Primary objectives:Cohort 1 and 21. To evaluate the safety and tolerability of multiple doses of belcesiran in patients with AATLD2. To characterize the pharmacodynamics of belcesiran in patients with AATLDCohort 3 1. To characterize the…
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Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcomes
Cohort 1 and 2:
1. The incidence and nature of treatment emergent adverse events (TEAEs), and
the change from Baseline in pulmonary function tests (PFTs), 12-lead ECGs,
physical examination findings, vital signs, and clinical laboratory tests.
2. Changes from baseline to weeks 24 (Cohort 1)/48 (Cohort 2) in serum AAT
protein concentrations
Cohort 3:
1. Change from baseline to week 24 in serum Z-AAT protein levels
2. Change from baseline to week 24 in liver Z-AAT protein levels
Secondary outcome
1. Pharmacokinetics profile of belcesiran
2. Change from Baseline up until week 96 in liver fibrosis
3. Change from Baseline up until week 96 in diastase-resistant PAS-positive AAT
globules
Background summary
Alpha-1 antitrypsin deficiency (AATD) is caused by inherited autosomal
mutations in SERPINA1, the gene that encodes the Alpha-1 antitrypsin (AAT)
protein. The resultant mutant AAT protein (Z-AAT) is prone to misfolding and
aggregation as homopolymers in hepatocytes, rather than secretion into the
blood. In individuals homozygous for the Z-allele (known as PiZZ patients),
impaired degradation of the aggregated protein leads to putatively toxic
accumulation of Z-AAT in the liver (toxic gain-of-function) and exerts
continuous stress on the hepatocytes. Over time, this constant stress can lead
to liver fibrosis, cirrhosis, and hepatocellular cancer. Currently, there is no
treatment for this severe liver disease, also called alpha-1 antitrypsin
deficiency-associated liver disease (AATLD), aside from liver transplantation.
The study drug, Belcesiran, uses an RNAi strategy to silence SERPINA1, which
reduces the total hepatic Z-AAT expression leading to decreased accumulation of
toxic Z-AAT in the liver. Non-clinical studies indicate that without the
continuous putative toxic stimulus, the progression of AATLD may be halted, or
potentially even reversed by providing the liver an opportunity to heal.
Furthermore, the study drug was well tolerated in the ongoing phase 1 study in
healthy volunteers.
Study objective
Primary objectives:
Cohort 1 and 2
1. To evaluate the safety and tolerability of multiple doses of belcesiran in
patients with AATLD
2. To characterize the pharmacodynamics of belcesiran in patients with AATLD
Cohort 3
1. To characterize the pharmacodynamics of belcesiran in patients with AATLD
Secondary objectives:
1. To characterize the pharmacokinetics of belcesiran in the plasma of patients
with AATLD
2. To assess the effect of belcesiran on liver histology in patients with AATLD
Exploratory objectives:
1. To assess the effect of belcesiran on liver stiffness in patients with AATLD
2. To assess the effect of belcesiran on liver fibrosis and/ or inflammation in
patients with AATLD
Study design
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 AATLD (liver fibrosis F1, F2, F3, or F4 in the METAVIR scoring
system).
Intervention
The study drug, Belcesiran, uses an RNAi strategy to silence SERPINA1, which
reduces the total hepatic Z-AAT expression leading to decreased accumulation of
toxic Z-AAT in the liver.
The study will be conducted in 3 parallel cohorts:
1. Cohort 1 (N=8): These subjects will be randomized 3:1 to either belcesiran
210 mg or placebo and a liver biopsy will be performed at week 24 to assess the
effect of belcesiran. In addition, participants will have the option to
continue treatment for an additional 72 weeks so that the total treatment
duration will be 96 weeks.
2. Cohort 2 (N=8): These subjects will be randomized 3:1 to either belcesiran
210 mg or placebo and a liver biopsy will be performed at week 48 to assess the
effect of belcesiran. In addition, participants will have the option to
continue treatment for an additional 48 weeks so that the total treatment
duration will be 96 weeks.
3. Cohort 3 (N=30): These subjects will be randomized 2:1:2:1 to belcesiran 210
mg, the equivalent amount of placebo for belcesiran 210 mg, belcesiran 50 mg or
the equivalent amount of placebo for belcesiran 50 mg. Participants will be
blinded within each dose level. Participants will have a liver biopsy performed
at week 24 to assess the effect of belcesiran and thereafter continue treatment
until 96 weeks of treatment have been completed.
After the EOT visit, all participants will be followed up for 48 weeks. If a
participant in Cohorts 1 and 2 does not wish to extend the treatment period to
96 weeks, they will proceed to the 48 week follow-up period instead.
Randomization will be stratified based on fibrosis stage (METAVIR Score F1, F2,
F3 or F4) in all cohorts.
All Participants in Cohorts 1 to 3 will have the option to undergo a liver
biopsy at End of Trial/week 96.
The study drug is administered via a subcutaneous injection.
Study burden and risks
Procedures: medical history, medication and demographics review, PiZZ
genotyping, pulmonary X-ray, vital signs (blood pressure, pulse and respiratory
rate, and oral temperature), physical examinations (height, weight, BMI and
review of body systems), 12-lead ECG, fibroscan and magnetic resonance
elastography (MRE), spirometry and diffusion capacity of the lungs for carbon
monoxide (DLCO).
Patients should prevent heavy exercise and heavy drinking. They should use
effective contraceptive methods and should not donate sperm during the
treatment period and for at least 12 weeks after the last dose.
Risks related to study drug:
In the ongoing first-in-human study, the study drug was well tolerated and no
severe adverse events (SAEs) and dose-limiting toxicities were reported.
Potential risks include exacerbation of emphysema, a decline in lung function,
stimulation of expression of receptors leading to cytokine release,
inflammation, injection site reactions, elevations of liver function tests, a
prolonged activated partial thromboplastin time (aPTT), hepatocellular
carcinoma, mild liver toxicity and a transient decrease in sperm motility. All
these risks are monitorable and should be reversible after drug discontinuation
or could potentially be treated.
Risk related to subcutaneous injection of the study drug:
This injection is associated with pain and may cause vasovagal reactions,
allergic reactions, infections, and bleeding.
Blood sampling:
This might cause the subject some slight discomfort and the subject might be
bruised for a few days around the area of the needle insertion. There could be
some bleeding and vessel damage. There is a slight risk for vessel blockage,
inflammation and infection in the area where the needle is inserted. Some
people become dizzy when providing blood sample.
Percutaneous liver biopsy:
Milder and more common risks include pain and bruising at the biopsy or
incision site. More serious complications include prolonged bleeding from the
biopsy or incision site, internal bleeding (which may require hospitalization,
transfusion, and sometimes surgery or another procedure to stop the bleeding),
infection of the biopsy site or incision site that may cause sepsis, and
pneumothorax, hemothorax, or puncture of other organs. The overall risk of
serious complications following liver biopsy is approximately 1%. The risks are
minimized through the selection of suitable subjects through eligibility
criteria and by the safety precautions outlined in the Liver Biopsy Manual. The
low risk of respiratory compromise in the elective setting of procedural
sedation and anesthesia is minimized through the standard-of-care monitoring
and the presence of a healthcare provider with the knowledge and skills to
recognize and treat airway complications.
Benefit:
Currently, there is no treatment for AATLD. Non-clinical studies indicate that
belcesiran may halt or even reverse the progression of AATLD.
The risk-benefit profile of belcesiran is favorable.
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Age
Inclusion criteria
1. Age 18 to 75 years, inclusive, at the time of signing the informed consent
form (ICF).
2. Documented diagnosis of PiZZ-type AATD, confirmed by genotyping. Historical
genotyping data may be used, if available.
3. AATLD, with a liver fibrosis score categorized as F1, F2, F3, or F4 in the
METAVIR scoring system, documented by liver biopsy during Screening.
4. Post-bronchodilator FEV1> 45% of predicted at Screening
5. Participants receiving augmentation therapy on a regular basis and intending
to continue augmentation therapy during the study are eligible to participate.
6. Estimated glomerular filtration rate at Screening >= 60 mL/min/1.73
7. Non-smokers (defined as having not smoked cigarettes daily for at least the
preceding12 months) with current non-smoking status confirmed by urine cotinine
at Screening AND any previous smoking history prior to 12 months must be < 15
pack years, including use of e-cigarettes. Participants may be on nicotine
replacement (patch or gum). A positive urine cotinine result due to nicotine
replacement is acceptable for enrollment at the discretion of the Investigator.
8. Male or female:
- Male: A male participant with a partner of childbearing potential must agree
to use contraception, as detailed in Section 10.4.2 of the Protocol, during the
treatment period and for at least 12 weeks after the last dose of study
intervention and refrain from donating sperm during this period. Contraceptive
use should be consistent with local regulations regarding the methods of
contraception for those participating in clinical studies.
- Female: A female participant is eligible to participate if she is not
pregnant and not breastfeeding. Women of childbearing potential (WOCBP) must be
using a highly effective method of contraception, as defined in Section 10.4.1.
of the Protocol.
9. Capable of giving signed informed consent, which includes compliance with
the requirements (including consent to undergo paired liver biopsies) and
restrictions listed in the ICF and in the protocol.
Exclusion criteria
Medical Conditions
1. Any condition which, in the investigator's opinion might jeopardize
participant's safety or compliance with the protocol.
2. History of chronic liver disease other than non-alcoholic fatty liver
disease from any cause other than PiZZ-type AATD.
3. Child-Pugh Score B or C
4.History of one single severe exacerbation of underlying lung disease in the
past year prior to randomization. A severe exacerbation is defined as an
exacerbation that requires hospitalization or a visit to the emergency room.
5. History of rapid decline in pulmonary function, as assessed by the
Investigator.
6. Known or suspected abuse of drugs in the opinion of the Investigator.
7. Known or suspected excessive consumption of alcohol (>= 21 units of alcohol
per week in men and >= 14 units of alcohol per week in women; where a "unit" of
alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1 ounce
shot of hard liquor as defined by the World Health Organization)
8. Any of the following: myocardial infarction, stroke, classification of heart
failure New York Heart Association (NYHA) Class IV, hospitalization for
unstable angina pectoris or transient ischaemic attack within the past 90 days
prior to the day of screening (V2A) and between screening and randomization.
9. History of malignancy, unless the malignancy (other than hepatocellular or
lung cancer) has been in complete remission off chemotherapy and without
additional medical or surgical interventions within the preceding 5 years, or
unless the malignancy has been an adequately treated skin cancer (other than
melanoma) or, superficial bladder tumor, or in situ cervical cancer in the
preceding 1 year.
Prior/Concomitant Therapy
10. Use of an RNAi drug at any time.
11. History of one or more of the following reactions to an
oligonucleotide-based therapy:
a. severe thrombocytopenia (platelet count < 100,000/ mm3)
b. hepatotoxicity, defined as alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) > 3 × upper limit of normal (ULN) and total bilirubin >
2 × ULN or INR > 1.5
c. severe flu-like symptoms leading to discontinuation of therapy
d. localized skin reaction from the injection (graded severe) leading to
discontinuation of therapy
e. coagulopathy/clinically significant prolongation of clotting time
Prior/Concurrent Clinical Study Experience
12. Participation in any clinical study in which they received an IMP within 4
months (or 5 times the half-life, whichever is longer) before Screening
Diagnostic assessments
13. AST and ALT > 5 × ULN at Screening For individuals with any serum
aminotransferase elevation > 2 × ULN, autoimmune hepatitis should be ruled out
through the appropriate screening tests, which may include total IgG or
gamma-globulin levels and/or serologic markers (antinuclear antibodies,
anti-smooth-muscle antibodies at a titer of at least 1:40, anti-liver/kidney
microsomal-1 antibodies, anti-liver cytosol antibody [anti-LC 1], or
antisoluble liver/liver pancreas [anti-SLA/LP] antibodies).
14. alkaline phosphatase (ALP) 2 × ULN at Screening
15. Serum AFP value > 100 ng/mL at Screening If AFP at screening is > ULN but <
100 ng/mL, the participant is still eligible if an appropriate hepatic imaging
study reveals no lesions
16. Positive screening for antimitochondrial antibodies (only required if
primary biliary cirrhosis is suspected)
17. Platelets < 100,000/mm3 at Screening
18. international normalized ratio (INR) > 1.6 × ULN at Screening
19. Positive screening for Hepatitis B surface antigen (HBsAg), Hepatitis C
Virus (HCV) antibodies, or human immunodeficiency virus (HIV)1 and 2
antibodies. If a participant has been tested in the past 3 months, medical
record documentation of this testing can be used for eligibility.
NOTE: In participants with previous treatment for hepatitis C with
direct-acting HCV medication and seropositivity for HCV, or in participants
with prior infection and spontaneous resolution, HCV RNA must be undetectable
(at least two negative HCV RNA tests at least 12 weeks apart), and the HCV
infection must have been resolved or cured > 3 years prior to enrollment.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-003313-35-NL |
| CCMO | NL76935.000.21 |