Key PrimaryPart A• To determine the efficacy of acoramidis (AG10) in the treatment of subjects with symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM) by evaluating the difference between the acoramidis and placebo groups in the change from…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Key Primary
Part A
• Change from baseline to Month 12 of treatment in distance walked during the
6MWT
Part B
• A hierarchical combination of All-Cause mortality, CV-related
hospitalization, and change from baseline in 6MWT over a 30-month period
Secondary outcome
Key Secondary
Part A
• Change from baseline to Month 12 of treatment in Kansas City Cardiomyopathy
Questionnaire Overall Score (KCCQ-OS)
Part B
• Change from baseline to Month 30 of treatment in distance walked during the
6MWT
• Change from baseline to Month 30 of treatment in KCCQ-OS
Secondary
Part A
• Safety parameters to be assessed: treatment- emergent serious adverse events
(SAEs) and adverse events (AEs), AEs leading to treatment discontinuation,
abnormal physical exam findings of clinical relevance, abnormal vital signs of
clinical relevance, abnormal ECG parameters of clinical relevance, and changes
in clinical safety laboratory parameters of potential clinical concern
• Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR
stabilization) at Month 12
• TTR stabilization as measured in established ex-vivo assays (fluorescent
probe exclusion [FPE] and Western blot) at Month 12 in the PK-PD substudy
Part B:
• A hierarchical combination of All-Cause mortality and CV-related
hospitalization over a 30-month period
• All-Cause Mortality by Month 30
• Cumulative frequency of CV-related hospitalization by Month 30
• CV mortality by Month 30
• Safety parameters: treatment-emergent SAEs and AEs, AEs leading to treatment
discontinuation, abnormal physical exam findings of clinical relevance,
abnormal vital signs of clinical relevance, abnormal ECG parameters of clinical
relevance, and changes in clinical safety laboratory parameters of potential
clinical concern
• Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR
stabilization) at Month 30
• TTR stabilization measured in established ex-vivo assays (FPE and Western
blot) in the PK-PD substudy
Background summary
Background
Acoramidis is a potent and selective stabilizer of transthyretin (TTR) that is
being developed by Eidos Therapeutics, Inc. for the treatment of TTR
amyloidosis (ATTR), a progressive, fatal disease in which deposition of amyloid
derived from either mutant or wild-type TTR causes severe organ damage and
dysfunction.
Clinically, ATTR presents as either a cardiomyopathy (ATTR-CM), an
infiltrative, restrictive cardiomyopathy characterized by progressive left and
right heart failure, or as a peripheral polyneuropathy (ATTR-PN), a
length-dependent neurodegenerative disease affecting sensorimotor and autonomic
functions.
Familial ATTR-CM (ATTRm-CM), or FAC, and familial ATTR-PN or familial amyloid
polyneuropathy (FAP), are driven by pathogenic point mutations in the TTR gene;
over 140 such mutations have been described. In addition, older individuals may
develop ATTR derived from wild-type TTR (ATTRwt, formerly called Senile
Systemic Amyloidosis [SSA]). In ATTRwt, the major organ involved is the heart
(ATTRwt-CM), although carpal tunnel syndrome and tendon involvement are also
common.
Destabilization, misfolding, and aggregation of TTR lead to deposition of TTR
amyloid and tissue damage. Several small molecules have been shown to bind to
and stabilize TTR, potentially preventing the initiating event in
amyloidogenesis. Eidos* therapeutic hypothesis is that a highly effective TTR
stabilizer will halt or slow ATTR disease progression in ATTR-CM (both mutant
ATTR [ATTRm] and ATTRwt) and ATTR-PN.
Acoramidis is a potent, highly selective, small molecule TTR stabilizer. It has
demonstrated ability to stabilize TTR in vivo following oral dosing to nonhuman
mammals, in healthy volunteers and in patients with ATTR-CM.
Study objective
Key Primary
Part A
• To determine the efficacy of acoramidis (AG10) in the treatment of subjects
with symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM) by evaluating
the difference between the acoramidis and placebo groups in the change from
baseline in the Six-Minute Walk test (6MWT)
Part B
• To determine the efficacy of acoramidis in the treatment of subjects with
symptomatic ATTR-CM by evaluating the difference between the acoramidis and
placebo groups in the combined endpoint of All-Cause Mortality and the
cumulative frequency of cardiovascular (CV) related hospitalization, and change
from baseline in 6MWT
Key Secondary
Part A
To evaluate the effects of acoramidis on quality of life (QoL) in subjects with
symptomatic ATTR-CM
Part B
• To evaluate the effects of acoramidis on 6MWT
• To evaluate the effects of acoramidis on health-related QoL as measured by a
heart failure (HF)-specific instrument (KCCQ) in subjects with symptomatic
ATTR-CM
Secondary
Part A
• To assess safety and tolerability of acoramidis in subjects with symptomatic
ATTR-CM
• To assess the pharmacodynamic (PD) effects of acoramidis as assessed by
o circulating prealbumin (transthyretin, TTR) concentration as an in vivo
biomarker of stabilization and
o established ex vivo assays of TTR stabilization
Part B:
• To determine the efficacy of acoramidis treatment as measured by the
components of the primary endpoint
• To determine the efficacy of acoramidis in reducing CV mortality in subjects
with symptomatic ATTR-CM
• To evaluate the safety and tolerability of acoramidis administered for 30
months in subjects with symptomatic ATTR-CM
• To assess the pharmacodynamic (PD) effects of acoramidis as assessed by
o circulating prealbumin (transthyretin, TTR) concentration as an in vivo
biomarker of stabilization and
o established ex vivo assays of TTR stabilization
Exploratory
Part A and B:
• To evaluate the effects of acoramidis on circulating biomarkers of myocardial
wall stress and microvascular ischemia in subjects with symptomatic ATTR-CM
• To characterize PK of acoramidis and its predominant metabolite administered
orally twice daily (BID) in subjects with symptomatic ATTR-CM
• To describe the population PK (PopPK) of acoramidis in subjects with ATTR-CM
• To describe the PD properties and the pharmacokinetic (PK)-PD relationship of
acoramidis as assessed by circulating prealbumin (transthyretin, TTR)
concentration as an in vivo biomarker of stabilization and by established ex
vivo assays of TTR stabilization, and correlated with acoramidis PK
• To evaluate the effects of acoramidis on health-related QoL as measured by
EuroQol Health Outcomes Assessment tool (EQ-5D-5L) in subjects with symptomatic
ATTR-CM
• To assess the ability of acoramidis to bind and stabilize a diverse array of
pathogenic and likely pathogenic variant TTR tetrameric species, representing
amino acid substitutions located throughout the sequence of TTR that are
responsible for a spectrum of clinical presentations, from sera and/or plasma
of subjects with ATTR-CM
Study design
Study Design and Investigational Plan
This prospective, Phase 3, randomized, multicenter, parallel-group study will
evaluate the efficacy and safety of acoramidis in symptomatic subjects compared
to placebo, administered on a background of stable heart failure therapy.
Screening and randomization will be followed by a total of 30 months of
blinded, placebo-controlled treatment. At the end of 12 months of treatment
(Part A) efficacy of acoramidis will be assessed through analyses of the
functional (6MWT) and health-related QoL (as measured by HF-specific instrument
KCCQ) endpoints. At the end of 30 months of treatment (Part B), efficacy of
acoramidis will be further assessed through analysis of All-cause mortality,
CV-related hospitalizations, and change from baseline in 6MWT.
Subjects are not allowed to be treated with any ATTR-CM specific therapy during
the first 12 months of the study. If a subject chooses treatment with ATTR-CM
specific therapy, they will be asked to complete an early termination visit
prior to discontinuation/withdrawal.
If, during participation in the study, tafamidis becomes available for the
indication of ATTR-CM and subjects have access to it, subjects will be
permitted to initiate therapy with tafamidis as a concomitant medication if
they have completed at least 12 months of blinded study therapy. Currently,
tafamidis is approved for the treatment of ATTR-CM in some regions. Subjects
initiating therapy with tafamidis indicated for ATTR-CM must have completed the
Month 12 visit. If a subject plans to initiate therapy with tafamidis more than
7 days after the Month 12 visit or a later scheduled visit, that subject should
have an unscheduled visit with study assessments prior to initiation of the
concomitant therapy. No other approved or investigational treatments, or
therapies used off-label or as nonprescription supplements for the treatment of
ATTR-CM will be permitted at any time during the study.
If a subject chooses to discontinue investigational medicinal product (IMP),
discontinue or withdraw from the trial at any time, they will be asked to
complete an early termination visit and associated procedures. If a subject
chooses to initiate treatment with another therapy, including tafamidis in the
first 12 months of the study, they will be asked to complete an ET visit and
associated procedures prior to discontinuation/withdrawal. Subjects will
continue monthly telephone contact up to Month 30. All participating subjects
will be asked to consent to determination of vital status (alive, death, heart
transplant, receiving cardiac mechanical assist device [CMAD]) at Month 30,
either via direct contact or through public records, regardless of
discontinuation or withdrawal status. Unless precluded by governing law or
regulation, consent for determination of vital status through public records
may not be withdrawn.
All subjects who complete 30 months of blinded study therapy and the final
assessments of the double-blind treatment period (Month 30 visit) may be
eligible to participate in an Open Label Extension (OLE) study (Study AG10-304,
a separate protocol) of long-term acoramidis treatment.
Eligible subjects will be randomized in a 2:1 ratio to acoramidis HCl 800 mg or
matching placebo administered orally BID. Subjects will be stratified at
randomization based on whether they have wild-type ATTR-CM (ATTRwt CM) or
mutant ATTR-CM (ATTRm-CM) with a target of 20% of subjects with ATTRm-CM.
Subjects will also be stratified according to NT-proBNP level (<= 3000 vs > 3000
pg/mL) and renal function defined by eGFR (>= 45 vs < 45 mL/min/1.73 m2) at
Screening. Samples for plasma PK and serum/plasma PD will be collected in the
PK-PD substudy.
Information on AEs and concomitant medications will be collected throughout the
study. The safety and conduct of the study will be monitored by an independent
Data Monitoring Committee (DMC).
Intervention
Test Product, Dosage, and Mode of Administration:
Day 1 through end of Double-blind Treatment: 800 mg acoramidis hydrochloride
(HCl) or matching placebo, BID, by mouth
Study burden and risks
See ICF section 7.0
1800 Owens Street Suite C-1200
San Francisco CA 94158
US
1800 Owens Street Suite C-1200
San Francisco CA 94158
US
Listed location countries
Age
Inclusion criteria
To be eligible to participate in the study, subjects must meet all the
following criteria:
1. Have the ability to understand and sign a written informed consent form,
which must be obtained prior to initiation of study procedures.
2. Male or female >= 18 to <= 90 years of age at time of randomization.
3. Have an established diagnosis of ATTR-CM with either wild-type TTR or a
variant TTR genotype (confirmed by genotyping) based on either:
1. endomyocardial biopsy with confirmatory TTR amyloid typing by either mass
spectrometry, immunoelectron microscopy, or immunohistochemistry; or
2. positive technetium-99m (99mTc)-pyrophosphate (PYP) or bisphosphonate (DPD
or HMDP/HDP) scan, combined with accepted laboratory criteria excluding a
diagnosis of AL amyloidosis (based on both immunofixation electrophoresis (IFE)
of serum and urine, and serum free light chain (sFLC) analysis).
Subjects with concurrent monoclonal gammopathy of undetermined significance
(MGUS) may require confirmation of the diagnosis of ATTR-CM by tissue biopsy
with confirmatory TTR amyloid typing by either mass spectrometry,
immunoelectron microscopy, or immunohistochemistry.
4. Have
a. a history of heart failure evidenced by at least one prior hospitalization
for heart failure or
b. clinical evidence of heart failure without prior heart failure
hospitalization manifested by signs or symptoms of volume overload or elevated
intracardiac pressures (e.g., elevated jugular venous pressure, shortness of
breath or signs of pulmonary congestion on x-ray or auscultation, or peripheral
edema) or
c. heart failure symptoms that required or require ongoing treatment with a
diuretic.
5. Have NYHA Class I-III symptoms due to ATTR-CM.
6. Female subjects of childbearing potential who engage in heterosexual
intercourse must agree to use a highly effective method of contraception
beginning with randomization and continuing for 30 days after the last dose of
IMP. A male subject who is sexually active with a female of childbearing
potential and has not had a vasectomy must agree to use a double-barrier method
of birth control.
7. Subjects taking cardiovascular medical therapy, with the exception of
diuretic dosing, must be on stable doses (defined as no greater than 50% dose
adjustment and no categorical changes of medications) for at least 2 weeks
prior to Screening.
8. Have completed >= 150 m on the 6MWT on at least 2 tests > 24 hours to <= 3
weeks apart and prior to randomization. The distance walked must be within 15%
on two tests.
If one of the first two tests is not >= 150 m or the first two tests are not
within 15% of distance walked, a third test must be conducted <= 3 weeks of the
first test. If the third test is still not >= 150 m or within 15% of one of the
first two tests, the subject will not be eligible for participation.
9. Must have NT-proBNP levels >= 300 pg/mL at Screening.
10. Must have LV wall (interventricular septum or LV posterior wall) thickness
>= 12 mm as measured by transthoracic echocardiogram (ECHO) or cardiac magnetic
resonance (CMR) documented in medical history within 10 years of Screening or
at Screening ECHO or CMR.
Exclusion criteria
Subjects who meet any of the following criteria at the Screening visit will not
be eligible to participate in the study:
1. Acute myocardial infarction, acute coronary syndrome or coronary
revascularization within 90 days prior to Screening.
2. Stroke or transient ischemic attack (TIA) within 90 days prior to Screening.
3. Has hemodynamic instability at Screening or Randomization that, in the
judgment of the Investigator, would pose too great a risk for participation in
the study.
4. Is likely to undergo heart transplantation within a year of Screening.
5. Has confirmed diagnosis of light-chain (AL) amyloidosis.
6. Has abnormal liver function tests at Screening, defined as alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of
normal (ULN) or total bilirubin > 3 × ULN.
7. Has NT-proBNP levels >= 8500 pg/mL at Screening.
8. Has estimated glomerular filtration rate (eGFR) by modification of diet for
renal disease (MDRD) formula < 15 mL/min/1.73 m2 at Screening.
9. Known hypersensitivity to IMP (acoramidis or placebo), its metabolites, or
formulation excipients.
10. Treatment for ATTR-CM with tafamidis, with marketed drug products lacking a
labeled indication for ATTR-CM (e.g., diflunisal, doxycycline), or with natural
products or derivatives used as unproven therapies for ATTR-CM (e.g., green tea
extract, tauroursodeoxycholic acid [TUDCA]/ursodiol) within 14 days prior to
dosing; treatment with patisiran, inotersen, or other gene silencing agent:
within 90 days for patisiran, 180 days for inotersen, and 5 half-lives for any
other gene silencing agent, prior to dosing.
If, during participation in the study, subjects gain access to tafamidis, they
will be permitted to initiate therapy with tafamidis as a concomitant
medication if they have completed at least 12 months of blinded study therapy.
11. Requires treatment with calcium channel blockers with conduction system
effects (e.g., verapamil, diltiazem). The use of dihydropyridine calcium
channel blockers is allowed. The use of digitalis will only be allowed if
required for management of atrial fibrillation with rapid ventricular response.
12. Females who are pregnant or breastfeeding. Lactating females must agree to
discontinue nursing before IMP is administered. A negative urine pregnancy test
at Screening and at Randomization are required for female subjects of
childbearing potential.
13. In the judgment of the Investigator or Medical Monitor, has any clinically
important ongoing medical condition or laboratory abnormality or condition that
might jeopardize the subject*s safety, increase their risk from participation,
or interfere with the study.
14. Participation in another investigational clinical trial within 30 days
prior to dosing with potential residual effects that might confound the results
of this study. Participation in observational and/or registry studies should be
discussed with the Medical Monitor.
15. Has any condition that, in the opinion of the Investigator or Medical
Monitor, would preclude compliance with the study protocol such as a history of
substance abuse, alcoholism or a psychiatric condition.
Design
Recruitment
Medical products/devices used
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 | EUCTR2018-004280-32-NL |
| ClinicalTrials.gov | NCT03860935 |
| CCMO | NL70635.056.19 |