AMT-191 Phase I/IIa Update: Durable α‑Gal A, Hepatic Signals, and Nephrology Implications

Preliminary open-label data from the AMT-191 Phase I/IIa program in Fabry disease highlight two operationally linked signals: durable, dose-dependent supraphysiologic α‑galactosidase A (α‑Gal A) activity—enabling some participants to discontinue enzyme replacement therapy (ERT)—and asymptomatic Grade 3 ALT/AST elevations that prompted independent review and pauses in additional dosing at higher dose levels.

For nephrology investigators, the relevance sits at the intersection of organ-domain need and trial execution. Fabry kidney involvement is a major driver of morbidity, and background ERT schedules, withdrawal rules, and safety-monitoring requirements can materially shape how renal status is interpreted early after gene transfer. In practice, this update sharpens a core tension sites must manage: biologic activity that may change ERT use, alongside hepatic monitoring considerations that can slow enrollment and reconfigure on-study workflows.

The efficacy-adjacent signal in this sponsor update is a dose-response pattern. Eleven treated adult male participants were distributed across three intravenous dose cohorts (2×10^13, 4×10^13, and 6×10^13 gc/kg). α‑Gal A activity was reported as elevated in all dosed participants, with fold increases above mean normal rising with dose and durability described across observed windows, including follow-up exceeding one year in one patient at the highest dose. Plasma lyso‑Gb3 was described as stable post-dose across cohorts regardless of ERT status—biochemical corroboration that remains insufficient, in a small open-label dataset, to establish organ outcome benefit. The early readout supports durable expression signals over initial follow-up, while remaining exploratory and not outcome-defining.

Renal endpoints are not characterized in the update. No on-study trajectories are provided for estimated glomerular filtration rate (eGFR), albuminuria/proteinuria, or kidney clinical outcomes. That gap matters because renal stability and progression are pivotal questions in Fabry trials and are hard to interpret when background therapy changes and follow-up is short relative to typical kidney event rates. Renal interpretation in this program will therefore depend on prespecified renal assessments over planned follow-up, rather than on biochemical signals alone.

ERT transition rules are protocol-driven and threshold-based, creating an analytically important “bridge period” even when α‑Gal A expression appears robust. Six of 11 dosed participants reportedly discontinued ERT after meeting prespecified withdrawal criteria that included elevated α‑Gal A activity; others continued regular ERT until criteria were met. The update does not specify which dose cohorts contributed to ERT discontinuations, so cohort-level attribution is not supported by the available description. This design makes ERT withdrawal both a gate for effectiveness/safety and a time-varying background exposure that can confound short-term renal assessments—reinforcing the need for tight coordination of infusion calendars, laboratory review workflows, and AE attribution during the transition window.

Hepatic safety is the near-term constraint on dose escalation and a major driver of monitoring burden. The sponsor reports asymptomatic Grade 3 transaminase elevations in higher-dose cohorts (two patients at 4×10^13 gc/kg and one previously at 6×10^13 gc/kg). An Independent Data Monitoring Committee review confirmed dose-limiting toxicity and triggered a pause in additional dosing in the mid- and high-dose cohorts pending further evaluation. Corticosteroids were used for management; affected patients were reported to have responded and to remain in follow-up. The update does not report event timing relative to dosing, limiting inference about onset patterns. For trial teams, the message is clear: hepatic monitoring intensity and immune/inflammatory management planning are central to near-term feasibility.

Operations follow from the study’s current posture: a multi-center, open-label trial in adult males with planned follow-up to 24 months, with additional dosing paused in the mid/high cohorts while the hepatic signal is evaluated. Sites typically translate evolving safety signals into concrete, protocol-driven steps—more frequent AST/ALT checks around dosing windows, predefined thresholds that trigger escalation or steroid initiation, rapid communication pathways for lab abnormalities, and consistent attribution language in source documentation—while awaiting sponsor direction on whether monitoring schedules, eligibility criteria, or dose-escalation rules will change. Screening and consent conversations may also need to reflect the possibility of asymptomatic Grade 3 liver enzyme abnormalities and cohort-level dosing pauses that affect timing expectations. For nephrology sites, the next meaningful updates are likely to involve hepatic monitoring schemas and how renal endpoints will be captured and interpreted during ERT transitions across the 24-month follow-up window.