PosterA Novel Title Small Here-Molecule PPARδ Modulator for the Treatment of Fatty Acid Oxidation Disorders Matthew Goddeeris, PhD1, Andrew Basinski, BS1, Jennifer Truong, BS1, Michael Bennet, PhD2, Nicola Longo, MD, PhD3, Catherine Kochersperger, MS4, Al-Walid Mohsen, PhD4, Jerry Vockley, MD, PhD4, Yoh Terada, PhD5, Mike Patane, PhD1, Dominique Stickens, PhD1, Effie Tozzo, PhD1

1 Mitobridge, Inc., 1030 Massachusetts Avenue, Cambridge MA 02138. 2 University of Pennsylvania School of Medicine, Depts. of Pathology and Laboratory Medicine, Philadelphia, PA 19104, USA. 3 University of Utah, Departments of Pediatrics and Pathology, Salt Lake City, UT 84132, USA. 4 University of Pittsburgh School of Medicine, Dept. of Pediatrics, Pittsburgh, PA 15224, USA. 5 Astellas Innovation Management, LLC, Cambridge, MA 02138 MA-0211: VLCAD patient derived MA-0211: LCHAD and trifunctional Abstract fibroblasts deficient patient derived fibroblasts

Fatty acid oxidation disorders (FAODs) are a heterogeneous FIBROBLASTS FROM PATIENT WITH MILD VLCAD MUTATION FIBROBLASTS WITH LCHAD MUTATION FIBROBLASTS WITH TF DEFICIENCY group of inborn errors of metabolism that are characterized by H A D H A m R N A reduced metabolic flexibility leading to hypoglycemia, reduced a A C A D V L m R N A b A C A D V L P ro te in a c H A D H B m R N A 3 5 0 0 2 8 0 0 4 0 0 0 + 1 1 2 % 1 8%

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which lead to reduced fatty acid metabolism. MA-0211 (a.k.a. l

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MTB-1) is a novel, orally-available, small molecule currently in a p

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M M M M M M O n n O S n n n n Administration of MA-0211 in multiple animal models has .3 3 0 S 3 3 0 0 0 .0 M 3 . 0 M 0 3 D D

M M M O M M demonstrated significant improvements in several FAOD related O n n n S n n M A -0211 M A -0211 S 3 0 3 0 . 3 M 3 M 0 3 D manifestations, such as increasing exercise endurance, D P a lm ita te fa tty a c id P a lm ita te fa tty a c id M A -0211 M A -0211 b protecting against cardiac dysfunction and acute kidney injury. o x id a tio n d o x id a tio n

In the present report, we evaluated whether MA-0211 can 4 2 .0

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deficiency. The results show that MA-0211 increases VLCAD h 1 .0

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0 n 0 .0 LCHAD cells: E510Q/E510Q (common mutation) acid oxidation were observed in patient fibroblasts derived from M M O n n S 3 0 O M M M 3 n n n M S 3 D . 3 0 TFD cells: HADHB, G182A/G182A, R28H long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) M 0 3 D M A -0211 deficiency and mitochondrial trifunctional protein (TFP) M A -0211 *p<0.05, **p<0.01 ***p<0.001, ****p<0.0001; (a, b, c, d) One- deficiency. In conclusion, the significant improvements seen in Way ANOVA Dunnett’s test. FAOD patient fibroblasts together with previous demonstrations VLCAD cells: ACADVL heterozygote, Allele 1: V283A; Allele 2: of in vivo pharmacological activity, support studying MA-0211 in A161V MA-0211: Acylcarnitines in healthy patients with FAODs. *p<0.05, **p<0.01 ***p<0.001, ****p<0.0001; (a, b, d) One way mice and non-human primates ANOVA Dunnett’s test .

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Introduction FIBROBLASTS FROM PATIENT WITH SEVERE VLCAD MUTATION 2

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↓ Muscle function M M M O n n S n O M M .3 3 0 S n n Exercise intolerance M 0 3 3 0 *p<0.05, **p<0.01, ***p<0.00; 1 (a) unpaired two-tailed t-test D M 3 Weakness D M A -0211 (b) One-Way ANOVA Dunnett’s test. Cardiomyopathy M A -0211

• MA-0211 was tested in a number of animal models with the c P a lm ita te fa tty a c id d Target Engagement o x id a tio n following benefits: P D K 4 m R N A 8 0 0 + 2 9 9 6 %

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 Protection from kidney injury A

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 Reduction of inflammatory cytokines 3 1 * * * *

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Hypothesis: MA-0211 will increase a 1 0 0 0 • In vivo MA-211 has shown benefits in a variety of disease

long-chain fatty acid x

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n n n o S 3 . 0 N 5 0 0 3 ( oxidation in fibroblasts derived FAOD patients by M 0 3 models such as mdx, DIO, AKI and increased long chain D 0 M A -0211 increasing the expression of the mutated gene and M M M acylcarnitines in healthy mice and non-human primates O n n S n .3 3 0 M 0 3 D protein thereby increasing the residual enzymatic M A -0211 • MA-0211 is currently in Phase 1 studies for Duchenne activity VLCAD cells: ACADVL heterozygote, Allele 1: I373T; Allele 2: R453Q Muscular Dystrophy in partnership with Astellas Pharma ****p<0.0001; (a-c) One way ANOVA Dunnett’s test

1