BMN 270-301: Gene Therapy Study in Severe Haemophilia A Patients
Research type
Research Study
Full title
A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector–Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual FVIII Levels ≤ 1 IU/dL Receiving Prophylactic FVIII Infusions
IRAS ID
234684
Contact name
Gillian Lowe
Contact email
Sponsor organisation
BioMarin Pharmaceutical Inc.
Eudract number
2017-003215-19
Duration of Study in the UK
6 years, 4 months, 30 days
Research summary
Research Summary:
This study is being conducted by BioMarin Pharmaceutical Inc. as a Phase 3, open label study in order to determine the safety and efficacy of BMN 270 (an Adeno-Associated Virus based gene therapy vector) in participants with severe Haemophilia A.Haemophilia A (HA) is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males. It is caused by deficiency in the activity of coagulation factor VIII (FVIII), which is essential to blood clotting. Severe HA is classified as FVIII activity less than 1%. Clinical manifestations of severe HA are frequent spontaneous bleeding episodes, predominantly in joints and soft tissues, with a substantially increased risk of death from haemorrhage when the brain is involved. Haemophilia A is well suited for a gene transfer approach because clinical manifestations are attributable to the lack of a single gene product (FVIII) that circulates in minute amounts in the plasma. BMN 270 is an AAV5 gene therapy drug that contains a FVIII gene. Phase 1/2 studies have demonstrated it can lead to expression of therapeutic amounts of FVIII and stop bleeding symptoms.
As a phase 3 programme, approximately 40 participants will receive a single dose of BMN 270 as an intravenous infusion. BMN 270 offers the potential of disease modification through continuous endogenous production of FVIII levels following a single intravenous administration and is designed to achieve stable, potentially life-long expression of active hFVIII in the blood.
Participants will be in the study for up to 5 years.
Lay summary of study results:
Study 270-301 represents the largest gene therapy investigation for severe haemophilia A to date, with 134 participants receiving BMN 270. The study population was representative of the severe haemophilia A demographic, with participants experiencing a mean baseline ABR of 5.42 treated bleeds/year despite receiving standard-of-care prophylactic FVIII replacement, aligning with recently published data from similar patient cohorts. These real-world findings demonstrate the persistent unmet need in this population.
BMN 270 successfully met all primary and secondary endpoints, demonstrating both statistical significance and clinical relevance. The gene therapy restored FVIII activity to clinically therapeutic levels, with the majority (58%) of participants achieving FVIII levels exceeding the threshold for mild haemophilia at the end of the study. There was a significant reduction in bleeding events (83% reduction in ABR) and approximately half of patients had 0 treated bleeds. Mean annualised FVIII utilization declined sharply (95%) from baseline in the Rollover Population and the mean annualised FVIII infusion rate also decreased by almost 95%. Treatment with BMN 270 has not only largely abrogated the risk of bleeds, but also significantly reduced the current treatment burden of more than 130 injections on average per year to very few (< 7). Notable improvements in meaningful HRQoL outcomes, including Haemo-QoL-A scores demonstrating statistically and clinically significant improvements that exceeded the CID derived for this scale, suggest that overall, efficacy benefits were achieved with BMN 270 treatment, indicating observable improvements that are considered meaningful in the lives of participants with severe haemophilia A.
BMN 270 has an acceptable safety and tolerability profile, with most adverse events being mild to moderate in severity. No new safety signals were identified since the 4-year analysis cut and no new Grade 3 or higher ALT elevations were reported in Year 5. No participants have discontinued from the study as a result of an AE, and no important potential/theoretical risks such as thromboembolic events, development of FVIII inhibitors, malignancies related to BMN 270, and horizontal (person-to-person) or vertical (germline) transmission were observed. Two deaths occurred during the study, an event of suicide in a participant with a long history of major depression and event of head trauma resulting from a fall, both were assessed as unrelated to BMN 270.
Liver biomarker abnormalities and infusion-associated events have been the most important treatment-related adverse events. Transient ALT elevations typically occurred around 16 weeks post-infusion and generally responded to corticosteroid management. There was no evidence of major impacts upon liver function, which remained stable over time. Infusion-associated events were effectively mitigated by managing infusion rate and medications and generally resolved without clinical sequelae within 48 hours following medical management if needed.
The COVID-19 pandemic did not substantively impact study integrity or conclusions, as mitigation strategies including mobile nursing and virtual visits maintained data collection quality throughout the disruption.
In conclusion, the results from the 270-301 demonstrate a positive benefit-risk profile for BMN 270 in the treatment of patients with severe haemophilia A without FVIII inhibitors who do not have detectable antibodies to AAV5. BMN 270 has been shown to have an acceptable safety profile over a 5-year year period and offers a durable FVIII expression that significantly reduces both disease burden (bleeding events) and treatment burden (frequent infusions), and improves quality of life for a meaningful period of time. Participants who completed 5 years of follow-up in 270-301 will be followed for an additional 10 years in Study 270-401, for a total of 15 years of post-infusion monitoring of safety and efficacy. BMN 270 addresses the unmet medical for a treatment that is efficacious, safe, more convenient, and less burdensome for patients with severe HA than the current standard of care.REC name
London - West London & GTAC Research Ethics Committee
REC reference
17/LO/1695
Date of REC Opinion
25 Nov 2017
REC opinion
Further Information Favourable Opinion