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Gene therapy results in long-term normalization of factor VIII activity in severe hemophilia A
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ATLANTA — A gene therapy approach resulted in sustained, clinically relevant factor VIII activity for certain patients with severe hemophilia A, according to study results presented at ASH Annual Meeting and Exposition.
Patients who received the highest dose of valoctocogene roxaparvovec (Biomarin) — which consisted of a single IV dose of adeno-associated virus type 5 vector that contained a codon-optimized factor VIII gene — experienced “profoundly reduced” self-reported bleeding and exogenous factor VIII use, according to K. John Pasi, MB, ChB, PhD, professor of hemostasis and thrombosis at Barts and the London School of Medicine and Dentistry at Queen Mary University of London and director of the hemophilia center at Royal London Hospital.
In the highest-dose cohort, participants achieved Factor VIII levels within the normal range. Factor VIII levels among patients treated with a slightly lesser dose rose steadily, approaching or reaching the lower end of the normal range.
The results “massively” exceeded researchers’ expectations, Pasi said.
“Our original target — based on what has been observed in previous studies of hemophilia B — was 5% of normal. When we hit it, we thought, ‘This is phenomenal,” Pasi told HemOnc Today. “When we started to see normal levels, we could not believe it. We were thunderstruck. It was like hitting the lottery.”
Gene therapy has long been regarded as a “potential Holy Grail” for hemophilia A management given it is a single-gene disorder and there is a clear cause-and-effect relationship between clotting factor level and outcome, Pasi said. In addition, if successful, it could alleviate the need for demanding treatment with expensive replacement products.
Multiple patients with hemophilia A have undergone successful gene transfer within multiple dose cohorts; however, extended follow-up has not been reported, according to study background.
Pasi and colleagues conducted an ongoing phase 1/phase 2 study that evaluated adeno-associated virus 5 factor VIII gene transfer with valoctocogene roxaparvovec for heavily pretreated patients with severe hemophilia A.
At ASH, he presented interim, long-term efficacy and safety results from 13 patients who received one of the two highest doses: 613 vector genomes per kg (n = 7) and 413 vector genomes per kg (n = 6).
Endpoints included safety, efficacy and immunogenicity.
Pasi presented factor VIII activity as median levels over 4-week intervals.
Among patients dosed at 613 vector genomes per kg, with 1.5 years of follow-up, factor VIII levels reached the normal range. Median level was 90 IU/dL at 78 weeks.
Among patients dosed at 413 vector genomes per kg, with up to 1 year of follow-up, factor VIII levels increased steadily toward or within the lower end of the normal range. Median level was 49 IU/dL at 48 weeks.
From 4 weeks after infusion through the final follow-up visit, median annualized factor VIII infusions declined from 138.5 (IQR, 122-157) to 0 (IQR, 0-0) among those dosed at 613 vector genomes per kg, and from 155.5 (IQR, 112-183) to 0 (IQR, 0-0) among those dosed at 413 vector genomes per kg.
Both doses also eliminated occurrence of spontaneous bleeds.
Researchers assessed annualized bleeding rate from 4 weeks after infusion through last follow-up visit for 12 patients — six in each dosing cohort — who underwent prior prophylactic therapy. Results showed mean annualized bleeding rates declined from 16.5 (IQR, 1-24) to 0 (IQR, 0-0) among those dosed at 613 vector genomes per kg, and from 8 (IQR, 1-15) to 0 (IQR, 0-0) among those dosed at 413 vector genomes per kg.
Five patients in each cohort reported no bleeding episodes.
Pasi and colleagues also reported considerable improvements in quality of life. Among five study participants who received the highest dose, mean total change in Haemo-QoL-A scores from baseline to week 78 increased by 16.6 points (95% CI, 1.8-31.3). The quality-of-life improvements were observed in all six domains analyzed: emotional impact, physical functioning, role functioning, consequences of bleeding, treatment concern and worry.
Valoctocogene roxaparvovec also appeared well tolerated. No study participants developed factor VIII inhibitors.
Researchers reported two serious adverse events. One patient experienced pyrexia with myalgia and headache at the time of infusion, and another underwent a planned total knee replacement for chronic arthropathy.
All seven patients assigned the highest dose, as well as four of the six patients assigned the second-highest dose, experienced mild, grade 1, asymptomatic alanine aminotransferase level increases. Peak levels ranged from 44 U/L to 141 U/L (upper limit of normal = 43 U/L).
All but one patient — dosed at 413 vector genomes per kg — had normal alanine aminotransferase levels at data cutoff. All but one patient — also dosed at 413 vector genomes per kg — had stopped corticosteroid therapy; the dose was being tapered in the one patient who remained on corticosteroid therapy.
Although both doses appear to enable achievement of long-term normalization of factor VIII activity among patients with severe hemophilia A, optimal dosing will be further evaluated in upcoming phase 3 trials, Pasi said.
“Our goal is to maximize flexible dosing and individualize treatment for our patients,” Pasi said.
Longer follow-up also will be necessary to assess the durability of this regimen’s benefit.
“When you get normal levels, you could argue a patient is cured, but durability is a big question that hangs over everybody’s gene therapy program” Pasi told HemOnc Today. “Only time will tell what this has actually achieved. We’re cautious about using the word ‘cured,’ naturally, because of that reason.
“In dogs treated with hemophilia gene therapy, the benefit has lasted their lifetime,” Pasi added. “We don’t know at the moment if that will be the same for humans. We have to be a bit circumspect. We have to follow it through and keep our fingers crossed. However, these results give us cause for optimism, which is something we haven’t had much of in gene therapy over the past 25 years.” – by Mark Leiser
For more information:
Pasi KJ, et al. Abstract 603. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Pasi reports research funding from, consultant roles with, honoraria from, board or advisory committee roles with, speakers bureau roles with or other relationships with Alnylam Pharmaceuticals, Bayer, Biogen, BioMarin, Biotest, Bioverativ, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and Sobi. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Anne Neff, MD
I first heard these results this summer at the International Society for Thrombosis and Haemostasis Congress in Berlin. The audience was aghast at the results, which showed the first few patients treated achieved normal levels of factor VIII and stopped bleeding entirely. We have not seen this in prior gene therapy trials. Previously, we were ecstatic about levels of 8% to 10% of normal.
Long-term follow-up will be important. Gene therapy trials in the past, unfortunately, have had some very notorious events related to lack of safety. The buzz after this abstract was presented seemed to be, ‘Oh my goodness, we can do this, and it looks safe.’ However, it is very early. We still need to confirm it is safe. We also need to make sure factor levels do not eventually fade back down, which has been the case with other trials. However, so far so good, and it is extremely exciting.
The timeline for adoption of gene therapy in practice, of course, will be up to the regulatory agencies. It also will depend on what happens with regard to durability and safety as these patients continue to be followed. Ideally, this is something that could be done for children with hemophilia. The dream would be to fix people with gene therapy at a very young age so they don’t suffer the horrible consequences and long-term complications of hemophilia, which are just debilitating. However, there have been no children enrolled in any of these studies. We’re still doing adult trials, and pediatric trials will only follow after the safety and efficacy have been confirmed.
Perspective
Back to TopMargaret V. Ragni, MD, MPH
One of the things we have learned over time is that we should individualize treatment for patients with hemophilia. Patients with more mild or more moderate disease may want to stay on their standard drug. However, if they are feeling burdened by IV dosing and could, for example, have a subcutaneous dose once a week, why not give that a try?
We pose all of these options to our patients, and we should continue to do so. Not everyone wants to go on gene therapy, but as more experience builds, I suspect the interest will continue to increase. I think individualizing therapy is the name of the game in hemophilia.
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