Celiprolol for Ehlers-Danlos Syndrome

(DiSCOVER Trial)

Overseen By Jonathan Cotliar, MD; Ph.D.

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Acer Therapeutics Inc.

Must not be taking: β-blockers

Disqualifiers: Pregnancy, Arterial rupture, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 40 months

150 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing celiprolol, a medication, in patients with a genetic condition called COL3A1-positive vEDS. The goal is to see if it can make their blood vessels stronger and reduce medical issues related to their condition. Celiprolol has shown protective effects in patients with vascular Ehlers-Danlos syndrome (vEDS).

Will I have to stop taking my current medications?

You will need to stop taking β-blockers (a type of heart medication) before joining the trial. The protocol does not specify about other medications.

What data supports the effectiveness of the drug celiprolol for treating vascular Ehlers-Danlos syndrome?

Research shows that celiprolol, a type of beta-blocker, significantly reduces the risk of arterial events like dissections and ruptures in patients with vascular Ehlers-Danlos syndrome. This drug helps by lowering heart rate and pressure, which reduces stress on the arteries, and has shown significant benefits in clinical trials. ^{1 2 3 4 5}

How does the drug Celiprolol differ from other treatments for Ehlers-Danlos Syndrome?

Celiprolol is unique for Ehlers-Danlos Syndrome because it is a beta-blocker that may help strengthen blood vessels, which is particularly important for this condition that affects connective tissue. Unlike other treatments, Celiprolol specifically targets the cardiovascular complications associated with Ehlers-Danlos Syndrome, offering a novel approach compared to general supportive care. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for individuals with genetically confirmed vascular Ehlers-Danlos Syndrome (vEDS) who are at least 15 years old. Participants must not have had certain medical events like arterial rupture in the past 6 months, be pregnant, or use β-blockers within 28 days prior to starting the study.

Inclusion Criteria

I can stop taking β-blockers 28 days before joining the study.

I have a confirmed genetic mutation in the COL3A1 gene.

I am 15 years old or older.

Exclusion Criteria

Any medical condition that in the opinion of the Investigator may pose a safety risk to the patient in this study, which may confound efficacy or safety assessment, or may interfere with study participation

I am not taking any medications that are not allowed in the study.

I have not had any major artery, uterus, or intestine ruptures in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either celiprolol or placebo in a double-blind manner, with titration over the first 4 months

40 months

Decentralized visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term with celiprolol

Treatment Details

Interventions

• Celiprolol

Trial Overview The study tests Celiprolol's effectiveness against a placebo in patients with vEDS. It's a Phase 3 trial where participants are randomly assigned to receive either Celiprolol or a placebo twice daily, and it uses remote monitoring methods.

Participant Groups

Group I: Placebo BID Experimental Treatment 1 Intervention

Placebo twice daily (BID) Placebo given orally to mimic ACER-002 (celiprolol) administration

Group II: ACER-002 (celiprolol) 200 mg BID Experimental Treatment 1 Intervention

ACER-002 200 mg twice daily (BID) (after titration): 200 mg morning and 200 mg evening: 400 mg total daily dose Titration: Day 1 to Month 1 - 100 mg once daily (QD) evening: 100 mg total daily dose Month 2 to Month 3 - 100 mg morning and 100 mg evening: 200 mg total daily dose Month 3 to Month 4 - 100 mg morning and 200 mg evening: 300 mg total daily dose Month 4 to End of Treatment Period (BID) - 200 mg morning and 200 mg evening: 400 mg total daily dose

Celiprolol is already approved in European Union for the following indications:

Approved in European Union as Celiprolol for:

• Hypertension
• Angina pectoris
• Vascular Ehlers-Danlos syndrome

Who Is Running the Clinical Trial?

Acer Therapeutics Inc.

Lead Sponsor

Trials

3

Recruited

220+

Findings from Research

In a study involving 53 patients with vascular Ehlers-Danlos syndrome, celiprolol significantly reduced the occurrence of arterial events (ruptures or dissections) compared to a control group, with only 20% of the celiprolol group experiencing these events versus 50% in the control group.

The trial, which lasted an average of 47 months and was stopped early due to positive results, suggests that celiprolol could be an effective preventive treatment for this severe condition, although further research is needed to determine its efficacy in patients without the specific collagen mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Ong, KT., Perdu, J., De Backer, J., et al.[2022]

Celiprolol is a unique β-blocker that not only blocks β1 receptors but also partially activates β2 receptors, which may provide additional benefits in treating conditions like vascular type Ehlers-Danlos syndrome.

In a significant study, celiprolol showed promising results in reducing arterial events in patients with vascular Ehlers-Danlos syndrome, leading to the premature termination of the trial due to its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiprolol: A Unique Selective Adrenoceptor Modulator. Nawarskas, JJ., Cheng-Lai, A., Frishman, WH.[2019]

In a study of 40 Swedish patients with vascular Ehlers-Danlos syndrome (vEDS) treated with the beta blocker celiprolol, 65% were able to reach the target dose of 400 mg daily, indicating good tolerability for most patients.

The annual risk of major vascular events was 4.7%, which is comparable to the protective effect observed in the BBEST trial, suggesting that celiprolol may help reduce the risk of serious complications in vEDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome. Baderkhan, H., Wanhainen, A., Stenborg, A., et al.[2021]

In a study involving two children with Ehlers-Danlos syndrome (types VIII and VI), intravenous DDAVP (desmopressin acetate) successfully corrected prolonged bleeding times and provided excellent hemostasis during surgical procedures.

Both patients experienced no postoperative bleeding, suggesting that DDAVP could be a beneficial treatment option for managing bleeding tendencies in patients with EDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DDAVP therapy controls bleeding in Ehlers-Danlos syndrome. Stine, KC., Becton, DL.[2019]

In a study using a mouse model of vascular Ehlers-Danlos syndrome (vEDS), the β-blocker celiprolol significantly improved the biomechanical integrity of the thoracic aorta, potentially reducing the risk of aortic rupture.

In contrast, the angiotensin II receptor antagonist losartan did not show any significant effect on aortic integrity, suggesting that celiprolol may be a more suitable long-term treatment option for patients with vEDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome. Dubacher, N., Münger, J., Gorosabel, MC., et al.[2022]

The DVO guidelines established in 2003 provide evidence-based strategies for diagnosing and treating osteoporosis, particularly in postmenopausal women and those with glucocorticoid-induced osteoporosis.

Effective treatments include calcium and vitamin D supplementation, as well as antiresorptive therapies like bisphosphonates (alendronate, ibandronate, risedronate) and the SERM raloxifene, which have proven antifracture efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacotherapy of osteoporosis: evidence-based clinical practice]. Fassbender, WJ., Stumpf, UC., Jockenhövel, F.[2007]

In a study of 66 postmenopausal women over 3 years, Tibolone did not increase the volume of uterine myomas, suggesting it is safe for women with these growths.

Tibolone had a notable early effect on uterine blood flow, decreasing the pulsatility index in women without myomas while increasing it in those with myomas, indicating changes in uterine hemodynamics based on myoma presence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long term effects of Tibolone on postmenopausal women with uterine myomas. Gregoriou, O., Konidaris, S., Botsis, D., et al.[2019]

In a study of 1497 women with postmenopausal osteoporosis, over 90% showed good compliance with raloxifene therapy, indicating that patients generally adhered well to their treatment regimen over the 18-month period.

Higher treatment satisfaction and better quality of life were significantly associated with adherence to raloxifene, suggesting that effective osteoporosis management relies on patient cooperation and satisfaction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Raloxifene in clinical practice. Results of the non-interventional study CORAL (COmpliance with RALoxifene)]. Rosa, J., Vanuga, P., Payer, J., et al.[2015]

Raloxifene hydrochloride (RLX) was successfully formulated into a semisolid self-nanoemulsifying system (SSNES) that significantly improved its solubility and tumor penetration, with an optimized globule size of 109.19 nm.

The RLX-loaded SSNES demonstrated strong anti-cancer effects in MCF-7 breast cancer cells by inducing apoptosis through caspase-3 activation and cell cycle arrest, suggesting it could be an effective treatment option for breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimized semisolid self-nanoemulsifying system based on glyceryl behenate: A potential nanoplatform for enhancing antitumor activity of raloxifene hydrochloride in MCF-7 human breast cancer cells. Badr-Eldin, SM., Aldawsari, HM., Ahmed, OAA., et al.[2021]

In a study of 1145 healthy postmenopausal women over 24 months, raloxifene significantly improved bone mineral density (BMD) and reduced low-density lipoprotein cholesterol (LDL-C) compared to placebo, indicating its potential as a beneficial treatment for osteoporosis and cardiovascular health.

Approximately 50% of women taking raloxifene showed improvements in both BMD and LDL-C, while only 19.1% of the placebo group experienced similar benefits, highlighting the efficacy of raloxifene in promoting bone and heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinically favorable effects of raloxifene on bone mineral density and serum lipids: population assessment via bivariate analysis. Shah, A., Iversen, P., Mitlak, B.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Celiprolol: A Unique Selective Adrenoceptor Modulator. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

DDAVP therapy controls bleeding in Ehlers-Danlos syndrome. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

[Pharmacotherapy of osteoporosis: evidence-based clinical practice]. [2007]

7. Ireland pubmed.ncbi.nlm.nih.gov

Long term effects of Tibolone on postmenopausal women with uterine myomas. [2019]

8. Czech Republic pubmed.ncbi.nlm.nih.gov

[Raloxifene in clinical practice. Results of the non-interventional study CORAL (COmpliance with RALoxifene)]. [2015]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Optimized semisolid self-nanoemulsifying system based on glyceryl behenate: A potential nanoplatform for enhancing antitumor activity of raloxifene hydrochloride in MCF-7 human breast cancer cells. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Clinically favorable effects of raloxifene on bone mineral density and serum lipids: population assessment via bivariate analysis. [2020]