Steven W. Pipe, MD of the University of Michigan, Ann Arbor speaks about ASH 2020 abstract – Gene Therapy for Hemophilia B Found Safe and Effective in First Phase III Trial.
(WASHINGTON, Dec. 8, 2020)-In the largest and most inclusive hemophilia B gene therapy trial to date, gene therapy etranacogene dezaparvovec dramatically improved the development of the blood-clotting protein factor IX among 52 patients. The study was also the first to include patients with such markers of the immune system and found that no elevated risks appeared to be conferred, a result that could greatly expand the number of patients eligible for gene therapy.
After undergoing gene therapy, the majority of trial participants (96 percent) successfully discontinued factor IX replacement therapy and developed their own factor IX for six months. The results indicate that gene therapy could, according to researchers, give patients the ability to sustain factor IX levels with a single therapy and reduce or remove the need for additional factor IX replacement therapy.
Hemophilia B, which accounts for nearly one-fifth of the cases of hemophilia, is caused by an inherited factor IX gene mutation. Patients with hemophilia B who lack the ability to produce blood clotting factor IX can experience uncontrolled bleeding, including internal and joint bleeding, resulting in joint deterioration and chronic pain.
Replacement therapy with factor IX can minimize hemophilia B-associated bleeding but requires weekly or biweekly infusions to maintain the level of factor IX, a burdensome regimen that costs several hundred thousand dollars annually. Viral particles are used in gene therapy to shuttle programmed genes to cells in the liver. These genes replace the defective factor IX gene of the patient, enabling factor IX to be generated continuously by the patient’s own body. Although some hemophilia gene therapies have shown promise in early phase studies, the research is the first phase III trial in a wide and diverse variety of patients to evaluate the method.
Fifty-four patients were enrolled in the study; all were dependent on factor IX replacement therapy, and, despite this prophylactic treatment, 70% had bleeding episodes in the six months prior to the study. Factor IX activity increased rapidly from a baseline of up to 2 percent (moderate to extreme hemophilia) to a mean of 37 percent (very mild hemophilia) at 26 weeks after receiving etranacogene dezaparvovec gene therapy via a single infusion lasting approximately one hour, reaching the primary endpoint of the study. At that point, the bleeding risk of a patient is exactly the same as that of someone without hemophilia.
In the 26 weeks after undergoing gene therapy, 72 percent of patients reported no bleeding events. “This tells us that through this treatment, which is a remarkable achievement, the bleeding phenotype can be corrected,” said Dr. Pipe. Some bleeding was experienced by 15 patients, which the researchers indicate is not surprising considering that many of the patients entered the trial with badly affected joints.
In patients with neutralizing antibodies, the trial is also the first to attempt gene therapy, a part of the immune system that helps the body combat pathogens. Around 40 percent of the participants in the trial had antibodies to the serotype 5 or AAV5 adeno-associated virus, the viral vector used in dezaparvovec etranacogene.
Previous studies have removed patients using viral vectors from gene therapy on the basis that antibodies may either obstruct the liver’s absorption of viral vectors or cause a harmful immune response to the therapy. The trial found no evidence of either issue, indicating that effective gene therapy is not prevented by neutralizing antibodies.
Two patients did not respond to the treatment of the gene. One did not receive a full dose because after the patient displayed signs of a reaction to the infusion, the infusion was halted. The other had a neutralizing antibody level that was about five times greater than any other patient. Because other patients with neutralizing antibodies, irrespective of their level of antibodies, responded well to therapy, this finding indicates that antibodies may pose a problem only at extremely high levels.
No severe adverse effects associated with treatment have been reported. Adverse effects, occurring in 68 percent of patients, were relatively common, but most were mild and linked to the infusion itself. Nine patients displayed signs of an immune reaction to therapy that was overcome with a corticosteroid course in all cases.
For five years, the researchers will continue to monitor patients. As well as patient-reported outcome indicators to determine the effects on quality of life, patients will be tested for continuous factor IX development and successful bleed control over 52 weeks.