Amyloidosis Clinical Trial Monitor — ATTR-CM, AL Amyloidosis & hATTR Trials 2026

The amyloidosis trial landscape in 2026

Amyloidosis is not a single disease. It is a family of protein-misfolding disorders united by one pathological feature: insoluble amyloid fibrils accumulate in tissues and organs, disrupting their function. The clinical consequences range from peripheral neuropathy to progressive heart failure to renal failure, depending on the protein involved and the organs targeted. In 2026, the two forms driving the most active clinical trial activity are transthyretin amyloidosis (ATTR) — primarily its cardiac variant — and light chain amyloidosis (AL), where the unmet need remains acute despite recent advances.

The therapeutic landscape has transformed dramatically since 2019. Pfizer's tafamidis approval for ATTR cardiomyopathy (ATTR-CM) marked the first time a treatment demonstrated mortality benefit in this condition. Alnylam's RNA interference approvals (patisiran, vutrisiran) established a new mechanism for hATTR polyneuropathy. And AstraZeneca's eplontersen (Wainua) — an antisense oligonucleotide — added a subcutaneous monthly option for the hereditary polyneuropathy form. These approvals did not end the competitive race; they intensified it. With approved drugs on the market, competitors are now targeting the same patient populations with mechanistically distinct approaches, while AL amyloidosis — which still has no specific FDA-approved fibril-directed therapy — remains a critical battleground.

ATTR cardiomyopathy: who is challenging Pfizer's tafamidis?

ATTR-CM is caused by aggregation of transthyretin protein — either from a hereditary mutation (hATTR-CM) or from wild-type TTR aggregation in aging (ATTRwt-CM, the more common form). Pfizer's tafamidis stabilizes the TTR tetramer, slowing the disease. It became the dominant standard of care after the ATTR-ACT trial demonstrated reduced mortality and fewer cardiovascular hospitalizations. But tafamidis has limitations: it does not eliminate existing amyloid deposits, it requires early diagnosis in a disease that is frequently underdiagnosed, and its price exceeds $200,000 per year.

Novo Nordisk enters ATTR-CM with CLEOPATTRA Phase 3 (NCT07207811)

The most consequential new development in the ATTR-CM pipeline is Novo Nordisk's CLEOPATTRA trial, which began enrolling in October 2025. This Phase 3 study (NCT07207811) is currently actively recruiting participants with ATTR-CM. The CLEOPATTRA trial represents Novo Nordisk's direct challenge in the ATTR-CM space — a significant strategic move from a company building cardiovascular and metabolic portfolio depth. The mechanism and drug candidate are the focus of this placebo-controlled, randomized trial. Novo Nordisk's entry signals institutional confidence in the ATTR-CM market and will generate comparative efficacy data against the tafamidis standard of care.

AstraZeneca tracks ATTR outcomes across all phenotypes (NCT06465810)

AstraZeneca is conducting a non-interventional observational study (NCT06465810) of patients across all ATTR amyloidosis subtypes — ATTR-CM, ATTRv-PN (hereditary polyneuropathy), ATTR-Mixed, and hATTR. Recruiting since June 2024 and last updated in March 2026, this study is collecting real-world outcome data across a broad population. AstraZeneca's commercial interest in ATTR amyloidosis stems from its partnership with Ionis for eplontersen — understanding real-world disease burden and treatment patterns across phenotypes supports both commercial and clinical development decisions.

AI-based ECG diagnostics for ATTR-CM (NCT06978660)

Idoven 1903 S.L., a Spain-based AI cardiac diagnostics company, is conducting a multicenter validation study for an AI-based ECG platform designed for early detection of transthyretin cardiac amyloidosis (NCT06978660). This study, which began in May 2025, represents a different angle on the ATTR-CM opportunity: earlier, cheaper diagnosis. The core challenge in ATTR-CM is that most patients are diagnosed late, often years after disease onset, when cardiac dysfunction is already significant. A validated AI ECG tool could dramatically change detection rates, expanding the treated population and the commercial opportunity for all ATTR-CM therapeutics.

AL amyloidosis: the search for fibril-directed therapy

Light chain amyloidosis (AL amyloidosis) is caused by a plasma cell clone — frequently in the setting of monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma — producing abnormal immunoglobulin light chains that misfold and deposit in organs. The heart and kidneys are most commonly affected. Unlike ATTR, the plasma cell clone is the primary target: daratumumab-based combinations (daratumumab, bortezomib, cyclophosphamide, dexamethasone — dara-VCd) have dramatically improved hematologic response rates and become the standard of care at diagnosis. But achieving a deep hematologic response does not necessarily translate to organ recovery, and the amyloid deposits that have already accumulated are not cleared by plasma cell-directed therapy. This is the rationale for fibril-depleting approaches.

Alexion birtamimab Phase 3 program: two trials by Mayo Stage (NCT04504825, NCT04512235)

Birtamimab (formerly CAEL-101) is a monoclonal antibody designed to directly bind and deplete amyloid fibrils in affected organs — not to target the plasma cell clone, but the deposits themselves. Alexion Pharmaceuticals (now part of AstraZeneca) acquired Caelum Biosciences and launched two parallel Phase 3 trials stratified by Mayo cardiac staging:

• NCT04504825: Mayo Stage IIIa AL amyloidosis. Started August 2020, now active but no longer enrolling. Birtamimab plus standard of care vs. placebo plus standard of care.
• NCT04512235: Mayo Stage IIIb AL amyloidosis (the highest-risk, most advanced cardiac stage). Started November 2020, now active but no longer enrolling.

These trials are among the most consequential in the AL amyloidosis field. If birtamimab demonstrates organ improvement — specifically cardiac improvement — on top of plasma cell-directed therapy, it would represent the first fibril-depleting agent approved for AL amyloidosis and a new treatment standard. Results are anticipated in 2026.

CAR-T for relapsed/refractory AL amyloidosis: two programs

The emerging story in refractory AL amyloidosis is CAR-T cell therapy targeting both CD19 and BCMA — the same dual-targeting strategy that has shown deep responses in multiple myeloma. Two industry programs are actively recruiting in this space:

• Alexion/AstraZeneca (NCT07081646): A Phase 1b/2 study of a CD19/BCMA-targeting CAR-T in participants with relapsed or refractory AL amyloidosis. Started August 2025. This is a notable program given Alexion/AstraZeneca's simultaneous investment in both the fibril-depleting approach (birtamimab) and cell therapy for earlier failures.
• Gracell Biotechnologies GC012F (NCT07250269): A Phase 1 study of GC012F, a CD19/BCMA CAR-T being evaluated in Chinese participants with relapsed/refractory AL amyloidosis. Started October 2025. Gracell (now acquired by AstraZeneca) has reported deep responses with GC012F in multiple myeloma, and this study extends that program into the amyloidosis space where the same plasma cell target is relevant.

The convergence of Alexion/AstraZeneca assets (birtamimab for fibril depletion, CAR-T for refractory disease) reflects a broad bet on AL amyloidosis as a therapeutic area — combining approaches that target different stages of the disease cascade.

GSK belantamab mafodotin in amyloidosis (NCT07224672)

GlaxoSmithKline is initiating a Phase 2 study of belantamab mafodotin in amyloidosis (NCT07224672), which was not yet recruiting as of March 2026. Belantamab mafodotin (Blenrep) is a BCMA-targeting antibody-drug conjugate with proven activity in relapsed/refractory multiple myeloma. Its use in amyloidosis extends the BCMA-directed rationale: if the AL-producing clone expresses BCMA, belantamab could eliminate it. This study adds GSK to the growing list of companies investing in BCMA-directed strategies for plasma cell-related amyloidosis.

NCI venetoclax combination in relapsed AL amyloidosis (NCT04847453)

The National Cancer Institute (NCI) is studying venetoclax (BCL-2 inhibitor), ixazomib (oral proteasome inhibitor), and dexamethasone in relapsed or refractory AL amyloidosis (NCT04847453, Phase 1). This started in August 2022 and remains actively recruiting. Venetoclax has demonstrated activity in t(11;14) multiple myeloma, and given the shared plasma cell biology with AL amyloidosis, this combination is testing whether BCL-2-directed therapy can be active in the amyloidosis setting — particularly in patients with the t(11;14) translocation that confers BCL-2 dependency.

Actively recruiting amyloidosis trials (2026)

NCT ID	Sponsor	Phase	Type	Status	Start
NCT07207811	Novo Nordisk	Phase 3	ATTR-CM	Recruiting	Oct 2025
NCT07081646	Alexion / AstraZeneca	Phase 1/2	AL — CAR-T (CD19/BCMA)	Recruiting	Aug 2025
NCT07250269	Gracell / AstraZeneca	Phase 1	AL — CAR-T GC012F	Recruiting	Oct 2025
NCT07151690	Inst. of Hematology (China)	Phase 2	AL — BCMA/CD3 bispecific	Recruiting	Sep 2025
NCT06465810	AstraZeneca	Observational	ATTR all phenotypes	Recruiting	Jun 2024
NCT04847453	NCI	Phase 1	AL — Venetoclax + Ixazomib	Recruiting	Aug 2022
NCT06978660	Idoven 1903 S.L.	Observational	ATTR-CM — AI ECG diagnostics	Recruiting	May 2025
NCT04504825	Alexion / AstraZeneca	Phase 3	AL Stage IIIa — Birtamimab	Active, not recruiting	Aug 2020
NCT04512235	Alexion / AstraZeneca	Phase 3	AL Stage IIIb — Birtamimab	Active, not recruiting	Nov 2020
NCT07224672	GlaxoSmithKline	Phase 2	AL — Belantamab mafodotin	Not yet recruiting	Mar 2026

The competitive dynamics: AstraZeneca's multi-pronged amyloidosis strategy

The competitive picture in amyloidosis in 2026 is notable for AstraZeneca's unusual breadth of exposure. Through its Alexion unit's acquisition of Caelum Biosciences, AstraZeneca controls the birtamimab fibril-depleting Phase 3 program. Through its Gracell acquisition, it controls the GC012F CAR-T being studied in relapsed AL. Through its commercial partnership with Ionis, it commercializes eplontersen (Wainua) for hATTR polyneuropathy. And its observational study tracks the real-world ATTR patient population across phenotypes. This is an unusually comprehensive stake across different disease mechanisms and stages — suggesting AstraZeneca views amyloidosis as a strategic priority, not a single-asset bet.

Novo Nordisk's entry into ATTR-CM with CLEOPATTRA creates the most significant competitive challenge to Pfizer's tafamidis franchise. Pfizer has benefited from first-mover advantage since 2019, building tafamidis into a multi-billion dollar product. A mechanistically distinct competitor (presumably an RNA-based approach given Novo Nordisk's cardiovascular RNA pipeline) entering Phase 3 in 2025 sets up a potential head-to-head dynamic that will be watched closely by the cardiology and investment community.

Why monitor amyloidosis trials?

Amyloidosis is a high-stakes therapeutic area with several features that make trial monitoring particularly valuable:

• Binary Phase 3 readouts: Both birtamimab trials (NCT04504825, NCT04512235) are active but no longer enrolling — their readouts are imminent. A positive result for birtamimab in AL amyloidosis would be the first approval for a fibril-depleting therapy and a category-defining event.
• Competitive displacement risk: Novo Nordisk's CLEOPATTRA Phase 3 threatens Pfizer's tafamidis franchise if the new agent demonstrates superior efficacy or safety. Tracking enrollment and any protocol amendments is relevant for any stakeholder with ATTR-CM exposure.
• CAR-T pipeline inflection: Two CAR-T programs targeting CD19/BCMA in AL amyloidosis started in late 2025. Early Phase 1 results from these programs will establish whether cell therapy has a role in amyloidosis — informing decisions for both the AL and multiple myeloma fields given the shared target biology.
• Diagnostic disruption: The Idoven AI ECG study may change how ATTR-CM is diagnosed at scale. Expanded diagnosis means an expanded patient population for all ATTR therapeutics — a potential tailwind for the entire class.

Related clinical trial monitors

Amyloidosis frequently intersects with other therapeutic areas covered by DataLookout:

• Multiple myeloma clinical trials — shared plasma cell biology; daratumumab, BCMA, and CAR-T programs overlap
• Heart failure clinical trials — ATTR-CM is a significant underdiagnosed cause of heart failure with preserved ejection fraction (HFpEF)
• Rare disease clinical trials — amyloidosis shares the rare disease trial infrastructure and patient advocacy landscape
• Rare disease monitor — AL amyloidosis is classified as a rare disease (<200,000 US patients)