Gene Therapy Corrects Factor VIII Levels in Hemophilia A

Daniel M Keller, PhD

August 07, 2017

BERLIN, GERMANY — Patients with hemophilia A who received a gene for coagulation factor VIII (FVIII) packaged in a viral vector had sustained levels of FVIII during 1 year of observation, eliminating spontaneous bleeds[2]. Most of them did not need FVIII infusions even in the case of major trauma or surgery.

In a late-breaking abstract session here at the International Society on Thrombosis and Hemostasis 2017 Congress, Dr John Pasi (Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK) said six out of the seven patients in one dose cohort have achieved normal factor VIII levels.

"The one patient who did not achieve the lower limit of normal (50–150 international units [IU]/dL) "is running around 20 IU/dL, which is still way more significant than our original target of 5 IU/dL," he said.

Current FVIII-replacement products must be given up to several times a week and produce a "sawtooth" response pattern of blood levels. Microbleeding can occur when levels are low.Gene therapy can maintain blood levels of FVIII and ideally could be given once or only a few times in a lifetime, the researchers point out. As even low levels of FVIII can be effective, this approach should also prevent bleeding and the need for factor infusions, the researchers said.

Speaking with | Medscape Cardiology, Dr Wolfram Ruf (Johannes Gutenberg University in Mainz, Germany) commented that "this is a very exciting field"—to be able to produce safe levels of FVIII using gene-transfer therapy. Noting that AAV5 targets liver cells, he said, "You can get prolonged lasting effects of liver synthesis of the coagulation factor."

In a phase 1/2 study using adeno-associated virus type 5 containing a shortened, B-domain–deleted form of the FVIII gene (AAV5-FVIII; BMN270, BioMarin), patients received a single intravenous dose containing varying numbers of the viral genomes (vg), ranging from 6x1012 vg/kg to 6x1013 vg/kg. If a patient's level of FVIII was less than 5 IU/dL at week 3, the dose was escalated.

The B-domain was deleted because some previous attempts at gene-transfer therapy have been hampered by the size of the FVIII gene.

To be cautious, some of the dosage cohorts received prophylactic corticosteroids to prevent loss of FVIII expression. Patients receiving prophylactic FVIII were switched to an "on-demand" regimen.

Patients (n=15) were males 18 years or older (mean 31 years) with severe hemophilia A (FVIII levels less than 1 IU/dL). The one patient who had been on an on-demand FVIII regimen had a historical annualized bleeding rate (ABR) of 25. The rest had been on FVIII prophylaxis before enrollment and had a median ABR of 6.5. Five patients had a history of hepatitis B or C.

Among the exclusion criteria were preexisting immunity to AAV5 capsid, HIV positivity, significant liver dysfunction, acute or chronic hepatitis B infection, or hepatitis C infection.

For the seven patients in the cohort receiving AAV5-FVIII at 6x1013 vg/kg, FVIII activity began to rise at 8 weeks, reached the lower limit of normal (50 IU/dL) at 12 weeks, and the mean levels persisted in the midrange of normal out to 52 weeks. Values within 72 hours of exogenous FVIII administration were excluded.

A lower dose of 4x1013 vg/kg AAV5-FVIII produced lower levels of FVIII but still reached about 40 IU/dL by 16 weeks and persisted through 24 weeks, with observation continuing.

Western blot analysis of plasma from the subjects showed that they were expressing the B-domain–deleted FVIII heavy chain coded for by the genome in the viral vector.

Bleeding Episodes Stopped Without FVIII Infusions

"In our patients, when expression levels were greater than 5%, our actual target, the ABR in both [dose] cohorts has basically collapsed to zero," Pasi said. "I'm not sure what else I can really say. This is impressive."

For the cohort receiving the higher dose, the pretreatment ABR was 16.5, and for the lower dose cohort it was eight. The figures were annualized based on the number of bleeding events during the observation period.

Similarly, annualized exogenous FVIII usages were reduced to zero from 138.5 infusions/year for the higher AAV5-FVIII cohort and from 155.5 infusions/year for the lower-dose one.

The therapy was safe and well tolerated across all doses. "Nobody has developed an inhibitor, which is clearly an important question in hemophilia A gene therapy," Pasi noted, "and nobody has chosen to withdraw."

Ten subjects experienced alanine-aminotransferase (ALT) elevations, which were all less than three times the upper limit of normal and of short duration. Half reported arthralgias, and one-third experienced back pain, fatigue, or headache. Two serious adverse events occurred: one involving grade 2 fever with myalgia and headache at the time of infusion that resolved without sequelae and the other a planned total knee replacement.

Considering all subjects in the higher-dose cohort, mean quality-of-life scores as measured on the Haem-A-QOL instrument improved by week 16 and were maintained over 52 weeks. Improvements were observed on all six domains evaluated: consequences of bleeding, emotional impact, physical functioning, role functioning, treatment concern, and worry.

Pasi concluded that AAV5-FVIII treatment at 6x1013 vg/kg caused the expression of normal levels of FVIII, eliminating spontaneous bleeds and the need for exogenous FVIII for these patients even in cases of major trauma or surgery.

The one patient with a level of endogenous FVIII of approximately 20 IU/dL required a perioperative FVIII infusion. The therapy was well tolerated, and the next step will be to initiate phase 3 studies using this dose.

Expression of FVIII persisted over the course of the study. "We don't know exactly how long, but we can expect from other studies that the effect stays for at least maybe 5 to 10 years," Oldenburg predicted.

One apparent caution emerging during the study is that the effect was not very predictable. Although the median levels of FVIII expression were in the normal range, "when you apply a dose to a patient you don't know whether he's staying below the correction or is even overcorrected," he said. "But if you go for the single patient the variability could be significant . . . but this is a minor problem."

Dr Johannes Oldenburg (University Clinic Bonn, Germany), who chaired the late-breaking abstract session and is on the advisory board of BioMarin, called the therapy "absolutely state-of-the-art technology . . . and a major step forward in the hemophilia phenotype.

"There was almost full correction, in a few patients even overcorrection of the hemophilia phenotype to completely normal values," he said. "It's a curing of a hemophilia phenotype, and it has been very clearly shown in this study that the therapy looks very safe."

The study was sponsored by BioMarin Pharmaceutical. Pasi receives grant and/or research support from BioMarin, Alnylam Pharmaceuticals, and Bioverativ and honoraria from Pfizer, Sobi, Genzyme, Octapharma, Bayer, Alnylam, BioMarin, Biotest, and Shire. He is a paid instructor for Roche, Novo Nordisk, and Pfizer. Ruf had no relevant financial relationships. Oldenburg is a member of the advisory board of BioMarin and has received grants and personal fees and served as a member of a board of directors or advisory committee for Baxter, Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and Sobi.

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