 and joined the MJH Life Sciences team in April 2021. He graduated from The College of New Jersey with a degree in Journalism and Professional Writing. He enjoys listening to records, going to concerts, and playing with his cat Squish. You can reach him at 

Connor Iapoce

Marianna Fontana, MD, PhD: Nex-Z Shows Promise in ATTR-CM Phase 1 Trial

A groundbreaking CRISPR-based gene-editing therapy has demonstrated early success in treating 

transthyretin amyloidosis cardiomyopathy (ATTR-CM)

, a progressive and often fatal disease that can lead to heart failure, according to late-breaking at the 

American Heart Association (AHA) Scientific Sessions 2024

Interim results from the Phase 1 trial of nexiguran ziclumeran (nex-z) revealed a single infusion of the therapy reduced serum TTR levels by approximately 90% over 12 months, offering a potential one-time treatment for this debilitating condition.

“After a single infusion of nex-z, there was a deep, rapid, and durable reduction in the circulating TTR levels and the reduction was similar across patients, with all patients achieiving a similar level, despite the genotype or the TTR at baseline,” primary investigator Marianna Fontana, MD, PhD, a professor of cardiology and honorary consultant cardiologist at the National Amyloidosis Centre, division of medicine, University College London, told 

The study involved 36 patients with ATTR-CM, making it the largest gene-editing trial in cardiovascular disease. Participants, of which 50% had advanced heart failure (NYHA class III), experienced stabilization in biomarkers of disease progression, including NT-proBNP and hsTroponin-T, and a median increase of 5 meters in a 6-minute walk distance. Additionally, 92% of patients either maintained or improved their NYHA class over the 12 months of study.

Mild-to-moderate infusion-related reactions were the most common adverse events, with no major safety concerns reported. Overall, these results suggested that nex-z could alter the natural course of ATTR-CM by slowing or halting disease progression. With confirmation needed in larger trials, nex-z could become the first CRISPR-based therapy to successfully treat a cardiovascular condition, providing new hope for patients with few existing treatment options.

“The Phase 3 study, which is a randomized, multicenter, placebo-controlled trial, are sensing the efficacy and safety of nex-z in a large population of patients with ATTR-CM,” Fontana told 

. “Hopefully, very soon, the enrollment will be completed and we’ll see the results of the Phase 3 trials.”

Disclosures: Relevant disclosures for Fontana include Alnylam Pharmaceuticals, Bayer, Intellia Therapuetics, Janssen Pharmaceuticals, Novo Nordisk, and others.

Fontana M, Taubel J, Gane E, Pilebro B, Adam D et al. Nexiguran ziclumeran (nex-z, also known as NTLA-2001), an investigational in vivo CRISPR-based therapy for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM): interim report of the Phase 1 study. Presented at the American Heart Association (AHA) Scientific Sessions 2024. Chicago, Illinois. November 16-18, 2024.

Intellia announces first clinical evidence from ongoing phase 1 study that nexiguran ziclumeran (nex-Z), an in vivo CRISPR/cas9-based gene editing therapy, may favorably impact disease progression in transthyretin (ATTR) amyloidosis. Intellia Therapeutics. November 16, 2024. Accessed November 16, 2024. https://ir.intelliatx.com/news-releases/news-release-details/intellia-announces-first-clinical-evidence-ongoing-phase-1-study.

Videos

A novel CRISPR-based gene-editing therapy, nexiguran ziclumeran (nex-z), shows promise in treating transthyretin amyloidosis cardiomyopathy (ATTR-CM), a severe condition leading to heart failure. Interim results from a Phase 1 trial indicate a single infusion of nex-z reduces serum TTR levels by 90% over 12 months, stabilizing disease biomarkers and improving patient outcomes. The study, involving 36 patients, reported mild-to-moderate adverse events without major safety concerns. Larger trials are needed to confirm efficacy, potentially making nex-z the first successful CRISPR therapy for cardiovascular disease.

Marianna Fontana, MD, PhD discusses Phase 1 interim results on the CRISPR-based gene-editing therapy, nex-z, for ATTR-CM.

Zerlasiran Achieves Durable Lp(a) Reductions at 60 Weeks, with Stephen J. Nicholls, MD, PhD

Data from the ALPACAR-360 trial, presented at the 

, confirm that zerlasiran (formerly SLN360) achieves sustained reductions in lipoprotein(a) [Lp(a)] through 60 weeks. Zerlasiran, a gene-silencing therapy, offers a potential treatment for elevated Lp(a), a genetic risk factor affecting 20% of the global population and a significant driver of 

Launched in 2023, the Phase 2 trial randomized 178 patients with baseline Lp(a) levels >125 nmol/L and high cardiovascular risk to 3 dosing regimens of zerlasiran or placebo therapy. Upon analysis, at 36 weeks, zerlasiran showed a least-squares mean time-averaged Lp(a) reduction of –81.3% to –85.6%.

“I think there’s two elements to the efficacy. There’s the degree of Lp(a) lowering that we can but then there’s the durability,” Stephen J. Nicholls, MD, PhD, Victorian Heart Institute, Monash University, told HCPLive. “If we follow patients out 3-, 6-, and 12-months after an injection, what we’re seeing with these agents is that your Lp(a) doesn’t come back to beeline. Our ability to show more and more durability, more Lp(a) lowering 6-, 12-months after injections, has implications for potentially less frequent dosing.”

These dose reductions were observed in the zerlasiran 450 mg every 24 weeks (–85.6%; 95% CI, –90.9% to −80.3%), 300 mg every 16 weeks (–82.8%; 95% CI, –88.2% to –77.4%), and 300 mg every 24 weeks (–81.3%; 95% CI, –86.7 to 76.0) cohorts, respectively. These reductions remained consistent through 60 weeks, and zerlasiran was well-tolerated. A total of 20 serious adverse events in 17 patients, but none were deemed to be related to the study drug—injection site reactions were the most common treatment-related adverse event.

Nicholls indicated data from the ALPACAR-360 trial demonstrate the competitive profile of zerlasiran as a potential long-term, infrequent-dose therapy. Zerlasiran will progress into Phase 3 trials as a potentially promising new treatment for patients with high Lp(a).

“I think that finding suggests that if you do big enough trials, you do see adverse events.,” Nicholls told HCPLive. “...All seemed to be pretty mild in severity, and they resolve pretty quickly. These are important, not only in terms of the conversation we have with our patients about starting therapy, but then about kind of keeping patients on treatment long term.”

Disclosures: Nicholls reports relevant disclosures including Amgen, Eli Lilly, Novartis, Sanofi-Regeneron, Silence Therapeutics, and others.

Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. JAMA. Published online November 18, 2024. doi:10.1001/jama.2024.21957

Packer M. Tirzepatide for Patients with Heart Failure with Preserved Ejection Fraction and Obesity: the SUMMIT Trial. Paper presented at: American Heart Association Scientific Sessions 2024; November 15 - 18; Chicago, Il. Accessed November 16, 2024.

Zerlasiran, a gene-silencing therapy, has shown promising results in the ALPACAR-360 trial, achieving sustained reductions in lipoprotein(a) [Lp(a)] levels over 60 weeks. This Phase 2 trial involved 178 patients with high cardiovascular risk and elevated Lp(a) levels, demonstrating significant Lp(a) reductions across various dosing regimens. Zerlasiran was well-tolerated, with no serious adverse events linked to the drug. The trial's findings suggest zerlasiran's potential as a long-term, infrequent-dose therapy for managing elevated Lp(a), a genetic risk factor for cardiovascular disease, warranting progression to Phase 3 trials.

Stephen J. Nicholls, MD, PhD discusses the robust efficacy and tolerability of zerlasiran for Lp(a) lowering, paving the way for Phase 3 development.

Marianna Fontana, MD, PhD: Declines in Kidney Function Frequent in ATTR-CM 

A decline in kidney function was common in patients with 

transthyretin amyloid cardiomyopathy (ATTR-CM)

 and linked to an elevated likelihood of mortality, even after adjustment for relevant biomarkers, according to new data presented at the 

This retrospective, observational, single-center cohort study assesed individuals with ATTR-CM at the National Amyloidosis Centre (NAC) in the United Kingdom, who underwent an assessment of baseline estimated glomerular filtration rate (eGFR) and 1-year follow-up between January 2000 and April 2024.

“We took a large population of patients, more than 2000 patients, with a ATTR-CM, and we did a landmark analysis at 12 months, where we measured the eGFR. We found, at 12 months, a change of 20% decline, an independently predictive prognosis,” Marianna Fontana, MD, PhD, a professor of cardiology and honorary consultant cardiologist at the National Amyloidosis Centre, division of medicine, University College London, told 

The study’s primary outcome was the risk of all-cause mortality associated with a decline in kidney function, considered a decrease in eGFR of >20%.

Upon analysis, the decline in kidney function was associated with a 1.7-fold higher risk of mortality (hazard ratio [HR], 1.71; 95% CI, 1.43-2.04; 

 < .001), with a similar risk across all 3 genotypes (wild type: HR, 1.64; 95% CI, 1.31-2.04; p.(V142I): HR, 1.70; 95% CI, 1.21-2.39; non-p.(V142I): HR, 1.51; 95% CI, 0.87-2.61) (

 for interaction = .93) and the 3 NAC disease stages (stage 1: HR, 1.69; 95% CI, 1.22-2.32; stage 2: HR, 1.69; 95% CI, 1.30-2.18; stage 3: HR, 1.61; 95% CI, 1.11-2.35) (

Importantly, the decline in kidney function was consistently, independently associated with mortality, after adjustment for increases in NT-proBNP and outpatient diuretic intensification (HR, 1.48; 95% CI, 1.23-2.76; 

“This is just the first step, one of the things that will need to be assessed is, for example, using this treatment to guide treatment response and [determine if] it improves management of the patients,” Fontana told 

Ioannou A, Razvi Y, Porcari A, et al. Kidney Outcomes in Transthyretin Amyloid Cardiomyopathy. JAMA Cardiol. Published online November 17, 2024. doi:10.1001/jamacardio.2024.4578

Decline in kidney function is prevalent in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and correlates with increased mortality risk, even after adjusting for biomarkers. A study at the National Amyloidosis Centre in the UK analyzed over 2000 patients, revealing a 20% decline in eGFR at 12 months as a significant prognostic indicator. The decline was linked to a 1.7-fold higher mortality risk across genotypes and disease stages. This association remained significant after adjusting for NT-proBNP and diuretic use, suggesting potential implications for patient management.

Marianna Fontana, MD, PhD describes the prognostic importance of a decline in eGFR in a retrospective cohort of patients with ATTR-CM.

A nasal spray form of bumetanide achieved a comparable reduction in tissue swelling from 

 as the standard oral and intravenous formulation of the medication, according to late-breaking science at the 

The RSQ-777-02 clinical trial evaluated the effect of the novel nasal spray form on healthy adults, including its absorption and ability to reduce tissue swelling, among a population of adults without heart failure or risk factors for heart failure at the time of enrollment.

“In patients with heart failure, the body’s ability to absorb oral medications in the stomach and gut often decreases as fluid overload builds up and, thus, oral medications are often least effective when the body needs them most,” said Daniel Bensimhon, MD, medical director of the Advanced Heart Failure/Mechanical Circulatory Support Program at Cone Health.

 “Having a diuretic that does not rely on gut absorption to be effective may be a very important tool to help patients with heart failure and other conditions without having to rely on intravenous administration of these medications, which can only be done at hospitals and in heart failure clinics.”

Heart failure medications include oral or intravenous diuretics which can reduce heart-failure-related tissue swelling, including bumetanide, which removes excess salt and water through the urine. The RSQ-777-02 trial, conducted at the Orange County Research Center between December 2023 and April 2024, involved 68 adults aged 18 to 55 years.

Among the study population, 66.2% self-identified as men and 33.8% as women. Approximately 60.3% identified as White, 27.9% as Black, 10.3% as Asian, and 1.5% as “Other” race—32.4% identified as Hispanic or Latino, and 67.6% as not Hispanic or Latino ethnicity.

The study administered nasal, oral, and intravenous bumetanide to each participant in a varied order and monitored study participants on-site for 10 days. Overall, bumetanide nasal spray was absorbed effectively and remained tolerable, with consistent side effects with other forms of administration and fewer treatment-emergent adverse events (TEAEs) than the oral version.

Compared with oral and IV bumetanide, the nasal spray achieved a similar amount of urine output and reached a similar blood concentration, with a 33% faster absorption rate.

 Although the absorption rate of IV bumetanide outpaced both other forms, the onset of sodium excretion in urine was faster with the nasal form.

As all participants received all 3 forms of bumetanide in various order, the nasal and IV forms were absorbed at “more reliable rates” than the oral form for each participant, according to Bensimhon and colleagues.

In particular, the nasal and IV bumetanide exhibited a variability of absorption of 27%, compared with >40% for the oral form, suggesting the nasal and IV forms are more stable and pointing to an advantage of the nasal spray over the oral form for at-home self-administration.

Overall, Bensimhon indicated the investigator’s surprise at the speed of the nasal spray, and the variability of the oral drug’s absorption, even in healthy individuals.

 The team suggested the value of bumetanide nasal spray to promote care at home and potentially lower the need for hospital admission and re-admission could ease the burden on health systems.

“Patients who require diuretic treatment for swelling associated with chronic heart failure and liver disease may now have a new, self-administered option, particularly when they are unable to take their oral medication or it no longer works,” Bensimhon added.

Bonatto MG, Ferreira SA, Avila MS, et al. Effects of Sacubitril-Valsartan on Prevention of Cardiotoxicity in High-Risk Patients Undergoing Anthracycline Chemotherapy: A Double-Blind Randomized Placebo-Controlled Clinical Trial – The SARAH Trial. Presented at the American Heart Association (AHA) Scientific Sessions 2024. Chicago, Illinois. November 16-18, 2024.

Nasal spray version of common diuretic has potential to help treat heart failure. American Heart Association. November 18, 2024. Accessed November 18, 2024. https://newsroom.heart.org/news/nasal-spray-version-of-common-diuretic-has-potential-to-help-treat-heart-failure.

Articles

A nasal spray form of bumetanide demonstrated comparable efficacy in reducing tissue swelling from heart failure as oral and intravenous forms, according to findings from the RSQ-777-02 clinical trial. Conducted on healthy adults, the trial highlighted the nasal spray's effective absorption and tolerability, with fewer adverse events than the oral version. The nasal spray showed a 33% faster absorption rate and more reliable absorption compared to oral administration. This novel form could facilitate at-home care, reducing hospital admissions and easing healthcare system burdens.

A nasal spray form of bumetanide reduced tissue swelling from heart failure as effectively as the oral and intravenous formulations.