Etranacogene dezaparvovec safe, effective for haemophilia B patients with HIV

Treatment with etranacogene dezaparvovec demonstrates efficacy with a favourable safety profile in a subset of adult patients with severe or moderately severe haemophilia B living with HIV, according to a recent study presented at ASH 2023.

“People living with HIV represent an important subset within the haemophilia community,” said the researchers, led by Dr Steven Pipe from the University of Michigan in Ann Arbor, Michigan, US.

“Concerns about increased hepatotoxicity of liver-directed adeno-associated viral (AAV) vectors in patients receiving potentially hepatotoxic HIV medications (eg, efavirenz) have excluded this population from participating in many of gene therapy haemophilia trials,” they added. 

Pipe and his team conducted this post hoc analysis of the phase IIb and phase III HOPE-B trials, which evaluated the efficacy and safety of etranacogene dezaparvovec (formerly AMT-061), an AAV5 vector containing a codon-optimized, highly active factor IX (FIX) Padua R338L transgene under the control of the liver-specific promoter LP-1.

Patients with moderate-to-severe haemophilia B received a single intravenous administration of 2x10¹³ gc/kg etranacogene dezaparvovec. Those with HIV infections uncontrolled by antiviral therapy as shown by CD4+ counts ≤200/µL were excluded from the analysis.

The research team also assessed individual safety and efficacy outcomes of patients with controlled HIV infection treated with etranacogene dezaparvovec. A central laboratory analysed the levels of liver enzyme and aPTT-based FIX. Finally, results were reported via descriptive statistical analyses, with a data cutoff at 3 years after administration of etranacogene dezaparvovec.

Five of the 57 patients treated with etranacogene dezaparvovec in the phase IIB and phase III HOPE-B trials had comorbid HIV infection (median age 49 years). Of these, four had a history of treated hepatitis C virus with a negative viral load, and three had pre-existing AAV5 neutralizing antibodies (median titre 20). [ASH 2023, abstract 2256]

Bleeding event

Compared with previous FIX prophylaxis regimen with extended half-life FIX products, treatment with etranacogene dezaparvovec reduced the annualized bleeding rate (ABR) for all patients with controlled HIV (median ABR during FIX prophylaxis, 5).

Two patients had no bleeding events at 36 months after being treated with etranacogene dezaparvovec (median ABR post-treatment, 0.64). FIX activity levels in these patients were evident from week 3 and were maintained in the mild/normal range for four (80 percent) participants with controlled HIV.

At 3 years post-treatment, the median uncontaminated endogenous FIX was 32.3 percent. Two patients had contaminated FIX measurements at 36 months: one returned to prophylaxis after 24 months, and the other took on-demand replacement therapy a day prior to the 36-month visit.

Serious treatment-related adverse events (TRAEs) were not recorded, with only seven TRAEs observed in three participants.

In addition, annualized FIX use decreased between 34 percent and 100 percent, with three patients receiving no FIX infusions up to 36 months post-treatment.

“These results support the use of etranacogene dezaparvovec, the first approved liver-directed AAV-based gene therapy product for the treatment of patients with severe or moderately severe haemophilia B in the US and Europe, for eligible patients with controlled … HIV infection,” the researchers said.

“Owing to the small number of patients with HIV being enrolled in trials, long-term collection of data and special attention in the real-world setting is recommended,” they added.