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Coagulation Corner

Monday, February 5, 2018

Advances In Hemophilia

Written By Donna Castellone, MS, MT (ASCP) SH | LinkedIn

Hemophilia is a sex-linked autosomal recessive disorder. Hemophilia A results in a deficiency of factor VIII while patients with Hemophilia B present with a deficiency in factor IX. Patients are classified as mild (levels between 6-30% ) moderate with factor levels 1-5% and severe patients with levels <1%. Treatment has ranged from factor concentrate, cryoprecipitate, recombinant factor as well as extended half life products. These products minimize infusions and allow patients to have a better quality of life. Patient can be treated prophylactically to minimize bleeding events. Patients with hemophilia A on prophylaxis require intravenous injections every other day or three times per week, while those with hemophilia B are usually treated twice weekly, owing to the longer half-life of FIX over FVIII (18-20 h instead of 10-12 h).

Hemophilia A is four times more common that type B and occurs in approximately 1 in 5000 males. There are about 400,000 people worldwide with the disease.

Patients present with bleeding into joints which can cause progressive damage. A brain bleed can lead to seizures and or paralysis. A complication is the development of antibodies to the treatment. These inhibitors can develop in up to 30% of hemophilia patients. The annual cost of factors in a hemophilia patient is about $400,000/year, however in patients with inhibitors the cost can exceed $1 million dollars annually.

Gene therapy has also been explored as a long term therapy and or cure for hemophilia. In December 2017 the New England Journal of Medicine published the results of a study ( Sparks therapeutics and Pfizer) using a high specific activity factor IX variant. The procedure used a single stranded adeno-associated viral vector. This consisted on a liver specific promoter and factor IX Padua transgene. This was infused into 10 men with hemophilia B having factor IX activity of </=2%. They were monitored for FIX levels, and utilization of IX concentrate.

The results were better than expected. After 18 months of observation, the average FIX level is 34%, 9/10 had no bleeding episodes. Additionally, 8/10 no longer needed FIX injections every few days. Two patients had elevated liver enzymes, but were treated with prednisone. One patient required factor for arthroplasty, but used 91% less than prior to having the vector infusion. The outcome demonstrated sustained FIX coagulation activity in 10 patients post vector infusion. This resulted in almost the elimination of bleeding and factor replacement.

The New England Journal also reported on advances made in gene therapy in patients with hemophilia A. Due to the large size of FVIII coding region, hemophilia A gene therapy has been problematic. Patients were infused with a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. One patient received a low dose, one an intermediate dose and seven received a high dose. Patients were followed for 52 weeks. Those who received a low or intermediate dose maintained levels of 3 IU or less, while those who had a high dose achieved levels of more than 5 IU between weeks 2 and 9. The level in six participants increased to normal values (>50 IU) and remained for 1 year.

The bleeding rate in patients from the high dose cohort who had previously gotten prophylactic therapy went from 16 events before the gene transfer to only 1 event post transfer. All bleeding ceased in all participants by week 22, and no antibodies to FVIII were detected. The study was funded by BioMarin Pharmaceuticals.

The exclusion criteria for the trial did not admit people whose immune system might reject the AAV vector used to carry the corrective gene. Patients also could not have a history of developing inhibitors to FVIII or the presence of hepatitis. This may eliminate a lot of people with hemophilia A.

This mechanism of using viruses to implant new genes into patients' cells has the potential to eliminate treatment by replacement products in hemophiliacs. Based on the results of these two studies, a cure for hemophilia may be closer than ever could have been imagined. This would greatly improve the quality of life for these patients.



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