mivelsiran (ALN-APP) / Alnylam, Regeneron - LARVOL DELTA

cAPPricorn-1: A Phase 2 Trial of ALN-APP in Patients With Cerebral Amyloid Angiopathy (clinicaltrials.gov) - P2 | N=210 | Active, not recruiting | Sponsor: Alnylam Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • APP

A Study to Evaluate Mivelsiran in Adult Participants With Early-Stage Down Syndrome-Associated Alzheimer's Disease (DS-AD) (clinicaltrials.gov) - P2 | N=58 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Genetic Disorders

The design of APPLAUDS, the first phase 2 study evaluating an RNA interference (RNAi) therapeutic in people with Down syndrome (DS) and early-stage Alzheimer disease (AD), was presented at the 2026 Alzheimer's Association International Conference (AAIC) in London. (NeurologyLive) - "The study comprises a 24-month double-blind treatment period and a 12-month open-label extension. During the double-blind period, a pharmacokinetic/pharmacodynamic cohort will be randomized 1:1:1 to placebo or one of two doses of mivelsiran, after which a second larger cohort will receive placebo or the dose selected based on PK/PD cohort outcomes. All participants will receive mivelsiran in the open-label extension. The primary endpoint is change from baseline in amyloid PET at month 24 while other secondary endpoints include CSF concentrations of sAPPbeta, sAPPalpha, and amyloid-ß42; plasma phosphorylated tau 217 (p-tau217); and the modified Cued Recall Test. Enrollment is expected to begin in 2026 across approximately 30 sites worldwide."

Clinical protocol • Alzheimer's Disease • Tauopathies And Synucleinopathies

In the phase 1 single ascending dose study (NCT05231785), 20 patients with early-onset AD were randomized to mivelsiran doses of 25 mg, 50 mg, or 75 mg intrathecally or placebo. (NeurologyLive) - "Overall, data showed that all adverse events from the study were mild or moderate in severity, with no serious adverse events or deaths. Reductions from baseline in CSF soluble APPalpha and APPbeta were rapid and sustained through month 6 at the 50 mg dose and month 10 at the 75 mg dose, accompanied by sustained reductions in CSF Abeta42 and Abeta40."

P1 data • Alzheimer's Disease

Design Of Applauds, A Phase 2 Study Of Mivelsiran In People With Down Syndrome And Early-stage Alzheimer'S Disease (AAIC 2026) - No abstract available

P2 data • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Genetic Disorders

Amyloid-related Imaging Abnormalities In A Phase 1 Study Of Mivelsiran In Patients With Early-onset Alzheimer's Disease (AAIC 2026) - No abstract available

Clinical • P1 data • Alzheimer's Disease • CNS Disorders

A Study to Evaluate Mivelsiran in Adult Participants With Early-Stage Down Syndrome-Associated Alzheimer's Disease (DS-AD) (clinicaltrials.gov) - P2 | N=58 | Not yet recruiting | Sponsor: Alnylam Pharmaceuticals

New P2 trial • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Genetic Disorders

Drug Development. (PubMed, Alzheimers Dement) - P1 | "In this first report of multiple-dose clinical data for a CNS-targeting RNAi therapeutic, single and multiple doses of mivelsiran were generally well tolerated and continued to demonstrate robust, durable, dose-dependent CSF sAPPβ reductions. Further sAPPβ lowering was observed after a second dose of mivelsiran 50mg. These results support further evaluation of mivelsiran in patients with Alzheimer's disease or cerebral amyloid angiopathy."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • APP

Drug Development. (PubMed, Alzheimers Dement) - P1 | "Treatment with APP-lowering siRNA reduced AD pathology in the 5xFAD mouse model. Early intervention with the highest dose regimen prevented the emergence of behavioral deficits and substantially improved many aspects of disease phenotype. These results support the continued development of mivelsiran, an investigational, first-in-class APP-lowering RNAi therapeutic, in patients with AD (NCT05231785)."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Mood Disorders • Psychiatry • APP • Aβ42 • NEFL • Plasma NfL

Amyloid-related imaging abnormalities in an ongoing Phase 1 study of mivelsiran, an investigational RNA interference therapeutic targeting amyloid precursor protein, in patients with Alzheimer's disease (CTAD 2025) - No abstract available

Clinical • P1 data • Alzheimer's Disease • CNS Disorders • APP

In the fourth quarter of 2025, Alnylam expects to (Businesswire) - "Initiate a Phase 2 trial of mivelsiran in patients with Alzheimer’s disease."

New P2 trial • Alzheimer's Disease

A Study to Evaluate the Safety and Tolerability of ALN-APP in Patients With EOAD (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Trial primary completion date: Jul 2025 ➔ Mar 2029

Trial primary completion date • Alzheimer's Disease • CNS Disorders

Key Upcoming Events (Businesswire) - "Alnylam announces today that it will present results from the KARDIA-3 Phase 2 trial of zilebesiran in patients with hypertension during a Hot Line Session at the European Society of Cardiology (ESC) Congress in Madrid, Spain on August 30, 2025...In addition, in the second half of 2025, Alnylam expects to: Initiate a Phase 3 cardiovascular outcomes trial of zilebesiran, in collaboration with its partner Roche; Initiate the TRITON-PN Phase 3 trial of nucresiran in hATTR-PN; Initiate a Phase 2 trial of mivelsiran in Alzheimer’s disease....In addition, Alnylam's partner, Regeneron Pharmaceuticals, plans to share results from the Phase 3 trial of cemdisiran tested as a monotherapy and in combination with pozelimab in patients with myasthenia gravis in the second half of 2025."

Clinical data • New P2 trial • New P3 trial • Alzheimer's Disease • Amyloidosis • Cardiovascular • Hypertension • Myasthenia Gravis

Alnylam Announces Preliminary Fourth Quarter and Full Year 2024 Global Net Product Revenues and Provides 2025 Combined Net Product Revenue Guidance and Pipeline Goals (Businesswire) - "Vutrisiran...Secure additional global approvals and reimbursement in Japan and the EU for the treatment of adults with ATTR amyloidosis with cardiomyopathy in the second half of 2025. Nucresiran (ALN-TTRsc04) – an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. Alnylam expects to: Initiate a Phase 3 study in patients with ATTR amyloidosis with cardiomyopathy in the first half of 2025...Mivelsiran – an investigational RNAi therapeutic in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA). Alnylam expects to: Report interim results from Part B of the Phase 1 study in Alzheimer’s disease in the second half of 2025. Initiate a Phase 2 study in Alzheimer’s disease in the second half of 2025...In 2025, Vir expects to initiate a Phase 3 chronic hepatitis delta registrational study and to report functional cure results from a Phase 2 chronic hepatitis B study."

Approval • New P2 trial • New P3 trial • P1 data • P2 data • Reimbursement • Alzheimer's Disease • Amyloidosis • CNS Disorders

A Phase 2 Study Evaluating the Effects of Mivelsiran, an Investigational RNA Interference Therapeutic, on Hemorrhagic and Nonhemorrhagic Manifestations of Cerebral Amyloid Angiopathy (ISC 2025) - P2 | "Patients with an ICH within 90 days before randomization, moderate/severe AD, severe cognitive impairment, or use of antithrombotics (except aspirin) are excluded...The study enrolled its first patient in mid-2024 and will continue to enroll in 2025. Mivelsiran is an investigational first-in-class RNAi therapeutic designed to target the underlying pathophysiology of CAA by lowering APP, thereby reducing Aβ accumulation. To date, cAPPricorn-1 is the only active global interventional study for the treatment of patients with CAA."

P2 data • Alzheimer's Disease • Cerebral Hemorrhage • CNS Disorders • Cognitive Disorders • Hematological Disorders

Targeting Cerebral Amyloid Angiopathy at its Source: An Amyloid Beta Precursor Protein-Targeted siRNA Reduced Vascular Amyloid Beta and Hemorrhage in Rodent Models (ISC 2025) - "Lowering APP production with siRNA in models of Aβ overproduction significantly reduced vascular amyloid burden, and CMB occurrence and size. These results provide the first preclinical evidence to support the rationale that lowering APP with an RNAi therapeutic could slow or halt the progression of CAA. A proof-of-concept Phase 2 study (cAPPricorn-1) has been initiated to assess the efficacy and safety of mivelsiran in patients with CAA."

Late-breaking abstract • Preclinical • Alzheimer's Disease • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • APP • NOS2

A Study to Evaluate the Safety and Tolerability of ALN-APP in Patients With EOAD (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Trial completion date: Jul 2027 ➔ Mar 2029

Trial completion date • Alzheimer's Disease • CNS Disorders

Drug Development. (PubMed, Alzheimers Dement) - P1 | "In this ongoing Phase 1 single ascending dose study, mivelsiran 50mg and 75mg were well tolerated and produced robust, durable reductions in CSF levels of soluble APP and downstream Aβ42 and Aβ40, key proteins implicated in progression of AD and CAA. These interim results support further evaluation of mivelsiran in patients with AD or CAA."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • APP • Aβ42 • CSF Aβ40 • CSF Aβ42

Alnylam Pharmaceuticals Reports Third Quarter 2024 Financial Results and Highlights Recent Period Activity (Businesswire) - "Continued growth momentum in total TTR, achieving global net product revenues for ONPATTRO and AMVUTTRA for the third quarter of $50 million and $259 million, respectively, which combined represent 34% TTR annual growth compared to Q3 2023...Alnylam will present additional findings from the ongoing Phase 1 study of ALN-TTRsc04 in patients with ATTR amyloidosis at the American Heart Association Scientific Sessions 2024. The Company plans to share its Phase 3 development plan for ALN-TTRsc04 in the first quarter of 2025. Alnylam intends to initiate a Phase 2 study of mivelsiran in patients with Alzheimer’s disease at or around year-end."

Commercial • New P2 trial • New P3 trial • P1 data • Alzheimer's Disease • Amyloidosis • CNS Disorders • Metabolic Disorders

Alnylam Pharmaceuticals Reports Third Quarter 2024 Financial Results and Highlights Recent Period Activity (Businesswire) - P1 | N=60 | NCT05231785 | Sponsor: Alnylam Pharmaceuticals | "Today announced positive initial results from the multiple dose portion of the Phase 1 study of mivelsiran in patients with Alzheimer’s disease. Following a second 50 mg dose of mivelsiran at month 6, further reductions of sAPPβ were observed at month 7, with patients achieving greater than 90% lowering of sAPPβ. No new safety signals have been identified, and no significant abnormalities have been seen on CSF safety labs such as total protein and CSF white cell count, or on the exploratory biomarker neurofilament light chain."

P1 data • Alzheimer's Disease • CNS Disorders

Design and Rationale of cAPPricorn-1, A Phase 2 Study of Mivelsiran in Patients with Cerebral Amyloid Angiopathy (CTAD 2024) - No abstract available

Clinical • P2 data

Alnylam Pharmaceuticals Reports Second Quarter 2024 Financial Results and Highlights Recent Period Activity (Businesswire) - "In mid- and late 2024, Alnylam intends to: Submit a supplemental New Drug Application (sNDA) for vutrisiran to the FDA using a Priority Review Voucher. Initiate a Phase 3 study of ALN-TTRsc04 in patients with ATTR-CM at or around year-end. Report interim results from Part B of the Phase 1 study of mivelsiran (ALN-APP) in patients with Alzheimer’s disease. Initiate a Phase 2 study of mivelsiran in patients with Alzheimer’s disease at or around year-end. Initiate a Phase 1 study of ALN-BCAT, in development for the treatment of hepatocellular carcinoma."

FDA filing • New P1 trial • New P2 trial • New P3 trial • P1 data • Alzheimer's Disease • Amyloidosis • Cardiomyopathy • CNS Disorders • Hepatocellular Cancer • Liver Cancer • Metabolic Disorders • Oncology • Solid Tumor

Developing Topics. (PubMed, Alzheimers Dement) - P1 | "This first clinical study of a CNS-administered RNAi therapeutic demonstrates target engagement of APP, with reductions in CSF sAPPα and sAPPβ. To date, ALN-APP remains generally well tolerated with all reported AEs mild or moderate. These interim results support further evaluation of ALN-APP in patients with EOAD. Reference: 1. Hampel H et al. Molecular Psychiatry (2021). 26:5481-5503."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • Psychiatry • APP

Single ascending dose results from an ongoing Phase 1 study of mivelsiran (ALN-APP), the first investigational RNA interference therapeutic targeting amyloid precursor protein for Alzheimer’s disease (AAIC 2024) - P1 | "In this ongoing Phase 1 single ascending dose study, mivelsiran 50mg and 75mg were well tolerated and produced robust, durable reductions in CSF levels of soluble APP and downstream Aβ42 and Aβ40, key proteins implicated in progression of AD and CAA. These interim results support further evaluation of mivelsiran in patients with AD or CAA."

P1 data • Alzheimer's Disease • CNS Disorders • Dementia • APP • Aβ42 • CSF Aβ40 • CSF Aβ42

cAPPricorn-1: A Phase 2 Trial of ALN-APP in Patients With Cerebral Amyloid Angiopathy (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open