eP280: Continued improvement in adults with acid sphingomyelinase deficiency after 2 years of olipudase alfa in the ASCEND placebo-controlled trial

Acid sphingomyelinase deficiency (ASMD), also historically known as Niemann-Pick disease A (OMIM #257200) and B (OMIM#607616), is a rare debilitating lysosomal storage caused by pathogenic variants in SMPD1 gene. Deficient activity of the enzyme acid (ASM) leads to sphingomyelin accumulation various organs. Visceral manifestations ASMD include interstitial lung pulmonary dysfunction, splenomegaly, hepatomegaly, dyslipidemia, thrombocytopenia, anemia are present across phenotypes (ASMD type A, A/B). In more severe cases A), there central nervous system manifestations. No disease-specific treatment currently approved for patients with ASMD. Olipudase alfa, an intravenous-recombinant-human ASM, late-stage development (Sanofi Genzyme) non-central-nervous-system children adults. Two open-label trials, phase 1b trial 5 adults (NCT01722526) 1/2 20 chronic (ASCEND-Peds, NCT02292654) demonstrated improvement function, reduction liver spleen volume, reversal decreased biomarkers, children, improved growth. 2/3 placebo-controlled trial, ASCEND study (NCT02004691) 36 who had splenomegaly has completed its primary analysis. Olipudase-alfa-treated compared placebo-treated (1:1 randomization) statistically significant increases percent-predicted diffusing capacity carbon monoxide (DLCO) decreases volume after 1 year placebo or olipudase alfa. Thirty-five continued extension including 17 18 initially received first all Here we report Year 2 results former group alfa initial years treatment. All underwent gradual dose-escalation 3.0 mg/kg every weeks approximately 14 when starting Efficacy outcomes DLCO, high-resolution computerized tomography (HRCT) scores ground glass appearance, histopathologic clearance liver, platelet count, plasma lyso-sphingomyelin, lipid profile. Change from baseline presented least-square mean (analysis covariance [ANCOVA]) percent change ± standard error (SEM), except which ANCOVA absolute baseline, tissue area occupied changes deviation (SD). Absolute values at Baseline, 1, SD (Table). Overall, 33 35 ASCEND; one patient withdrew due COVID-19 travel restrictions, continuing consent. restrictions resulted least missed assessment six patients. 2, improvements paralleled analysis while clinical For group, DLCO increased 28.0 ±6.2% (n=10); 36.0 ±3.0% (n=11); 30.7 ±2.5% (n=11), count 21.7 ±6.4% (n=15). treatment, 22.2 ±3.4% (n=17) 28.5±6.2% 39.5 ±2.4% 47.0 ±2.7% (n=14) 2; 27.8 33.4 ±2.2% 16.6 ±4.0% (n=18) 24.9 ±6.9% (n=13) 2. HRCT appearance score 0.30 ±0.5 0.45 ±0.13 0.48 ±0.07 (n=16) receive Liver was 93.3 ±5.0% (n=10) 92.7 ±5.8% 98.4 ±2.0% Plasma lyso-sphingomyelin 79.4 ±11.3% 78.0 ±11.1% 64.4 ±28.5% (n=15) alfa; several transient infusions. Alanine aminotransferase 45.2 ±34.4% 36.5 ±8.4% 32.0 ±10.2% (n=12) high-density lipoprotein cholesterol (HDL-C) 59.7 ±9.7% low-density (LDL-C) 27.5 ±6.8% HDL-C 40.0 ±10.5% LDL-C 25.8 ±4.8% 23.0 ±7.1% 99% treatment-emergent adverse events were mild moderate, treatment-related serious event (extrasystoles previously documented cardiomyopathy). discontinued event. During ASCEND, crossing over same magnitude time course seen receiving year, olipudase-alfa sustained further improvements. reduced plasma. Clinically, function dyslipidemia up years. These consistent published 30- 42-month data reported long-term Phase study. Treatment reduces efficacy.Tabled 1ParameterPlacebo-Olipudase (N=18) (Mean ±SD)Olipudase alfa-olipudase ±SD)Trial BaselineYear 1Year 2Trial 2% predicted DLco48.5 10.849.9 ±11.161.9 ±11.449.4 11.059.4 ±12.566.9 ±15.4(n=18)(n=17)(n=10)(n=18)(n=17)(n=10)Spleen (multiples normal)11.2 3.811.2 ±4.27.7 ±2.911.7 4.97.2 ±3.66.0 ±2.7(n=18)(n=17)(n=11)(n=18)(n=18)(n=14)Liver normal)1.62 0.51.6 ±0.51.1 ±0.31.44 0.31.0 ±0.21.0 ±0.1(n=18)(n=17)(n=11)(n=18)(n=17)(n=14)Platelet (109/L)115.6 36.3120.2 43.1140.0 50.8107.2 26.9123.1 25.8133.6 29.6(n=18)(n=16)(n=15)(n=18)(n=18)(n=13)Lung score0.53 ±0.60.70 ±0.70.22 0.40.65 ±0.70.15 ±0.30.13 ±0.3(n=18)(n=17)(n=14)(n=18)(n=18)(n=16)ALT (IU/L)44.7 ±30.842.2 ±25.417.3 ±6.840.8 ±28.320.5 ±9.919.7 ±8.5(n=18)(n=16)(n=15)(n=18)(n=18)(n=12)HDL (mg/dL)20.7 ±9.819.9 ±7.930.7 ±12.723.8 ±8.431.5 ±9.438.6 ±11.2(n=18)(n=16)(n=14)(n=18)(n=18)(n=12)LDL (mg/dL)154.8 ±65.1137.3 ±34.0106.5 ±36.8137.4 ±28.699.5 ±27.3105.5 ±41.91.0 (n=17)(n=15)(n=14)(n=18)(n=18)(n=12) Open table new tab