Breakthrough Findings from the KARDINAL Trial

The KARDIAL trial, a phase 2 multicenter study led by Cleveland Clinic researchers including those at the Abu Dhabi campus, has brought new attention to tonlamarsen, an experimental antisense oligonucleotide designed to target angiotensinogen (AGT), the precursor protein in the renin-angiotensin-aldosterone system (RAAS). This system plays a central role in blood pressure regulation by promoting vasoconstriction and sodium retention. In patients with uncontrolled hypertension—defined as systolic blood pressure exceeding 135 mmHg despite two to five oral medications—the trial demonstrated that a single subcutaneous injection of 90 mg tonlamarsen reduced plasma AGT levels by 23% at week 20, while five monthly doses achieved a remarkable 67.2% reduction. Surprisingly, both regimens lowered office systolic blood pressure by approximately 6.7 mmHg, with no significant difference between groups.

This outcome highlights the complex relationship between AGT suppression and blood pressure control, prompting further investigation into tonlamarsen's long-lasting effects, as its half-life of 2-4 weeks did not predict the persistent AGT lowering observed even after a single dose.

Hypertension Burden in the United Arab Emirates

Hypertension affects over 30% of adults in the UAE, with age-adjusted prevalence in Abu Dhabi rising from 24.5% to 35.2% between baseline surveys and 2023. The Ministry of Health and Prevention (MoHAP) reports 28.8% of adults have high blood pressure, contributing to cardiovascular disease, the leading cause of death. Resistant hypertension, where BP remains elevated despite multiple therapies, impacts a significant subset, making innovations like tonlamarsen particularly relevant for UAE healthcare.

Cleveland Clinic Abu Dhabi's involvement underscores the UAE's growing role in global clinical research, aligning with national strategies to combat non-communicable diseases through advanced trials and localized data.

How Tonlamarsen Targets the RAAS Pathway

The renin-angiotensin-aldosterone system (RAAS) begins with renin cleaving angiotensinogen (AGT), produced primarily by the liver, into angiotensin I, which is then converted to angiotensin II—the potent vasoconstrictor. Tonlamarsen, developed by Kardigan Inc., uses antisense technology to inhibit hepatic AGT mRNA, reducing circulating AGT and disrupting RAAS overactivation without the hyperkalemia risk of aldosterone synthase inhibitors like baxdrostat.

• Step 1: Antisense oligonucleotide binds AGT mRNA.
• Step 2: RNase H degrades the complex, halting AGT protein synthesis.
• Step 3: Reduced AGT limits substrate for renin, lowering downstream effectors.

This upstream intervention offers a novel approach for patients intolerant to ACE inhibitors or ARBs, common in 82% of KARDINAL participants.

Trial Design and Participant Profile

KARDINAL enrolled 198 adults (mean age 61, 41% female, 49% Black) across 39 sites, including Cleveland Clinic Abu Dhabi, after a placebo lead-in and active run-in with one 90 mg dose. Participants were randomized to five monthly tonlamarsen doses or one dose plus placebo. Baseline systolic BP was 147 mmHg on 2-5 antihypertensives.

Safety was favorable, with serious adverse events in 5% (monthly) vs 2.1% (single dose), mainly injection-site reactions in ongoing therapy.

Detailed Results: AGT Suppression vs Blood Pressure Response

Co-primary endpoints showed superior AGT reduction with monthly dosing (-67.2% vs -23.0%; P<0.0001), but equivalent systolic BP drop (-6.7 mmHg; P=0.97). Home BP, diastolic BP, and control rates (<130 mmHg) were similar. Lead investigator Luke J. Laffin, M.D., noted the unexpected persistence: "The continued decrease in blood pressure after a single dose surprised us."

This disconnect suggests BP lowering plateaus despite deeper AGT suppression, possibly due to compensatory mechanisms or carryover effects.

Safety Profile and Adverse Events

Tonlamarsen was well-tolerated, with no hyperkalemia, hypotension, or renal issues exceeding placebo. Injection-site reactions were more common with repeated dosing but mild. No discontinuations due to adverse events were reported, supporting its subcutaneous monthly administration for adherence-challenged patients.

Implications for Resistant Hypertension Management

Resistant hypertension affects 10-30% of treated patients globally, with higher rates in UAE due to lifestyle factors like high salt intake and obesity. Tonlamarsen addresses adherence barriers with infrequent dosing, potentially reducing cardiovascular events. Visit the JACC publication for full results.

For more on RAAS, see Cleveland Clinic's press release.

UAE Context: Aligning with National Health Priorities

The UAE's National Program for Chronic Non-Communicable Diseases targets hypertension reduction. Cleveland Clinic Abu Dhabi's participation positions it as a hub for innovative trials, complementing local efforts like renal denervation recently introduced there. With prevalence at 35% in Abu Dhabi, such research could transform care.

Comparing Tonlamarsen to Existing Therapies

• ACEIs/ARBs: Daily pills, cough side effect risk.
• Aldosterone antagonists: Hyperkalemia concern.
• Tonlamarsen: Monthly injection, upstream RAAS block, adherence advantage.

Unlike lorundrostat (aldosterone synthase inhibitor), tonlamarsen avoids mineralocorticoid excess.

Future Directions and Ongoing Research

A follow-up trial starts April 2026 for acute severe hypertension post-discharge. Phase 3 could confirm efficacy in diverse populations, including UAE expatriates. Researchers hypothesize 6-7 mmHg additive BP reduction to standard therapy.

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Stakeholder Perspectives and Real-World Impact

Experts like Dr. Laffin emphasize: "It’s important to study tonlamarsen in patients who struggle with daily medications." Patients in UAE, facing cultural dietary habits exacerbating hypertension, stand to benefit from simplified regimens.

Actionable Insights for Healthcare Providers

1. Screen for resistant hypertension using 24-hour ambulatory monitoring.
2. Consider adherence counseling alongside novel therapies.
3. Monitor AGT levels in RAAS trials for surrogate endpoints.
4. Participate in UAE research networks for trial access.

This study advances precision medicine in cardiovascular health, with Cleveland Clinic Abu Dhabi at the forefront.

Photo by Markus Winkler on Unsplash