Alnylam Pharmaceuticals has announced plans to advance zilebesiran, their subcutaneously administered RNA-interfering therapeutic, into a phase 3 cardiovascular outcomes trial in patients with 

According to the August 30, 2025 announcement, the ZENITH trial’s design is based on data from the KARDIA phase 2 program, including the KARDIA-3 trial, which missed its primary endpoint but met the objective of informing the design, patient population, and dose and was presented at the 

European Society of Cardiology (ESC) Congress 2025

“I’m excited by the KARDIA-3 results, which together with the additional Phase 2 data from the KARDIA program, support zilebesiran’s potential to achieve clinically meaningful, sustained blood pressure reductions in high-risk patients. This, in turn, may lead to more consistent long-term blood pressure control and improve cardiovascular outcomes,” explained KARDIA-3 principal investigator Neha Pagidipati, MD, MPH, associate professor of Medicine, Cardiology at Duke Clinical Research Institute. “Zilebesiran’s emerging profile, now including the KARDIA-3 findings, underscores its ability to address the well-known challenges of managing patients with hypertension, and warrants further exploration in a multi-year Phase 3 cardiovascular outcomes trial.”

According to Alnylam Pharmaceuticals, the company, along with partner Roche, expects the trial to initiate by the end of 2025 and to enroll approximately 11,000 patients. The trial will evaluate zilebesiran against placebo in patients with uncontrolled hypertension with either established cardiovascular disease or at high risk for cardiovascular disease on 2 or more antihypertensives, with at least 1 being a diuretic.

The ZENITH’s trial primary endpoint is risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or urgent heart failure visit relative to placebo therapy.

“Cardiovascular disease, largely driven by uncontrolled hypertension, is a global health crisis and remains the leading addressable cause of cardiovascular morbidity and mortality,” said Pushkal Garg, MD, chief research and development officer of Alnylam.

KARDIA-3 was a double-blind, placebo-controlled, randomized trial of 270 adult patients with established cardiovascular disease or at high cardiovascular risk with uncontrolled hypertension on 2 to 4 antihypertensives from 5 countries. The phase 2 study included 2 cohorts, referred to as cohort A and cohort B, which leveraged the same primary endpoint of change in office systolic blood pressure (SBP) at 3 months.

Investigators presented the results of Cohort A, which included patients with an eGFR of at least 45 mL/min/1.73 m² or more, during a Hot Line presentation at the ESC Congress 2025. Cohort B data, which includes a population with more advanced kidney dysfunction, will be presented at an upcoming medical conference, according to Alnylam Pharmaceuticals.

Cohort A included a total of 270 individuals. The cohort had a mean baseline office SBP of 143.6 mmHg and a 24-hour mean ambulatory SBP of 142.4 mmHg. These patients were randomized 1:1:1 to a single dose of zilebesiran 300 mg, zilebesiran 600 mg, or placebo therapy.

Among the 270 included patients, 53.3%, 35.6%, and 11.1% were on 2, 3, or more than 3 antihypertensives, respectively. Additionally, 90.7% of patients were taking ACE inhibitors or ARBs, 65.9% were taking a diuretic, and 57.7% were taking calcium channel blockers.

Primary results suggested zilebesiran 300 mg was placebo-adjusted reductions of office SBP at the month 3of -5.0 mmHg (95% Confidence Interval [CI], -9.9 to -2.2; 

= .0431), with sustained benefits out to month 6 (-3.9 mmHg; 95% CI, -8.5 to 0.7), with no additional benefits observed with the 600 mg dose at month 3 (-3.3 mmHg; 

= .1830) or month 6 (-3.6 mmHg; 95% CI, -8.2 to 1.0).

The trial missed its primary endpoint. As the release from Alnylam Pharmaceuticals notes, per the trial’s design, statistical testing of change in office SBP at the month 3 primary endpoint was controlled for multiplicity, which required both doses to have a 

-value of <.025, to be considered statistically significant.

Safety data through month 6 indicated adverse events occurred among 43.2%, 51.6%, and 50.5% of the placebo, zilebesiran 300 mg, and zilebesiran 600 mg groups, respectively. Serious events occurred among 4.5%, 1.1%, and 6.6% of the placebo, zilebesiran 300 mg, and zilebesiran 600 mg groups, respectively.

“The totality of the evidence from the phase II programme supports the conduct of a phase III outcomes trial to further assess the potential of zilebesiran for improving cardiovascular outcomes in patients with uncontrolled hypertension,” Pagidipati said.

. KARDIA-3: Zilebesiran as add-on therapy in adults with hypertension and established cardiovascular disease or at high cardiovascular risk.

 Presented at the European Society of Cardiology (ESC) Congress 2025. Madrid, Spain. August 29-September 1, 2025.

Alnylam Pharmaceuticals, Inc. Alnylam to Advance Zilebesiran into Global Phase 3 Cardiovascular Outcomes Trial. Investor Relations | Alnylam Pharmaceuticals, Inc. Published August 30, 2025. Accessed August 31, 2025. 

https://investors.alnylam.com/press-release?id=29246

European Society of Cardiology. KARDIA-3 trial examines blood-pressure lowering effects of zilebesiran in hypertensive patients at high cardiovascular risk. Escardio.org. Published August 30, 2025. Accessed August 31, 2025. 

https://www.escardio.org/The-ESC/Press-Office/Press-releases/KARDIA-3-trial-examines-blood-pressure-lowering-effects-of-zilebesiran-in-hypertensive-patients-at-high-cardiovascular-risk#

Articles

Alnylam Pharmaceuticals is advancing zilebesiran, an RNA-interfering therapeutic, into a phase 3 trial named ZENITH, targeting patients with uncontrolled hypertension. The trial design is informed by the KARDIA phase 2 program, including KARDIA-3, which, despite missing its primary endpoint, provided valuable insights. The ZENITH trial will assess zilebesiran's efficacy in reducing cardiovascular events in approximately 11,000 patients. Initial phase 2 results showed modest blood pressure reductions with zilebesiran, and safety data indicated a manageable adverse event profile, supporting further investigation in a phase 3 trial.

Alnylam Pharmaceuticals debuts phase 2 KARDIA-3 data at ESC 2025 and advances zilebesiran into a phase 3 outcomes trial.

Zilebesiran, RNAi for Hypertension, Heads to Phase 3 Cardiovascular Outcomes Trial

Brian Bergmark, MD
Credit: Brigham and Women's Hospital

Results of ESSENCE-TIMI 73b suggest use of olezarsen (Tryngolza), an apolipoprotein C-III RNA-targeting therapy administered monthly, could help more than 80% of patients with 

 achieve normal triglyceride (TG) levels at 12 months.

Presented at the European Society of Cardiology (ESC) Congress 2025, results of the phase 3 ESSENCE-TIMI 73b trial indicate use of the agent, which received 

approval from the US food and Drug Administration for familial chylomicronemia syndrome (FCS)

 in 2024, was associated with a statistically significant placebo-adjusted 61% and 58% reduction in TG levels at 6 months with the 80 mg and 50 mg monthly doses, respectively, among patients with moderate hypertriglyceridemia and elevated cardiovascular risk.

“High levels of triglycerides are an important risk factor for atherosclerotic cardiovascular disease and yet the effects of current therapies are modest,” said principal investigator Brian Bergmark, MD, an investigator in the TIMI Study Group and an Interventional Cardiologist in the Division of Cardiovascular Medicine at Brigham and Women's Hospital, in a press release. “Olezarsen targets the mRNA of apolipoprotein C-III, which inhibits triglyceride clearance.”

Launched in 2022 based on positive phase 2 findings in the Bridge-TIMI 73a and another small trial, the ESSENCE-TIMI 73b trial was a double-blind, randomized, placebo-controlled trial, to assess the safety and efficacy of olezarsen 50 mg and 80 mg doses among patients with moderate hypertriglyceridemia and elevated cardiovascular risk or with severe hypertriglyceridemia. Per trial protocol, investigators defined hypertriglyceridemia as TG levels of 150 to 499 mg/dL and severe hypertriglyceridemia as TG levels of 500 mg/dL or greater.

The International trial recruited patients from 160 sites across North America and Europe, with 1478 individuals undergoing randomization in a 1:3 ratio to a 50-mg or 80-mg cohort. They were subsequently randomized in a 3:1 ratio to receive monthly subcutaneous olezarsen or a matching placebo within each cohort.

The primary outcome of interest for the trial was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, which investigators reported as placebo-adjusted change.

Overall, 1349 participants were included in the primary analysis. Of these, 254 received olezarsen 50 mg, 766 received olezarsen 80 mg, and 329 received placebo every 4 weeks via subcutaneous injection for 12 months. This study population had a median age of 64 years, 40% were women, and the median TG level at baseline was 238.5 mg/dL.

Primary results of the trial suggested the placebo-adjusted least-squares mean change in TG level was −58.4 percentage points (95% confidence interval [CI], −65.1 to −51.7; P <.001) in the olezarsen 50 mg group and −60.6 percentage points (95% CI, −67.1 to −54.0; 

<.001) in the olezarsen 80 mg group. The least-squares mean change from baseline in triglyceride level was −55.6% (95% CI, −58.0 to −53.2) in the olezarsen 50 mg group, −57.8% (95% CI, −59.6 to −55.9) in the olezarsen 80 mg group, and 2.8% (95% CI, −3.5 to 9.0) in the placebo group. Investigators highlighted 85.0% of the olezarsen 50 mg group, 88.7% of the olezarsen 80 mg group, and 12.5% of the placebo group had a TG level of less than 150 mg/dL at 6 months (

Analysis of safety data from the trial suggested serious adverse events occurred among 9% with olezarsen 50 mg, 14% with olezarsen 80 mg, and 11% with placebo. Additionally, investigators pointed out liver transaminase elevations to any degree above the upper limit of the normal range were more common with olezarsen 50 mg (34.2%) and olezarsen 80 mg (38.3%) than with placebo (17.6%) (both 

<.001), but suggested clinically meaningful increases were rare and similar across groups.

“The positive results of this study are an important step in bringing forward a potential new treatment for people with severely elevated triglycerides. Following the FDA approval and encouraging launch of [olezarsen] for people living with FCS, a rare, genetic form of severely elevated TGs, these data support olezarsen’s potential to benefit the much broader population of people living with sHTG,” said Sam Tsimikas, MD, senior vice president, global cardiovascular development at Ionis, at the time the company 

Bergmark BA, Marston NA, Prohaska TA, et al. Targeting 

 with Olezarsen in Moderate Hypertriglyceridemia. 

. Published online August 30, 2025. doi: 

European Society of Cardiology. Olezarsen reduces levels of the blood fat, triglycerides, in patients at high cardiovascular risk. Escardio.org. Published August 30, 2025. Accessed August 31, 2025. 

https://www.escardio.org/The-ESC/Press-Office/Press-releases/Olezarsen-reduces-levels-of-the-blood-fat-triglycerides-in-patients-at-high-cardiovascular-risk

Ionis Pharmaceuticals, Inc. Ionis announces positive topline results from Essence study of olezarsen in people with moderately elevated triglycerides | Ionis Pharmaceuticals, Inc. Ionis Pharmaceuticals, Inc. Published May 19, 2025. Accessed August 31, 2025. 

https://ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-topline-results-essence-study-olezarsen

Olezarsen, an apolipoprotein C-III RNA-targeting therapy, demonstrated significant efficacy in reducing triglyceride levels in patients with hypertriglyceridemia, according to the ESSENCE-TIMI 73b trial. The study, presented at the ESC Congress 2025, showed that monthly doses of 50 mg and 80 mg led to a 58% and 61% reduction in triglyceride levels, respectively, at six months. The trial also highlighted the potential of olezarsen to benefit a broader population beyond those with familial chylomicronemia syndrome, despite some safety concerns regarding liver transaminase elevations.

Olezarsen shows promise in significantly lowering triglyceride levels in patients with hypertriglyceridemia.

ESSENCE-TIMI 73b: Olezarsen Normalizes TGs in 80% of Patients With HTG

Baxdrostat Proves Role of Aldosterone Inhibition in Hypertension, With Jenifer Brown, MD

Baxdrostat, AstraZeneca’s investigational aldosterone synthase inhibitor, significantly reduced systolic blood pressure in patients with uncontrolled and resistant 

, according to results of the phase 3 BaxHTN trial presented at the 

2025 European Society of Cardiology Congress


The trial randomized 794 patients with seated systolic blood pressures between 140 mm Hg and <170 mm Hg, all receiving stable background therapy, to baxdrostat 1 mg, baxdrostat 2 mg, or placebo once daily for 12 weeks. At study completion, patients on baxdrostat demonstrated substantial reductions in seated systolic blood pressure compared with placebo: -14.5 mm Hg for 1 mg, -15.7 mm Hg for 2 mg, versus -5.8 mm Hg with placebo. Hyperkalemia >6 mmol/L occurred in 2.3% of patients on 1 mg, 3% on 2 mg, and 0.4% on placebo.


An editorial in the New England Journal of Medicine by Tomasz Guzik, MD, PhD, highlighted three clinical takeaways. First, baxdrostat achieved reductions in blood pressure comparable to spironolactone and other aldosterone synthase inhibitors, despite concomitant RAAS blockade and near-universal diuretic use, suggesting potential to overcome aldosterone breakthrough. Second, biochemical changes emerged early but were generally well managed, with few discontinuations for hyperkalemia. Third, during randomized withdrawal, blood pressure rebounded only modestly, hinting at possible physiologic resets in sodium balance or vascular tone that could support durable control.


“It’s exciting, because now we’re looking at a completely new class of blood pressure medication,” said Jenifer Brown, MD, of Brigham and Women’s Hospital, in an interview with 

. “Beyond just being a new class, it’s targeting aldosterone, which we believe is a prevalent and important driver of hypertension and cardiovascular disease. The benefits appeared consistent across subgroups, suggesting a broad role for aldosterone antagonists.”
Investigators concluded that baxdrostat represents a promising therapeutic option for patients with uncontrolled or resistant hypertension, potentially broadening long-term strategies for cardiovascular protection.

Flack J, Azizi M, Brown J, et al. Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension. 

 August 30, 2025. Accessed August 30, 2025. DOI: 10.1056/NEJMoa2507109.

Guzik T, Tomaszewski M. Aldosterone Synthase Inhibition for Hypertension. 

. August 30, 2025. Accessed August 30, 2025. DOI: 10.1056/NEJMe2511533.

Videos

Jenifer Brown, MD | Image Credit: Cardiolovascular Life Sciences

Baxdrostat, AstraZeneca’s investigational aldosterone synthase inhibitor for the treatment of uncontrolled and resistant 

, achieved its primary endpoint of change in seated systolic blood pressure compared to placebo in the phase 3 BaxHTN trial.

 in Madrid, Spain, on August 30, 2025, the trial showed a significantly lower seated systolic blood pressure at 12 weeks in patients assigned to baxdrostat added to background therapy versus those assigned to placebo. According to investigators, these data represent a step towards broader protection against hypertension, targeting mitigation of aldosterone-driven fibrosis, renal damage, and vascular injury, as well as avoidance of cortisol effects.

“It’s exciting, because now we’re looking at a completely new class of blood pressure medication with these aldosterone synthase inhibitors,” said trial investigator Jenifer Brown, MD, a cardiovascular specialist at Brigham and Women's Hospital, in an interview with 

. “And beyond just being a new class, it’s targeting a hormone, aldosterone, that we think is a really prevalent and important driver of high blood pressure that doesn’t just lead to sodium and fluid retention, but also potentially directly to cardiovascular disease.”

The phase 3, multinational, double-blind, randomized, placebo-controlled BaxHTN trial included patients with seated systolic blood pressures between 140 mm Hg and <170 mm Hg. Additionally, patients must have received stable treatment with 2 antihypertensive medications (uncontrolled hypertension) or ≥3 such medications (resistant hypertension), including a diuretic.

After a 2-week placebo run-in period, investigators randomly assigned patients with a seated systolic blood pressure of ≥135 mm Hg in a 1:1:1 ratio to baxdrostat 1mg, baxdrostat 2mg, or placebo daily for 12 weeks. A total of 264 patients received baxdrostat 1mg, 266 received baxdrostat 2mg, and 264 received placebo, in addition to background therapy.

At 12 weeks, investigators noted a change from baseline in least-squares mean seated systolic blood pressure of -14.5 mm Hg (95% CI, -16.5 to -12.5) with 1mg baxdrostat. The 2mg group saw a change of -15.7 mm Hg (95% CI, -17.6 to -13.7), and the placebo group saw a change of -5.8 mm Hg (95% CI, -7.9 to -3.8). Additionally, a potassium level of >6 mmol per liter was reported in 6 patients (2.3%) with baxdrostat 1mg, in 8 patients (3%) with baxdrostat 2mg, and in 1 patient (0.4%) with placebo.

"Aldosterone is a well-known driver of hypertension, but for decades, scientists have struggled to block its production in a precise way," said Bryan Williams, MB.BS, in a press release by the ESC. "Baxdrostat is one of the first therapies to do so selectively, showing meaningful BP reductions in uncontrolled or resistant hypertension."

Tomasz Guzik, MD, PhD, highlighted 3 distinct clinical messages from the trial. First, baxdrostat’s lowering of systolic blood pressure was similar to that of spironolactone and other aldosterone synthase inhibitors. This occurred on top of existing RAAS blockades and near-universal diuretic use, highlighting the potential of these inhibitors to overcome aldosterone breakthrough in salt-retaining hypertension.

Second, adverse biochemical changes emerged within 2 weeks and were monitored by lab checks at baseline, at 1 to 2 weeks, and after 4 weeks. Discontinuations due to hyperkalemia were rare, indicating a solid safety profile. Finally, durability was established during the randomized-withdrawal phase, which saw blood pressure rise only modestly despite drug clearance. This suggests physiological resets of sodium balance or vascular tone. These results could support steadier blood-pressure control and reduced rescue therapy.

European Society of Cardiology. Blood-pressure reductions with baxdrostat in patients with uncontrolled or resistant hypertension. News Release. August 30, 2025. Accessed August 30, 2025.

AstraZeneca's investigational drug, baxdrostat, an aldosterone synthase inhibitor, demonstrated significant efficacy in reducing seated systolic blood pressure in patients with uncontrolled and resistant hypertension during the phase 3 BaxHTN trial. The trial, presented at the 2025 European Society of Cardiology Congress, showed that baxdrostat effectively targets aldosterone, a key driver of hypertension, offering a new therapeutic class. The trial also highlighted baxdrostat's safety profile, with minimal adverse effects, and its potential to maintain blood pressure control even after drug withdrawal.

The investigative aldosterone synthase inhibitor reduced seated systolic blood pressure in patients with uncontrolled or resistant hypertension compared to placebo.

BaxHTN: Baxdrostat Achieves Primary Endpoint in Treating Hypertension

Aficamten Outperforms Metoprolol in Obstructive Hypertrophic Cardiomyopathy, With Pablo Garcia-Pavia, MD, PhD

Aficamten demonstrated superior clinical and functional benefits compared with metoprolol in patients with 

symptomatic obstructive hypertrophic cardiomyopathy (HCM)

, according to results from the MAPLE-HCM trial presented at the 

The international, double-blind study randomized 175 adults with obstructive HCM to receive aficamten (5–20 mg daily) or metoprolol (50–200 mg daily). The primary endpoint was change in peak oxygen uptake (pVO₂) at 24 weeks, with secondary endpoints including New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and hemodynamic measures.

At 24 weeks, pVO₂ increased by 1.1 mL/kg/min in the aficamten group but decreased by 1.2 mL/kg/min in the metoprolol group, yielding a significant between-group difference of 2.3 mL/kg/min (95% CI, 1.5–3.1; P <.001). Aficamten recipients also experienced greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradients, NT-proBNP levels, and left atrial volume index.

“I think this trial is going to profoundly change the way we approach pharmacological therapy in HCM,” said lead investigator Pablo Garcia-Pavia, MD, PhD. “Currently, we have been using beta-blockers, and the results show that aficamten is superior to metoprolol, the most commonly used beta-blocker for this indication.”

Despite these promising results, investigators noted several limitations, including potential bias due to the recognizable chronotropic effects of metoprolol and uncertainty about how other nonvasodilating beta-blockers might compare. Additionally, the trial design did not address long-term outcomes.

, Amrut Ambardekar, MD, emphasized that MAPLE-HCM confirms the efficacy and safety of aficamten, echoing findings from the earlier SEQUOIA-HCM trial. “Although head-to-head comparisons are lacking, the current data show that myosin inhibition with either mavacamten or aficamten could be a suitable option for symptomatic obstructive HCM,” he wrote.

Garcia-Pavia P, Maron M, Masri A, et al. Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy. 

. August 30, 2025. Accessed August 30, 2025. DOI: 10.1056/NEJMoa2504654

Ambardekar A. Expanding the Role of Myosin Inhibition in Hypertrophic Cardiomyopathy – A Tale of Two Conditions. 

. August 30, 2025. Accessed August 30, 2025. DOI: 10.1056/NEJMe2512100

Aficamten shows significant benefits over metoprolol in treating symptomatic obstructive HCM, potentially changing first-line therapy approaches.

Pablo Garcia-Pavia, MD, PhD | Image Credit: Novo Nordisk

Aficamten, a cardiac myosin inhibitor from Cytokinetics which reduces left ventricular outflow tract gradients, decreases 

 symptoms, and improves exercise capacity when added to standard of care medications, has proven noninferiority versus beta-blockers in the recent MAPLE-HCM trial.

European Society of Cardiology Congress 2025

 in Madrid, on August 30, 2025, the trial’s primary endpoint was change in peak oxygen uptake at week 24, and secondary endpoints included improvement at week 24 in the New York Heart Association (NYHA) functional class and Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCO-CSS).

“I think this trial is going to profoundly change the way we approach pharmacological therapy in HCM,” lead investigator Pablo Garcia-Pavia, MD, PhD, head of the heart failure and inherited cardiac diseases unit at the Hospital Universitario Puerta de Hierro, said in an interview with 

. “Currently, we have been using beta-blockers, and the results of this trial show that aficamten is superior to meoprolol, the most commonly used beta-blocker for this indication. So with this, I think we have a strong ground in order to change the algorithm of therapies that we use for this disease.”

The international, double-blind, double-dummy trial included 175 adult participants with symptomatic obstructive HCM, with a mean age of 58 years and a mean left ventricular outflow tract gradient of 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. After a 1:1 ratio random assignment, 88 patients were included in the aficamten group and 87 in the metoprolol group.

At 24 weeks, peak oxygen uptake had changed by 1.1 ml per kilogram of body weight per minute (95% CI, 0.5 to 1.7) in the aficamtent group and -1.2 ml per kilogram per minute (95% CI, -1.7 to -0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; 

 <.001). Patients receiving aficamten also had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients given metoprolol.

However, despite these results, Garcia-Pavia and colleagues also noted several limitations, which they described as precluding assessment of the relative effect of aficamten and metoprolol on longer-term outcomes. First, the team noted the possibility for bias regarding investigator assumption of treatment assignment, given the negative chronotropic effect of metoprolol. Additionally, other nonvasodilating beta-blockers may have effects different from those of metoprolol, and the dose-adjustment protocol used for metoprolol may differ from strategies implemented in local practice.

“The MAPLE-HCM trial confirmed the therapeutic safety and efficacy of aficamten in obstructive HCM, similar to the previous SEQUOIA-HCM trial,” Amrut Ambardekar, MD, wrote in a related editorial for NEJM. “Although head-to-head comparisons are lacking, the current data shows that myosin inhibition with either mavacamten or aficamten could be a suitable option for symptomatic obstructive HCM.”

Aficamten, a cardiac myosin inhibitor, has demonstrated noninferiority to beta-blockers in the MAPLE-HCM trial for treating obstructive hypertrophic cardiomyopathy (HCM). The trial, presented at the European Society of Cardiology Congress 2025, showed aficamten's superiority over metoprolol in improving peak oxygen uptake, NYHA class, and KCCQ-CSS. Despite these findings, limitations such as potential bias and differences in beta-blocker effects were noted. The trial supports aficamten as a viable treatment option, aligning with previous SEQUOIA-HCM trial results.

Aficamten displayed superior improvements in peak oxygen uptake and hemodynamics compared to the most commonly used beta-blocker for symptomatically obstructive HCM.

MAPLE-HCM: Aficamten Proves Superiority to Metoprolol in Hypertrophic Cardiomyopathy

Don't Miss a Beat: Verciguat in Heart Failure - The VICTOR Trial

06:08 - Event Rates in Design Versus Execution

07:54 - VICTOR Results and Interpretation

10:34 - Reducing Heart Failure Mortality Without Impacting Hospitalization

15:57 - Is Worsening HF So Different from Outpatient HF?

17:29 - VICTOR Related to Mortality Reducing Therapies

20:15 - Is Vericiguat Not Primarily a Heart Failure Drug?

The VICTOR trial, investigating vericiguat in patients with ambulatory 

heart failure with reduced ejection fraction (HFrEF)

 who had received contemporary background therapy, failed to achieve its primary endpoint of reduction in cardiovascular mortality and heart failure hospitalizations. However, it did display fewer cardiovascular and all-cause deaths. Investigators suggested vericiguat may prove beneficial in ambulatory patients with HFrEF on top of optimal background therapy.

 in Madrid, hosts Steve Greene, MD, and Muthiah Vaduganathan, MD, MPH, sat down with Javed Butler, MD, to review the results of the highly anticipated VICTOR trial, a companion study to the pivotal VICTORIA trial evaluating vericiguat in heart failure with reduced ejection fraction (HFrEF). While VICTORIA focused on patients recently hospitalized or otherwise destabilized, VICTOR deliberately enrolled the opposite population—ambulatory, stable patients, systematically excluding anyone with a recent hospitalization or outpatient IV diuretic use. As Butler noted, this created one of the most stable trial cohorts in HFrEF to date, with nearly 90% of participants free from hospitalization for over a year at baseline.

The rationale, Butler explained, stemmed from post-hoc signals in VICTORIA suggesting a cardiovascular mortality benefit in patients with lower NT-proBNP levels, as well as a trend toward curve separation late in follow-up. VICTOR was thus powered specifically for cardiovascular mortality while retaining the same primary composite endpoint of CV death or HF hospitalization. With a longer median follow-up of more than two years and excellent baseline therapy - including >50% use of SGLT2 inhibitors, >50% on ARNIs, and nearly half on quadruple therapy - the trial provided a rigorous test of vericiguat in a contemporary, optimally treated HFrEF population.

The results, presented by Butler, were mixed but thought-provoking. The trial did not meet its primary composite endpoint, with only a 7% nonsignificant relative reduction (p=0.22). Yet vericiguat achieved consistent, statistically significant reductions in multiple mortality endpoints: CV mortality, all-cause mortality, sudden cardiac death, and HF-related death. With over 600 mortality events accrued, the findings were robust, matching the predicted event rates despite the cohort’s stability.

Discussion turned to interpreting this unusual pattern of mortality benefit without a reduction in HF hospitalizations. Butler argued that VICTOR and VICTORIA should not be viewed as contradictory, but rather as capturing different phases of the HF trajectory. In VICTORIA’s higher-risk post-hospital population, reductions in hospitalization predominated. In VICTOR’s stable cohort, early worsening often manifests as outpatient oral diuretic intensification, a marker strongly associated with subsequent mortality. Indeed, over half of the first worsening events in VICTOR were oral intensifications rather than hospitalizations, suggesting vericiguat may exert benefits earlier in the decompensation continuum.

The conversation also addressed the broader implications. Butler emphasized that vericiguat’s effects appear additive to guideline-directed therapy, with no differences in outcomes based on ARNI or device use. Pooled analyses of VICTORIA and VICTOR demonstrate consistent benefit across the spectrum of HFrEF, particularly in patients with NT-proBNP <6000 pg/mL, where relative risk reductions for mortality approach 15–17%. The group noted that while VICTOR was technically neutral, its mortality signal challenges conventional thinking. While many therapies reduce HF hospitalizations without a robust mortality benefit, vericiguat may represent the reverse. This raises the possibility that its mechanism, through the stimulation of soluble guanylate cyclase and nitric oxide signaling, exerts systemic benefits beyond traditional congestion pathways.

The episode closed with a reflection on the clinical and guideline implications. Although VICTOR did not meet its composite primary endpoint, the magnitude and consistency of mortality reduction may argue for serious consideration of vericiguat as a mortality-reducing therapy in HFrEF, potentially forming part of an emerging “quintuple therapy” standard. As Butler concluded, mortality remains the “true north” in heart failure management, and these results underscore the persistent residual risk even in optimally treated patients and the potential for novel therapies like vericiguat to address it.

European Society of Cardiology. Vericiguat did not meet its primary endpoint but lowered the risk of cardiovascular death in patients with heart failure. News Release. August 30, 2025. Accessed August 30, 2025.

Reddy YNV, Butler J, Anstrom KJ, et al. Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial. Eur J Heart Fail. 2025;27(2):209-218. 

Podcasts

Cohosts Stephen Greene, MD, and Muthiah Vaduganathan, MD, MPH, sit down with Javed Butler, MD, to discuss the results of this major trial.

Don't Miss a Beat: Vericiguat in Heart Failure and the VICTOR Trial, With Javed Butler, MD

Welcome to The HCPFive, your go-to roundup for the latest healthcare news and breakthroughs, curated specifically for busy healthcare professionals.

Each week, we highlight 5 key developments or headlines from healthcare that you need to know—whether it's a cutting-edge treatment, regulatory updates, or innovations shaping the future of medicine. This week's top stories include the US Food and Drug Administration (FDA) Priority Review of omidubicel for 

, the approval of an updated Risk Evaluation and Mitigation Strategy (REMS) label for sparsentan (Filspari) for 

, a Complete Response Letter (CRL) issued to ONS-5010 for the treatment of wet 

, new American College of Cardiology guidance on respiratory disease vaccines for adults with 

, and phase 3 ATTAIN-2 trial data for orforglipron in adults with obesity or 

With The HCPFive, you'll get the essential takeaways to stay informed and ahead of the curve. Here’s your quick dive into the top stories for the week of August 24, 2025—let’s jump in!

FDA Accepts Priority Review Application of Omidubicel for Severe Aplastic Anemia

On August 25, 2025, the FDA accepted the priority review application for Ayrmid’s omidubicel, an investigative cell therapy, for the treatment of severe aplastic anemia. With the acceptance, the FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of December 10, 2025.

FDA Approves REMS Label Update for Sparsentan (Filspari) in IgA Nephropathy

On August 27, 2025, Travere Therapeutics announced the FDA approval of an updated REMS labeling for sparsentan (Filspari) for the treatment of IgAN, reducing the frequency of liver function monitoring from monthly to every 3 months from the onset of treatment with sparsentan and removing the embryo-fetal toxicity monitoring requirement.

FDA Issues CRL to Outlook Therapeutics' ONS-5010 for the Treatment of Wet AMD

On August 28, 2025, the FDA issued a CRL to Outlook Therapeutics' Biologics License Application for ONS-5010 for the treatment of wet AMD, citing the agent’s failure to achieve the primary efficacy endpoint in the phase 3 NORSE EIGHT trial. With the CRL, the FDA suggested the Company submit confirmatory evidence of efficacy to support the next application. The Agency did, however, reiterate the achievement of NORSE TWO's primary effectiveness endpoint.

ACC Releases Respiratory Disease Vaccination Guidelines for Adults with Heart Disease

On August 26, 2025, the American College of Cardiology released Concise Clinical Guidance recommending vaccines to protect adults with cardiovascular disease against a variety of respiratory diseases, including 

, respiratory syncytial virus (RSV), and 

. The guidelines also aim to improve access to vaccines, effectively circumventing financial barriers to access, providing accurate and practical education, and assuaging concerns that give rise to vaccine hesitancy and resistance.

Orforglipron Delivers Weight Loss, A1C Reductions in Phase 3 ATTAIN-2 Trial

On August 26, 2025, Eli Lilly and Company announced positive topline results from the phase 3 ATTAIN-2 trial evaluating orforglipron, an investigational oral GLP-1 receptor agonist, in adults with obesity or overweight and type 2 diabetes. In the trial, all 3 doses of orforglipron met the primary and all key secondary endpoints, delivering significant weight loss, meaningful A1C reductions, and improvements in cardiometabolic risk factors at 72 weeks. With the completion of ATTAIN-2, Lilly now has the full clinical data package required to initiate global regulatory submissions for orforglipron.

The FDA has accepted the priority review application for omidubicel, a cell therapy for severe aplastic anemia, with a PDUFA target date set. Sparsentan's REMS label update for IgA nephropathy now requires less frequent liver monitoring and removes embryo-fetal toxicity monitoring. A CRL was issued for ONS-5010 for wet AMD due to unmet efficacy endpoints. The ACC released guidelines for respiratory disease vaccinations in adults with cardiovascular disease. Orforglipron showed promising results in a phase 3 trial for weight loss and A1C reduction in type 2 diabetes patients.

Stay updated with the latest healthcare breakthroughs, including FDA news, vaccine guidelines, and orforglipron data, in this week's essential news roundup.

The HCPFive: Top News for Healthcare Providers from the Week of 08/24

Cemdisiran monotherapy has met its trial’s key endpoints and demonstrated significant improvements over placebo in 

 Activities of Daily Living (MG-ADL) total score, paving the way for Regeneron’s planed Biologics License Application submission for the first quarter of 2026.

“Our pipeline approach to treating complement-mediated diseases allows us to tailor treatment to the underlying disease biology,” L. Andres Sirulnik, MD, PhD, Senior Vice President and Hematology Clinical Development Unit Head at Regeneron, said in a statement.

 “The results of the NIMBLE trial confirm that, in MG, robust efficacy can be achieved without complete complement blockade, whereas in other diseases such as paroxysmal nocturnal hemoglobinuria (PNH), complete inhibition is likely to be necessary. We have previously released data from the lead-in portion of our PNH Phase 3 trial, supporting the potential for the cemdisiran and pozelimab (cemdi-poze) combination to deliver best-in-class efficacy in PNH.

 We are also investigating systemic administration of both cemdisiran monotherapy and the cemdi-poze combination in our Phase 3 program for geographic atrophy secondary to age-related macular degeneration.”

Cemdisiran is an siRNA that reduces circulating levels of complement factor 5 (C5) and is being evaluated as monotherapy and in the cemdi-poze combination (200 mg cemdisiran and 200 mg pozelimab) in the Phase 3 NIMBLE trial in adults with generalized MG (gMG) who have antibodies to the acetylcholine receptor (anti-AChR) and may be receiving standard of care immunosuppressants based on the investigator’s discretion. Pozelimab works by binding to and inhibiting complement factor C5.

NIMBLE is a double-blind trial, randomly assigned adults with gMG to either cemdisiran 600 mg monotherapy (n = 64) every 12 weeks, cemdi-poze (n = 67) every 4 weeks, or placebo (n = 59) every 4 weeks for a 24-week treatment period. Its primary endpoint was total score changes from baseline to week 24 in the MG-ADL total score, a patient-reported questionnaire that measures daily functions impacted by gMG, and its key secondary endpoint was total score changes from baseline in the Quantitative Myasthenia Gravis (QMG) total score, a physician-administered assessment evaluating vision, speaking/swallowing, breathing and limb function.

All told, both treatment groups outperformed placebo, with greater effects observed in the monotherapy group. At the conclusion of the 24-week period, investigators recorded placebo-adjusted treatment differences of –2.30 (P = .0005) and –1.74 (P = .0086) for the cemdisiran monotherapy and cemdi-poze groups, respectively, on MG-ADL. Regeneron also noted that cemdisiran was associated with an average of 74% inhibition of complement activity and cemdi-poze resulted in nearly 99% inhibition of complement activity. Detailed data from NIMBLE will be presented at an upcoming medical meeting.

In terms of safety, treatment-emergent adverse events (TEAEs) occurred in 69% of patients treated with cemdisiran, 81% with cemdi-poze, and 77% with placebo; these were serious in 3%, 9%, and 14% of the groups, respectively. Common TEAEs included worsening of MG (1%, 5%, 17%), upper respiratory tract infection (12%, 8%, 11%), urinary tract infection (5%, 6%, 3%), nasopharyngitis (5%, 3%, 4%), headache (5%, 11%, 10%), rash (5%, 3%, 1%), injection site reaction (4%, 8%, 1%), diarrhea (3%, 14%, 7%), arthralgia (1%, 6%, 1%), pain in extremity (1%, 5%, 1%), cough (1%, 5%, 1%), and pruritus (0%, 5%, 0%). There were no deaths during the 24-week placebo-controlled portion of the trial but there was 1 death each in the cemdisiran and cemdi-poze arms in the extension period, due to pneumonia and septic shock, respectively, in patients who were on concomitant immuno-suppressive therapies.

“The NIMBLE trial results underscore the potential for cemdisiran to offer a best-in-class profile for those suffering with myasthenia gravis, providing for robust efficacy with a convenient quarterly subcutaneous administration,” George D. Yancopoulos, MD, PhD, Board co-Chair, President and Chief Scientific Officer at Regeneron, added.

 “The potential for best-in-class efficacy with less than complete complement blockade with cemdisiran monotherapy may also provide for a more favorable safety profile. These exciting results highlight the transformative potential of our siRNA and genetic medicines pipeline to deliver paradigm-changing therapies for patients.”

Regeneron Announces Positive Results from Phase 3 Trial in Generalized Myasthenia Gravis. News release. Regeneron. August 26, 2025. 

https://www.globenewswire.com/news-release/2025/08/26/3139144/0/en/Regeneron-Announces-Positive-Results-from-Phase-3-Trial-in-Generalized-Myasthenia-Gravis.html

Novel Combination of Pozelimab and Cemdisiran (Poze-Cemdi) Achieved Greater Control of Intravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria Compared to Ravulizumab. December 7, 2025. Accessed August 26, 2025. 

https://investor.regeneron.com/news-releases/news-release-details/novel-combination-pozelimab-and-cemdisiran-poze-cemdi-achieved

Cemdisiran monotherapy has shown significant efficacy in improving Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, surpassing placebo in the NIMBLE trial. This success supports Regeneron's plan to submit a Biologics License Application in early 2026. Cemdisiran, an siRNA targeting complement factor 5, demonstrated robust efficacy without complete complement blockade, offering a potential best-in-class profile for myasthenia gravis. The trial also highlighted the safety profile of cemdisiran, with treatment-emergent adverse events comparable to placebo. Detailed results will be presented at an upcoming medical meeting.

Regeneron is planning a BLA submission for the first quarter of 2026.

Positive Cemdisiran Phase 3 Data Paves Way for Myasthenia Gravis BLA Submission

On August 29, 2025, Biogen announced that the US Food and Drug Administration (FDA) approved Eisai’s Biologics License Application (sBLA) for once weekly subcutaneous lecanemab-irmb (LEQEMBI) subcutaneous to treat patients with early 

, including those with mild cognitive impairment or mild dementia.

 Manufacturers plan to launch the product in the US on October 6, 2025.

“LEQEMBI IQLIK is the first and only anti-amyloid treatment to offer an at-home injection to help patients and care partners continue to treat this progressive, relentless disease after initial treatment of 18 months,” Biogen wrote in a statement.

Lecanemab-irmb is a subcutaneous autoinjector containing 360 mg/1.8 mL (200 mg/mL that clinicians can administer in approximately 15 seconds. Lecanemab targets both amyloid plaque and protofibrils, which can influence downstream tau pathology.

The approval relied on subcutaneous sub-studies from the Phase 3 Clarity AD open-label extension trial. Researchers found that switching to weekly subcutaneous dosing maintains clinical and biomarker benefits at levels comparable to continued intravenous administration. Investigators evaluated safety in over 600 patients across multiple subcutaneous doses, including 49 patients receiving the 360 mg weekly dose, none of whom experienced injection-related adverse events.

Patients experienced systemic reactions in fewer than 1% of cases, compared with approximately 26% of intravenous patients. Mild-to-moderate local injection-site reactions affected roughly 11% of patients and did not interrupt treatment. Clinicians observed that rates of amyloid-related imaging abnormalities were similar to intravenous maintenance therapy and matched background rates in untreated patients, with most events occurring early in therapy.

In the Clarity AD core study, intravenous lecanemab reduced cognitive decline by 27% at 18 months on the Clinical Dementia Rating-Sum of Boxes compared with placebo. Follow-up data through 48 months showed that treatment continued to slow cognitive decline relative to expected trajectories in external cohorts.

Human factors and tolerability studies confirmed that patients and care partners can safely use the autoinjector at home. Clinicians noted that subcutaneous administration reduces the time and resources required for intravenous infusion while enabling patients who respond to therapy to maintain treatment.

Subcutaneous lecanemab shares the safety profile of intravenous treatment, including the potential for amyloid-related imaging abnormalities, infusion- or injection-related reactions, and hypersensitivity. Clinicians should perform baseline and periodic brain imaging and monitor patients closely during the first 14 weeks. They should also evaluate risk factors such as ApoE ε4 status, cerebral amyloid angiopathy, and concomitant antithrombotic therapy when initiating treatment.

The FDA had previously approved lecanemab-irmb administered via an intravenous injection on January 26, 2025.

 Now after 18 months of lecanemab-irmb (10 mg/kg) injections every 2 weeks, patients can either continue IV infusions at same dose every 4 weeks or start the new weekly 360 mg subcutaneous injection.

“From the perspective of patients and care partners, benefits included the ability to use the device at home, shortening treatment time and to continue treatment without having to worry about visiting an infusion center,” Biogen wrote in a statement.

 “Healthcare providers reported that the device has the potential to provide a new option for patients who are responding well to LEQEMBI and should continue treatment.”

 (lecanemab-irmb) Subcutaneous Injection for Maintenance Dosing for the Treatment of Early Alzheimer’s Disease | Biogen. Biogen. Published 2025. Accessed August 29, 2025. 

https://investors.biogen.com/news-releases/news-release-details/fda-approves-leqembir-iqliktm-lecanemab-irmb-subcutaneous

Biogen. FDA Approves LEQEMBI® (lecanemab-irmb) IV Maintenance Dosing for the Treatment of Early Alzheimer’s Disease | Biogen. Biogen. Published 2025. 

https://investors.biogen.com/news-releases/news-release-details/fda-approves-leqembir-lecanemab-irmb-iv-maintenance-dosing

The FDA has approved Eisai's subcutaneous lecanemab-irmb (LEQEMBI) for early Alzheimer's treatment, allowing at-home administration. This subcutaneous form maintains clinical benefits comparable to intravenous dosing, with fewer systemic reactions and similar safety profiles. The approval is based on Phase 3 Clarity AD trial data, showing reduced cognitive decline. The subcutaneous option offers convenience, reducing the need for infusion centers and enabling continued treatment. Clinicians should monitor patients closely, considering risk factors like ApoE ε4 status and cerebral amyloid angiopathy when initiating therapy.

FDA approval of weekly subcutaneous lecanemab-irmb offers at-home maintenance therapy for early Alzheimer’s after initial intravenous treatment.

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