setrusumab (UX143) / Novartis, Mereo Biopharma, Ultragenyx - LARVOL DELTA

Sustained Reduction in Fracture Rate with Setrusumab in Osteogenesis Imperfecta: Data from Month 14 of Phase 2 of the Orbit Study (ENDO 2025) - P2/3 | "Taken together, these results support the data analyzed at 6 months of setrusumab therapy, confirming a robust and durable response to treatment in patients with OI.*. .*"

P2 data • Cardiovascular • Genetic Disorders • Musculoskeletal Diseases • Orthopedics

Setrusumab vs Placebo for Osteogenesis Imperfecta (clinicaltrials.gov) - P2/3 | N=182 | Active, not recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Trial completion date: Mar 2026 ➔ Apr 2027 | Trial primary completion date: Mar 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Genetic Disorders • COL1A1

Consistent Reduction in Rate of Fracture with Setrusumab Therapy in Patients with Osteogenesis Imperfecta: Month 14 Data from Phase 2 of the Orbit Study (ESPE-ESE 2025) - No abstract available

Clinical • P2 data • Genetic Disorders • Musculoskeletal Diseases • Orthopedics

Mereo BioPharma’s SWOT analysis: setrusumab, alvelestat drive rare disease stock potential (Investing.com) - "Mereo’s lead candidate, setrusumab, an anti-sclerostin monoclonal antibody, is currently in a Phase 3 study for the treatment of osteogenesis imperfecta (OI), commonly known as brittle bone disorder. The company is anticipating the second interim analysis (IA2) of this study in mid-2025...The company is nearing finalization of the Phase 3 trial design for alvelestat, a crucial step in securing a potential partnership....Mereo is actively engaged in discussions with potential partners for alvelestat, with a partnership potentially materializing in 2025."

Clinical protocol • Commercial • P3 data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

Mereo BioPharma Reports Full Year 2024 Financial Results and Provides Corporate Highlights (GlobeNewswire) - "Setrusumab (UX143): The Phase 3 portion of the Orbit Study is continuing to dose pediatric and young adult patients, with the second interim analysis expected mid-2025 and potential final analysis in the fourth quarter of 2025....Alvelestat (MPH-966): In the first quarter of 2025, the European Commission granted Orphan Designation to alvelestat for the treatment of AATD-LD. This designation followed a positive recommendation from the EMA Committee for Orphan Medicinal Products in January 2025....Total research and development ('R&D') expenses increased by $3.5 million from $17.4 million in 2023 to $20.9 million in 2024. The increase was primarily due to increases of $6.2 million and $2.6 million in R&D expenses for alvelestat and setrusumab, respectively..."

Commercial • Orphan drug • P3 data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

Clinical development of BPS804 for osteogenesis imperfecta: from failure to fruition? (PubMed, Expert Opin Investig Drugs) - No abstract available

Journal • Genetic Disorders • Musculoskeletal Diseases • Orthopedics

Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta (clinicaltrials.gov) - P3 | N=6 | Active, not recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Pediatrics

Non-invasive quantification of bone (re) modeling dynamics in adults with osteogenesis imperfecta treated with Setrusumab using timelapse HR-pQCT. (PubMed, J Bone Miner Res) - "We verified the accuracy of our method and then used it on longitudinal scans (baseline, 6, 12, 18 and 24 month) from 78 participants to assess bone formation and resorption induced by an anabolic (setrusumab) and anti-catabolic (zoledronic acid) treatments as part of the ASTEROID trial. This study identifies a timelapse method that minimizes measurement error, which can be used in future studies to improve the uniformity of results. This noninvasive imaging biomarker revealed dose dependent bone (re) modeling outcomes from one year of setrusumab treatment in adults with OI."

Journal • Genetic Disorders

Setrusumab in Pediatric Japanese Subjects with Osteogenesis Imperfecta (clinicaltrials.gov) - P3 | N=5 | Recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Pediatrics

Setrusumab in Pediatric Japanese Subjects with Osteogenesis Imperfecta (clinicaltrials.gov) - P3 | N=5 | Not yet recruiting | Sponsor: Ultragenyx Pharmaceutical Inc

New P3 trial • Genetic Disorders • Pediatrics

Ultragenyx Receives Breakthrough Therapy Designation for Setrusumab (UX143) in Osteogenesis Imperfecta (GlobeNewswire) - "Ultragenyx Pharmaceutical Inc...announced that it has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for setrusumab (UX143) as a treatment to reduce the risk of fracture associated with osteogenesis imperfecta (OI) Type I, III, or IV in patients 2 years of age and older....The FDA’s decision is based on preliminary clinical evidence including the positive 14-month results from the Phase 2 portion of the Orbit study...and from the completed Phase 2b ASTEROID study."

Breakthrough therapy • Osteoporosis

Population Pharmacokinetics (PK) and PK/Pharmacodynamics Analyses to Select the Phase 3 Dose of Setrusumab in Pediatric Patients with Osteogenesis Imperfecta: Results From Phase 2 of the Orbit Study (ASBMR 2024) - No abstract available

Clinical • P2 data • P3 data • PK/PD data • Genetic Disorders • Pediatrics

Integrated Bone Biomarker Analyses to Define Setrusumab Mechanism of Action in Pediatric and Young Adult Subjects With Osteogenesis Imperfecta and to Inform Dose Selection in the Orbit Study (ASBMR 2024) - No abstract available

Biomarker • Clinical • Genetic Disorders • Pediatrics

Integrated Bone Biomarker Analyses to Define Setrusumab Mechanism of Action in Pediatric and Young Adult Subjects With Osteogenesis Imperfecta and to Inform Dose Selection in the Orbit Study (ASBMR 2024) - No abstract available

Biomarker • Clinical • Genetic Disorders • Pediatrics

Integrated Bone Biomarker Analyses to Define Setrusumab Mechanism of Action in Pediatric and Young Adult Subjects With Osteogenesis Imperfecta and to Inform Dose Selection in the Orbit Study (ASBMR 2024) - No abstract available

Biomarker • Clinical • Genetic Disorders • Pediatrics

Sustained Reduction in Fracture Rate in Patients with OI Treated with Setrusumab: Fourteen Month Data from Phase 2 of the Phase 2/3 Orbit Study (ASBMR 2024) - No abstract available

Clinical • Late-breaking abstract • P2/3 data • Musculoskeletal Diseases • Orthopedics

Bone matrix properties in adults with osteogenesis imperfecta are not adversely affected by Setrusumab - a sclerostin neutralizing antibody. (PubMed, J Bone Miner Res) - "Here, we investigate bone matrix material properties in tetracycline-labeled trans-iliac biopsies from three groups: i) control: individuals with no metabolic bone disease, ii) OI: individuals with OI, iii) SclAb-OI: individuals with OI after six months of setrusumab treatment (as part of the ASTEROID trial). Therefore, fragility in OI may stem from contributions from other yet unexplored aspects of bone organization at higher length scales. We conclude that SclAb treatment leads to increased bone mass while not adversely affecting bone matrix properties in individuals with OI."

Journal • Genetic Disorders • Musculoskeletal Diseases • Orthopedics

Setrusumab for the Treatment of Osteogenesis Imperfecta: 12-Month Results from the Phase 2b Asteroid Study. (PubMed, J Bone Miner Res) - P2b | "Two adults in the 20 mg/kg group experienced related serious adverse reactions. Asteroid demonstrated a beneficial effect of setrusumab on estimates of bone strength across the different types of OI and provides the basis for additional phase 3 evaluation."

Journal • P2b data • Genetic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Rare Diseases • COL1A1 • COL1A2

Assessing the Efficacy and Safety of Setrusumab for Osteogenesis Imperfecta: Updated Phase 2 Data from the Phase 2/3 Orbit Study (ENDO 2024) - P2/3, P2b | "Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO."

Clinical • P2/3 data • Genetic Disorders • Infectious Disease • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Pain • Pediatrics • Respiratory Diseases

ENGULF: Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta (clinicaltrials.gov) - P3 | N=69 | Active, not recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Pediatrics • COL1A1 • COL1A2

Study to Assess Dose, Efficacy and Safety of Setrusumab in Participants With Osteogenesis Imperfecta (clinicaltrials.gov) - P2/3 | N=182 | Active, not recruiting | Sponsor: Ultragenyx Pharmaceutical Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • COL1A1 • COL1A2

Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta. (PubMed, Calcif Tissue Int) - "Several therapeutics, including teriparatide, setrusumab, anti-TGF-β antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade."

Journal • Review • Genetic Disorders • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • DKK1 • TGFB1

ENGULF: Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta (clinicaltrials.gov) - P3 | N=66 | Recruiting | Sponsor: Ultragenyx Pharmaceutical Inc

Trial completion date • Trial primary completion date • Genetic Disorders • Pediatrics • COL1A1 • COL1A2

Study to Assess Dose, Efficacy and Safety of Setrusumab in Participants With Osteogenesis Imperfecta (clinicaltrials.gov) - P2/3 | N=219 | Recruiting | Sponsor: Ultragenyx Pharmaceutical Inc

Trial completion date • Trial primary completion date • Genetic Disorders • COL1A1 • COL1A2

"Option 2 is the best choice and the cheapest Setrusumab alone could be worth right now +$ 600M/ $5 per share or +$2Bn/ $10-$15 shares if phase 3 readouts positive in 2024/2025. $MREO" (@ej23ny)

P3 data