21, 2021. Abstract PB0660
2. Witkop M, Morgan G, O’Hara J, et al. Preferences of people with hemophilia A and B for treatments including gene therapies in the US: A discrete choice experiment. Presented at: ISTH 2021 Congress; July 17-21, 2021. Abstract PB0658

Presentations at ISTH 2021 revealed attributes most important to patients when considering gene therapies and where further research is needed. 

Gene Therapies for Hemophilia Have Positive Real-World Impact, Studies Show 

The World Federation of Hemophilia (WFH) is developing a Gene Therapy Registry (GTR) to collect long-term data on safety and efficacy in people with 

 to learn more about durability and variability of therapies.

The registry was introduced at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Congress by Donna Coffin, MSc, director of research & public policy, World Federation of Hemophilia.

“Gene therapy for hemophilia is an evolving therapeutic modality, with many challenges and unresolved questions that will not be fully answered at the completion of current ongoing clinical trial programs,” Coffin and colleagues wrote.

The prospective, observational, and longitudinal registry will be overseen by a steering committee made up of health care professionals and patients advocates as well as representatives from regulatory agencies and pharmaceutical industry. The WFH hopes to eventually enroll all eligible people with hemophilia in the registry.

Hemophilia B Gene Therapy AMT-060 Shows Durable Effect

"The WFH GTR will ensure that rare adverse events, in a small patient population over a large geographical area, will be detected. The many unknowns of gene therapy for hemophilia make it critical that the bleeding disorders community ensures all patients are followed over their lifetimes,” Coffin and colleagues said.

The registry steering committee developed a standardized set of core data to collect from patients through an iterative process under the guidance of the European Medicines Agency and FDA. These data will be collected every 3 months for up to 24 months after gene therapy infusion and annually after that point. Participating hemophilia treatment centers will collect the data, which will be combined with data from existing hemophilia registries. Outreach to these centers began in Fall 2020. Additionally, in the US, data will be collected from the American Thrombosis and Hemostasis Network. In terms of data security, a scientific advisory board of patient and physician advocates is developing policies regarding data usage. 

“Our current knowledge leaves many unanswered questions about the safety and long-term efficacy of gene therapy. These gaps in evidence dictate that we must all contribute to strengthening the evidence base. This data collection/surveillance effort should be a shared responsibility. Health care providers and patients will need to work together to collect standardized data on patients who receive gene therapy, ensuring that their experiences are captured in a registry, over their entire lifetime,” Coffin and colleagues wrote in an editorial published in 

Coffin and colleagues outlined unmet needs, pointing to small patient populations and too short follow-up as pressing current issues that exist within clinical trials investigating gene therapies. Additionally, the use of a global registry overcomes the issue of limited data in rare diseases.

“Integrating the collection of data into the clinical practice of physicians and the daily lives of patients requires a harmonious and uniform data collection methodology that will be accepted and used by all stakeholders. Only through cohesive efforts by all treating physicians, patients, regulatory agencies and manufacturers worldwide, will we be successful in ensuring gene therapy is safe and efficacious for our patients today, and in the future,” Coffin and colleagues wrote.

1. Konkle BA, Coffin D, Naccache M, et al. The world federation of hemophilia gene therapy registry. Presented at: ISTH 2021 Congress; July 17-21, 2021. Abstract PB0661.
2. Konkle BA, Coffin D, Pierce GF, et al. World federation of hemophilia gene therapy registry. 

The World Federation of Hemophilia’s registry will include long-term safety and efficacy data in people with hemophilia treated with gene therapies. 

Fidanacogene elaparvovec is well tolerated in patients with 

, with mild long-term effects on liver health, according to data from a recent study.

These data, from a phase 1/2a study (NCT03861273) and a subsequent long-term follow-up (LTFU) study, were presented at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Congress by Lindsey A. George, MD, attending physician, Division of Hematology, Children's Hospital of Philadelphia. The study aimed to evaluate liver health following treatment with fidanacogene elaparvovec, which utilizes a hepatotropic Adeno-associated virus (AAV) vector.

"AAV–based gene therapy for the treatment of hemophilia has generally targeted hepatocytes. As such, liver health is an important aspect of screening assessments for these studies. The hemophilia population has a high percentage of patients with prior hepatitis C (HCV) and/or B (HBV) virus infections, which places additional importance on better understanding the role of AAV gene therapy on long-term liver health,” George and colleagues wrote.

The study enrolled 15 adult male patients with moderate to severe hemophilia B that were administered fidanacogene elaparvovec and 14 into the LTFU. One participant withdrew from the LTFU 3 years post-infusion. Of the participants in the LTFU, 10 had prior resolved HCV and 7 had prior HBV. Patients were followed for between 32 and 60 months.

Valoctocogene Roxaparvovec’s Treatment Durability in Hemophilia A in Question

Common safety findings included mild sustained elevations of alanine aminotransferase of uncertain etiology. Annual liver ultrasounds were conducted; these revealed fatty liver in 1 participant. No significant elevations in plasma alfa-fetoprotein were observed. Factor IX (FIX) activity has remained relatively stable in all participants.

“With up to 5 years of follow up, fidanacogene elaparvovec continues to be generally well tolerated. Long-term impacts to overall liver health currently appear to be mild in patients with moderately severe/severe hemophilia B. Longer term monitoring is ongoing to consolidate this initial result,” George and colleagues concluded.

Findings from other gene therapies for hemophilia B were also presented at ISTH. These included efficacy findings of AMT-060, which was seen to produce 

 and sustained reductions in bleeding over 5 years of follow-up.

 gc/kg dose of AMT-060 had a mean FIX activity of 5.2% through 5 years compared with patients who received a 2 x 10

 gc/kg dose and had a mean FIX activity of 7.2% through 5 years. Additionally, during the last 12 and 6 months of observation, lower-dose participants had a mean annualized bleeding rate (ABR) of 6.5 and higher-dose patients had a mean ABR of 0.0, representing a 55% and 100% reduction in ABR compared with the year before treatment, respectively.

AMT-060 was also found to be well-tolerated. No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. Treatment-related AEs mostly occurred in the first 3.5 months after treatment. These included 3 cases of transient mild alanine aminotransferase. Final 5-year data will be presented at a later date. Study participants will also be able to enroll in a LTFU study over an additional 5 years.

1. George LA, Sullivan SK, Rasko JE, et al. Evaluation of liver health after fidanacogene elaparvovec gene therapy: Data from study participants with up to 5 years of follow-up. Presented at ISTH 2021 Congress; July 17-21. Abstract PB0532.
2. Miesbach W, Meijer K, Coppens M, et al. Five year data confirms stable FIX expression and sustained reductions in bleeding and factor IX use following AMT-060 gene therapy in adults with severe or moderate-severe Hemophilia B. Presented at ISTH 2021 Congress; July 17-21. Abstract OC 26.3

No concerning effects to liver health were observed in the phase 1/2a study. 

Fidanacogene Elaparvovec Well-Tolerated in Hemophilia B 

AMT-060 was shown to produce stable Factor IX (FIX) expression and sustained reductions in bleeding in

in 5-year data presented at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Congress.

Patients in cohort 1 that received a 5 x 1012 gc/kg dose of AMT-060 had a mean FIX activity of 5.2% through 5 years compared with patients in cohort 2, who received a 2 x 1013 gc/kg dose and had a mean FIX activity of 7.2% through 5 years. Additionally, during the last 12 and 6 months of observation, cohort 1 had a mean annualized bleeding rate (ABR) of 6.5 and cohort 2 had a mean ABR of 0.0, representing a 55% and 100% reduction in ABR compared with the year before treatment, respectively. 

“Gene therapy in hemophilia aims to provide long-term therapeutic benefit from a single administration,” Investigator Wolfgang Miesbach, MD, University Hospital Frankfurt, and colleagues wrote. “Sustained endogenous FIX activity and reductions in ABR and use of FIX replacement were maintained through 5 years following a single administration of AMT-060, with no additional safety concerns.”

Miesbach and colleagues worked to evaluate the safety and efficacy of AMT-060, an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human FIX gene and liver-specific promoter. The phase 1/2 study (NCT02396342) enrolled 10 male participants with moderate to severe hemophilia B, FIX activity of at most 2%, and a severe bleeding phenotype. These participants received a single intravenous infusion of AMT-060 at the 2 doses with 5 participants in each cohort.

Investigators assessed FIX activity, ABR, FIX replacement use, and treatment-related adverse events (AEs). Cohort 1 had mean FIX activity rates of 4.4%, 6.8%, 7.3%, 7.0%, and 5.2% at years 1 to 5, respectively. Cohort 2 had mean FIX activity rates of 7.1%, 8.4%, 7.9%, 7.4%, and 7.2% at years 1 to 5, respectively. FIX replacement therapy consumption declined by 84% in cohort 1 and 99% in cohort 2 by 5 years. No participants who discontinued prophylaxis resumed its use. 

No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. Treatment-related AEs mostly occurred in the first 3.5 months after treatment. These included 3 cases of transient mild alanine aminotransferase. UniQure will present final 5-year data at a later date. Study participants will also be able to enroll in a long-term follow-up study over an additional 5 years. 

The phase III HOPE-B trial (NCT03569891) of the enhanced construct of AMT-060 with the Padua variant of the FIX gene, etranacogene dezaparvovec (AMT-061) is ongoing. UniQure recently announced data from the trial that showed that participants treated with AMT-061 

FIX activity increased from 39.0% of normal mean FIX activity at 26-weeks of follow-up to 41.5% of normal mean FIX activity at 52 weeks. A single dose of the treatment was prospectively found to significantly reduce ABR requiring treatment by 80%, from 3.39 per year at baseline to 0.68 per year at 52 weeks (

 <.0001). The annualized rate of spontaneous bleeding requiring treatment was also significantly reduced by 85% from 1.16 bleeds per year at baseline to 0.18 bleeds per year at 52 weeks (

FIX replacement therapy use was reduced by 96% in all patients during the interventional period, and 52 patients (96%) discontinued the therapy entirely. Of the 2 non-responders, 1 received a partial dose due to an infusion reaction and the second had an unusually high pre-existing NAb titer of 3212.

“The 52-week data show mean FIX activity in the normal range and increase our confidence in the potential durability and long-term benefits of etranacogene dezaparvovec, bringing us one step closer to our goal of delivering this groundbreaking therapy to fulfill an unmet medical need for patients living with hemophilia B,” Ricardo Dolmetch, PhD, president, research and development, uniQure, said in a statement.

1. Five year data confirms stable FIX expression and sustained reductions in bleeding and factor IX use following AMT-060 gene therapy in adults with severe or moderate-severe Hemophilia B. Presented at ISTH 2021 Congress; July 17-21. Abstract OC 26.3
2. uniQure announces positive 52-week clinical data from HOPE-B pivotal trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B and provides regulatory update. News release. UniQure. June 22, 2021. https://www.globenewswire.com/news-release/2021/06/22/2251227/0/en/uniQure-Announces-Positive-52-Week-Clinical-Data-from-HOPE-B-Pivotal-Trial-of-Etranacogene-Dezaparvovec-Gene-Therapy-in-Patients-with-Hemophilia-B-and-Provides-Regulatory-Update.html

Phase 3 studies are continuing in the enhanced Padua FIX variant AMT-061 for hemophilia B. 

Long term data from a phase 1/2 study (NCT04684940) of valoctocogene roxaparvovec (valrox) for the treatment of 

 demonstrated that although the treatment is efficacious up to 5 years post-treatment, Factor VIII expression did fall over the long-term, raising concerns over the one-time infusion’s treatment durability.

Investigators found that the 6 x 1013 vg/kg dose cohort (n = 7) experienced a 95% reduction in mean ABR from baseline to 5 years and a 96% reduction in mean annualized Factor VIII utilization from baseline to 5 years post-treatment. However, Factor VIII activity levels fell from treatment to 5-year follow-up as measured by both chromogenic substrate assay (CSA) and one-stage assay (OSA).

"The consistent and impressive bleed control in the majority of the study participants out to 5 years in this study, which is the longest duration of clinical experience for any gene therapy in hemophilia A, increases our understanding of the interplay between Factor VIII expression, ABR, and Factor VIII infusion rate as it relates to hemostatic efficacy," said principal investigator Michael Laffan, BMBCh, DM, FRCP, FRCPath, professor, Department of Immunology and Inflammation, Imperial College London, and Director, Hammersmith Hospital Haemophilia Centre, in a statement. "These data show that most of the study participants have not had a bleed or had to infuse Factor VIII in the last five years after one infusion of valrox, which has the potential to provide a treatment choice that addresses many of the unmet needs in hemophilia."

The highest dose cohort experienced a reduced mean ABR from 16.3 (median, 16.5) at baseline to 0.8 (median, 0.0) episodes per year among the 6 participants previously treated with FVIII prophylaxis (mean follow-up, 266.1 weeks [5.1 years]). In year 5, 86% (n = 6) of participants in the high dose cohort had no treated bleeds.

Gene Therapy for Hemophilia B Efficacious, Well-Tolerated

The lower dose cohort (n = 6), treated with 4 x 1013 vg/kg showed that a single infusion of valrox reduced mean ABR by 92% from 12.2 (median, 8.0) at baseline to 1.0 (median, 0.5) bleeding episodes per year (mean follow-up, 218.6 weeks [4.2 years]). In year 4, 50% (n = 3) of participants had no treated bleeds.

High dose cohort participants experienced a 96% reduction in mean annualized Factor VIII utilization from 135.6 (median, 136.5) to 5.2 (median, 0.1) infusions per year among the 6 participants previously treated with FVIII prophylaxis. Lower dose participants experienced a 95% reduction in mean annualized Factor VIII utilization from 142.8 (median, 155.8) to 7.8 (median, 1.4) infusions per year. Exogenous Factor VIII was used as treatment for bleeding, surgery or procedures, and as one-time prophylaxis during follow-up in both cohorts.

Participants in both cohorts continued to experience substantial decline in levels of endogenous Factor VIII expression as confirmed by both CSA and OSA assays. In the low dose cohort, Factor VIII expression decreased from a mean of 5.6 IU/dL (standard deviation [SD], 5.6) to a median of 4.8 IU/dL after 4 years via CSA and from a mean of 9.5 IU/dL (SD, 7.0) to a median of 7.5 IU/dL after 4 years via OSA. In the high dose cohort, Factor VIII expression decreased from a mean of 11.6 IU/dL (SD, 12.2) to a median of 8.2 IU/dL at 5 years via CSA and from a mean of 18.7 IU/dL (SD, 17.5) to a median of 15.7 IU/dL after 5 years.

As of the most recent year of observation, 6 participants in the high dose cohort were in the mild to moderate hemophilia range, and 1 participant was below the lower limit of quantification as measured by CSA. One participant was in the non-hemophilic range, 4 were in the mild range, and 1 was in the moderate range as measured by OSA. Four participants in the low dose cohort were in the mild to moderate hemophilia range, and 2 were below the lower limit of quantification as measured by CSA. All 6 were in the mild to moderate range as measured by OSA.

Valrox has continued to be well-tolerated, with no delayed-onset treatment related adverse events (AEs). All participants continue to remain off corticosteroids since the first year, none developed inhibitors to Factor VIII, and none withdrew from the study. Common AEs included short-lived infusion-associated reactions and transient, asymptomatic, and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae.

"We are optimistic that ABR may be maintained acceptably low through years 3, 4, and 5 after treatment with valrox in the GENEr8-1 study given the predictable, and not sudden or dramatic, change in Factor VIII expression in the later years following treatment in the Phase 1/2 study," added Hank Fuchs, MD, president, Worldwide Research and Development, BioMarin. "The data show excellent hemostatic efficacy in the 6e13 and 4e13 vg/kg dose cohorts, which is maintained into year 5 and 4, respectively. We look forward to sharing topline two-year data from all participants in the pivotal Phase 3 GENEr8-1 study in early 2022."

 from the phase 3 GENEr8-1 study (NCT03370913) which showed that participants treated with valrox experienced a significant, 84% reduced mean ABR (

 <.001) from baseline and a 99% reduced mean annualized Factor VIII utilization rate (

"The demonstrated bleed control at 52 weeks and beyond in this pivotal study supports our thesis that gene therapy can play an important role in the treatment of severe hemophilia A and potentially creates the possibility for a new treatment paradigm," said lead principal investigator Margareth C. Ozelo, MD, PhD, director, INCT do Sangue Hemocentro UNICAMP, University of Campinas, in another statement. "It is encouraging to see meaningful endogenous Factor VIII expression and decreases in bleeding and Factor VIII infusions for people in this study. These pivotal results contribute to the growing body of data to increase understanding of the safety and efficacy of gene therapy treatment over time."

The FDA previously rejected BioMarin’s biologics license application for valrox in August 2020, issuing a complete response letter that cited the need for additional durability data. The FDA requested 2-year follow-up data from the phase 3 study to confirm the durability of the treatment. The last patient in the study will complete 2 years of follow up study in November 2021.

On the European side, BioMarin resubmitted their marketing authorization application to the European Medicines Agency (EMA) in June 2021 after the EMA granted the company's request for accelerated assessment in May 2021. The agency had previously requested 52-week data from the phase 3 GENEr8-1 study. The EMA Committee for Medicinal Products for Human Use opinion is expected in the first half of 2022.

1. BioMarin announces oral presentation at ISTH 2021 Virtual Congress with 5 years of clinical data from ongoing phase 1/2 study of valoctocogene roxaparvovec in adults with severe hemophilia a, demonstrating continued, durable clinical benefit. News release. BioMarin. July 21, 2021. 

https://www.biospace.com/article/releases/biomarin-announces-oral-presentation-at-isth-2021-virtual-congress-with-5-years-of-clinical-data-from-ongoing-phase-1-2-study-of-valoctocogene-roxaparvovec-in-adults-with-severe-hemophilia-a-demonstrating-continued-durable-clinical-benefit/


2. BioMarin announces oral presentation of positive one-year results from phase 3 pivotal trial with valoctocogene roxaparvovec gene therapy in adults with severe hemophilia A at ISTH 2021 Virtual Congress. News release. BioMarin. July 19, 2021. https://investors.biomarin.com/2021-07-19-BioMarin-Announces-Oral-Presentation-of-Positive-One-Year-Results-from-Phase-3-Pivotal-Trial-with-Valoctocogene-Roxaparvovec-Gene-Therapy-in-Adults-with-Severe-Hemophilia-A-at-International-Society-on-Thrombosis-and-Haemostasis-ISTH-2021-Virtua
3. FDA turns down BioMarin's hemophilia A gene therapy. News release. BioMarin. August 19, 2020. Accessed July 27, 2021. https://www.biospace.com/article/fda-rejects-biomarin-s-hemophilia-a-gene-therapy/
4. BioMarin resubmits marketing authorization application (MAA) to European Medicines Agency for valoctocogene roxaparvovec to treat severe hemophilia A. News release. BioMarin. June 28, 2021. https://www.biospace.com/article/releases/biomarin-resubmits-marketing-authorization-application-maa-to-european-medicines-agency-for-valoctocogene-roxaparvovec-to-treat-severe-hemophilia-a/

A drop in endogenous Factor VIII expression was observed from treatment to 5-year follow-up despite continued demonstration of efficacy. 

 over baseline factor VIII prophylactic therapy in data from the phase 3 GENEr8-1 study announced by BioMarin.

These results, presented at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Congress, showed that participants treated with valoctocogene roxaparvovec experienced a significant, 84% reduced mean annualized bleeding rate (ABR; 

"The demonstrated bleed control at 52 weeks and beyond in this pivotal study supports our thesis that gene therapy can play an important role in the treatment of severe hemophilia A and potentially creates the possibility for a new treatment paradigm," said lead principal investigator Margareth C. Ozelo, MD, PhD, director, INCT do Sangue Hemocentro UNICAMP, University of Campinas, in a statement. "It is encouraging to see meaningful endogenous Factor VIII expression and decreases in bleeding and Factor VIII infusions for people in this study. These pivotal results contribute to the growing body of data to increase understanding of the safety and efficacy of gene therapy treatment over time." 

The GENEr8-1 study is evaluating 134 participants with severe hemophilia A at baseline, defined as less than or equal to 1 IU/dL of Factor VIII activity. All participants received a single 6e13 vg/kg dose of valoctocogene roxaparvovec and had a minimum of 12 months of follow-up at the data cut off.

Phase 1/2 Study of SIG-001 for Hemophilia A on Hold Following Serious Adverse Event

New data showed that over 90% (N=134) of all participants had an ABR of 0 or a lower bleed rate than baseline after week 4 after treatment with valoctocogene roxaparvovec. In the rollover population of 112 participants, mean Factor VIII prophylaxis utilization decreased from 3961.2 IU/kg per year (median, 3754.4) at baseline to 56.9 IU/kg per year (median, 0) after week 4 of treatment (

 <.001). Previously presented topline data demonstrated that the mean annualized Factor VIII infusion rate was reduced by 99% from 135.9 infusions (median, 128.6) to 2.0 infusions (median, 0.0) per year (

Investigators also found that, in 132 participants in the modified intent-to-treat population, there was a significant increase in mean endogenous Factor VIII expression level from an imputed baseline of 1 IU/dL to 42.9 IU/dL (median, 23.9; 

 <.001), as measured by the chromogenic substrate assay. In a subset of 17 participants dosed at least 2 years prior to the data cutoff, Factor VIII expression decreased from a mean of 42.2 IU/dL (median, 23.9) at the end of the first year to 24.4 IU/dL (median, 14.7) at the end of the second year with continued hemostatic efficacy.

"From the start of our valoctocogene roxaparvovec program, our goal remains to advance treatment options for people with severe hemophilia A in light of the unmet need in bleed control. Current prophylactic therapies for hemophilia A cannot maintain Factor VIII levels for sustained periods, leading to the need for frequent, regular infusions or injections while still having a risk of ongoing, unpredictable bleeds and unavoidable, irreversible joint damage even with standard of care treatment," added Hank Fuchs, MD, president, worldwide research and development, BioMarin, to the statement.

Valoctocogene roxaparvovec was overall well-tolerated by participants, with no discontinuations due to adverse events (AEs), although 1 participant was lost to follow-up. No participants developed inhibitors to Factor VIII or experienced thromboembolic events. AEs occurring within 48 hours post-infusion were categorized as infusion reactions. The most common infusion reactions were nausea (14.2%), fatigue (7.5%), and headache (6.0%). Four participants (3.0%) had an interrupted infusion due to infusion-related symptoms but were able to complete their infusion by slowing or pausing its and treating symptoms. Serious AEs (AEs) were reported by 22 (16.4%) participants that experienced a total of 43 SAEs.

The most common AE was aspartate transaminase (ALT) elevation and 79% of participants received corticosteroids as ALT treatment. Corticosteroid treatment lasted an average of 33 weeks and 72% of participants reported corticosteroid-related AEs such as acne, insomnia, cushingoid changes, and weight increases. Corticosteroid-related SAEs were reported by 3 participants. Some participants (29%) used other immunosuppressants due to contraindication, AEs, or poor response to corticosteroids. No Grade 4 ALT elevations occurred, and no participants met Hy's law criteria for drug-induced liver injury.

"These data build upon the foundation for a potential transformative treatment option that addresses the root cause of severe hemophilia A. Later at ISTH, we look forward to sharing 5 years of clinical data from the ongoing phase 1/2 study with the longest duration of clinical experience, which complements this pivotal phase 3 study, the largest study of a gene therapy in hemophilia A,” Fuchs added.

The FDA previously granted regenerative medicine advanced therapy designation to valoctocogene roxaparvovec in March 2021, breakthrough therapy designation in 2017, and orphan drug designation in 2016. 


BioMarin Announces Oral Presentation of Positive One-Year Results from Phase 3 Pivotal Trial with Valoctocogene Roxaparvovec Gene Therapy in Adults with Severe Hemophilia A at ISTH 2021 Virtual Congress. News release. BioMarin. July 19, 2021. https://investors.biomarin.com/2021-07-19-BioMarin-Announces-Oral-Presentation-of-Positive-One-Year-Results-from-Phase-3-Pivotal-Trial-with-Valoctocogene-Roxaparvovec-Gene-Therapy-in-Adults-with-Severe-Hemophilia-A-at-International-Society-on-Thrombosis-and-Haemostasis-ISTH-2021-Virtua

Over 90% participants had an annualized bleeding rate of 0 or a lower bleed rate than baseline after week 4 after treatment. 