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

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

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 2025 ➔ Jul 2027

Trial completion date • Alzheimer's Disease • CNS Disorders

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

New P2 trial

AN RNAI THERAPEUTIC TARGETING APP REDUCED BETA-CTF AND CORRECTED ENDOSOMAL ABNORMALITIES IN MULTIPLE HUMAN ALZHEIMER'S DISEASE IPSC LINES (ADPD 2024) - P1 | "By lowering both intracellular and extracellular drivers of AD pathology, an RNAi therapeutic targeting APP may potentially alter the cascade of pathological events that result in neurodegeneration. The Phase 1 first-in-human study of ALN-APP, an investigational RNAi therapeutic targeting APP mRNA, is ongoing in patients with early-onset AD (NCT05231785)."

Alzheimer's Disease • CNS Disorders • Metabolic Disorders • APP • RAB5A

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

Phase 1 safety, tolerability, and pharmacological results of ALN-APP, the first investigational RNA (CTAD 2023) - P1 | "In Part A of this first clinical study of a novel central nervous system-administered RNAi therapeutic, ALN-APP has been well-tolerated and associated with rapid, robust, and durable reductions in CSF sAPPα and sAPPβ levels, reflecting target engagement of APP mRNA. Part A is ongoing and additional, longer-term data may provide more insights into duration of effect and the impact of ALN-APP on biomarkers associated with Alzheimer’s disease progression."

Clinical • Late-breaking abstract • P1 data • Alzheimer's Disease • CNS Disorders • Dementia • APP • Aβ42 • CSF Aβ40

Alnylam Reports Additional Positive Interim Phase 1 Results for ALN-APP, in Development for Alzheimer’s Disease and Cerebral Amyloid Angiopathy (Businesswire) - P1 | N=60 | NCT05231785 | Sponsor: Alnylam Pharmaceuticals | "Alnylam Pharmaceuticals, Inc...announced additional positive interim results for the ongoing single ascending dose portion of the Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA)....Patients treated with a single dose of 75mg ALN-APP experienced rapid and sustained reduction in CSF of both soluble APPα (sAPPα) and soluble APPβ (sAPPβ), biomarkers of target engagement, with maximum reductions of 84% and 90%, respectively. These effects were highly durable, with mean reductions in sAPPα and sAPPβ of 33% and 39%, respectively, at 10 months after a single 75mg dose."

P1 data • Alzheimer's Disease • CNS Disorders

Alnylam Pharmaceuticals Reports Second Quarter 2023 Financial Results and Highlights Recent Period Activity (Businesswire) - "Alnylam Pharmaceuticals...today reported its consolidated financial results for the second quarter ended June 30, 2023 and reviewed recent business highlights.....Presented Updated Positive Interim Results from Phase 1 Study of ALN-APP in Patients with Early-Onset Alzheimer’s Disease....Reported updated positive interim results for the ongoing single ascending dose (SAD) portion of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease (EOAD) at the 2023 Alzheimer’s Association International Conference (AAIC)."

P1 data • Alzheimer's Disease • CNS Disorders

Interim phase 1 part A results for ALN-APP, the first investigational RNAi therapeutic in development for Alzheimer’s disease (AAIC 2023) - 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."

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

Alnylam and Regeneron Report Positive Interim Phase 1 Clinical Data on ALN-APP, an Investigational RNAi Therapeutic for Alzheimer’s Disease and Cerebral Amyloid Angiopathy (Businesswire) - P1 | N=60 | NCT05231785 | Sponsor: Alnylam | "Early data for neurofilament light chain from a subset of cohorts (2 of 3 studied) looked comparable to placebo. Patients treated with ALN-APP experienced dose-dependent, rapid and sustained reduction in cerebrospinal fluid of both soluble APPα (sAPPα) and APPβ (sAPPβ), biomarkers of target engagement, with maximum reduction of 84% and 90%, respectively. Median decreases of both biomarkers of greater than 70% was sustained for at least three months at the highest dose tested. Detailed interim results from this study are planned to be reported at an upcoming scientific conference."

P1 data • Alzheimer's Disease • CNS Disorders

DISCOVERY AND NONCLINICAL DEVELOPMENT OF ALN-APP, AN INVESTIGATIONAL RNAI THERAPEUTIC (ADPD 2023) - "ALN-APP inhibits APP mRNA and reduces APP protein in vivo, consistent with its therapeutic potential, and displays a safety profile supporting the single-ascending dose trial currently in progress in patients with early-onset AD (EOAD)."

Alzheimer's Disease • CNS Disorders • APP

Alnylam Announces 2023 Product and Pipeline Goals and Provides Program Updates at R&D Day (Businesswire) - “Vutrisiran, a commercial-stage RNAi therapeutic for the treatment of polyneuropathy in patients with hATTR amyloidosis, and in development for the treatment of the cardiomyopathy of ATTR amyloidosis. Alnylam plans to: Report data from the evaluation of a biannual dosing regimen in early 2023. Submit a Supplemental New Drug Application (sNDA) for a biannual dosing regimen in early 2023. ALN-TTRsc04, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. Alnylam plans to: Report topline Phase 1 results in late 2023….ALN-APP, an investigational RNAi therapeutic in development for the treatment of Alzheimer’s Disease and Cerebral Amyloid Angiopathy. Alnylam plans to: Report topline Phase 1 results in early 2023.”

Clinical data • P1 data • sNDA • Alzheimer's Disease • Amyloidosis • CNS Disorders • Tauopathies And Synucleinopathies

Alnylam Pharmaceuticals Reports Second Quarter 2022 Financial Results and Highlights Recent Period Activity (Businesswire) - “Upcoming Events: In addition, in mid- and late-2022, Alnylam intends to: Launch vutrisiran in the EU...for the treatment of hATTR amyloidosis patients with polyneuropathy; Report results on a biannual dose regimen for vutrisiran; File an Investigational New Drug (IND) application and initiate a Phase 1 study for ALN-TTRsc04 in healthy volunteers; Report preliminary results from the Phase 1 study of ALN-APP in patients with early-onset Alzheimer's disease.”

Clinical data • IND • Launch Europe • New P1 trial • P1 data • Alzheimer's Disease • Amyloidosis • CNS Disorders

A Study to Evaluate the Safety and Tolerability of ALN-APP in Patients With EOAD (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders • APP