Compound 21 for Preeclampsia

Overseen By Kelsey Schwartz

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: Anna Stanhewicz, PhD

Must not be taking: Antihypertensives, Statins

Disqualifiers: Hypertension, Metabolic disease, Gestational diabetes, others

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

Compensation: Varies

Number of Visits: 2

Duration: 1 hour

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores why women who experienced preeclampsia during pregnancy might face higher risks of heart disease later. Researchers examine how the body's tiny blood vessels function in these women and whether activating certain receptors with Compound 21 (an Angiotensin II Type 2 Receptor Agonist) can restore normal function. The study focuses on women 12 weeks to 5 years post-pregnancy, comparing those who had preeclampsia to those who did not. Women who had preeclampsia but not other conditions like hypertension or diabetes before pregnancy might be suitable for this study. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

If you are currently taking antihypertensive or cholesterol-lowering medications, you cannot participate in this trial. The protocol does not specify about other medications, so it's best to discuss with the trial team.

Is there any evidence suggesting that Compound 21 is likely to be safe for humans?

Research has shown that Compound 21 has potential based on earlier studies. It activates the angiotensin type 2 receptor, which can protect blood vessels. In animal studies, this compound improved blood flow and reduced high blood pressure.

This trial remains in the early stages, so detailed safety information for humans is limited. However, some studies suggest that the compound is generally well-tolerated. These early results are promising, but more research is needed to fully understand its safety and effects in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for preeclampsia?

Unlike the standard treatments for preeclampsia, which typically focus on managing symptoms like high blood pressure with medications such as antihypertensives, Compound 21 works differently by targeting the microvasculature. Researchers are excited about this treatment because it involves delivering Compound 21 directly to the skin's tiny blood vessels using a technique called intradermal microdialysis. This approach not only offers a novel mechanism by potentially improving blood vessel function, but also allows for localized treatment, reducing the risk of systemic side effects. This innovative method could pave the way for more effective and safer management of preeclampsia.

What evidence suggests that Compound 21 might be an effective treatment for preeclampsia?

Research has shown that Compound 21, administered to participants in this trial, might address issues related to preeclampsia. Compound 21 improves blood flow and relaxes blood vessels by targeting specific areas that regulate blood pressure and inflammation. Dysfunction in these areas has been linked to preeclampsia. Additionally, Compound 21 may reduce inflammation, offering extra protection. This raises hope that Compound 21 could aid in managing long-term heart and blood vessel issues associated with preeclampsia. ^{1 2 3 6 7}

Who Is on the Research Team?

Anna Reid-Stanhewicz, PhD

Principal Investigator

University of Iowa

Are You a Good Fit for This Trial?

This trial is for women aged 18-45 who experienced preeclampsia between 12 weeks and 5 years ago. It's also open to those who had healthy pregnancies. Participants should not be currently pregnant, planning pregnancy, have a history of hypertension or metabolic disease before pregnancy, use tobacco, or take certain medications like antihypertensives or statins.

Inclusion Criteria

Women who had preeclampsia and women who did not have preeclampsia

I gave birth between 12 weeks and 5 years ago.

Exclusion Criteria

Known allergy to study drugs

Current tobacco use

Body mass index less than 18.5 kg/m2

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo intradermal microdialysis for the local delivery of compound 21 and L-NAME to the cutaneous microvasculature

1 hour

1 visit (in-person)

Follow-up

Participants are monitored for changes in microvascular blood flow response and angiotensin receptor expression

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Compound 21

Trial Overview The study tests Compound 21 on the microvascular function in the skin of women post-preeclampsia. Researchers are investigating if activating angiotensin II receptors can repair blood vessel damage caused by preeclampsia and reduce future cardiovascular disease risk.

How Is the Trial Designed?

Group I: assessment of microvascular function Experimental Treatment 1 Intervention

The investigators use intradermal microdialysis to deliver compound 21 and L-NAME to the cutaneous microvasculature

Who Is Running the Clinical Trial?

Anna Stanhewicz, PhD

Lead Sponsor

Trials

12

Recruited

460+

Published Research Related to This Trial

Preeclampsia is primarily caused by systemic maternal vascular dysfunction due to oxidative stress and excessive anti-angiogenic factors from a dysfunctional placenta, leading to hypertension and other complications during pregnancy.

Currently, the only definitive treatment for preeclampsia is the delivery of the placenta, often resulting in preterm birth, highlighting the urgent need for new therapies that specifically target the underlying vascular dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the vascular dysfunction: Potential treatments for preeclampsia. Marshall, SA., Cox, AG., Parry, LJ., et al.[2019]

A study involving 168 women (84 with early-onset preeclampsia and 84 controls) found that certain genetic variations in the angiotensin II receptor genes (AT1R and AT2R) are associated with a higher risk of developing early-onset preeclampsia, particularly in those with three mutant receptor combinations.

The presence of these genetic variants could help predict susceptibility to early-onset preeclampsia and may guide future research on targeted treatments for hypertensive disorders in pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia. Satra, M., Samara, M., Alatsathianos, G., et al.[2022]

Activation of AT2 receptors (AT2Rs) by Compound 21 (C-21) in rats significantly increased urinary sodium excretion by 10-fold, demonstrating its efficacy in promoting natriuresis without affecting renal blood flow.

C-21 not only induced natriuresis but also lowered blood pressure in a model of hypertension, suggesting that targeting AT2Rs could be a promising strategy for treating conditions related to fluid retention and high blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AT₂ receptor activation induces natriuresis and lowers blood pressure. Kemp, BA., Howell, NL., Gildea, JJ., et al.[2021]

The PI2 Trial is a phase II clinical study involving 150 women with preterm pre-eclampsia, testing the efficacy of extended-release metformin compared to a placebo, with the primary goal of delaying delivery by at least 5 days.

Metformin is already known to be safe during pregnancy and may provide a new therapeutic option to manage preterm pre-eclampsia, potentially improving outcomes for both mothers and their babies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol. Cluver, C., Walker, SP., Mol, BW., et al.[2023]

The soluble forms of the type-1 receptor for vascular endothelial growth factor (sFlt1) and endoglin (sEng) are promising biomarkers for preeclampsia, as they significantly increase in maternal blood weeks before clinical symptoms appear, potentially aiding in early identification of high-risk women.

Defective placental steroidogenesis and altered angiotensin-2 receptor tolerance are implicated in the pathophysiology of preeclampsia, suggesting these pathways could lead to new biomarkers and therapeutic strategies, although more research is needed in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New markers in preeclampsia. Hertig, A., Liere, P.[2015]

Preeclampsia affects 3-8% of pregnancies and is a major cause of complications for mothers and babies, highlighting the urgent need for effective treatments.

Therapies that improve endothelial function, such as PDE-5 inhibitors and endothelin type A receptor antagonists, may offer promising options to manage preeclampsia and improve outcomes for both mothers and infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging drugs for preeclampsia--the endothelium as a target. Sasser, JM., Murphy, SR., Granger, JP.[2018]

Preeclampsia affects about 5% of women after the 20th week of pregnancy and currently has no specific therapy or cure, highlighting the need for new treatment options.

The review identifies several promising G protein-coupled receptor (GPCR) targets, such as the calcitonin receptor-like receptor and angiotensin receptors, which could lead to new therapeutic strategies for managing preeclampsia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPCRs as potential therapeutic targets in preeclampsia. McGuane, J., Conrad, K.[2021]

Pravastatin has emerged as a promising candidate for preventing preeclampsia, showing beneficial effects in preclinical studies and early clinical trials, with several large prevention trials currently underway to confirm its efficacy.

Other potential treatments, including proton-pump inhibitors, metformin, and natural compounds, are also being evaluated for their ability to target the underlying mechanisms of preeclampsia, indicating a broad interest in repurposing existing drugs and exploring new therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia. Tong, S., Kaitu'u-Lino, TJ., Hastie, R., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8660162/

Activation of angiotensin type 2 receptor attenuates ... Administration of AT 2 R agonist C21 to T dams abolished the hypertensive response, improved UA blood flow, and reversed the exaggerated vasoconstriction to ...

2. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.124.24098

Reduced AT2R Signaling Contributes to Endothelial ... Reductions in AT 2 R-mediated dilation contribute to attenuated or impaired endothelial function in women who had a pregnancy complicated by preeclampsia.

3. withpower.com withpower.com/trial/early-phase-1-pre-eclampsia-5-2023-6d742

Compound 21 for Preeclampsia Compound 21 is unique because it targets GPCRs (G protein-coupled receptors), which are promising candidates for treating preeclampsia, unlike other treatments ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11430795/

Stimulation of Angiotensin II Receptor Subtype 2 Reduces ... We investigated the effect of AT2R on the pathogenesis of PE using a mouse model and recently developed AT2R agonist (compound 21 [C21]).

5. ahajournals.org ahajournals.org/doi/10.1161/hypertensionaha.114.03189

Role of Inflammation and the Angiotensin Type 2 Receptor ... A recent study using the AT2R agonist compound 21 showed that the AT2R reduces stimulation of a proinflammatory cytokine, interleukin-6, by inhibiting the ...

6. mdpi.com mdpi.com/1467-3045/46/9/579

Stimulation of Angiotensin II Receptor Subtype 2 Reduces ... A recently developed AT2R agonist (compound 21 [C21]) [33] has been shown to activate AT2R, resulting in protective effects for the lungs, ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05937841?term=NAME

Sensitivity of Angiotensin II Type II Receptors in Women ... The purpose of this study is to examine the microvascular differences in women who have had preeclampsia following activation of protective angiotensin ...