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Palmitate Fatty Acid Oxidation

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Palmitate Fatty Acid Oxidation 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 exercise tolerance, and multi-organ dysfunction. They are 4 0 0 0 + 1 1 2 % + 1 8 % 1 8% ) + 9 3 % * * * * 1 .0 ) * + 1 8 0 % s + 3 3 % 4 2% * s 2 6 0 0 t t caused by mutations in metabolism-related genes, including ) n s n 3 0 0 0 n s * * * * * * * * * * * * u t + 6 5 % u n n o n + 2 2 % 3 0 0 0 o 2 4 0 0 o ) 0 .8 o i C u i those coding for key enzymes of the fatty acid β-oxidation cycle, * * * C s n H * * s o d s d o s D n e i C e 2 5 0 0 e e 2 2 0 0 z P r o z s r i which lead to reduced fatty acid metabolism. MA-0211 (a.k.a. i i l d 0 .6 p l A s p s a x a e x e 2 0 0 0 s G / z E r m E 2 0 0 0 e i m r MTB-1) is a novel, orally-available, small molecule currently in a l r r D p o 2 0 0 0 a p o x A 0 .4 x N N E C ( m ( 1 8 0 0 E Phase 1 clinical study that modulates PPARδ, a key nuclear r L o 1 0 0 0 V ( N 0 .2 1 5 0 0 hormone receptor which regulates cellular metabolic flexibility. ( 1 6 0 0 M M O M M M M n n n O n n n Administration of MA-0211 in multiple animal models has S 3 3 0 S 0 0 .0 . 3 .3 3 0 M 0 M 0 3 D D demonstrated significant improvements in several FAOD related M M M O M M O n n n S n n M A -0211 M A -0211 S 3 0 .3 3 0 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 n i n P a lm ita te fa tty a c id i C 1 6 S p e c ific A c tiv ity e * * * e t * * * c t improve fatty acid oxidation in fibroblasts derived from patients o o d r o x id a tio n r p 3 p 1 .5 * * * * 1 - 1 - with very long-chain acyl-CoA dehydrogenase (VLCAD) g 4 g m * 2 .5 n s m 1 * - 1 n 2 - deficiency. The results show that MA-0211 increases VLCAD i h 1 .0 y h e t t i A * * * * A o F v F - i mRNA, protein levels, and enzymatic activity in a dose 3 r 2 .0 - t H p H 3 c 1 3 1 l 0 .5 - l A responsive manner. MA-0211 increases utilization of palmitate o o g . 1 .5 m m m p n 2 n 1 S and changes the acyl-carnitine profile in a manner consistent - 0 , 0 .0 h D A 1 .0 M M M with increased long-chain fatty acid oxidation in patient cells O n n n O M M M A F S 3 n n n - . 0 S M 3 .3 3 0 C 1 0 3 M 0 3 H D D L that are expected to have some residual enzymatic activity 3 l V 0 .5 M A -0211 M A -0211 o based on their mutation. Additionally, improvements in fatty m 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 M M M 3 O 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 . 28 DAYS OF DOSING IN 7 DAYS OF DOSING IN a NON-HUMAN PRIMATES b Introduction FIBROBLASTS FROM PATIENT WITH SEVERE VLCAD MUTATION C57BL6 MICE ) ) 2 : 2 : 8 8 1 1 C + L o n g C h a in A c y lc a rn itin e C + , 1 L o n g C h a in A c y lc a rn itin e s : A C A D V L m R N A + 1 A C A D V L P ro te in 1 : : 4 a 1 : 4 4 1 FATTY ACID OXIDATION DISORDERS RESULTS FROM b 3 8 8 1 1 C * 1 C C + 4 0 0 0 + 9 9 % C + 4 0 .2 0 , MUTATIONS IN FATTY ACID OXIDATION PATHWAY GENES + 6 1 8 % + 4 ** *** ** 1 8 8 3 + 9 5 % 1 1 * * * * C 1 n i C + n C ) * * * * i C a 2 2 + + * * * * a s : + 2 h 2 t h 2 2 : : : ) Hypoglycemia C 1 2 6 n C 2 3 0 0 0 6 + 5 3 5 % 1 1 C g ↓ATP H 0 .1 5 u 1 Muscle damage, g + C n C n n ↓ Fatty acid C o + 5 5 % D n 1 + + o o : + * * * * o 1 i 1 1 L P C o 2 1 L : : rhabdomyolysis i : s 1 1 2 oxidation * * * * 6 A 6 s d s 1 1 C 1 s e G + e 2 0 0 0 C C / C z 2 r e 0 .1 0 + + i + 1 r D 2 l 6 p ↑ Inflammation 6 0 1 C 1 p a 0 1 x A ( C C x C k k k ) ( e k E ) C l m 8 + M p p p p + 8 c E 2 r 2 i 2 m m m m 2 L h y : : y e 3 0 0 0 o 1 0 0 0 a a 4 V 1 3 4 V 0 0 .0 5 D D 1 ( ( ( 1 1 N k ( e l C C p ic FAOD mutation h m e 0 V 1 0 0 .0 0 ↓ Muscle function M M M O n n n S 3 3 0 O M M . 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 % Conclusions ) s * * * * 1 t n 6 0 0 Improved cellular FAO and ATP in multiple cell types u n o + 2 1 8 0 % o i C s * * * * d s e e 4 0 0 z r 4 i l Protection from muscle damage p a x n E m i r e o 2 0 0 • MA-0211 is a potent and selective modulator of PPARδ that t N ( o Increased endurance r p 3 0 increases the expression of genes encoding proteins involved 1 - M M O M g n n n S Preservation of cardiac function .3 3 0 M 0 3 m D in fatty acid oxidation in fibroblasts from FAOD patients 1 M A -0211 - 2 h Protection from kidney injury A F C P T 1 A m R N A - • In VLCAD patient derived fibroblasts MA-0211 can increase 2 5 0 0 + 1 5 7 % H + 1 4 4 % Reduction of inflammatory cytokines 3 1 * * * * ) l * * * * s t 2 0 0 0 o FAO when there is sufficient residual protein present n u m n o + 8 2 % o i n C 1 5 0 0 s * * * * d s e e 0 z r i l Hypothesis: MA-0211 will increase p 1 0 0 0 • long-chain fatty acid a In vivo MA-211 has shown benefits in a variety of disease x E m O M M M r n n n o S 5 0 0 3 N .
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