Disc Medicine, Inc. · NASDAQ:IRON
Disc Medicine — ASH 2021 (American Society of Hematology Annual Meeting)
13 slides from Disc Medicine's conference presentation, Nov 8, 2021
Slide 1: Proof of Mechanism Studies with Bitopertin, a Selective GlyT1 Inhibitor, in EPP and XLPP
Proof of Mechanism Studies with Bitopertin, a Selective Glycine Transporter 1 Inhibitor Under Development for the Treatment of Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLPP) Vu Hong, Sarah Ducamp, Dean Campagna, Min Wu, Pavan Reddy, Brian MacDonald, Mark Fleming, Maria G. Bec
Slide 2: Disclosure
Disclosure Disc Medicine provided research funding
Slide 3: Erythroid Heme Synthesis pathway
Erythroid Heme Synthesis pathway Fe
Slide 4: Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLPP)
Erythropoietic Protoporphyria (EPP) and EPP X-linked Protoporphyria (XLPP) XLPP Glycine + EPP and XLPP Patients Free PPIX in erythrocytes causes Glycine + Succinyl CoA photosensitivity Succinyl CoA and rarely liver disease ALAS2 ALAD ALAS2 ALAD FECH loss-of-function or ALAS2 gain- of-function mutati
Slide 5: SLC6A9 (GlyT1) is the Glycine Importer in Early Erythroid cells
SLC6A9 (GlyT1) is the Glycine Importer in Early Erythroid cells Glycine GlyT1 • GlyT1 supplies extracellular glycine for Glycine the initial step of heme biosynthesis in erythroid cells • The role GlyT2 plays in this process is uncertain Garcia-Santos et al, Haematologica 2017;102(8):1314-1323
Slide 6: Bitopertin: GlyT1 inhibitor
Bitopertin: GlyT1 inhibitor Glycine • Well-established tolerability GlyT1 Bitopertin profile in 4,000+ human subjects • Established modulation of Glycine heme synthesis • Hypothesis: by inhibiting glycine uptake into erythroid precursors, bitopertin can reduce the disease-causative PPIX accumulation
Slide 7: Generation of a K562-EPP Cell Model
Generation of a K562-EPP Cell Model 500 400 pmol/1x106 cells Free PPIX 300 ↑ PPIX (K562-EPP cell model) 200 Modified from: Gouya et al, Nat Genet 30, 27–28 (2002) 100 BLQ 0.5 0.0 WT EPP clone • K562-EPP clone with IVS3-48C/KO genotype was generated by CRISPR-Cas9 • LC-MS/MS was employed to measure P
Slide 8: Bitopertin Reduced PPIX in a K562-EPP Cell Model
Bitopertin Reduced PPIX in a K562-EPP Cell Model 100 100 80 Bitopertin 80 pmol/1x106 cells Free PPIX Bitopertin % remaining Heme ↓ 5-ALA 60 5-ALA 60 ↓ PPIX 40 40 Bitopertin 20 20 Heme unaffected 0 0 -12 -10 -8 -6 -12 -10 -8 -6 log[M] log[M] • Effects of Bitopertin on 5-ALA, PPIX and heme were measur
Slide 9: Generation of a CD34+ Model of EPP
Generation of a CD34+ Model of EPP Relative FECH mRNA 1.5 600 ↓ FECH ↓ FECH 400 PPIX (MFI) 1.0 ↑ PPIX mRNA FECH protein 0.5 200 GAPDH 0.0 0 L H L H TR C TR C FE FE C C sh sh sh sh • Human cord blood CD34+ cells transduced with lentiviral vectors expressing shRNA of FECH • ~75% reduction in FECH mRNA
Slide 10: Bitopertin Reduced PPIX in a hCD34+ Model of EPP
Bitopertin Reduced PPIX in a hCD34+ Model of EPP 450 400 350 Free PPIX 300 250 Bitopertin MFI 200 ↓ PPIX Bitopertin, EC50 = 32nM 150 100 50 0 10 -1 10 0 10 1 10 2 10 3 10 4 Concentration (nM) • Transduced cells were treated for 9 days with Bitopertin or GlyT2 inhibitor ORG-25543 in the presence of e
Slide 11: Bitopertin Treatment in Fechm1pas and Alas2Q548X Mice
Bitopertin Treatment in Fechm1pas and Alas2Q548X Mice • Fechm1Pas allele is an ethylnitrosourea • The Alas2Q548X animals were generated by (ENU)-induced missense mutation that employing CRISPR-Cas9 editing technology to retains approximately 5% residual introduce a known human gain-of-function ferro
Slide 12: Bitopertin Treatment in Fechm1pas and Alas2Q548X Mice
Bitopertin Treatment in Fechm1pas and Alas2Q548X Mice EPP mouse model XLPP mouse model (Fechm1pas /Fechm1pas) (Alas2Q548X/Y ) 100 15 90 80 Hemoglobin (g/dL) Free PPIX (MFI) 50 10 40 45% ↓ 30 73% ↓ 5 20 10 0 0 Control Bitopertin Control Bitopertin Diet 100ppm Diet 100ppm ↓ Free PPIX Hemoglobin ↓ Free
Slide 13: Conclusions
Conclusions • Bitopertin is a selective GlyT1 inhibitor with a well-established tolerability profile in human clinical trials • Bitopertin reduced free PPIX in K562 and CD34+ cellular models of EPP • Bitopertin reduced free PPIX in mouse models of EPP and XLPP without diminishing hemoglobin • Bitope
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