Liver enzyme elevations may recur after hemophilia B gene therapy
Case report highlights challenges managing a known gene therapy side effect
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- Liver enzyme elevations may recur after Hemgenix gene therapy for hemophilia B, potentially signaling liver inflammation or damage.
- A case report found that liver enzymes rose again during corticosteroid tapering, even though clotting factor IX activity remained stable.
- Researchers called for closer monitoring of liver enzyme levels after the first three months and clearer guidance on managing repeated elevations.
Liver enzyme levels may rise again as corticosteroid doses are gradually reduced in people with hemophilia B treated with Hemgenix, a case report suggests. Elevated liver enzymes are a known side effect of the gene therapy that can signal liver inflammation or damage. Corticosteroids are used to treat these elevations.
The report describes the first patient treated with Hemgenix in Spain. It also shows that liver enzyme levels can rise again even when factor IX (FIX) activity remains stable. FIX is a protein that helps blood clot but is deficient in people with hemophilia B. Hemgenix helps the body produce FIX.
The researchers called for clearer guidance on monitoring liver enzyme levels and managing repeat elevations after Hemgenix treatment.
The researchers said more evidence is needed to identify patients at greater risk and determine when and how to intensify treatment. In the meantime, “systematic communication of cases such as this one between haemophilia centres may be the most practical tool we have,” they wrote.
Case report highlights gaps in managing liver enzyme elevations
The report, “Biphasic Transaminitis During Corticosteroid Tapering After Etranacogene Dezaparvovec Gene Therapy for Haemophilia B: Management Lessons From the First Spanish Case,” was published in Haemophilia as a letter to the editor.
Hemophilia B is caused by mutations in the F9 gene that leave the body without enough working FIX. This makes it harder for blood to clot properly and can cause prolonged or excessive bleeding.
Hemgenix is a one-time gene therapy that uses a modified virus to deliver a working copy of the F9 gene to liver cells, allowing them to produce FIX. One of its known side effects is transaminitis, an increase in blood levels of liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST).
In the HOPE-B trial, 11 patients experienced transaminitis within the first 12 weeks after Hemgenix infusion. Each had a single episode that responded to corticosteroids, medications that reduce inflammation and suppress immune activity.
The therapy’s label recommends checking transaminase (liver enzyme) levels weekly for the first three months after treatment, then monthly for up to one year. It also advises doctors to consider corticosteroids if these levels rise, as clinically indicated.
A similar pattern of recurring liver enzyme elevations during corticosteroid tapering has also been reported in a patient with hemophilia A who received a different gene therapy.
“A second episode arising during [corticosteroid] dose reduction is not covered by any existing protocol,” the researchers wrote. “There is no guidance on whether, when, or with what to escalate immunosuppression (IS) if it occurs.”
The report describes the first patient treated with Hemgenix in Spain, a 41-year-old man with moderately severe hemophilia B and severe joint damage from repeated bleeding. He had been cured of hepatitis C, a viral infection that affects the liver, and had no evidence of active liver disease.
Liver enzyme elevations return during steroid tapering
Before Hemgenix, he received Alprolix (eftrenonacog alfa) to prevent bleeding. His FIX activity increased within one week of the Hemgenix infusion and reached an initial peak about four weeks after treatment.
At that initial FIX peak, his ALT level briefly rose above normal but fell again within two days, without a drop in FIX activity. About a week later, ALT rose again, this time accompanied by a 14% decrease in FIX activity. The researchers suggested that this episode might reflect an immune response damaging liver cells that had received the new F9 gene.
Doctors started prednisone, a corticosteroid, at 60 mg daily. ALT returned to normal within seven days, and FIX activity rose further by month four. However, as doctors gradually lowered the prednisone dose, ALT began rising again about 3.5 months after Hemgenix treatment. It eventually reached twice the patient’s pretreatment baseline level.
Unlike the first treated episode, this second ALT increase was not accompanied by a drop in FIX activity. FIX levels later stabilized. Tests found no evidence of viral infections, autoimmune hepatitis (liver inflammation caused by an abnormal immune response), or other causes examined.
Doctors raised the prednisone dose back to 60 mg daily. ALT began to fall after two weeks, and doctors then reduced the prednisone dose more slowly. No other immunosuppressive medication was added.
The man received prednisone continuously for 335 days, or about 11 months. This was much longer than the longest course reported in the HOPE-B trial, which lasted 130 days, or just over four months, the researchers noted. Long-term treatment with corticosteroids can cause side effects, and the man gained 5 kg (about 11 pounds), but his blood sugar and blood pressure remained normal.
Another increase follows the end of steroid treatment
After prednisone was stopped, ALT levels rose again but the elevation resolved without further treatment. FIX activity remained stable overall, although it briefly peaked at the same time as ALT.
At 14 months after Hemgenix treatment, the patient had experienced no bleeding and had not needed FIX replacement treatment since the day after infusion. An assessment of his joint damage also showed no change.
The researchers questioned whether liver enzyme monitoring should be more frequent beyond the first three months, particularly for patients who have already needed corticosteroids for transaminitis.
“This case shows that [immunosuppression-based] management of transaminitis, apparently straightforward in trial protocols, can be difficult in practice,” the researchers wrote.
The researchers said that sharing real-world cases between treatment centers may help guide monitoring and treatment decisions until stronger evidence is available. Such communication may be “the most practical tool we have,” they concluded.
Three of the five authors reported advisory-board and speaking relationships with CSL Behring, which markets Hemgenix.
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