belcesiran (NN6021) / Alnylam - LARVOL DELTA

Alpha-1 antitrypsin deficiency: genetics, clinical manifestations, AI prognostics, and advanced imaging in liver disease. (PubMed, Ann Med Surg (Lond)) - "Novel therapies are reshaping AATD management, including small interfering RNA therapies (fazirsiran, belcesiran), gene-editing techniques (CRISPR-Cas9), regenerative approaches, autophagy-enhancing drugs, proteostasis regulators, aerosolized AAT, and artificial intelligence (AI) for real-time disease tracking via wearable devices. The integration of AI, advanced imaging, and emerging therapies represents a paradigm shift in AATD diagnosis and treatment. This review highlights the need for a multidisciplinary approach, early intervention, and personalized medicine to improve outcomes in both pulmonary and hepatic complications."

Journal • Review • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Fibrosis • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • SERPINA1

ESTRELLA: A Study of Belcesiran in Patients With AATLD (clinicaltrials.gov) - P2 | N=16 | Terminated | Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company | N=46 ➔ 16 | Trial completion date: Dec 2026 ➔ May 2024 | Active, not recruiting ➔ Terminated; Development project was discontinued

Enrollment change • Trial completion date • Trial termination • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • AFP • CRP

ESTRELLA: A Study of Belcesiran in Patients With AATLD (clinicaltrials.gov) - P2 | N=46 | Active, not recruiting | Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company | Recruiting ➔ Active, not recruiting

Enrollment closed • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • AFP • CRP

Study of DCR-A1AT in Healthy Adult Volunteers (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company | Active, not recruiting ➔ Completed

Trial completion • Alpha-1 Antitrypsin Deficiency • Hepatology • Pulmonary Disease • Respiratory Diseases

BELCESIRAN WAS WELL-TOLERATED AND REDUCED SERUM AAT LEVELS IN HEALTHY VOLUNTEERS IN A PHASE 1 STUDY: FINAL RESULTS (AASLD 2023) - P1 | "In this first-in-human Phase I study, belcesiran was well-tolerated with dose-dependent and reversible effects on serum AAT levels in HVs."

Clinical • P1 data • Alpha-1 Antitrypsin Deficiency • Dermatology • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Infectious Disease • Pain • Pulmonary Disease • Rare Diseases • Respiratory Diseases • SERPINA1

ESTRELLA: A Study of Belcesiran in Patients With AATLD (clinicaltrials.gov) - P2 | N=46 | Recruiting | Sponsor: Dicerna Pharmaceuticals, Inc. | Phase classification: P2a ➔ P2 | Trial completion date: Dec 2023 ➔ Dec 2026 | Trial primary completion date: Dec 2022 ➔ Sep 2023

Phase classification • Trial completion date • Trial primary completion date • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • AFP • CRP

Study of DCR-A1AT in Healthy Adult Volunteers (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: Dicerna Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2022 ➔ May 2023

Enrollment closed • Trial completion date • Alpha-1 Antitrypsin Deficiency • Hepatology • Pulmonary Disease • Respiratory Diseases

An Extension Study of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATLD) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Dicerna Pharmaceuticals, Inc. | N=54 ➔ 0 | Trial completion date: Dec 2025 ➔ May 2022 | Enrolling by invitation ➔ Withdrawn | Trial primary completion date: Dec 2025 ➔ May 2022

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

An extension study to evaluate Safety and Pharmacodynamics of Belcesiran in patients with PiZZ Alpha-1 Antitrypsin Deficiency. Un estudio de extensión para evaluar la seguridad y farmacodinamia de Belcesiran en pacientes con deficiencia de PiZZ alfa-1 antitripsina. (clinicaltrialsregister.eu) - P2 | N=54 | Ongoing | Sponsor: Dicerna Pharmaceuticals, Inc.

New P2 trial • Alpha-1 Antitrypsin Deficiency • Fibrosis • Gastrointestinal Cancer • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor

An Extension Study of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATLD) (clinicaltrials.gov) - P2; N=54; Enrolling by invitation; Sponsor: Dicerna Pharmaceuticals, Inc.

Clinical • New P2 trial • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] BELCESIRAN WAS WELL-TOLERATED AND REDUCED SERUM AAT LEVELS IN HEALTHY VOLUNTEERS (PHASE 1 INTERIM RESULTS) (AASLD 2021) - P2a | "Belcesiran demonstrated a favorable safety and tolerability profile while inducing a dose-dependent and durable reduction in serum AAT. Belcesiran is currently being investigated in patients with liver disease associated with alpha-1 antitrypsin deficiency (NCT04764448)."

Clinical • P1 data • Alpha-1 Antitrypsin Deficiency • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Infectious Disease • Pain • Pulmonary Disease • Respiratory Diseases • SERPINA1

A clinical study to evaluate safety, tolerability, Pharmacokinetics and Pharmacodynamis of Belcesiran in patients with PiZZ Alpha-1 Antitrypsin Deficiency. (clinicaltrialsregister.eu) - P2; N=54; Ongoing; Sponsor: Dicerna Pharmaceuticals, Inc.

Clinical • New P2 trial • Alpha-1 Antitrypsin Deficiency • Fibrosis • Gastrointestinal Cancer • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • AAT

ESTRELLA: A Study of Belcesiran in Patients With A1ATD-Associated Liver Disease (clinicaltrials.gov) - P2a; N=54; Recruiting; Sponsor: Dicerna Pharmaceuticals, Inc.

Clinical • New P2a trial • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Respiratory Diseases

Study of DCR-A1AT in Healthy Adult Volunteers (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Dicerna Pharmaceuticals, Inc.; Phase classification: P1/2 ➔ P1; N=60 ➔ 36

Clinical • Enrollment change • Phase classification • Alpha-1 Antitrypsin Deficiency • Hepatology • Respiratory Diseases

Dicerna Announces Second Quarter 2020 Financial Results and Provides a Business Update (Businesswire) - "DCR-A1AT Phase 1/2 Trial and ALN-AAT02 Program Update. In late April 2020, the Scientific Review Committee for the DCR-A1AT phase 1/2 trial confirmed that the study could continue, and the Company began enrolling the following dosing cohort in May, which has since been completed. The Company is currently targeting program selection and potential initiation of patient dosing in the first quarter of 2021."

Trial status • Alpha-1 Antitrypsin Deficiency

Dicerna Announces Third Quarter 2020 Financial Results and Provides a Business Update (Businesswire) - "Anticipated Upcoming Milestones: DCR-A1AT/ALN-AAT02: Program selection for advancement into Phase 2 in the first quarter 2021."

Clinical • Alpha-1 Antitrypsin Deficiency

Dicerna announces first quarter 2020 financial results and provides a business update (Businesswire) - "...enrollment of healthy volunteers in the Phase 1/2 trial of DCR-A1AT was effectively paused due to site restrictions related to the COVID-19 pandemic. All subjects in the current dosing cohort are expected to complete their remaining visits, as feasible....Scientific Review Committee for the DCR-A1AT Phase 1/2 trial confirmed that the study could continue and begin enrolling healthy volunteers in the next dosing cohort....Completion of dosing in healthy volunteers...and initiation of dosing in patients in the Phase 1/2 trial of DCR-A1AT will be determined based on the timing and pace of enrollment..."

Enrollment status • Trial status • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

Alnylam and Dicerna form RNAi therapeutics collaboration on alpha-1 antitrypsin deficiency-associated liver disease and complete cross-license agreement for primary hyperoxaluria programs (Businesswire) - "Alnylam Pharmaceuticals, Inc....and Dicerna Pharmaceuticals, Inc....announced today the formation of a development and commercialization collaboration on investigational RNAi therapeutics for the treatment of alpha-1 antitrypsin (A1AT) deficiency-associated liver disease (alpha-1 liver disease)....Under the agreement, Dicerna assumes responsibility for both ALN-AAT02 and DCR-A1AT at its cost, and may progress one or both of these investigational medicines through clinical development....At the completion of Phase 3, Alnylam has the no-cost opportunity to opt-in to commercialize the selected candidate in countries outside the U.S...."

Licensing / partnership

Dicerna addresses business continuity in response to Covid-19 pandemic (Dicerna Press Release) - “The initial enrollment of healthy volunteers has proceeded according to plan in Dicerna’s Phase 1/2 trial of DCR-A1AT. However, given the potential for increased respiratory risk from COVID-19 for future participants in this trial, the Company currently expects that a pause in enrollment at higher doses in the Phase 1/2 trial is likely, pending further developments in management of the COVID-19 situation.”

Trial status

Dicerna receives Orphan Drug Designation from U.S. Food and Drug Administration for DCR-A1AT for treatment of alpha-1 antitrypsin deficiency (Dicerna Press Release) - "Dicerna Pharmaceuticals...today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to Dicerna’s DCR-A1AT for the treatment of alpha-1 antitrypsin (A1AT) deficiency."

Orphan drug

Dicerna announces fourth quarter and full year 2019 financial results and provides corporate update (Businesswire) - "We also began clinical development of DCR-A1AT, all while progressing and expanding programs under our existing collaboration agreements....Dicerna is conducting a clinical trial program investigating DCR-A1AT for the treatment of A1AT deficiency-associated liver disease....DCR-A1AT: First patient dosing in Phase 1/2 trial – second half of 2020."

Trial status

DCR-A1AT: Initiation of P2 portion of P1/2 trial (NCT04174118) in patients with A1ATD-Associated liver disease in H2 2020 (Evercore ISI 2nd Annual HealthCONx Conference, Dicerna)

Trial initiation date

DCR-A1AT: Initiation of P2 portion of P1/2 trial (NCT04174118) in patients with A1ATD-Associated liver disease in H2 2020 (Evercore ISI 2nd Annual HealthCONx Conference, Dicerna)

Trial initiation date

Dicerna receives Orphan Drug Designation from European Commission for DCR-A1AT for treatment of congenital alpha-1 antitrypsin deficiency (Businesswire) - "Dicerna Pharmaceuticals...today announced that the European Commission (EC) has granted orphan drug designation to Dicerna’s DCR-A1AT for the treatment of congenital alpha-1 antitrypsin (A1AT) deficiency based on a positive opinion from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA)."

Orphan drug

A Study of DCR-A1AT in Healthy Adult Volunteers and Patients With A1ATD-Associated Liver Disease (clinicaltrials.gov) - P1/2; N=60; Recruiting; Sponsor: Dicerna Pharmaceuticals, Inc.

Clinical • New P1/2 trial