CRISPR Gene Therapy Nexiguran Ziclumeran Shows Promise in Early-Stage Study of ATTR Amyloidosis With Polyneuropathy

David Adams, MD, PhD

Interim data from a phase 1 trial (NCT04601051) testing nexiguran ziclumeran (Intellia Therapeutics), an investigational CRISPR-based therapy designed to inactivate the TTR gene, was safe and resulted in rapid and durable reductions in serum TTR in patients with hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). These data are the first to show that a CRISPR-based approach can favorably impact multiple disease-relevant measures in ATTRv-PN.¹

Presented at the 2025 Peripheral Nerve Society (PNS) Annual Meeting, held May 17-20, in Edinburgh, Scotland, the data comprised 36 patients with ATTRv-PN who received a weight-based (0.1, 0.3, 0.7 or 1.0 mg/kg) or fixed dose (55 or 80 mg) of the gene therapy as a one-time intravenous infusion. After just 28 days of treatment, investigators recorded a –90% (95% CI, –92 to –87) change in serum TTR levels among treated patients. This change would remain stable throughout the study, with observed reductions of –91% (95% CI, –93 to –89) at month 12 and –92% (95% CI, –97 to –86) at month 24.

Led by David Adams, MD, PhD, a neurologist at Université Paris-Saclay, the mean change from baseline to month 12 in neuropathy impairment score (NIS), modified NIS+7, and modified body mass index (mBMI) was –1.9 (SD, 5.4), –0.6 (SD, 11.1), and 13.4 (SD, 93.2), respectively. More notably, Norfolk QOL-DN scores remained stable through month 12, and at month 24, the mean (SD) change from baseline in NIS and mBMI was -4.5 (7.4) and 39 (87.1), respectively.

Safety, a concern for most gene-based approaches, was also reassuring for nexiguran ziclumeran. The one-time therapy resulted in mild to moderate, transient infusion-related reactions (58%) and headache (28%) as the most common adverse events.

READ MORE: New Treatments, Global Collaboration Highlight 2025 Peripheral Nerve Society Annual Meeting

Data from the phase 1 study, including findings on secondary outcomes, were previously published in the New England Journal of Medicine in November 2024. Results showed that after 12 months, treated patients had a geometric mean factor change of 1.02 (95% CI, 0.88-1.17) in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and 0.95 (95% CI, 0.89-1.01) in the high-sensitivity cardiac troponin T level. In addition, the median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, –33 to 49).²

Nexiguran ziclumeran, also known as nex-z, is designed to inactivate the TTR gene that encodes for the TTR protein. This innovative approach more recently received Regenerative Medicine Advanced Therapy designations by the FDA for both cardiomyopathy and polyneuropathy, as well as orphan drug designation by the FDA and European Commission. To date, there are medications approved to slow the accumulation of misfolded TTR protein; however, there are no genetic-based medications that work to treat ATTRv-PN.

The phase 1 data helped inform the design behind Intellia’s phase 3 MAGNITUDE-2 trial (NCT06672237), a global, placebo-controlled study of nex-z in approximately 50 patients with ATTRv-PN. With dosing beginning last month, the study primarily assesses safety and efficacy of the CRISPR-based therapy, with change in mNIS+7 and serum TTR levels as the primary end point. In the trial, adults will be randomized 1:1 to either 55 mg infusion of nex-z or placebo, followed for a 12-month period. Participants will have the option to crossover to the opposite study arm at month 12 or month 18, depending on study criteria.³

To be included in MAGNITUDE-2, patients must have a diagnosis of ATTRv-PN and a Karnofsky Performance Status 60 or better. Patients with other causes of amyloidosis, diabetes mellitus, liver failure, or other known causes of sensorimotor or autonomic neuropathy will be excluded. Furthermore, those with New York Heart Association Class III or IV heart failure, those with a prior receipt of a TTR silencer, and those with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2 will also not be allowed in the trial.

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REFERENCES
1. Adams D, Gillmore JD, Taubel J, et al. CRISPR Gene Editing With Nexiguran Ziclumeran in Hereditary ATTR With Polyneuropathy: Phase 1 Interim Report. Presented at: 2025 PNS Annual Meeting; May 17-20. Edinburgh, Scotland. ABSTRACT O539
2. Fontana M, Solomon SD, Kachadourian J, et al. CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy. N Engl J Med. 2024;391:2231-2241. doi:10.1056/NEJMoa2412309
3. Intellia Therapeutics Announces First Patient Dosed in the MAGNITUDE-2 Phase 3 Study of Nexiguran Ziclumeran (nex-z), a One-Time Gene Editing-Based Treatment for Transthyretin (ATTR) Amyloidosis with Polyneuropathy. News release. Intellia Therapeutics. April 3, 2025. Accessed May 15, 2025. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-first-patient-dosed-magnitude-2