Gene Therapies for Fabry and Gaucher Disease Show Sustained Benefits in Early Trials

Gene therapies for two rare diseases showed sustained benefits in early-stage clinical trials, with all 11 Fabry disease patients treated with uniQure's AMT-191 able to stop enzyme replacement therapy, and four of six Gaucher disease patients treated with Spur Therapeutics' avigbagene parvec remaining off standard treatment for up to about two years.

uniQure's investigational gene therapy AMT-191 markedly boosted the levels of the enzyme whose deficiency causes Fabry disease in all patients dosed thus far in a small clinical trial. Further, each of the 11 adults with Fabry taking part in the Phase 1/2 study (NCT06270316) was able to stop enzyme replacement therapy (ERT), according to a company press release providing updates on the ongoing U.S. trial.

AMT-191 is an investigational one-time gene therapy designed to deliver a working copy of the gene that carries instructions for alpha-galactosidase A (alpha-Gal A). Its goal is to allow the body to make its own enzyme on an ongoing basis rather than relying on repeated infusions. The Phase 1/2 clinical trial is testing AMT-191 in men with Fabry disease, ages 18 to 50, all of whom had an inadequate response to ERT. The study is being conducted at eight sites across the U.S. and may still be recruiting participants.

The new data come from 11 patients treated at three different dose levels and followed for periods ranging from three months to longer than 1.5 years. These data show that AMT-191 treatment led to dose-dependent increases in alpha-Gal A activity. At the lowest dose, enzyme activity rose to between one and 16.2 times above the mean normal range. At the mid dose, activity rose to between 14.5 and 229.6 times, and at the highest dose, activity rose to between 58.7 and 143.6 times above the range. Alongside these enzyme changes, plasma lyso-Gb3 levels, a metabolite of Gb3, remained stable after dosing across all three dose groups, regardless of whether patients had previously been on ERT.

On safety, the therapy demonstrated a manageable profile across all dose levels, the developer reported. No serious adverse events (SAEs) related to AMT-191 occurred in the low- or mid-dose groups, and no new SAEs were seen at the high dose beyond the two cases previously reported last year. However, under the study protocol, additional dosing in the mid- and high-dose groups remains paused while the company further evaluates asymptomatic (symptom-free) liver enzyme elevations that occurred in two patients in the mid-dose group. These elevations were confirmed as dose-limiting toxicities, meaning they were significant enough to limit how much of the therapy could be safely given. Both cases resolved by the end of May following a course of immunosuppressive treatment, as called for in the study protocol.

Separately, avigbagene parvec, a one-time gene therapy being developed by Spur Therapeutics for Gaucher disease type 1, helped four of six adults in a Phase 1/2 study remain off their standard treatment for up to about two years, trial data show. While stopping treatment typically leads to a rapid increase in disease biomarkers and worsening symptoms, these patients showed improvements or stable clinical outcomes that were sustained throughout follow-up.

The findings, which come from the completed GALILEO-1 Phase 1/2 clinical trial (NCT05324943) and its ongoing long-term extension, GALILEO-2 (NCT06545136), were presented at this year's WORLDSymposium, held Feb. 2-6 in San Diego. The findings support the company's decision to move avigbagene parvec into a confirmatory Phase 3 clinical trial (NCT07223944), which is already underway and may support both accelerated and full approval for Gaucher disease type 1.

Avigbagene parvec, formerly known as FLT201, is designed to deliver a modified version of the GBA1 gene, enabling cells to produce a more stable version of glucocerebrosidase (GCase) that stays in circulation longer. In the GALILEO-1 trial, six adults with Gaucher disease type 1 received a single infusion of low-dose avigbagene parvec. All had been on ERT or SRT for at least two years before enrolling. Four patients were able to discontinue their standard treatments within about 11 weeks after receiving the gene therapy, while the remaining two continued on their prior therapy. All six later enrolled in the GALILEO-2 extension study, and have been followed for a total of 20 to 29 months.

Consistent with earlier results from those four patients, avigbagene parvec led to sustained increases in GCase activity and durable reductions in blood levels of lyso-Gb1, a biomarker of disease burden. On average, lyso-Gb1 levels dropped by 83%. Researchers also reported clearance of fat-laden cells from the bone marrow of one patient who had been on stable ERT/SRT for nine years. Patient-reported outcomes, measured using the 36-Item Short Form Survey, showed improvements in pain, fatigue, and mental health after treatment. Avigbagene parvec also led to sustained benefits in hemoglobin, the protein that carries oxygen in red blood cells, and platelets, the blood components that help blood clot. Spleen and liver volumes also remained stable.

Although two patients experienced increases in liver enzyme levels deemed related to the therapy, these resolved spontaneously or were managed with immune therapy. Infusions with the gene therapy were generally well tolerated, with no infusion-related reactions reported.