Primary Objective:• To select a single dose for use in later stage development based on a combined evaluation of safety and pharmacodynamic effects of ARO-AAT
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
• Percent change from baseline at Week 16 in serum Z-AAT
Secondary outcome
Secundary endpoints:
• Safety of ARO-AAT versus placebo based on frequency of adverse events (AEs)
at Week 16 and over time through End of Study (EOS)
• Absolute and percent change from baseline in total liver Z-AAT (insoluble +
soluble) protein at post-dose biopsy visit
• Absolute and percent change from baseline in liver Z-AAT soluble protein at
postdose biopsy visit
• Absolute and percent change from baseline in liver Z-AAT insoluble protein at
postdose biopsy visit
• Absolute and percent change from baseline in liver function tests including
ALT, AST, alkaline phosphatase, GGT, total bilirubin, direct bilirubin and INR
at Week 16 and over time through EOS
• Absolute and percent change in serum Z-AAT over time through EOS
• Change over time in pharmacokinetic measurements of ARO-AAT at timepoints
specified in the Schedule of Assessments
Background summary
Alpha-1 antitrypsin deficiency is an autosomal co-dominant genetic disorder
with a prevalence range of 1/1500-1/5000 that causes early pulmonary disease in
adults and liver disease in children and adults (Nelson et al, 2012).
Alpha-1-antitrypsin (AAT) is a 52 kDa circulating glycoprotein protease
inhibitor of the serpin family. The primary function of AAT is to inhibit
neutrophil elastase to prevent excessive elastase-induced tissue damage.
Normally, AAT is synthesized primarily in hepatocytes and several grams daily
are secreted directly into the serum. In lung parenchyma, AAT is critical for
protection of alveolar interstitial elastin from degradation by neutrophil
elastase. A lack of adequate levels of functional AAT leads to damage of lung
elastin by neutrophil elastase and the development of early emphysema. It
generally takes decades for lung disease to manifest and usually requires
additional environmental insult, usually cigarette smoking. Low plasma AAT
levels that lead to pulmonary disease in individuals homozygous for the Z
mutation (PiZZ) are not from a lack of synthesis (except in null/null patients)
but from a disruption of its processing and secretion by hepatocytes. AAT is
normally secreted in monomeric form, but the mutant AAT protein (Z-AAT)
synthesized by PiZZ individuals contains a single point mutation that results
in low secretion, accumulation and polymer formation in hepatocytes leading to
liver disease. Lung disease is frequently treated with AAT replacement therapy,
and fewer than 10,000 patients are on replacement or *augmentation* therapy in
the U.S. (Stoller et al, 2012). However, augmentation therapy does nothing to
treat liver disease, and no specific therapy is available for AATD-associated
liver disease.
In clinical practice, over 90% of AAT deficiency is due to the PiZZ genotype
(DeSerres et al, 2012). PiZZ adult patients may initially present with clinical
signs of pulmonary disease such as dyspnea, cough, chronic bronchitis, or they
may initially present with signs of liver disease such as elevated
transaminases or bilirubin, hepatitis, or cirrhosis (American Thoracic
Society/European Respiratory Society 2003). Pediatric patients typically
present with clinical symptoms of liver disease, which may include asymptomatic
chronic hepatitis, failure to thrive, poor feeding or hepatomegaly and
splenomegaly. However, disease natural history in both pediatric and adult
patients is variable.
A 2018 publication by Clark et al., examined 94 PiZZ adults using liver biopsy
and various other noninvasive measures of liver disease (e.g. transient
elastography, FIB-4). In this cohort, the prevalence of clinically significant
liver disease (>=F2) was 35.1%. The presence of accumulated Z-AAT globules,
portal inflammation and hepatocellular degeneration were associated with
clinically significant fibrosis. Similarly, accumulation of Z-AAT globules,
portal inflammation and hepatocellular degeneration are seen on histologic
evaluation of the PiZ mouse model liver.
Study objective
Primary Objective:
• To select a single dose for use in later stage development based on a
combined evaluation of safety and pharmacodynamic effects of ARO-AAT
Study design
A multi-center, multi-dose placebo-controlled Phase 2 study will be conducted
to evaluate the safety, efficacy and tolerability of the investigational
product, AROAAT, administered subcutaneously to patients with AATD.
Intervention
The study will test three dose levels compared to placebo. Patients who have
signed an IRB/EC approved informed consent and have met all the protocol
eligibility criteria during Screening
will be assigned to one of three cohorts and be randomized 2:1 (active:
placebo) within each
cohort. The three cohorts of the study are as follows:
• Cohort 1: 25 mg dose of ARO-AAT or placebo
• Cohort 2: 100 mg dose of ARO-AAT or placebo
• Cohort 3: 200 mg dose of ARO-AAT or placebo
Within each cohort, requirements for biopsies, dosing schedules, and SOA will
be determined based on the patient*s fibrosis score during Screening.
Patients with no evidence of fibrosis
Patients who have a documented biopsy showing no evidence of fibrosis within 1
year of the Screening visit will not require liver biopsy at any point during
the study. Patients without fibrosis at screening will receive two doses of
ARO-AAT or placebo on Day 1 and Week 4, as per the Schedule of Assessments.
Following their Week 4 dose, these patients remain in the study with regular
visits per the SOA until Week 64.
Patients with evidence of fibrosis
Patients who have a pre-dose biopsy showing evidence of fibrosis (without
definitive cirrhosis) during Screening will have post-dose biopsy performed at
Week 48. If a patient is beyond Week 48 at the time of IRB/EC approval of
Protocol v4.0, then the post-dose biopsy will occur
at Week 72 or 96. The study will end when the last patient with fibrosis
reaches Week 48 visit. Patients with evidence of fibrosis at Screening will
receive a dose on Day 1, Week 4, and Week 16, then every 12 weeks for up to 15
doses total.
Study burden and risks
See also E9 and E9a
Liver biopsies are the greatest burden on the participants. However, the
effectiveness of the study drug cannot be demonstrated without these liver
biopsies.
There is also a risk of a decrease in lung function, which may require
augmentation therapy. The sponsor has therefore taken a number of risk
mitigation measures as described in the reply letter of 14 August 2019 to the
CCMO.
225 South Lake Ave., Suite 1050
Passadena 91101
US
225 South Lake Ave., Suite 1050
Passadena 91101
US
Listed location countries
Age
Inclusion criteria
1. Male or non-nursing female patients 18-75 years of age, inclusive, at the
time of
Screening with previous diagnosis of PiZZ genotype Alpha-1 Antitrypsin
Deficiency.
PiZZ diagnosis from source verifiable medical records is permitted. Otherwise,
patients
must undergo PiZZ confirmatory testing at Screening. PiMZ or PiSZ genotypes are
not
permitted.
2. Able and willing to provide written informed consent prior to the
performance of any
study specific procedures.
3. Liver biopsy indicating a liver fibrosis score less than F4 based on local
pathologist read.
a. A patient with no fibrosis may participate based in a previous biopsy
conducted
within one year if a source verifiable medical record specifies no evidence of
fibrosis.
4. A 12-lead ECG at Screening that, in the opinion of the Investigator, has no
new acute
abnormalities (e.g., new onset atrial fibrillation) that compromise patient*s
safety in this
study. Stable disease (e.g., stable atrial fibrillation) is acceptable.
5. Non-smoker (defined as does not smoke cigarettes daily for at least 12
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. Patients may be on
nicotine
replacement (patch or gum). e-cigarettes (vapor) is not permitted. A positive
urine
cotinine result due to nicotine replacement is acceptable for enrollment at the
discretion
of the Investigator.
6. Use highly effective contraception during the study and for 3 months
following the last
dose of ARO-AAT. Males must not donate sperm for at least 3 months post last
dose of
study treatment. Females of childbearing potential must have a negative urine
pregnancy
test at Screening and on Day 1 pre-dose. Females not of childbearing potential
must be
post-menopausal (defined as cessation of regular menstrual periods for at least
12 months
without an alternative medical cause), confirmed by follicle-stimulating
hormone (FSH)
consistent with post-menopausal state based on lab reference ranges.
* Using twice the normal protection of birth control by using a condom AND one
other
form of either birth control pills (The Pill), depot or injectable birth
control, IUD
(Intrauterine Device), birth Control Patch (e.g., Ortho Evra), NuvaRing®, OR
Surgical sterilization as a single form of birth control: i.e., tubal ligation,
hysterectomy, bilateral oophorectomy, vasectomy or equivalently effective
surgical
form of birth control, is acceptable.
* True abstinence for the duration of the study and 12 weeks after the dose of
AROAAT
is acceptable only when in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (calendar, symptothermal, post-ovulation methods),
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea
methods are not considered *true* abstinence and are not acceptable methods of
contraception.
* All laboratory tests used as inclusion criteria may be repeated once and the
repeat value may
be used for inclusion purposes.
Exclusion criteria
1. INR >= 1.2 at Screening (one retest permitted). If based on opinion of
Investigator and/or
prescribing physician patient is appropriate for anticoagulant holiday, patient
may stop
taking anticoagulant for an appropriate washout period and if indicated a
repeat INR
within < 1.2 would be acceptable. Vitamin K may be used for reversal. If INR is
not
indicated (direct thrombin inhibitors or Xa inhibitors) then appropriate
washout period
alone may be acceptable. (Note: Anti-platelet agents, aspirin, clopidogrel or
NSAIDS are
acceptable but must be held 7 days before and 7 days after liver biopsy)
2. Platelet count < 150 x 109/L at Screening (one retest permitted)
3. ALT and AST levels > 250 U/L at Screening (one retest permitted)
4. eGFR < 60ml/min/1.73m2 at Screening (one retest permitted)
5. FEV1 <65% of predicted (preferentially post-bronchodilatory reading) at
Screening (one
retest permitted)
6. Recent (last 3 months) pneumonia or lower respiratory infection (which must
be
verifiable from the medical record). Patient reported infection is not
sufficient to meet
this criterion.
7. Unavoidable exposure to inhaled environmental toxins that in the clinical
judgement of
the Investigator could impair pulmonary function significantly over the course
of the
study.
8. Human immunodeficiency virus infection, as shown by the presence of anti-HIV
antibody (sero-positive)
9. Seropositive for HBV (HBsAg positive at Screening) or HCV (detectable HCV
RNA at
Screening). Cured HCV (positive antibody test without detectable HCV RNA is
acceptable).
10. Uncontrolled hypertension (Systolic BP > 170 and diastolic BP >100 mmHg at
Screening). Patients may rescreen once BP is successfully controlled.
11. A history of torsades de pointes, ventricular rhythm disturbances (e.g.,
ventricular
tachycardia or fibrillation), untreated heart block (excluding first-degree
block, being PR
interval prolongation only), congenital long QT syndrome or new acute ST segment
elevation or depression or new acute Q wave on ECG. Stable atrial dysrhythmias
(e.g.,
stable atrial fibrillation) are acceptable.
12. Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial
infarction, severe cardiovascular disease (ejection fraction < 20%, transient
ischemic
attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to
Screening
13. History of malignancy within the last 1 year except for adequately treated
basal cell
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ
cervical
cancer. Patients with other curatively treated malignancies who have no
evidence of
metastatic disease and >1-year disease-free interval may be entered following
approval
by the Medical Monitor
14. History of major surgery within the prior 1 month prior to Screening
15. Regular use of alcohol within one month prior to the Screening visit (i.e.,
more than 14
units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of
40%
alcohol])
16. Use of illicit drugs (such as cocaine, phencyclidine [PCP]) within 1 year
prior to the
Screening visit or positive urine drug screen at Screening (a urine drug screen
positive for
benzodiazepines, opioids or THC is acceptable for enrollment at the discretion
of the
Investigator). The patient may still be eligible at discretion of Medical
Monitor and
Investigator if positive urine drug screen is due to a prescription medication.
17. Use of an investigational agent or device within 30 days prior to dosing or
current
participation in an investigational study involving a therapeutic intervention.
Patients
who have participated in the ARCAAT-1001 study or observational studies are
acceptable. Patients previously enrolled in but no longer enrolled in gene
therapy studies
are acceptable. Patients receiving AAT augmentation therapy as part of a
post-marketing
study or other access program for approved therapies are acceptable.
18. Blood donation (>=500 mL) within 7 days prior to study treatment
administration.
19. Any concomitant medical or psychiatric condition or social situation that
would make it
difficult to comply with protocol requirements or put the patient at additional
safety risk.
Patients with NASH, NAFLD, metabolic syndrome, well controlled diabetes mellitus
(even if on insulin) or hemochromatosis are acceptable if disease is stable and
does not
pose a significant threat to patient participation. Patients enrolled with NASH
should
have no plans to undergo bariatric surgery or have initiated or plan to initiate
pharmaceutical therapy for NASH (such as Vitamin E or pioglitazone) during the
course
of the study.
20. A history of thromboembolic disease (including deep vein thrombosis or
pulmonary
embolism), myocardial infarction, stroke within three (3) months of screening.
21. Any other condition or finding of clinical relevance at Screening, that in
the opinion of
the Investigator would render the patient unsuitable for enrollment or could
interfere with
participating in and completing the study.
22. Previous diagnosis of definitive liver cirrhosis based on biopsy or
complications of
cirrhosis (e.g., varices, ascites, hepatic encephalopathy) based on source
verifiable
medical record.
23. Patients who have undergone lung or liver transplant for AATD are excluded.
Note: Sponsor Medical Monitor has the option to exclude the enrollment of a
patient if, based
upon the patient*s medical history or Screening results, it is felt that a
patient*s safety may be at
risk.
* All laboratory tests used as exclusion criteria may be repeated once and the
repeat value may be used for exclusion purposes.
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 | EUCTR2018-003385-14-NL |
| CCMO | NL69848.000.19 |