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Highlights from

ISTH 2019

The International Society of Thrombosis and Haemostasis

Melbourne 6-10 July 2019

Gene therapy for severe haemophilia A: first-in-human evidence of durable efficacy and safety over 3 years

Take-home messages
  • Gene transfer with valoctocogene roxaparvovec provides substantial increases in factor VIII expression, sustained up to 3 years
  • Patients with severe haemophilia A had clinically relevant reductions in bleeding episodes and reductions in factor VIII replacement infusions
  • There were no unexpected events, and gene therapy had a favourable safety and tolerability profile
“[It] has been quite an achievement for what has been historically thought to be a very difficult disease to treat with the gene therapy approach.”

Dr John Pasi, Haemophilia Centre Director, Barts Health NHS Trust, Professor of Haemostasis and Thrombosis, Queen Mary University of London, UK.

"At 3 years after gene therapy [for] haemophilia A, we're getting continuous expression of factor VIII at levels that are clinically very meaningful, that have got patients off routine treatment and they’re no longer bleeding," explained Dr John Pasi, Haemophilia Centre Director, Barts Health NHS Trust, UK, who presented the latest data at the International Society on Thrombosis and Haemostasis (ISTH) 2019 Congress.

The phase I/II trial, BMN 270-201, observed clinical outcomes following gene therapy with AAV factor VIII vector, valoctocogene roxaparvovec (AAV5-hFVIII-SQ). Adult male patients with severe haemophilia A were included.

The analysis presented at ISTH 2019 focused on patients who received 6×1013 vector genomes (vg)/kg (n=7) or 4×1013 vg/kg (n=6), intravenously (there were also an additional two patients who received lower doses). Safety, tolerability and efficacy outcomes were assessed.

"What we had previously presented was a substantial reduction in bleeding rates across both cohorts, and we continue to see that across the year 3 data. And this is a very consistent response." The 6×1013 vg/kg cohort showed an impressive 96% reduction in mean annualised bleed rate (ABR), year 3 versus baseline. The 4×1013 vg/kg cohort had a 92% reduction in mean ABR, year 2 versus baseline.

Notably, all patients were able to discontinue their prophylactic treatment, and the 6×1013 vg/kg cohort had 100% resolution in target joints. 86% of patients in this cohort were bleed free at year 3 (compared with 14% at baseline).

"If we look at annualised [factor VIII] use, again, we will see a very similar picture: substantial reductions in both cohorts." Mean annualised factor VIII usage was reduced by 96% and 97% in patients receiving 6×1013 vg/kg and 4×1013 vg/kg doses, respectively.

In the 6×1013 vg/kg cohort, quality of life was improved in all six domains of the Haemo-QoL-A score, including consequences of bleeding, emotional impact, physical and role functioning, treatment concern and worrying (mean total score 11.9 by week 156; change from baseline).

Dr Pasi commented on the durable activity of factor VIII. "What we can see here is that there is a plateau forming between years 2 and 3 in terms of level of expression of factor VIII. I'd also like to point out […] we're showing chromogenic factor VIII levels." The original data used a less conservative one-stage assay.

"The other thing that we were particularly interested in looking at is the fate of the transgene," Dr Pasi noted, explaining that, after administration, the vector will potentially associate with all cells in the blood. Observing peripheral blood mononuclear cells (PBMCs) specifically, the percentage of inverted terminal repeat (ITR)-fused factor VIII DNA increased over 52 weeks, implying that circularisation was achieved.

Unlike other blood cells, PBMCs are long lived, and are therefore likely to have survived the initial point of transfection at gene therapy administration. The results imply that durability is related to the cellular turnover of the host cell, "which gives us some faith in the fact that the durable, circularised vectors will be stable over time."

So, what is next for the BMN-270 trials? "Having conducted a phase I/II on a limited number of patients, we've moved forward to a multicentre, global phase III study," Dr Pasi noted. “We have two elements to it, a direct entry, which has now got 20-odd patients that are being followed. Another 110 patients are being followed with a non-interventional 6 months, and then into the gene therapy phase."

The GENEr8-1 interim analysis (n=16; modified intent-to-treat; 6×1013 vg/kg) showed a substantial 85% reduction in mean ABR and a 95% reduction in mean factor VIII use, annualised after week 5, from baseline.

Dr Pasi mused over findings they expect to see in future trials. "We hope that we're going to see results very similar to the phase I/II. There is undoubtedly some variability that we saw in phase I/II, and the phase III data will help us understand that."

Valoctocogene roxaparvovec has demonstrated a favourable and consistent safety profile; no subjects have developed thrombotic events or inhibitors to factor VIII. "In terms of safety, we haven't had any particular anxieties," said Dr Pasi. "There have been some changes in liver function test, which is seen quite frequently in gene therapy programmes using AAV. But these are self-limiting and asymptomatic."

The results continue to show that gene therapy could be life changing for patients with severe haemophilia A. "Rather than having to inject themselves every other day, they have had essentially no treatment since the outset of the gene therapy, which now, in some patients, is more than 3 years. Along with that, not only did they not have any treatment to give themselves, they've stopped bleeding."

Based on Pasi K J, Rangarajan S et al. First-in-human evidence of durable therapeutic efficacy and safety of AAV gene therapy over three-years with valoctocogene roxaparvovec for severe haemophilia A (BMN 270-201 study) (abstract LB 01.2). Presented on 10 July 2019.

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