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Delpacibart zotadirsen (Del-zota) Showed Trends for Functional Improvement in the Phase 1/2 EXPLORE44® Study with Continued Trends After 1-Year of Treatment Compared to DMD44 Natural History Dr Kevin M. Flanigan, Nationwide Children’s Hospital, Columbus, Ohio, USA
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Disclosure • I have received clinical trial support from Sarepta, Dyne, Avidity, Ultragenyx, and Solid; received support for serving on advisory boards to Armatus, Encoded, Insmed, Dyne, and Solid; and have received past Royalties from Astellas. • This publication is based on research using data from data contributor CureDuchenne that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication. • This study was supported by Avidity Biosciences, Inc.
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3 CONFIDENTIAL AOC, antibody oligonucleotide conjugate; DMD, Duchenne muscular dystrophy; DMD44, Duchenne muscular dystrophy with mutations amenable to exon 44 skipping; mAb, monoclonal antibody. 1. Crisafulli S et al. Orphanet J Rare Dis. 2020;15(1):141. 2. Mah JK et al. Neuromuscul Disord. 2014;24(6):482-491. 3. Mendell JR et al. Ann Neurol. 2012;71(3):304-313. 4. Moat SJ et al. Eur J Hum Genet. 2013;21(10):1049-1053. 5. Aartsma-Rus A et al. Orphanet J Rare Dis. 2012;7(Suppl 2):A20. 6. Wang RT et al. Hum Mutat. 2018;39(9):1193-1202. 7. Bushby K et al. Lancet Neurol. 2010;9(2):177-189. 8. DMD is a severe, progressive neuromuscular disorder caused by mutations in the dystrophin gene, leading to muscle degeneration and early mortality1-4 • ~6–7% of individuals with DMD have mutations amenable to exon 44 skipping (DMD44), yet there are currently no exon skipping therapies available for DMD445, 6 • As such, there is a high unmet need for exon skipping therapies to treat DMD44, particularly those that can benefit a broad range of disease severities7 • Del-zota is an AOC designed to deliver a phosphorodiamidate morpholino oligonucleotide (PMO44) targeting dystrophin’s exon 44 to muscle cells • Del-zota induces exon 44 skipping and restores the dystrophin reading frame, enabling the production of a near full-length dystrophin that is expected to restore muscle cell integrity and protect against damage • The completed Phase 1/2 EXPLORE44® trial is the first clinical study to evaluate del-zota Delpacibart zotadirsen abbreviation: del-zota (formerly known as AOC 1044) mAb PMO
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4 CONFIDENTIAL Key information across EXPLORE44® and EXPLORE44-OLE *Doses expressed as PMO component. Participants at 10 mg/kg Q8W in EXPLORE44® were transitioned to 5 mg/kg Q6W. DMD44, Duchenne muscular dystrophy with mutations amenable to exon 44 skipping; OLE, open-label extension; PD, pharmacodynamics; PK, pharmacokinetics; Q6W, every 6 weeks; Q8W, every 8 weeks. EXPLORE44® Key Information • Randomized, double-blind, placebo controlled • Two cohorts: 5 mg/kg Q6W and 10 mg/kg Q8W* • Biopsies in all cohorts • N=19 del-zota, N=7 placebo • After 3 doses, participants eligible to rollover into EXPLORE44-OLE • Open-label extension of EXPLORE44® • EXPLORE44® cohorts maintained until 5 mg/kg selected as dose; all participants then transitioned to 5 mg/kg Q6W* • 16 additional participants enrolled at 5 mg/kg Q6W • No need for biopsies EXPLORE44-OLETM Key Information Key Participant Characteristics (N = 39) Ages 7 – 27, mean age 13 Ambulatory (67%) and non- ambulatory (33%) 90% on steroids • N=39 (EXPLORE44-OLE ) • Ages 7–27 years, mean age 13 • Ambulatory (67%, N=26) and non- ambulatory (33%, N=13) • 90% on steroids Participant Characteristics Today’s presentation includes data on functional outcomes in EXPLORE44® (4/5 month data compared to placebo) and in EXPLORE44-OLE (1 year data compared to DMD44 natural history) Together, these trials assess the safety, tolerability, PK, PD, and exploratory efficacy of del-zota in individuals with DMD44
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5 CONFIDENTIAL Placebo data are pooled and del-zota data are pooled (5 mg/kg and 10 mg/kg). January 2025 data cutoff for EXPLORE44® (final cut) and June 2025 data cutoff for EXPLORE44-OLE (interim cut). Safety data represents the number of participants (%) with ≥1 TEAE unless indicated. †SAEs considered unrelated to treatment include femur fracture and suicidal behavior. IRR, infusion-related reaction; OLE, open-label extension; TEAE, treatment-emergent adverse event. Del-zota demonstrated an acceptable safety profile TEAEs Placebo N=7 EXPLORE44® Del-zota N=19 EXPLORE44- OLE Del-zota N=39 Any TEAE 6 (86%) 16 (84%) 33 (85%) Related to study drug 0 6 (32%) 10 (26%) Serious TEAE 0 1 (5%) 3 (8%)† Serious TEAE related to study drug 0 1 (5%) 1 (3%) TEAE leading to treatment discontinuation 0 2 (11%) 1 (3%) TEAE leading to death 0 0 0 • Most TEAEs were mild or moderate • EXPLORE44®: • Most common TEAEs in del-zota arms (occurring in ≥ 3 participants): procedural pain and headache • 1 participant discontinued due to serious TEAE of anaphylaxis • 1 participant discontinued due to moderate IRR • EXPLORE44-OLE : • Most common TEAEs in del-zota arms (occurring in ≥ 3 participants): upper respiratory tract symptoms, diarrhea, fall, back pain, headache • 1 participant discontinued due to hypersensitivity
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6 CONFIDENTIAL Exploratory analysis: At 4/5 months, del-zota was associated with trends toward improvements in functional assessments in participants with DMD44 relative to placebo -4-2024 Del-zota (N=11)Placebo (N=5) 4SC -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 Total Score Del-zota (N=11)Placebo (N=5) NSAA -2 -1 0 1 2 Del-zota (N=17)Placebo (N=6) PUL -8-6-4-202468 Del-zota (N=6)Placebo (N=4) TTR -1.2-0.9-0.6-0.30.00.30.60.91.2 Time (s) Del-zota (N=11)Placebo (N=5) 10MWRT Worse Better Worse Better January 2025 data cutoff for month 4/5 data. Data are presented as mean change from baseline ± SEM. Del-zota data are pooled (5 mg/kg and 10 mg/kg). The del-zota group received del-zota throughout the EXPLORE44® trial. One participant excluded from ambulatory assessments due to an ankle sprain prior to month 4/5. For TTR, two participants could not complete at baseline, two additional participants could not complete without assistance; these two had baseline TTR >15 seconds. These are exploratory analyses. 10MWRT, 10-meter walk/run test; 4SC, 4-stair climb; DMD44, Duchenne muscular dystrophy with mutations amenable to exon 44 skipping; NSAA, North Star Ambulatory Assessment; PUL, performance of upper limb; TTR, time to rise.
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7 CONFIDENTIAL Baseline characteristics: del-zota versus DMD44 natural history Data are presented as means unless otherwise indicated. *Ambulatory participants only, with one participant excluded due to ankle sprain and one participant unable to complete assessment due to fractured femur. Baseline characteristics shown of participants with functional data at one year. †66 unique intervals. 10MWRT, 10-meter walk/run test; 4SC, 4-stair climb; DMD44, Duchenne muscular dystrophy with mutations amenable to exon 44 skipping; NSAA, North Star Ambulatory Assessment; OLE, open-label extension; PUL, performance of upper limb; TTR, time to rise. 1. CureDuchenne, analyzed by Analysis Group®. 2. Brogna C et al. Children. 2023;10(4):746. Data set reflects current standard of care for steroid use PRO-DMD-01 Natural History Study1 • Design: Observational, prospective natural history study (N=269) • Population: Subset of matched DMD44 participants (n=22) • Matching criteria: Exon 44 skip amenable, ambulatory, 7–27 years old, if on steroid stable ≥1 month, weight ≥23 kg • 100% on steroids • Key assessments: Clinical outcome assessments (i.e., timed tests, NSAA) progression over time PRO-DMD-01 DMD44 (N=22) EXPLORE44®/ OLE (N=10)* Age (yrs) 10.6 11.0 4SC (s) 4.3 7.5 10MWRT (s) 5.7 8.1 TTR (s) 7.2 10.2 NSAA (total) 23.6 19.6 Upper Limb Changes in DMD Patients Amenable to Skipping Exons 44, 45, 51 and 53: A 24-Month Study. Children 2023 Brogna 2023 Natural History Study2 • Design: Observational, prospective natural history study (N=66 unique intervals - DMD44) • Population: utilized subset of generally well matched DMD44 participants (n=27) • Matching criteria: Exon 44 skip amenable; includes ambulatory and non-ambulatory (same population as del-zota) • Key assessments: PUL 2.0 (assessed in EXPLORE44®/OLE) Brogna DMD441 (N=27)† EXPLORE44®/ OLE (N=17) Age (yrs) 12.2 13.3 Ambulatory, n (%) 48 (72.7%) 12 (70.6%) Non-ambulatory, n (%) 18 (27.3%) 5 (29.4%) PUL (total) 35.6 36.3
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8 CONFIDENTIAL Exploratory analysis: At 1 year, del-zota was associated with trends toward improvements in functional assessments in participants with DMD44 relative to matched external DMD44 natural history controls -4-2024 4SC Del-zota (N=10)Natural History (N=22) Natural History (N=20) -4 -2 0 2 4 Total Score Del-zota (N=10) NSAA Natural History (N=27) -3 -2 -1 0 1 2 3 PUL Del-zota (N=17) -6-4-20246 TTR Natural History (N=19) Del-zota (N=6) Worse -3-2-10123 Time (s) 10MWRT Natural History (N=22) Del-zota (N=10) Better Worse Better 4SC: Improved from baseline by 2.1 s; natural history group declined by 2.7 s TTR: Improved by 3.2 s; natural history group declined by 1.6 s 10MWRT: Improved by 0.7 s; natural history group declined by 1.5 s PUL: Improved by 1.5 points; natural history group declined by 0.7 pts • PUL improvements were seen in both ambulatory and non - ambulatory participants NSAA: Remained stable; natural history group declined by 2.4 pts June 2025 data cutoff for 1 year data. Data are presented as mean change from baseline ± SEM. Del-zota data are pooled (5 mg/kg and 10 mg/kg). The del-zota group received del-zota throughout the EXPLORE44® trial and for another 6 months in EXPLORE44-OLE . One participant excluded from ambulatory assessments due to an ankle sprain prior to month 4/5 and one participant unable to complete 1 year assessment due to fractured femur. For TTR, two participants could not complete at baseline, two additional participants could not complete without assistance; these two had baseline TTR >15 seconds. These are exploratory analyses. 10MWRT, 10-meter walk/run test; 4SC, 4-stair climb; DMD44, Duchenne muscular dystrophy with mutations amenable to exon 44 skipping; DMD QoL, DMD Quality of Life; NSAA, North Star Ambulatory Assessment; PUL, performance of upper limb; TTR, time to rise.
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9 CONFIDENTIAL These findings support continued clinical development of del-zota for the treatment of DMD44 Trends Towards Functional Improvement… …Support Continued Clinical Development Del-zota treatment led to trends towards improvement in functional outcomes compared to placebo at 4/5 months and matched DMD44 natural history controls at 1 year These findings, along with a favorable safety profile, support continued clinical development of del-zota for the treatment of DMD44 DMD44, Duchenne muscular dystrophy with mutations amenable to exon 44 skipping.
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10 CONFIDENTIAL Acknowledgements Authors: • Kevin M. Flanigan (Nationwide Children’s Hospital) • Aravindhan Veerapandiyan (Arkansas Children’s Hospital) • Jamie Eskuri (Gillette Children’s Hospital) • Chamindra G. Laverty (University of California, San Diego) • Craig M. McDonald (University of California Davis) • Han Phan (Rare Disease Research) • Edward Smith (Rare Disease Research) • Carolina Tesi Rocha (Stanford Medicine Children’s Health) • Brenda Wong (UMass Chan Medical School) • Marc Morris (Avidity Biosciences, Inc.) • Yvonne Tami (Avidity Biosciences, Inc.) • Tara Carmack (Avidity Biosciences, Inc.) • Julie Coats (Avidity Biosciences, Inc.) • Philip Kovach (Avidity Biosciences, Inc.) • Josiah J. Herzog (Avidity Biosciences, Inc.) • Steven G. Hughes (Avidity Biosciences, Inc.) • Yiming Zhu (Avidity Biosciences, Inc.) • Elizabeth J. Ackermann (Avidity Biosciences, Inc.) Medical Writing Support: Provided by Lauren Todd, Ph.D., CMPP of Sixsense Strategy Group, Inc., a Herspiegel company (T oronto, Canada), funded by Avidity Biosciences, Inc., in accordance with Good Publication Practice guidelines. Data Analysis: Analysis Group® analyzed the PRO -DMD-01 natural history data. A special thank-you to the study participants and their families!