Setrusumab vs Bisphosphonates for Osteogenesis Imperfecta

(Cosmic Trial)

Not currently recruiting at 28 trial locations

Overseen By HCPs Contact: Medical Information

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Ultragenyx Pharmaceutical Inc

Must be taking: IV bisphosphonates

Must not be taking: Growth hormone, Denosumab

Disqualifiers: Skeletal malignancies, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, setrusumab and intravenous bisphosphonates (IV-BP), to determine which more effectively reduces fractures in children with osteogenesis imperfecta (OI), a condition that causes fragile bones. The goal is to assess whether setrusumab can lower fracture rates more effectively than IV-BP. Children who have experienced at least one fracture in the past year and have a genetic diagnosis of certain types of OI may qualify for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but it does require that you have not used certain bone-impacting medications other than bisphosphonates before. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that setrusumab has been tested in other studies for treating osteogenesis imperfecta (OI), a condition that makes bones very fragile. Most side effects were mild or moderate, and no serious safety issues were reported. Patients previously treated with setrusumab experienced stronger bones.

The FDA has approved bisphosphonates, already used for bone conditions, for other uses. This approval indicates that their side effects and risks are well understood.

Overall, existing studies and approvals consider both treatments in the trial safe and well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for osteogenesis imperfecta, which typically involves bisphosphonates to slow bone loss, Setrusumab acts differently by targeting sclerostin, a protein that regulates bone formation. This new mechanism of action encourages new bone growth rather than just preserving existing bone mass. Researchers are excited about Setrusumab because it has the potential to improve bone strength and quality, offering a more comprehensive approach to managing this condition. Additionally, Setrusumab is administered as an intravenous infusion, which might offer a more controlled and effective delivery method compared to oral medications.

What evidence suggests that this trial's treatments could be effective for osteogenesis imperfecta?

Research has shown that setrusumab, one of the treatments studied in this trial, yields promising results for osteogenesis imperfecta, a condition that makes bones fragile. In studies, setrusumab reduced fractures by 67%, resulting in fewer broken bones for patients. It also strengthened bones without causing serious safety issues. Meanwhile, bisphosphonates, which participants in another arm of this trial may receive, are a common treatment for this condition and effectively increase bone density. Setrusumab's significant reduction in fractures suggests it could greatly benefit people with this bone disorder. ^{1 4 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Ultragenyx Pharmaceutical Inc

Are You a Good Fit for This Trial?

This trial is for children with Osteogenesis Imperfecta (OI) types I, III, or IV who have had fractures in the past year and are currently on or have had bisphosphonate therapy. They must not have severe kidney issues, untreated hypocalcemia, a history of certain bone diseases other than OI, cardiovascular disease without clearance, or recent use of certain bone-impacting drugs.

Inclusion Criteria

My Osteogenesis Imperfecta (Types I, III, IV) is confirmed by a genetic test.

I have had one or more bone fractures in the last 2 years.

I have or am receiving IV treatment for brittle bone disease.

Exclusion Criteria

I have a history of spinal nerve passage narrowing not caused by scoliosis.

I cannot use IV bisphosphonates as decided by my doctor.

I do not have severe kidney disease or disorders affecting my bones.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Active-controlled Period

Participants are randomized to receive either setrusumab or IV-BP for up to 24 months

24 months

Extension Period

All participants receive setrusumab for a minimum of 12 months or until it becomes commercially available

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Bisphosphonate
• Setrusumab

Trial Overview The study compares setrusumab to intravenous bisphosphonates in reducing fracture rates in pediatric patients with OI. It aims to see if setrusumab is more effective at preventing new fractures including specific spinal ones.

How Is the Trial Designed?

Group I: Setrusumab Experimental Treatment 1 Intervention

Participants will receive Setrusumab during the active-controlled and extension period

Group II: Intravenous Bisphosphonates (IV-BP) -> Setrusumab Active Control 2 Interventions

Participants on IV-BP will continue their existing dose/regimen per investigator discretion; for participants not on IV-BP, the dose/regimen will be determined by the investigator. After the active-controlled period, participants will receive Setrusumab during the extension period

Bisphosphonate is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in United States as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• Glucocorticoid-induced osteoporosis
• High calcium levels in cancer patients
• Bone metastases

Approved in Canada as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in Japan as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in China as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Approved in Switzerland as Bisphosphonates for:

• Osteoporosis
• Paget's disease
• High calcium levels in cancer patients
• Bone metastases

Who Is Running the Clinical Trial?

Ultragenyx Pharmaceutical Inc

Lead Sponsor

Trials

94

Recruited

104,000+

Dr. Emil D. Kakkis

Ultragenyx Pharmaceutical Inc

Chief Executive Officer since 2010

MD/PhD in Biological Chemistry from UCLA

Dr. Eric Crombez

Ultragenyx Pharmaceutical Inc

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Published Research Related to This Trial

Bisphosphonates are generally safe and well-tolerated for treating osteoporosis, with the most common side effects being gastrointestinal discomfort and flu-like symptoms, while serious adverse events are rare.

Skeletal complications like osteonecrosis of the jaw and atypical fragility fractures are infrequent compared to the risk of osteoporotic fractures, suggesting that the benefits of bisphosphonates often outweigh these risks, especially in patients with a similar fracture risk as those in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects of bisphosphonates. Abrahamsen, B.[2022]

Alendronate treatment over 2 years significantly improved bone mineral density in children with osteogenesis imperfecta (OI), with increases of 47.8% to 106.6% in the lumbar spine and 24% to 51.4% in forearm bones.

The treatment was found to be safe and well-tolerated, with no significant side effects reported, suggesting that alendronate could be a promising oral alternative to pamidronate for increasing bone density in OI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alendronate treatment in osteogenesis imperfecta. Madenci, E., Yilmaz, K., Yilmaz, M., et al.[2013]

Oral bisphosphonates, commonly used for osteoporosis, can cause various adverse events including gastrointestinal issues, musculoskeletal pain, and osteonecrosis of the jaw, while intravenous bisphosphonates are linked to similar issues but with added risks of renal toxicity.

The severity and frequency of adverse events from bisphosphonates are often related to the dosage and potency of the medication, highlighting the need for careful management in their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bisphosphonate-associated adverse events. Papapetrou, PD.[2022]

In a study of 161 children and adolescents with osteogenesis imperfecta, both intravenous zoledronic acid (ZOL) and oral alendronate (ALN) were effective in increasing bone mineral density (BMD), with ZOL showing a slightly higher increase in Z-scores.

ZOL was significantly more effective than ALN in reducing the clinical fracture rate, indicating it may provide better long-term safety and efficacy for patients with osteogenesis imperfecta.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZOLEDRONIC ACID VERSUS ALENDRONATE IN THE TREATMENT OF CHILDREN WITH OSTEOGENESIS IMPERFECTA: A 2-YEAR CLINICAL STUDY. Lv, F., Liu, Y., Xu, X., et al.[2021]

In a study of 90 adults with osteogenesis imperfecta (OI), bisphosphonate treatment, particularly intravenous pamidronate, significantly increased bone mineral density (BMD) in type I and type III/IV patients over an average treatment duration of 52 months.

While bisphosphonates improved BMD, they did not reduce fracture rates in type I OI patients, and only pamidronate treatment led to a decrease in fracture rates for type III/IV patients, suggesting that bisphosphonate therapy may not be suitable for all OI adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta. Shapiro, JR., Thompson, CB., Wu, Y., et al.[2018]

Intravenous zoledronic acid has been shown to be an effective treatment for children with mild osteogenesis imperfecta (OI), leading to an increase in bone mineral density (BMD) z-scores over 2 years of treatment.

The treatment was associated with some side effects, including transient decreases in serum calcium and phosphate levels, and two cases of symptomatic hypocalcemia, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoledronic acid treatment in children with osteogenesis imperfecta. Vuorimies, I., Toiviainen-Salo, S., Hero, M., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39012717/

Setrusumab for the treatment of osteogenesis imperfecta Overall, setrusumab improved the bones of patients with OI with no serious safety concerns. More studies will include even more patients to see ...

2. academic.oup.com academic.oup.com/jbmr/article/39/9/1215/7714798

12-month results from the phase 2b asteroid study | Journal of ... Overall, setrusumab improved the bones of patients with OI with no serious safety concerns. More studies will include even more patients to see ...

3. ir.ultragenyx.com ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-and-mereo-biopharma-announce-new-phase-2-data-phase

Ultragenyx and Mereo BioPharma Announce New Phase 2 ... 14-month data show treatment with setrusumab resulted in a large, sustained 67% reduction in annualized fracture rate and persistent median annualized fracture ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2949774425009355

P052: Durable fracture rate reduction in patients with OI ... Skeletal fracture rate was reduced considerably with setrusumab (67%). These data further build upon those reported after 6 months of setrusumab treatment, ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05125809

Setrusumab vs Placebo for Osteogenesis Imperfecta The primary objectives of the study are to identify a setrusumab dosing strategy in participants with OI and to evaluate the effect of setrusumab vs placebo on ...

6. academic.oup.com academic.oup.com/jes/article/8/Supplement_1/bvae163.358/7813303

6820 Assessing The Efficacy And Safety Of Setrusumab For ... In the ongoing Phase 2/3 Orbit study (NCT05125809), Phase 2 evaluated the efficacy and safety of setrusumab in pediatric and young-adult cohorts ...

7. yalemedicine.org yalemedicine.org/clinical-trials/efficacy-and-safety-of-setrusumab-in-subjects-with-osteogenesis-imperfecta-1

Study to Assess the Efficacy and Safety of Setrusumab in ... The primary objectives of the study are to identify a dose(s) of setrusumab based on safety and pharmacodynamic (PD) effects in participants with OI.

8. ir.ultragenyx.com ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-and-mereo-biopharma-announce-interim-phase-2-data

Ultragenyx and Mereo BioPharma Announce Interim ... Phase 2 data presented at ASBMR 2023 show treatment with setrusumab resulted in 67% reduction in annualized fracture rate associated with ...