A Study of Belcesiran in Patients With AATLD (ESTRELLA)

Dicerna Pharmaceuticals

Status and phase: Terminated; Phase 2

Conditions: Alpha 1-Antitrypsin Deficiency

Treatments: Drug: Belcesiran; Other: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT04764448

DCR-A1AT-201

Details and patient eligibility

About

This is a multiple dose, randomized, placebo-controlled, double-blind study of belcesiran to evaluate the safety, tolerability, PK, and PD in adult patients with PiZZ AATD-associated liver disease (AATLD).

The study will be conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.

Full description

AATD-associated liver disease is a progressive condition resulting in liver fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. The lack of functional alpha-1 antitrypsin (AAT) in individuals with the PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism may be addressed by use of intravenous augmentation therapy, which aims to substitute the missing AAT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.

While augmentation therapy can address the loss of AAT in the lung, no treatment exists for the associated liver disease.

Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and the lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help this particular patient population.

Enrollment: 16 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 18 to 75 years, inclusive, at the time of consent.
• Documented diagnosis of PiZZ-type alpha-1 antitrypsin deficiency, confirmed by genotyping. Historical genotyping data may be used, if available.
• AATD-associated liver disease documented by liver biopsy at Screening.
• Consent to undergo paired liver biopsies.
• Lung, renal and liver function within acceptable limits
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion criteria

• History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type alpha-1 antitrypsin deficiency.
• Child-Pugh Score B or C.
• History of one single severe exacerbation of underlying lung disease in the year prior to randomization.
• History of clinically significant respiratory infections (including pneumonia and lower respiratory tract infections), as determined by the Investigator, in the 3 months prior to screening
• Use of an RNAi drug at any time.

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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16 participants in 6 patient groups, including a placebo group

Belcesiran Cohort 1

Experimental group

Treatment:

Drug: Belcesiran

Drug: Belcesiran

Drug: Belcesiran

Placebo Cohort 1

Placebo Comparator group

Treatment:

Other: Placebo

Other: Placebo

Other: Placebo

Belcesiran Cohort 2

Experimental group

Treatment:

Drug: Belcesiran

Drug: Belcesiran

Drug: Belcesiran

Placebo Cohort 2

Placebo Comparator group

Treatment:

Other: Placebo

Other: Placebo

Other: Placebo

Belcesiran Cohort 3

Experimental group

Treatment:

Drug: Belcesiran

Drug: Belcesiran

Drug: Belcesiran

Placebo Cohort 3

Placebo Comparator group

Treatment:

Other: Placebo

Other: Placebo

Other: Placebo