FAYUVI Suspension for infusion Ref.[116937] Active ingredients: Rebisufligene etisparvovec

In Study 1, the mean (standard deviation [SD]) baseline cerebrospinal fluid heparan sulfate (CSF HS) concentration in the modified intention-to-treat (mITT) population (N=17) was 335.3 (156.9) nmol/L. The mean percent change from baseline (SD) in CSF HS concentration in the mITT population was -58.5% (13.84) at Month 1 post-FAYUVI infusion, -73.6% (11.12) at Month 6, -66.7% (13.46) at Month 12, and -57.1% (22.48) at Month 24 (n=16).

CSF HS exposure represents the time-normalized area under the curve (AUC) of the percent change from baseline in CSF HS concentration. In Study 1, the mean (SD) change from baseline in CSF HS exposure was -29.25% (6.92) at Month 1, -60.17 (9.43) at Month 6, -65.02 (9.42) at Month 12, and -63.78% (11.56) at Month 24 in the mITT population (N=17).

At Month 24, 93.8% of patients (15 of 16) in the mITT population maintained a reduction in CSF HS exposure of at least 50%.

Vector Distribution and Vector Shedding

Nonclinical Data

Biodistribution of vector genome DNA was evaluated following a single intravenous administration in healthy C57BL/6 mice at dose levels of 5.0 × 10¹³ vg/kg and 2.0 × 1014 vg/kg. At 26 weeks post administration of 5.0 × 10¹³ vg/kg to adult mice, vector genome DNA was detected in all major organs analyzed, with the highest quantities detected in the liver followed by lower levels in the heart, uterus with cervix, kidney, lung, brain, lymph node, spleen, and gonads. At 90 days post administration of 2.0 × 1014 vg/kg to adolescent and neonatal mice, vector genome DNA was detected in all major organs analyzed, with the highest quantities detected in the liver and heart followed by lower levels in the lung and kidney. Human SGSH mRNA transcripts were measured in the liver and brain, with highest expression in the liver.

Clinical Data

Biodistribution of vector genome DNA in plasma and vector shedding in stool, urine, and saliva were assessed at multiple time points in 22 patients following a single intravenous administration of FAYUVI at a dose of 3.0 × 10¹³ vg/kg in Study 1. In general, peak levels of vector genome DNA occurred within a median duration of 3 days for plasma, urine, saliva and stool after infusion. Peak vector genome DNA concentrations were highest in plasma followed by stool, saliva, and urine. After reaching the maximum in a matrix, the vector genome DNA concentration declined steadily.

Clearance of vector DNA was defined as measurement of at least 2 consecutive results below the lower limit of quantification (LLOQ; 5000 vg/mL for urine, saliva, plasma and 4000 vg/mL for stool samples). Based on this definition, vector genome DNA was cleared from urine, saliva, and stool within median values of 15, 30, and 84 days post-infusion, respectively. All patients achieved clearance of vector DNA in saliva, while 96% and 82% of the patients cleared the vector DNA in urine and stool, respectively, based on available data.

Pharmacokinetics in Specific/Special Populations

No dedicated pharmacokinetic studies using rebisufligene etisparvovec have been conducted in special populations.

No animal studies have been performed to evaluate the effects of FAYUVI on carcinogenesis, mutagenesis, or impairment of fertility.

Animal toxicology studies were conducted in healthy C57BL/6 mice at dose levels up to 2.0 x 10¹⁴ vg/kg. No adverse FAYUVI-related toxicological findings were observed.

The efficacy of FAYUVI was evaluated in a multi-center, open-label, single-arm, single dose, dose-escalation study (Study 1; NCT02716246) and a long-term follow-up study (Study 2; NCT04360265) in pediatric patients with mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome type A).

The primary efficacy population includes the modified intention-to-treat (mITT) population, which included 17 patients from Study 1 who received the recommended dose of 3.0 × 10¹³ vg/kg and were ≤2 years of age at treatment, or >2 years of age with a Cognitive Developmental Quotient (DQ) of ≥60 (indicating mild or moderate neurodevelopmental impairment) at treatment calculated by the Bayley Scales of Infant and Toddler Development - Third Edition (Bayley-III) or the Mullen Scales of Early Learning. Baseline anti-AAV9 total antibody titers were <1:100 at the time of enrollment. All patients received a prophylactic regimen of corticosteroids prior to FAYUVI. Patients were observed for 24 months in Study 1 with subsequent enrollment in Study 2. Across studies, the median duration of follow-up was 4.2 years (range: 2.9 to 7.8 years), with 14 of 17 patients reaching the age of 5 years (60 months).

Population characteristics are as follows: mean age at treatment 21.8 months (range: 3.0 to 32.9 months), mean weight at baseline 13.1 kg (range: 3.9 to 17.5 kg); 65% male; 100% White; and 12% Hispanic or Latino. Mean Bayley-III Cognitive raw score was 47.6 (range: 3 to 69) at baseline (n=14).

Efficacy was assessed based on the difference in mean change in Bayley-III Cognitive Scale raw score between 24 to 60 months of age (chronological age) between treated and natural history patients. The Bayley-III Cognitive subtest assesses sensorimotor development, exploration and manipulation, object relatedness, concept formation, memory, and other aspects of cognitive processing. Each item is scored 0 or 1, and scores range from 0 to 91 with higher scores indicating higher skill level. FAYUVI-treated patients from the mITT population (N=17) were compared to untreated patients with MPS IIIA from an external, natural history control (N=27).

Population characteristics for the natural history control population were as follows: mean age at enrollment 38.3 months (range: 12 to 58 months); 78% male; and 48% White and not Hispanic or Latino, with race and ethnicity not reported in 52%. Mean Bayley-III Cognitive raw score was 55.1 (range: 24 to 76) at baseline.

There was a statistically significant 23.5-point difference in the mean change in Bayley-III Cognitive raw score from 24 to 60 months of age favoring FAYUVI-treated patients in the mITT population (see Table 4) reflecting gain or maintenance of developmental skills in the treated population versus loss of developmental skills in the untreated natural history population.

Table 4. Mean Change^a in Bayley-III Cognitive Raw Score from 24 to 60 Months of Age (FAYUVI [mITT] and Natural History Populations):

CI=confidence interval; mITT=modified intention-to-treat; SE=standard error
^a Least squares mean changes were based on a non-linear mixed effects model adjusted for chronological age (months).
^b p-value is based on a non-linear mixed effects model with response variable Bayley-III Cognitive raw score and with chronological age (months) as a covariate.