Luke Laffin, MD, is the co-director of the Center for Blood Pressure Disorders, medical director of cardiac rehabilitation, and associate professor of medicine at Cleveland Clinic.

Luke Laffin, MD

Tonlamarsen treatment resulted in persistent and long-term reductions in angiotensin and 

 after withdrawal, according to a secondary analysis of the KARDINAL trial.

Tonlamarsen Produces Persistent, Long-Term Angiotensin and BP Improvements

European Society of Cardiology (ESC) Congress 2026

 in Munich, Germany, by Luke Laffin, MD, medical director of the Cleveland Clinic Coordinating Center for Clinical Research and lead investigator in the original KARDINAL trial.

“This is important because these are data to support that cardiovascular risk can be predicted by how high your blood pressure goes at a single time, not just on an ongoing basis,” Laffin told 

 in an exclusive interview. “What this really does is set the stage for our next trial, which is ongoing and enrolling right now – KARDINAL-ASH, which is for acute severe hypertension.”

KARDINAL was a multicenter, prospective, randomized, active run-in, double-blind, placebo-controlled phase 2 trial conducted across 39 sites in the US. Eligible patients were ≥18 years old, were receiving stable doses of 2 to 5 antihypertensive medications, and had an office systolic BP between 135 and 170 mmHg. Patients with known secondary causes of hypertension or serum potassium >5.1 mmol/L, among other criteria, were excluded.

The study’s coprimary endpoints included the percent change from baseline to week 20 in plasma angiotensin levels and the change in office systolic BP among patients receiving monthly tonlamarsen treatment, both compared with a single dose and subsequent placebo. Key secondary endpoints included the proportion of patients with systolic in-office BP <130 mmHg, change from baseline in mean self-assessed home systolic BP, and the change from baseline in mean office systolic BP, among others.

Patients were first given a single 90-mg dose of tonlamarsen subcutaneously during an active run-in period before being randomly assigned in a 1:1 ratio to 4 doses of tonlamarsen or matching placebo for the next 16 weeks. A total of 519 patients were initially screened, and 279 were administered placebo lead-in. A total of 206 received active run-in with a single dose of tonlamarsen, and a final total of 198 patients were randomized to either placebo (n = 98) or tonlamarsen (n = 100). At enrollment, 118 patients (60%) were taking a 2-drug antihypertensive regimen, while others were taking ≥3 drugs.

By week 20, the least squares mean percentage change in plasma angiotensin from baseline in patients treated with a single dose and then randomized to placebo was -23% (95% CI, -27.8% to -18.2%). Among patients treated with 20 weeks of tonlamarsen, angiotensin changed by -67.2% (95% CI, -71.9% to -62.4%). Change in office systolic BP in the single-dose arm was -6.7 mmHg (95% CI, -9.8 to -3.5 mmHg), while the change in the full treatment arm was -6.7 mmHg (97.5% CI, -51.9% to -36.4%; 

This secondary analysis extended both angiotensin and office BP measurements through 28 weeks, acting as a safety follow-up, as well as evaluating home BP time-in-target range (TTR) and incidence of markedly elevated home BP. Over this 28-week period, the placebo arm saw a reduction in angiotensin of 23.8%, while the treatment arm saw a 44% reduction. Office systolic BP also dropped by a mean of -7.1 mmHg in the placebo arm and -6.1 mmHg in the treatment arm.

Additionally, the percentage of home systolic BP TTR <140 mmHg was 75% with tonlamarsen and 67% without during this extended follow-up period (difference, -8; 95% CI, -22.9 to 7). The percent of home systolic BP TTR from 110 to 130 mmHg was 39% with tonlamarsen and 34% with placebo (difference, -4.7; 95% CI, -18.7 to 9.2).

Ultimately, Laffin and colleagues concluded that the analysis further underscores tonlamarsen’s efficacy and safety, highlighting the persistence of effect after an extended period post-treatment. Laffin also notes that these data pave the way for the next stage of trials, namely the KARDINAL-ASH trial, which is currently enrolling.

“Home blood pressure is really where we have to be able to generate evidence,” Laffin said. “We know that patients do it, and we have new technologies to measure blood pressure. Office blood pressure is a fine surrogate for cardiovascular outcomes, but we get a much higher fidelity of data, and really more informative data, if we can see home blood pressure reductions.”

Editors’ Note: Laffin reports relevant disclosures with AstraZeneca, Arrowhead, Medtronic, Eli Lilly, Mineralys, Crispr Therapeutics, Novartis, Novo Nordisk, and others.

Laffin L. Extended Follow-Up of the KARDINAL Trial Assessing the Effect of Tonlamarsen in Uncontrolled Hypertension. Presented at the European Society of Cardiology (ESC) Congress 2026, Munich, Germany. August 28-31, 2026.

Laffin, L, Wang, Q, Sarraju, A. et al. Efficacy of Tonlamarsen in Patients With Uncontrolled Hypertension: The KARDINAL Phase 2 Randomized Clinical Trial. 

https://doi.org/10.1016/j.jacc.2026.03.034

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Luke Laffin, MD, discusses his secondary analysis of the phase 2 KARDINAL trial, which demonstrated substantial improvements in uncontrolled hypertension.

A single infusion of CTX310, an investigational in vivo CRISPR-Cas9 gene-editing therapy targeting ANGPTL3, produced durable reductions in ANGPTL3, LDL cholesterol, and triglycerides through 1 year of follow-up in a phase 1a trial, according to data presented at the 

Luke Laffin, MD, principal investigator and medical director of the Cleveland Clinic Coordinating Center for Clinical Research, discussed the findings with 

Can One CRISPR Dose Lower Cholesterol for Years? With Luke Laffin, MD

"What we did was describe the durability of CTX-310 throughout the course of the study. This builds upon data that was presented at the American Heart Association in November of 2025, which showed ANGPTL3 reduction at day 30 and lipid biomarkers at the highest dose at day 60," Laffin said. "Now we have 12-month data for all participants who received gene editing via CRISPR-Cas9 with CTX310."

CTX310 Phase 1a Durability Data at 1 Year

The phase 1a portion of the open-label, dose-escalation trial was conducted in Australia and New Zealand, enrolling 15 adults with uncontrolled hypercholesterolemia, moderate to severe hypertriglyceridemia, or mixed dyslipidemia between May 2024 and August 2025. Participants received a single intravenous dose of CTX310 at 1 of 5 levels, ranging from 0.1 to 0.8 mg/kg lean body weight, across cohorts with homozygous or heterozygous familial hypercholesterolemia, severe hypertriglyceridemia, or mixed dyslipidemia.¹ Most participants were on background statins or ezetimibe, and 40% were taking PCSK9 inhibitors.²

Among the 4 participants who received the highest dose (0.8 mg/kg), the mean percent change from baseline at 1 year was -78.6% in ANGPTL3 (range, -89.0 to -63.1), -52.5% in LDL cholesterol (range, -84.2 to -24.4), and -47.8% in triglycerides (range, -77.6 to -14.7). Across the full highest-dose cohort, ANGPTL3 reductions reached up to 89%, with a mean reduction of 79% sustained at 1 year, alongside mean reductions of 52.0% in non-HDL cholesterol and 37.2% in apolipoprotein B.²

Asked how clinicians should interpret the variability in response among the 4 highest-dose participants, Laffin cautioned against overreading small numbers: “When you have small numbers, like four patients, there's going to be some variability... the means are really sort of a starting point, and then we have to do larger studies to really understand whether the response to CTX-310 is heterogeneous between the people that have severe hypertriglyceridemia versus those that have HeFH versus those with mixed dyslipidemia," Laffin said. "We enrolled a very broad population because when you do a first-in-human trial, you want to get anyone that you can to show the safety, and then the next step is really looking at the efficacy in these more dedicated cohorts."

Interpreting Variability, Safety, and What Comes Next for CTX310

The trial's primary endpoint was adverse events, including dose-limiting toxic effects, and no dose-limiting toxicity was reported through 1 year.¹ A pair of previously reported serious adverse events were assessed as unrelated to CTX310, with one subsequently determined to be a preexisting condition, and no new serious adverse events or adverse events of special interest occurred during extended follow-up.¹ Beyond a transient aminotransferase elevation in 1 participant shortly after treatment, no additional liver-function abnormalities occurred, and infusion-related reactions in 3 participants were grade 2 and resolved.²

Laffin said the data support advancing the program, though not yet a large outcomes study. "I don't think anyone's saying, based on this, we should start doing a 10,000-patient outcome study, but it's clearly enough to move into phase 2 to understand really what the effect is and the safety," Laffin said. "I think that at this point, we’re very confident that it looks safe."

On what would constitute a convincing efficacy signal in the next phase, Laffin said the relevant endpoints depend on the patient cohort: LDL cholesterol and apolipoprotein B for patients with familial hypercholesterolemia, triglycerides for those with severe hypertriglyceridemia, and both for mixed dyslipidemia. Asked when persistence at 1 year might be called permanence, Laffin noted participants have consented to 15-year follow-up, but cautioned drop-in of other lipid therapies over time complicates any such determination; he described the on-target ANGPTL3 effect as a convincing signal, though larger, longer-term studies in more patients are still needed before durability can be called permanent.

CRISPR Therapeutics is now evaluating a fixed 0.8 mg/kg dose of CTX310 in a phase 1b trial in patients with refractory dyslipidemias, with an update from the severe hypertriglyceridemia cohort expected in the second half of 2026. The company's broader in vivo cardiovascular gene-editing portfolio also includes CTX340, targeting angiotensinogen for refractory hypertension, and CTX321, targeting LPA for elevated lipoprotein(a).¹

Editors’ note: Laffin reports relevant disclosures with AstraZeneca, Arrowhead, Medtronic, Eli Lilly, Mineralys, Crispr Therapeutics, Novartis, Novo Nordisk, and others.

Laffin L, et al. Durability of CRISPR-Cas9 gene editing targeting ANGPTL3 with CTX310. N Engl J Med. 2026. Presented at: ESC Congress 2026; August 28, 2026; Munich, Germany.

CRISPR Therapeutics. CRISPR Therapeutics presents phase 1a data for CTX310 demonstrating deep and durable ANGPTL3 editing, triglyceride and LDL lowering at ESC Congress 2026. Published August 28, 2026. Accessed August 30, 2026. 

https://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-presents-phase-1a-data-ctx310r-demonstrating

Luke Laffin, MD, discusses 1-year data showing CTX310 produced durable reductions in ANGPTL3, LDL cholesterol, and triglycerides.

Gene Editing for Lipids: 1-Year CTX310 Data, With Luke Laffin, MD

Tonlamarsen Lowers Angiotensinogen, Mixed Results for Blood Pressure, With Luke Laffin, MD

Monthly tonlamarsen successfully reduced plasma angiotensinogen compared with a single tonlamarsen dose in patients with uncontrolled 

, but led to no additional blood pressure reduction, according to data from the Kardinal study.

American College of Cardiology (ACC) Scientific Sessions 2026

 in New Orleans, Louisiana, by Luke Laffin, MD, co-director of the Center for Blood Pressure Disorders, medical director of cardiac rehabilitation, and associate professor of medicine at Cleveland Clinic.

“It begs the question of whether you need that sustained angiotensinogen reduction to actually impact the pharmacodynamic marker of blood pressure long-term,” Laffin told 

 in an exclusive interview. “So how do we explain the changes in the angiotensinogen levels and the blood pressure levels in the study, which was not strictly placebo-controlled? We’ll have to establish that in future studies.”

Kardinal was a randomized, placebo-controlled trial investigating the safety and efficacy of 90 mg tonlamarsen delivered subcutaneously once a month for 5 months compared to a single dose of tonlamarsen and subsequent placebo. Patients were eligible for inclusion if they exhibited a systolic blood pressure >135 mmHg and were receiving 2-5 antihypertensive medications. Patients were excluded if they exhibited secondary causes of hypertension, an estimated glomerular filtration rate of <30 mL/min/1.73m2, or a serum potassium >5.1 mmol/L. The study included 2 primary endpoints – the between-group differences in change from baseline to week 20 in plasma angiotensinogen and in-office systolic blood pressure.

The study consisted of a 4-week placebo lead-in, a 4-week active run-in with 1 dose of tonlamarsen, and subsequent randomization to 4 further doses of either tonlamarsen or matching placebo for 16 weeks. Following enrollment, 270 patients received placebo lead-in, 206 received 90mg of tonlamarsen during an active run-in period, and 198 were eventually randomized to receive either placebo or continuous tonlamarsen doses. Mean blood pressure among these randomized participants before and after lead-in was 147/90 mmHg and 147/89 mmHg, respectively.

In the 20 weeks after the first dose of tonlamarsen, least squares (LS) mean percent change in plasma angiotensinogen levels were -23% (95% CI, -27.8 to 18.2) with a single dose and -67.2% (95% CI, -71.9 to -62.4) in patients receiving monthly doses, with a LS mean difference of -44.1% (97.5% CI, -51.9 to -36.4; 

 <.0001). LS mean changes in office systolic blood pressure were -6.7 mmHg (95% CI, -9.8 to -3.5) for patients receiving a single dose of tonlamarsen and subsequent placebo versus -6.7 mmHg (95% CI, -9.8 to -3.6) for those receiving monthly tonlamarsen, with a LS mean difference of -0.1 mmHg (95% CI, -4.5 to -4.4; 

Ultimately, despite the successful angiotensinogen reductions, Laffin and colleagues also observed negligible differences in office systolic blood pressure between treatment arms. The team determined that further placebo-controlled trials are necessary to determine the efficacy of tonlamarsen, assessing either single or multi-dose tonlamarsen regimens.

“The reason why new therapies for hypertension are so important is because, based on current guideline recommendations, less than 30% of Americans have their hypertension controlled,” Laffin said. “It’s great that we have a lot of generic options, but they’re not working for us right now. I think we need to think about different strategies, and I really believe that targeting angiotensinogen upstream is one such strategy that could be effective.”

Editors’ Note: Laffin reports disclosures with Medtronic, Novartis, Eli Lilly, Mineralys, Crispr Therapeutics, Idorsia, and others.

Laffin L, Sarraju A, Sclaich M, et al. Kardinal: A Phase 2 Study of Tonlamarsen for the Treatment of Uncontrolled Hypertension. Abstract presented at the American College of Cardiology Scientific Sessions 2026, New Orleans, LA. March 28-30, 2026.

Laffin L, Wang Q, Sarraju A, et al. Efficacy of Tonlamarsen in Patients with Uncontrolled Hypertension: The KARDINAL Phase 2 Randomized Clinical Trial. 

Laffin discusses results from the Kardinal study, which investigated a single dose of tonlamarsen followed by placebo against monthly tonlamarsen treatment in hypertension.

Luke Laffin, MD

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