Source: FDA, National Drug Code (US) Revision Year: 2026
GENGLYCOS is an adeno-associated virus serotype 8 (AAV8) based gene therapy designed to deliver a copy of the glucose-6-phosphatase (G6PC) gene with native human G6PC promoter and enhancer elements to hepatocytes, resulting in the production of normally functioning G6Pase.
The change of cornstarch intake after GENGLYCOS administration was evaluated in Study 1 [see Clinical Studies (14)].
Pariglasgene brecaparvovec-opnr vector DNA levels were measured and quantified in blood and various shedding matrices using a quantitative polymerase chain reaction (qPCR) assay. This assay is sensitive and specific to pariglasgene brecaparvovec-opnr vector DNA, including DNA fragments with an intact target sequence.
Biodistribution of vector genome DNA was evaluated following a single intravenous administration of pariglasgene brecaparvovec-opnr in adult C57BL/6N mice at a dose of 1.8 × 1013 gc/kg. At 13 weeks post dose, vector genome DNA was detected in all major organs analyzed, with the highest quantities detected in the liver followed by lower levels in the kidney, lung, heart, gonads, and spleen. The expression of human G6PC mRNA transcripts was primarily detected in the liver, with at least 100-fold higher level than those measured in extrahepatic tissues.
Vector genome determination in blood and vector shedding in urine, stool, saliva, and semen was evaluated in mice up to 90 days following an intravenous administration of pariglasgene brecaparvovec-opnr at 1.8 × 1013 gc/kg. The highest concentration of vector genome DNA was found in blood followed by stool, urine, semen, and saliva. Vector genome DNA dropped below the limit of detection in saliva after 1 week, in stool and urine after 1 month, and in semen and blood after 3 months.
Biodistribution of vector genome DNA in blood and vector shedding in urine, stool, and saliva were assessed in 12 patients at baseline and on follow-up (Day 2, Week 4, 6, 12, 24, 36, and 52 for blood samples, Day 4 and 12, Week 4, 6, and 12 for other urine, stool and saliva samples) until three consecutive measurements were below the limit of detection (LOD). Peak levels of vector genome DNA occurred at the first post-dose assessment on Day 2 in blood and between Day 3 and Day 13 in stool, saliva, and urine. At a dose of 6.0 × 1012 gc/kg measured using qPCR (which is equivalent to the recommended dose of 1.0 × 1013 gc/kg measured using digital droplet polymerase chain reaction (ddPCR), the highest individual peak concentration of vector genome DNA observed in blood was 6.8 × 107 gc/100 ng and in the stool was 1.7 × 106 gc/100 ng. Blood vector genome DNA in most patients reached below the limit of detection (LOD = 10 copies of target DNA/100 ng DNA) approximately 24 weeks post infusion. Clearance of vector DNA was defined as measurement of 3 consecutive results below the limit of detection. Based on this definition, vector genome DNA was cleared from saliva within 7 weeks and from urine and stool within 13 weeks post-infusion.
No dedicated pharmacokinetic studies using pariglasgene brecaparvovec-opnr have been conducted in special populations.
Carcinogenicity studies have not been conducted with GENGLYCOS.
Liver samples collected from offspring of C57BL/6N mice administered pariglasgene brecaparvovec-opnr at a dose of 1.3 × 1014 gc/kg showed no differences in integration patterns (using target enrichment sequencing) in the F1 offspring of treated vs untreated mice and therefore and correspondingly provide no evidence of germline transmission, despite vector DNA detection in the ovaries and testes of adult mice. At this dose level, there were no adverse effects on mating, fertility, pregnancy, lactation, or litter viability. Administration of pariglasgene brecaparvovec-opnr showed the presence of vector DNA in the blood (males only), liver, testes, and ovaries of treated mice; however, no vector DNA was observed in the blood and liver from the offspring, indicating no germline transmission to F1 offspring.
A single intravenous administration of up to 1.2 × 1014 gc/kg of pariglasgene brecaparvovec-opnr in C57BL/6 mice, followed by an observation period of up to 13 weeks, resulted in dose-dependent elevations in transaminases (ALT and AST) at Week 4 that were almost resolved by Week 13. Lymphoid hyperplasia was observed in the spleen and lymph nodes, as well as single cell necrosis/apoptosis with Kupffer cell hyperplasia in the liver, at 1.2 × 1014 gc/kg at Week 4 and was completely resolved by Week 13. Minimal neuronal degeneration in the cervical or thoracic dorsal root ganglia was observed in 2 male mice at 1.2 × 1014 gc/kg at Week 4; this change was not observed in male or female mice at Week 13.
A single intravenous administration of up to 1.3 × 1014 gc/kg of pariglasgene brecaparvovec-opnr in juvenile C57BL/6N mice, followed by an observation period of 4 or 13 weeks, resulted in moderate increases in transaminases (ALT and AST), increased spleen weights, and hepatocellular and/or single cell necrosis with mixed inflammatory cells in mice at doses of ≥1.8 × 1013 gc/kg at Week 4. These findings trended towards recovery or had full recovery by Week 13. These findings were observed at a dose which is approximately 11- to 12-fold above the recommended dose of 1.0 × 1013 gc/kg.
A single intravenous administration of up to 1.3 × 1014 gc/kg of pariglasgene brecaparvovec-opnr in cynomolgus monkeys, followed by an observation period of 26 weeks, resulted in pariglasgene brecaparvovec-opnr-related changes limited to minimal increases in ALT at Week 1 and 13 which were no longer present by Week 26.
The efficacy of GENGLYCOS was evaluated in a multicenter, randomized, double-blind, placebo- controlled (Week 1 to Week 48), cross-over (Week 48 to Week 96) study (Study 1, NCT05139316).
A total of 49 patients were randomized in a 1:1 ratio to receive a single intravenous infusion of either GENGLYCOS at a dose of 1.0 × 1013 genome copies per kilogram (gc/kg) body weight or placebo. Patients weighing >87 kg were dosed at the 87 kg weight. Three patients discontinued prior to receiving any treatment and the remaining 46 patients received the assigned treatment and were included in the efficacy analysis. Patients with detectable baseline anti-AAV8 total antibodies were excluded.
The demographic characteristics of the efficacy analysis population (N=46) were as follows: the mean age was 20.5 years (range 8 to 37 years), 27 (58.7%) patients were male, 41 (89.1%) patients were White, 2 (4.3%) patients were Asian, 3 (6.5%) patients were of unknown race or did not report race, and 6 (13.0%) patients were Hispanic or Latino.
Prior to randomization, all patients underwent a 16-week nutritional optimization and stabilization period during which cornstarch dosing and dietary intake were adjusted.
The primary efficacy endpoint was the percent change from baseline to Week 48 in total daily cornstarch (CS) intake in grams (g). Daily CS intake was recorded by patients and caregivers in an electronic diary and was prescribed and adjusted by the principal investigator based on blinded weekly assessments of continuous glucose monitoring data. The secondary efficacy endpoints included the change from baseline in the number of daily CS doses and the percent of glucose values in the hypoglycemic range (<70 mg/dL), averaged over a 4-week period.
The efficacy results from Study 1 are summarized in Table 5 below.
Table 5. Summary of Efficacy Results: Study 1 (N=46):
| Efficacy Endpointa (Week 48) | GENGLYCOS (N=21) | Placebo (N=25) | Difference (95% CI) |
| Daily Cornstarch Intake | |||
| Baseline; Mean (SD) (g) | 293.9 (83.2) | 271.7 (109.0) | |
| Percent Change from Baseline, LS Mean (SE) | -41.1% (3.9%) | -10.2% (3.6%) | -30.9% (-40.8%, -20.9%) |
| Number of Daily Cornstarch Doses | |||
| Baseline; Mean (SD) | 5.8 (1.3) | 5.1 (1.4) | |
| Change from Baseline, LS Mean (SE) | -1.2 (0.2) | -0.2 (0.2) | -1.0. (-1.4, -0.5) |
| Percentage of Glucose Values in the Hypoglycemic Range (<70 mg/dL) | |||
| Baseline; Mean (SD) | 2.5% (2.5%) | 1.9% (2.2%) | |
| Change from Baseline, LS Mean (SE) | 3.1% (0.8%) | 0.1% (0.8%) | 3.1% (0.9%, 5.2%) |
CI=Confidence Interval; LS=Least Square; SD=Standard Deviation; SE=Standard Error.
a The LS mean, SE, and 95% CI were estimated using a mixed model for repeated measures (MMRM).
In 15 of the 21 patients treated with GENGLYCOS with available data at Week 96, the observed mean (SD) percent change from baseline (pre-dosing) at Week 96 in daily cornstarch intake was -60.8% (19.7%) and the observed mean (SD) change from baseline (pre-dosing) at Week 96 in the number of daily cornstarch doses was -2.0 (1.3). In 19 of the 21 patients treated with GENGLYCOS with available data at Week 96, the observed mean (SD) change from baseline (pre-dosing) at Week 96 in percentage of glucose values in the hypoglycemic range (glucose <70 mg/dL) was 5.2% (6.3%).
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