MAGNITUDE-2: A Phase 3, Multinational, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of NTLA-2001 in Participants With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN)

This study will be conducted to evaluate the efficacy and safety of a single dose of nexiguran ziclumeran (NTLA-2001) compared to placebo in participants with ATTRv-PN.

Start Date22 Nov 2024

Sponsor / Collaborator

Intellia Therapeutics, Inc.

[+1]

NCT06128629

/ RecruitingPhase 3

MAGNITUDE: A Phase 3, Multinational, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of NTLA-2001 in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR-CM)

To evaluate the efficacy and safety of a single dose of NTLA-2001 compared to placebo in participants with ATTR-CM.

Start Date13 Dec 2023

Sponsor / Collaborator

Intellia Therapeutics, Inc.

[+1]

NCT04601051

/ CompletedPhase 1

Phase 1 Two-Part (Open-label, Single Ascending Dose (Part 1) and Open-label, Single Dose Expansion (Part 2)) Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN) and Patients With Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)

This study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NTLA-2001 in participants with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and participants with hereditary transthyretin amyloidosis with cardiomyopathy (ATTRv-CM) or wild type cardiomyopathy (ATTRwt-CM)

Start Date05 Nov 2020

Sponsor / Collaborator

Intellia Therapeutics, Inc.

100 Clinical Results associated with Nexiguran ziclumeran

100 Translational Medicine associated with Nexiguran ziclumeran

100 Patents (Medical) associated with Nexiguran ziclumeran

Literatures (Medical) associated with Nexiguran ziclumeran

05 Jan 2026·EUROPEAN HEART JOURNAL

Transthyretin amyloid cardiomyopathy: from cause to novel treatments

Review

Author: Fontana, Marianna ; Aimo, Alberto ; Porcari, Aldostefano ; Gillmore, Julian D ; Hawkins, Philip N ; Emdin, Michele ; Solomon, Scott D

Abstract:

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disorder marked by amyloid deposition in the heart, ultimately impairing cardiac function. Recent treatment advances have paralleled an evolving understanding of ATTR-CM pathophysiology. One emerging hypothesis suggests that an imbalance between in vivo amyloid production and natural clearance may drive disease progression, a conceptual framework that still requires validation. Transthyretin (TTR) stabilizers, such as tafamidis and acoramidis, mitigate amyloid formation by promoting the native tetrameric conformation of circulating TTR, thereby slowing functional decline and prolonging survival. Similarly, TTR gene silencers inhibit hepatic TTR synthesis, and gene-editing therapy with nexiguran ziclumeran offers an additional strategy to reduce amyloid production. However, these approaches do not enhance the body’s limited capacity to clear existing amyloid deposits, underscoring the need for novel agents that accelerate amyloid removal. Promisingly, monoclonal antibodies targeting TTR amyloid are under development, with early clinical trials suggesting that this passive immunotherapy may reverse disease progression and improve heart function. Ultimately, optimal management of ATTR-CM will require further elucidation of the complex interplay between amyloid formation, its structural and functional impacts, its clearance mechanisms, and the potential for myocardial reverse remodelling.

01 Dec 2025·Current heart failure reports

Etiological Treatment of Cardiac Amyloidosis: Standard of Care and Future Directions

Review

Author: Morfino, Paolo ; Emdin, Michele ; Vergaro, Giuseppe ; Chubuchna, Olena ; Aimo, Alberto ; Castiglione, Vincenzo ; Buda, Gabriele ; Ferrari Chen, Yu Fu ; Fabiani, Iacopo

Abstract:

Purpose of Review:

Cardiac amyloidosis (CA) is a condition caused by interstitial infiltration of misfolded proteins structured into amyloid fibrils. Transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis represent the most common forms of CA. CA was traditionally perceived as a rare and incurable disease, but diagnostic and therapeutic advances have undermined the conventional paradigm.

Recent Findings:

The standard of care for ATTR-CA include agents capable of selectively stabilizing the precursor protein (e.g., tafamidis), whereas the plasma cell clone is the main target of chemotherapy for AL-CA. For long, tafamidis represented the only drug approved for patients with ATTR-CA. Recent data from ATTRibute-CM led to the approval of acoramidis, whereas patisiran received refusal based on the APOLLO-B trial. Novel CRISPR-Cas9-based drugs (i.e., NTLA-2001) hold great potential in the setting of ATTR-CA. Several hematological regimens are available to treat AL-CA. The main limit of current therapies is their inability to trigger removal of amyloid from tissues. However, the investigation of monoclonal antibodies targeting misfolded ATTR (e.g., PRX004, NI301A) or AL (e.g., birtamimab, anselamimab) has led to encouraging results.

Summary:

Various cutting-edge strategies are being tested for treatment of CA and may change the prognostic landscape of this condition in the next years.

09 Oct 2025·NEW ENGLAND JOURNAL OF MEDICINE

Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy

Article

Author: Lebwohl, David ; Gane, Ed ; Xu, Yuanxin ; Smith, Derek ; Sonderfan, Alison ; Shahda, Safi ; Kachadourian, Jessica ; Haagensen, Alexandra ; Adams, David ; Kao, Justin ; Litchy, William ; Manvelian, Garen ; Ward, Jonathan H. ; Täubel, Jörg ; Gutstein, David E. ; Echaniz-Laguna, Andoni ; Gillmore, Julian D. ; Walsh, Liron ; Leung, Adia ; Zhu, Peijuan ; Pilebro, Björn

BACKGROUND:

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, multisystem, progressive, debilitating, and fatal disease characterized by tissue deposition of misfolded transthyretin (TTR) in peripheral nerves. Nexiguran ziclumeran (nex-z) is an investigational in vivo therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) that is designed to reduce serum TTR levels through selective inactivation of TTR in the liver.

METHODS:

In this phase 1, open-label study, we administered one infusion of nex-z to patients with ATTRv-PN. Primary objectives included assessment of the safety and pharmacodynamics of nex-z. Secondary end points included changes in the familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) level, modified body-mass index (modified BMI, defined as the conventional BMI [weight in kilograms divided by square of height in meters] multiplied by the albumin level in grams per liter), and modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment).

RESULTS:

A total of 36 patients received nex-z; the mean follow-up was 27 months. The mean percent change from baseline in the serum TTR level was -90% at day 28, which was sustained through month 24 (-92%). Treatment-related adverse events included transient infusion-related reactions (in 21 patients), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (in 8), and headache (in 4). One participant died from cardiac amyloidosis, and one withdrew owing to progressive decline in motor function. Serious adverse events were reported in 11 patients. At month 24, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. The mean change in the serum NfL level was -9.0 pg per milliliter, and the change in the modified BMI was 24.7. The mean change from baseline in the mNIS+7 was -8.5.

CONCLUSIONS:

A single administration of nex-z in patients with ATTRv-PN was associated with rapid, deep, and durable reductions in serum TTR levels. The results support further investigation of nex-z to treat ATTRv-PN. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

163

News (Medical) associated with Nexiguran ziclumeran

03 Mar 2026

·www.biospace.com

Intellia’s CRISPR Gene Therapy Free To Move Forward After FDA Fully Lifts Hold

iStock, Derikjohn The FDA last October paused Intellia Therapeutics’ late-stage CRISPR studies after detecting life-threatening enzyme elevations in one patient, who died a few days later. Intellia Therapeutics can now freely move ahead with the development of its investigational CRISPR gene therapy after the FDA on Monday released the second of two studies that had previously been under clinical hold. “The update sets the stage for substantial upside” potential, analysts at William Blair told investors in a Monday note. Without the regulatory overhang, the firm expects Intellia to be able to restart the program “quickly,” though no specific timeline has been given. William Blair said that the risk-benefit pro the therapy, nexiguran ziclumeran or nex-z, appears to be “attractive” with severe liver toxicity only occurring in a small amount of patients in the MAGNITUDE trial. The risk is manageable through enhanced monitoring and risk mitigation strategies, they continued. Nex-z is in late-stage testing for transthyretin amyloidosis with cardiomyopathy (ATTR-CM). In late October 2025, the FDA froze both the Phase 3 MAGNITUDE and MAGNITUDE-2 trials after a patient in MAGNITUDE developed life-threatening elevations in liver enzymes. This patient died a few days later due to “complicating comorbidities,” Intellia CEO John Leonard said at the time. In January this year, after agreeing to certain “modifications and mitigation measures,” including “enhanced safety monitoring of liver laboratory tests,” Intellia announced that the FDA released the hold on MAGNITUDE-2. On Monday, the biotech said that it had aligned with the regulator on similar safety mechanisms in the MAGNITUDE trial and noted that it will also implement short-term steroid interventions for patients who show elevated liver enzyme levels. Gene editing FDA Lifts One of Two Clinical Holds on Intellia’s ATTR Gene Editing Program After a patient safety signal and then death, the FDA in October 2025 placed holds on two of the company’s CRISPR programs for hereditary transthyretin amyloidosis. January 27, 2026 · 2 min read · Dan Samorodnitsky Read more MAGNITUDE will also now exclude patients with a recent history of cardiovascular instability and those with ejection fraction lower than 25%, indicative of underlying issues that could increase the risk of more serious complications. With both MAGNITUDE and MAGNITUDE-2 permitted to progress, “our attention now turns to completing enrollment in both ongoing trials,” Leonard said in a prepared statement on Monday. “We are very pleased to have aligned with the FDA on the path forward.” Nex-z is a CRISPR-edited gene therapy that deactivates the TTR gene, which in turn lowers the overall expression of the transthyretin protein. In ATTR-CM, misfolded transthyretin clump together and accumulate in various tissues across the body, including in nerves and in the heart. Intellia is advancing nex-z in partnership with Regeneron, which in April 2016 fronted $75 million to collaborate on the gene therapy. The gene editing biotech is also eligible for “ significant ” milestone and royalty payments, though an exact figure hasn’t been specified. In 2022, Intellia reported that a patient treated with nex-z developed “significant elevation in liver enzymes,” though at the time the biotech dismissed the episode as it resolved spontaneously. In May 2025, just months before the death, the biotech again reported one case of life-threatening liver toxicity. Analysts at BMO Capital Market brushed it off as a “non-concern” at the time. Intellia’s shares rose more than 12% on Monday to $15.44 apiece. Rare diseases Intellia Pauses Phase III ATTR Trials for CRISPR Gene Therapy After Life-Threatening Liver Toxicity Intellia earlier this year reported a similar grade 4 liver enzyme elevation associated with the gene therapy nexiguran ziclumeran, though analysts at BMO Capital Markets at the time brushed it off as a “non-concern.” October 27, 2025 · 2 min read · Tristan Manalac Read more

Gene TherapyPhase 3

02 Mar 2026

·www.fiercebiotech.com

FDA fully releases clinical hold on Intellia CRISPR gene therapy trials

Combined with the January lifting of the hold on related phase 3 trial Magnitude-2, Intellia Therapeutics is now focused on completing enrollment in both studies.\n The FDA has liberated the second of two Intellia Therapeutics clinical trials that were put on hold last October following a report of serious liver toxicity that later led to death.The agency has lifted the hold on Magnitude, a phase 3 trial of Intellia’s Regeneron-partnered CRISPR gene therapy nexiguran ziclumeran (nex-z) in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Magnitude and a related phase 3 trial, Magnitude-2, were both halted after a patient in the Magnitude study experienced elevated levels of liver enzymes that later led to death.The newly lifted hold comes with some safety caveats, Intellia announced in a March 2 release. The biotech will now exclude patients from Magnitude if they have certain liver issues, a heart ejection fraction of less than 25% or a “recent history of cardiovascular instability,” according to the release. For both trials, the company will also monitor liver enzymes more closely and provide guidance on short-term steroid treatments for patients who experience the potentially dangerous side effect.“We are very pleased to have aligned with the FDA on the path forward for our Magnitude clinical trial, with measures designed to further enhance patient safety and allow us to continue to investigate nex-z in a broad ATTR-CM population,” Intellia President and CEO John Leonard, M.D., said in the release.Combined with the January lifting of the hold on Magnitude-2, which is testing nex-z in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), “our attention now turns to completing enrollment in both ongoing trials,” he added.Analysts from Evercore ISI called the safety adjustments “modest” in a March 2 note, noting that the hold was lifted relatively quickly and “probably comes with minimal disruption to the clinical timeline.” However, the analysts also flagged that the reason behind the liver toxicity is still unknown. Until more clarity comes, doctors and patients may take a “wait and see” approach, they wrote, even if the drug delivers positive data and eventually wins FDA approval.Nex-z is designed to be a one-time treatment for ATTR-CM and ATTRv-PN by using CRISPR gene editing to disrupt the gene that makes the transport protein transthyretin. In these conditions, mutations in the transthyretin gene cause the protein to be misshapen and form clumps that damage the heart and other organs.Intellia’s stock unsurprisingly ticked up in the wake of the news, from $13.78 per share at Friday’s close to $14.12 at 10:00 a.m. ET today.Liver toxicity is a recurring issue for gene therapies, which often target the organ. While Intellia’s nex-z uses a lipid nanoparticle to deliver the CRISPR gene editing machinery, many other biotechs have faced issues using adeno-associated viruses (AAVs) as vectors.Recently, uniQure paused some dosing in a phase 1/2 Fabry disease trial after two patients given its AAV gene therapy experienced elevated liver enzymes. And Sarepta Therapeutics navigated a safety controversy last summer when its AAV-based muscular dystrophy therapies, including the approved Elevidys, caused three liver-related patient deaths.

Phase 3Gene Therapy

02 Mar 2026

·endpoints.news

FDA lifts hold on second Intellia Phase 3 gene editing trial

The FDA has allowed Intellia to restart a Phase 3 study of a gene editing therapy for a heart disease caused by misfolded proteins, lifting a hold that was ordered after a patient in the study faced a severe case of liver injury and subsequently died. The lift, announced Monday morning, comes after the regulator in January allowed Intellia to restart another related but smaller Phase 3 trial that had also been paused. The FDA had put both studies on hold at the end of October, after a patient who received Intellia’s experimental gene editing treatment, called nex-z, was hospitalized with liver toxicity. The patient then passed away in November. The two previously paused trials were examining a gene editing therapy for two manifestations of transthyretin amyloidosis (ATTR) — a disease in which misfolded proteins accumulate — that damage the peripheral nerves and the heart, respectively. Intellia has another gene editing treatment for a swelling disease called hereditary angioedema that’s also in Phase 3 studies, and the pivotal readout for that therapy is expected this year. Intellia’s treatments are among the furthest along of experimental therapies that edit genes directly in the body, and how they fare could influence the rest of the gene editing industry, which has faced chilled markets in recent years. The added weight of FDA turmoil around rare disease doesn’t help developers of gene editing therapies either, since most of these treatments are aimed at rare genetic conditions. The patient who faced the serious liver injury was in the trial called MAGNITUDE, a 1,200-patient study that looked at the manifestation of ATTR that affects the heart. It’s a much larger Phase 3 compared to the other trial called MAGNITUDE-2, which is expected to enroll 60 patients and is examining the manifestation of the disease that damages the nerves. The heart indication could open up a much larger potential market for Intellia as well. Moving forward, both studies will include enhanced monitoring of liver laboratory tests, a plan for steroid use, and exclude patients with “certain liver abnormalities,” Intellia said. The MAGNITUDE study will also exclude patients “with a recent history of cardiovascular instability and those with ejection fraction <25% at the time of screening.” Intellia’s shares $NTLA jumped 5% in premarket trading Monday morning.

Phase 3Gene Therapy

100 Deals associated with Nexiguran ziclumeran

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cranial Nerve Diseases	Phase 3	Argentina	Intellia Therapeutics, Inc.	22 Nov 2024
Cranial Nerve Diseases	Phase 3	Australia	Intellia Therapeutics, Inc.	22 Nov 2024
Cranial Nerve Diseases	Phase 3	Brazil	Intellia Therapeutics, Inc.	22 Nov 2024
Cranial Nerve Diseases	Phase 3	Mexico	Intellia Therapeutics, Inc.	22 Nov 2024
Cranial Nerve Diseases	Phase 3	New Zealand	Intellia Therapeutics, Inc.	22 Nov 2024
Cranial Nerve Diseases	Phase 3	Singapore	Intellia Therapeutics, Inc.	22 Nov 2024
Cranial Nerve Diseases	Phase 3	Taiwan Province	Intellia Therapeutics, Inc.	22 Nov 2024
Cranial Nerve Diseases	Phase 3	Thailand	Intellia Therapeutics, Inc.	22 Nov 2024
Neuromuscular Diseases	Phase 3	Argentina	Intellia Therapeutics, Inc.	22 Nov 2024
Neuromuscular Diseases	Phase 3	Australia	Intellia Therapeutics, Inc.	22 Nov 2024

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04601051 (Pubmed \| N Engl J Med)	Phase 1	Transthyretin-related (ATTR) familial amyloid polyneuropathy	36	Nexiguran Ziclumeran	fgkzveatdr(awfnlkgoag) = lmyfuwpaxs jyvpecqqch (dsimuroqvf ) View more	Positive	09 Oct 2025
NCT04601051 (Company_Website 1 \| Company_Website 2) Manual	Phase 1	Transthyretin-related (ATTR) familial amyloid polyneuropathy	36	Nexiguran ZiclumeranNexiguran Ziclumeran (nex-z) (Dose-escalation portion)	nzaifrfewu(qyucbqyway) = goirkmoyri dkdpivculb (zvrnovgjau ) View more	Positive	18 May 2025
NCT04601051 (Company_Website 1 \| Company_Website 2) Manual	Phase 1		36	Nexiguran ZiclumeranNexiguran Ziclumeran (nex-z) (Dose expansion portion)	iqgfkydapd(zweriifirg) = myewtpdgob mjywulgzkd (sblhlladlv, 10.2) View more	Positive	18 May 2025
NCT04601051 (Phase 1, Pubmed \| N Engl J Med)	Phase 1	Cardiomyopathies serum TTR level \| N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels \| high-sensitivity cardiac troponin T levels	36	Nexiguran Ziclumeran (Nex-Z)	dxcjxcqhms(ovysimhtqj) = lqmobtppik lycwlpsxjp (cculonlrec, -33 to 49) View more	Positive	12 Dec 2024
NCT04601051 (Literature) Manual	Phase 1	Transthyretin Amyloid Cardiomyopathy	36	Nexiguran ziclumeran (nex-z)	oqhuvtagfa(yfehqtcopa) = fqqkjqnljy qizrxqrraq (cytvtezxgk, -33 to 49) View more	Positive	16 Nov 2024
NCT04601051 (Biospace) Manual	Phase 1	Amyloidosis, Hereditary, Transthyretin-Related	62	NTLA-2001	yjomtozypr(damxrwghwo) = The most commonly reported adverse events were infusion-related reactions, which occurred in 38% of patients. The majority of adverse events, including infusion-related reactions, were Grade 1 or 2 in severity, transient and resolved spontaneously. Other adverse events that were reported in greater than 10% of patients included headache, diarrhea and back pain, and were all Grade 1 or 2. wznkcbvxan (mhccjokipx ) View more	Positive	02 Nov 2023
NCT04601051 (NTLA-2001, EASL2022)	Phase 1	Amyloidosis, Hereditary, Transthyretin-Related TTR protein	14	NTLA-2001 0.3 mg/kg	slpzcqlfxr(ghznrdevtn) = Mild and transient infusion reactions were the most common adverse event with NTLA-2001 zvizqxtmww (tuikbdfstk )	Positive	24 Jun 2022
NCT04601051 (Pubmed 1 \| Pubmed 2 \| Br Dent J \| N Engl J Med) Manual	Phase 1	Amyloidosis, Hereditary, Transthyretin-Related	6	NTLA-2001 (0.1 mg / kg)	taovqefvcn(nlmtbhxtcw) = pwjjkgulqt qcbyhdjdwd (pndodqfumq )	Positive	05 Aug 2021
	Phase 1	Amyloidosis, Hereditary, Transthyretin-Related	6	NTLA-2001 (0.3 mg / kg)	taovqefvcn(nlmtbhxtcw) = sisjyoxfgl qcbyhdjdwd (pndodqfumq )	Positive	05 Aug 2021

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