Enzyme Replacement Therapy Proves Safe and Stable in Chinese Patients with Fabry Disease

Fabry disease is one of medicine’s crueler inheritances. Caused by variants in the GLA gene on the X chromosome, the condition leaves the body starved of a working enzyme called alpha-galactosidase A. Without that enzyme, a fatty substance known as globotriaosylceramide, or Gb3, together with its soluble cousin globotriaosylsphingosine, or lyso-Gb3, accumulates inside lysosomes, the recycling compartments of virtually every cell in the body. Over years and decades, the buildup damages the kidneys, thickens the heart muscle, and attacks the blood vessels of the brain, producing kidney failure, cardiomyopathy, stroke, chronic neuropathic pain, and a shortened life expectancy. Because the disease is X-linked, male patients, who carry only a single copy of the gene, typically endure a more severe and rapidly progressive course than females, who have a second, sometimes partially functioning copy. Now a new phase 3 trial conducted across six centers in China has delivered the most comprehensive picture yet of how the standard enzyme replacement therapy performs in this population, and the results are reassuring.

The drug at the center of the study is agalsidase alfa, a recombinant form of the very enzyme that Fabry patients lack. Approved for long-term treatment of Fabry disease in China by the National Medical Products Administration in 2020 and added to the National Reimbursement Drug List in 2022, the therapy is given as a 0.2 milligram per kilogram body weight intravenous infusion over 40 minutes every other week. The idea is elegantly simple: supply the missing enzyme from outside, let it be taken up by cells, and allow it to cleave the accumulating Gb3 before it does irreversible damage. Yet approval in China rested largely on global clinical trials, and hard clinical data in Chinese patients, spanning safety, efficacy, and pharmacokinetics, remained sparse. That gap matters because a recent newborn screening study in Shanghai reported a birth prevalence of Fabry disease of roughly one in 6,264, about one in 3,300 males, suggesting the condition is far more common in China than the global estimate of one in 40,000 to one in 170,000 had implied.

To close that gap, an open-label, non-randomized, single-arm phase 3 study, registered as NCT04974749 and designed as a post-approval commitment, enrolled 20 treatment-naive Chinese patients aged 7 to 65 years between May 2022 and January 2024. Every participant had a confirmed diagnosis documented by a pathogenic GLA variant and, in males, reduced alpha-galactosidase A activity, and none had previously received any Fabry-specific therapy, including enzyme replacement, chaperone treatment, or substrate reduction. After screening and baseline visits, patients received the labeled regimen for up to 52 weeks, with safety and efficacy assessments at weeks 8, 16, 28, 40, and 52. Compliance was impressively high at a mean of 98.9 percent, and 16 of the 20 patients never missed a single infusion, providing unusually clean exposure data for a rare-disease trial.

The primary endpoint was the incidence of serious treatment-emergent adverse events, and here the verdict was favorable. Only two patients, 10 percent of the cohort, experienced a serious adverse event: one case of sepsis in a male patient under 18 and one ectopic pregnancy in an adult female. Neither was judged clearly related to the drug. No deaths occurred, and no adverse event forced anyone off treatment. Every patient reported at least one treatment-emergent adverse event of some kind, but 98.2 percent of these were mild or moderate, and only nine patients, 45 percent, had any event the investigator considered related to agalsidase alfa. The most frequently reported events reflected the timing of the trial rather than the therapy: 13 patients, 65 percent, contracted COVID-19 during the pandemic-era study period, while cough, upper respiratory tract infections, and fever were also common. Infusion-related reactions occurred in five patients and were overwhelmingly mild, with symptoms such as nausea, palpitations, urticaria, pruritus, and chest discomfort; none were serious and none led to discontinuation.

One of the most scientifically interesting threads of the study concerns immunogenicity, the immune system’s tendency to fight back against therapeutic proteins. At baseline, all patients were negative for anti-drug antibodies. During treatment, six male patients, 30 percent of the cohort and five of them under 18, developed binding anti-drug antibodies, and five of those also developed neutralizing antibodies that could, in principle, inhibit the enzyme’s activity. All were persistent for the remainder of the study. The concentration of affected patients among males fits a broader pattern: individuals with classic Fabry disease produce no endogenous enzyme, so their immune systems can perceive the infused recombinant protein as foreign. Crucially, however, the antibodies did not appear to undermine the therapy. Every patient who developed antibodies still achieved a reduction in plasma lyso-Gb3 of more than 45 percent from baseline by week 52, and the development of antibodies was not associated with infusion reactions or with any obvious loss of treatment effect, though the small sample size prevents firm conclusions.

On the efficacy front, the story is one of stability, which in a progressive degenerative disease is precisely the goal. Estimated glomerular filtration rate, the standard measure of kidney filtering capacity, remained essentially unchanged over 52 weeks, with a mean change from baseline of 4.1 milliliters per minute per 1.73 square meters, and the urine protein-to-creatinine ratio, a marker of kidney damage, stayed stable for most patients. Cardiac parameters held steady as well: the left ventricular mass index, which quantifies thickening of the heart muscle, changed by a mean of just 0.56 grams per meter to the power of 2.7, and the left ventricular ejection fraction, a measure of pumping strength, shifted by only 0.8 percentage points. Notably, among the three patients whose hearts had already hypertrophied before treatment, with a baseline left ventricular mass index of at least 50, the index fell by a mean of 13.16, a hint, though the authors caution the subgroup is too small to interpret, that early treatment may allow pathological cardiac remodeling to recede.

The molecular readouts told an equally compelling story. Plasma lyso-Gb3, the most sensitive biochemical marker of Fabry disease activity, dropped sharply by week 8 and remained suppressed through week 52, with mean percentage reductions of roughly 36 to 38 percent across the whole cohort. The declines were far more dramatic in younger patients and in males: in males, mean levels plunged from about 100.6 nanograms per milliliter at baseline to 37.2 by week 8 and stayed there. Among the seven patients who reported neuropathic pain at baseline, six of them children, both pain severity and pain interference scores improved at every post-baseline measurement, with the mean interference score falling by 3.64 points by week 52. No hearing loss was detected by audiology testing in the pediatric subgroup, an important finding since sensorineural hearing loss is a feared complication of the disease.

The pharmacokinetic data, the first ever collected in this population, confirmed that the drug behaves in Chinese patients much as it does elsewhere. Maximum serum concentration was typically reached by the end of the 40-minute infusion, and overall drug exposure, measured as both the area under the concentration-time curve and peak concentration, was generally similar at week 0 and week 28, indicating no systematic accumulation or loss of exposure over time. Children cleared the enzyme somewhat faster than adults, with slightly higher serum clearance and a shorter terminal half-life, a pattern common to many biologics and one that did not translate into differences in clinical response. In two pediatric patients with high antibody titers, serum drug levels were lower at week 28 than at baseline, but in the other four antibody-positive patients concentrations were unchanged, and the study found no consistent link between antibody development and altered pharmacokinetics.

The trial’s authors, led by Hong Ren and Nan Chen of Ruijin Hospital in Shanghai, are candid about its limitations: the open-label, single-arm design invites bias, 20 patients is small, GLA variants and disease phenotypes were not recorded, and patients with severe kidney disease were excluded. Yet the study still stands as the largest interventional trial of agalsidase alfa in Chinese patients to date and the first to characterize its pharmacokinetics, pharmacodynamics, and immunogenicity in this population. With Fabry disease now on China’s first national list of rare diseases and newborn screening revealing far more cases than historically assumed, the findings arrive at a pivotal moment. They reinforce the post-approval use of agalsidase alfa in China, extend the global evidence base for enzyme replacement therapy, and, perhaps most importantly, underscore a message that echoes throughout the rare-disease literature: for progressive lysosomal disorders, the earlier treatment begins, in males and females alike, the more organ function can be preserved.

Subject of Research: A phase 3 trial of agalsidase alfa enzyme replacement therapy in treatment-naive Chinese patients with Fabry disease

Article Title: Safety, Efficacy, and Pharmacokinetics of Agalsidase Alfa in Treatment-Naive Chinese Patients with Fabry Disease: 52-Week Phase 3, Open-Label, Single-Arm Study

Article References: Ren, H., Mao, J., Wang, R., Chen, Y., Qiu, Z., Peng, J., Ouyang, Y., Ji, J., Botha, J., Chen, G., & Chen, N. (2026). Safety, Efficacy, and Pharmacokinetics of Agalsidase Alfa in Treatment-Naive Chinese Patients with Fabry Disease: 52-Week Phase 3, Open-Label, Single-Arm Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03688-z

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03688-z

Keywords: Fabry disease, agalsidase alfa, enzyme replacement therapy, lysosomal storage disease, alpha-galactosidase A, GB3, lyso-Gb3, phase 3 trial, pharmacokinetics, anti-drug antibodies, rare disease, China