What is the mechanism of action of this treatment?

Alpha-1 Antitrypsin Deficiency (AATD) treatments primarily focus on either increasing functional AAT levels in the lungs or reducing the production of the mutant protein in the liver. Augmentation therapy involves infusions of purified AAT to protect the lungs. Investigational treatments like belcesiran use RNA interference (RNAi) to target the SERPINA1 gene, reducing the production of the mutant AAT protein. This is crucial for AATD patients as it addresses the root cause of liver damage, potentially preventing disease progression and improving liver function.

What side effects are associated with this type of intervention?

Common treatments for Alpha-1 Antitrypsin Deficiency (AATD) include augmentation therapy, which involves infusions of alpha-1 antitrypsin protein derived from human plasma. Side effects of augmentation therapy can include infusion reactions, such as fever, chills, and rash. Investigational RNA interference (RNAi) therapies like Belcesiran, which target the SERPINA1 gene to reduce the production of mutant alpha-1 antitrypsin protein, may have side effects including injection site reactions, flu-like symptoms, and potential liver enzyme elevations. As with any new therapeutic approach, ongoing clinical trials are essential to fully characterize the safety profile.

What prior FDA approvals exist?

Alpha-1 Antitrypsin Deficiency (AATD) has traditionally been treated with augmentation therapy, where patients receive infusions of alpha-1 antitrypsin protein derived from human plasma to increase the levels of the protein in the blood and lungs. FDA-approved drugs for this purpose include Prolastin, Aralast, Zemaira, and Glassia. These treatments aim to slow the progression of lung disease associated with AATD. However, there are no FDA-approved RNA interference (RNAi) therapies specifically targeting the SERPINA1 gene to reduce the production of mutant alpha-1 antitrypsin protein, which is the mechanism of action for the investigational drug Belcesiran.

What other types of research exist?

Promising novel alternatives to Belcesiran for Alpha-1 Antitrypsin Deficiency patients include: 1) CRISPR-Cas9 gene editing therapies targeting the SERPINA1 gene to correct the genetic mutation causing AATD. 2) Other RNA interference (RNAi) therapies that reduce the production of mutant alpha-1 antitrypsin protein. 3) Gene therapy approaches that introduce a functional copy of the SERPINA1 gene to produce normal alpha-1 antitrypsin protein. 4) Small molecule chaperones that stabilize the normal alpha-1 antitrypsin protein and enhance its function.

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Antisense Oligonucleotide

Belcesiran for Alpha-1 Antitrypsin Deficiency (ESTRELLA Trial)

Phase 2

Waitlist Available

Research Sponsored by Dicerna Pharmaceuticals, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Documented diagnosis of PiZZ-type alpha-1 antitrypsin deficiency, confirmed by genotyping. Historical genotyping data may be used, if available

18 to 75 years, inclusive, at the time of consent

Must not have

History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type alpha-1 antitrypsin deficiency

Use of an RNAi drug at any time

Timeline

Screening 3 weeks

Treatment Varies

Follow Up [cohort 1 + cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo

Summary

This trial is testing a new drug called belcesiran to see if it is safe and effective for adults with a specific genetic liver disease. These patients have a severe condition with no current treatments available for their liver problems. The drug aims to address the root cause of their liver damage.

Who is the study for?

This trial is for adults aged 18-75 with Alpha-1 Antitrypsin Deficiency-associated liver disease, confirmed by genotyping and liver biopsy. Participants must have normal lung, kidney, and liver function tests and agree to undergo two liver biopsies. Excluded are those with severe lung disease exacerbations in the past year, prior RNAi drug use, significant respiratory infections within three months before screening, or advanced liver disease (Child-Pugh Score B or C).

What is being tested?

The study tests Belcesiran's safety and effects on patients with AATLD compared to a placebo. It's randomized (participants are put into groups by chance), double-blind (neither participants nor researchers know who gets what treatment), involving multiple doses across three cohorts differing in treatment duration, dose count, and timing of a second biopsy.

What are the potential side effects?

While specific side effects for Belcesiran aren't listed here, common ones for similar treatments include injection site reactions, fatigue, abdominal pain or discomfort; potential risks may also involve changes in liver enzymes indicating possible organ stress.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My condition is confirmed PiZZ-type alpha-1 antitrypsin deficiency.

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I am between 18 and 75 years old.

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My liver disease linked to AATD was confirmed by a biopsy.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have a chronic liver condition not caused by PiZZ-type alpha-1 antitrypsin deficiency.

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I have used an RNAi drug before.

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My liver function is moderately to severely impaired.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ [cohort 1 + cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~[cohort 1 + cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo

This trial's timeline: 3 weeks for screening, Varies for treatment, and [cohort 1 + cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Secondary study objectives

Disease

Plasma concentration of Belcesiran on Day 1

Plasma concentration of Belcesiran on Day 29

+1 more

Trial Design

6Treatment groups

Experimental Treatment

Placebo Group

Group I: Belcesiran Cohort 3Experimental Treatment1 Intervention

Group II: Belcesiran Cohort 2Experimental Treatment1 Intervention

Group III: Belcesiran Cohort 1Experimental Treatment1 Intervention

Group IV: Placebo Cohort 1Placebo Group1 Intervention

Group V: Placebo Cohort 2Placebo Group1 Intervention

Group VI: Placebo Cohort 3Placebo Group1 Intervention

0 / 6Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Alpha-1 Antitrypsin Deficiency (AATD) treatments primarily focus on either increasing functional AAT levels in the lungs or reducing the production of the mutant protein in the liver. Augmentation therapy involves infusions of purified AAT to protect the lungs. Investigational treatments like belcesiran use RNA interference (RNAi) to target the SERPINA1 gene, reducing the production of the mutant AAT protein. This is crucial for AATD patients as it addresses the root cause of liver damage, potentially preventing disease progression and improving liver function.

RNA INTERFERENCE: NEW APPROACH TO THE TREATMENT OF ALLERGIC ASTHMA (A REVIEW).Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension.RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice.