Phase2a StudyOf Belcesiran in PatientsWith AATLD
Research type
Research Study
Full title
A Phase 2, Randomized, Double-blind, Placebo-controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
IRAS ID
289384
Contact name
Richard Parker
Contact email
Sponsor organisation
Dicerna Pharmaceuticals, Inc.
Eudract number
2020-003313-35
Clinicaltrials.gov Identifier
Duration of Study in the UK
3 years, 1 months, 21 days
Research summary
AATD happens when there is a lack of a protein in the blood called alpha-1 antitrypsin (AAT). This AAT protein is produced in liver cells. The main function of AAT is to protect the lungs from inflammation caused by infection and inhaled irritants. The low level of AAT in the blood occurs because the AAT is abnormal and cannot be released from the liver in the blood at the normal rate. This leads to build-up of abnormal AAT in the liver causing liver disease, and a decrease in the blood that can lead to lung disease. Liver biopsy can show that AAT has built up in the liver and cause damage, and this is referred to as fibrosis. Right now, there is no specific therapy to treat liver disease associated with AAT. General supportive therapy is available as well as liver transplantation when needed. Because of the high level of disease and mortality of patients with Alpha-1 Anti-trypsin Liver Disease and the burden of liver transplantation, there is a significant need for a safe and effective treatment.
The purpose of this study is to compare the effects of a study drug, belcesiran, with a placebo to determine if belcesiran is safe and effective for treating AATLD.
This is the first study to evaluate the safety and tolerability of multiple doses of belcesiran in adult patients with AATLD. The study will also assess the effect of belcesiran on different aspects of participants liver disease comparing the findings after a certain time to what was seen at the start of the study. How many doses and at which frequency and interval they will be administered is being defined by the results in an ongoing study. Data from this study will be used to develop a liver disease activity score in patients with AATD.
Lay summary of study results:
Estrella was a study of an experimental medicine called Belcesiran (injection under the skin), which is being developed by Dicerna Pharmaceuticals Inc, to treat Alpha-1 Antitrypsin Deficiency-associated Liver disease (AATLD). Belcesiran targets the gene that codes for the abnormal AAT protein present in AATLD, thereby hopefully reducing the accumulation of abnormal AAT in the liver.This study trialled multiple doses of Belcesiran in adult patients with AATLD, primarily to evaluate the drug’s safety & tolerability profile as well as exploring its effect on blood levels of AAT and the liver (potentially by taking liver biopsies). The study originally planned to evaluate 3 separate groups of participants (cohorts) and enrolment commenced in May 2021. However, the study was terminated for business reasons on 8 December 2023, and the 3rd cohort was not enrolled. A total of 16 participants received the study treatment – 8 in each of cohorts 1 & 2. Of these, 11 people were randomly assigned to receive monthly Belcesiran injections and 5 were assigned to receive Placebo .
Participants in Cohort 1 received 7 doses of study treatment (Belcesiran or Placebo) over 24 weeks, while Cohort 2 received 13 doses over 48 weeks. Participants had the option to then shift to quarterly dosing until Week 96. A follow-up period of 48 weeks from the end of treatment was also planned so that the duration of any treatment effects could be assessed.In all, 11 out of the 16 participants completed the treatment period. One participant decided to withdraw from the study and 4 people had to discontinue their treatment part-way through due to the study being terminated. The study’s termination also meant that no one completed the planned follow-up period. The last participant’s last visit date was 16 April 2024.
The study report found that Belcesiran was generally safe and well tolerated in participants with AATLD. The majority of adverse events experienced by participants during the study were mild in severity and most were not thought to be related to the study medication (the most common events were COVID-19 infection, coughs and colds). Only one participant who received Belcesiran reported an injection site reaction, which was mild in severity. There were no treatment-related significant trends in safety blood or urine test results, vital signs, physical examinations or ECGs that were monitored during the study.
Four serious adverse events occurred that were considered possibly related to Belcesiran – an episode of pneumonia; an episode of atrial fibrillation (an irregular, fluttering heart rhythm); deterioration in lung function test results; and worsening of liver function, which was explained by underlying cirrhosis due to AATLD. All participants recovered clinically.In terms of effect, the trial showed that repeated doses of Belcesiran produced a significant reduction in the level of AAT protein circulating in the blood of people with AATLD in the study. With continued dosing, a long-lasting effect could potentially be expected.
The URL to summary results: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fclinicaltrials.gov%252Fstudy%252FNCT04764448%253Fterm%253DNCT04764448%2526rank%253D1%2526tab%253Dresults%2FNBTI%2Fpp67AQ%2FAQ%2F6083656c-9592-4735-ad27-ce9474be96b0%2F1%2FP05jkZuTzW&data=05%7C02%7Cleicestercentral.rec%40hra.nhs.uk%7Cd59983d83f7645f7dbee08dd55ad4160%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638760924787811565%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=hLk0kkAjPwsIVfXvIuy7xTrjR4kIM7LvtxI2GtKwwyY%3D&reserved=0 and https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.clinicaltrialsregister.eu%252Fctr-search%252Ftrial%252F2020-003313-35%252Fresults%2FNBTI%2Fpp67AQ%2FAQ%2F6083656c-9592-4735-ad27-ce9474be96b0%2F2%2F69g5z3XeGu&data=05%7C02%7Cleicestercentral.rec%40hra.nhs.uk%7Cd59983d83f7645f7dbee08dd55ad4160%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638760924787840074%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=LDU9kdQnVeYgJaYeSmN8e%2BfSlZ%2FXDI48bZGv%2BJ7Mqpo%3D&reserved=0
REC name
East Midlands - Leicester Central Research Ethics Committee
REC reference
21/EM/0085
Date of REC Opinion
3 Jun 2021
REC opinion
Further Information Favourable Opinion