#1ECE 2023 25th European Congress of Endocrinology 13 - 16 May 2023, Istanbul Turkey European Society of Endocrinology AZP-3813, a Bicyclic, 16-Amino Acid Peptide Antagonist of the Human Growth Hormone Receptor, Effectively Suppresses IGF1 in Beagle Dogs Guillaume Ravel¹, Clémentine Chalmey¹, Corentin Berardet¹, David Duracher¹, Haruaki Kurasaki², Tatsuya Tomiyama², Patrick Reid², Michael D. Culler¹ ¹Amolyt Pharma, Ecully, France and Cambridge, Massachusetts, U.S.A, 2PeptiDream, Inc., Kawasaki-Shi, Kanagawa, Japan AMOLYT PHARMA PeptiDream 2000 25 th CONGRESS#2European Society of Endocrinology CONFLICT OF INTEREST Michael D. Culler X I have the following potential conflicts of interest to report: ☐ Research Contracts Consulting X Employment in the Industry (Employee of Amolyt Pharma) X Stockholder of a healthcare company ☐ Owner of a healthcare company ☐ Other(s) - please include details No commercial logos or product names to be included please. ☐ I declare that I have no potential conflict of interest.#3GH Receptor Antagonist to Suppress Excess IGF1 in Acromegaly GH Receptor Antagonist Pituitary GH Somatotroph Tumor Effectiveness Depends On: 3 GH Receptors Liver (*and extra-hepatic sites) Affinity for GH receptor • Sufficient concentration • Sufficient half-life IGF1 AMOLYT PHARM A#44 AZP-3813 - GH Receptor Antagonist AZP-3813: 16 Amino Acid, Bi-Cyclic Peptide • MW = 2479.9 ⚫ hGH-R affinity (KD) = 2.9nM . hGH-R antagonism (IC50) = 9.9nM AMOLYT PHARM A#55 Study Plan to Test AZP-3813 in Beagle Dogs AZP-3813 0.1mg/kg AZP-3813 10mg/kg Day -3 Day-2 Day -1 Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 ↑ Blood IGF1 Blood Blood IGF1 IGF1 Blood IGF1 Blood IGF1 Blood IGF1 T ↑ n=3 Blood Blood Blood Blood Blood 15, 30min 24h 48h 72h 96h 1, 2, 4, 8h PK PK PK PK PK Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 ↑ Blood Blood Blood Blood Blood 15, 30min 24h 48h 72h 96h 1, 2, 4, 8h PK PK PK PK PK AZP-3813 1.0mg/kg ↓ Day -3 Day -2 Day -1 Day 0 Day 1 It Day 2 ↑ Day 3 Day 4 Day 5 It Day 6 ↑ Day 7 I↑ Day 8 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 Blood IGF1 ↑ ↑ ↑ ↑ ↑ Blood Blood Blood Blood Blood Blood Blood Blood Blood 15, 30min 24h 48h 72h 96h 24h 48h 72h 96h 1, 2, 4, 8h PK PK PK PK PK PK PK PK n=3 PK Blood 15, 30min 1, 2, 4, 8h PK AMOLYT PHARM A#66 Dose-Related and Sustained Suppression of IGF1 in Beagle Dogs -5 -10 IGF1-% - Decrease from Pre-Treatment Levels -15 5 -2% -21.4% -20 -27.8% -25 ■AZP-3813 0.1mg/kg -30 AZP-3813 1.0mg/kg Means + SEM n=3 -35 ■AZP-3813 10mg/kg IGF-1 (ng/mL) A. 120 IGF-1 (ng/mL) B. 150 100 100 1 mg/kg AZP-3813 (repeated 5 days) 80 60 60 T T -3 0 1 T T T T T 2 3 4 5 6 7 8 Days 1 mg/kg (repeated - 4 days) 10 mg/kg (single) H 50 T T 1 2 3 Days AMOLYT PHARM A#77 AZP-3813 Pharmacokinetics in Beagle Dogs Increasing doses of AZP-3813 produce linear increases in blood concentration 1000 0.1mg/kg AZP-3813 (ng/mL) 800- 600- 400- 200 0 0 20 40 60 80 Hours 10000- AZP-3813 (ng/mL) 8000- 6000 4000 2000 1.0mg/kg 100000 10000 1000 100 10 mg/kg 10 1 mg/kg AZP-3813 (ng/mL) • 0.1 mg/kg 1 0 20 40 Hours 60 Η 80 80 Increasing doses of AZP-3813 produce parallel elimination curves 0 0 20 40 60 80 Hours 80000- Dose Half-Life (h) AZP-3813 (ng/mL) 10mg/kg 60000- 0.1mg/kg 15.1 Mean circulating half-life = 14.2 + 0.47 hours 40000 1.0mg/kg 13.2 20000- 10mg/kg 14.3 0 0 20 40 60 80 Hours AMOLYT PHARM A#88 Conclusion The results of the current study demonstrate that the potent GH receptor antagonist activity exhibited by AZP-3813 translates to effective, sustained in vivo suppression of IGF1 levels in normal Beagle dogs, and further support the development of AZP-3813 as a potential therapy for acromegaly For more detail, please visit our poster: RC 7.3 AZP-3813, a Bicyclic, 16-Amino Acid Peptide Antagonist of the Human Growth Hormone Receptor, Effectively Suppresses IGF1 in Beagle Dogs Guillaume Ravel¹, Clémentine Chalmey¹, Corentin Berardet¹, David Duracher¹, Haruaki Kurasaki², Tatsuya Tomiyama², Patrick Reid², Michael D. Culler¹ AMOLYT PHARM A#9AZP-3813 6 Thank you! AMOLYT PHARM A