Double-blinded part:The primary objectives of the study are as follows:• To investigate the safety and tolerability of 28 days of oral doses of SAR443060 in subjects with ALS.The secondary objectives of the study are as follows: • To characterize…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability:
AEs, clinical laboratory evaluations (hematology, clinical chemistry,
urinalysis), 12 lead ECGs, vital sign measurements, and physical examinations.
Responses obtained from the Columbia-Suicide Severity Rating Scale (C-SSRS)
will also be used to derive a category for suicidality according to the
Columbia Classification of Suicide Assessment (C-CASA).
Secondary outcome
Pharmacokinetics:
Blood and CSF will be collected for the analysis of plasma and CSF
concentrations of SAR443060. The following endpoints may be determined for
SAR443060 in plasma following each treatment. They will be derived by
noncompartmental analysis of the plasma concentration-time data:
• Cmax
• AUC from time zero to 12 hours (AUC0-12h), AUC from time zero to the last
measured concentration above the limit of quantification (AUC0-last), and/or
AUC from time zero extrapolated to infinity (AUC0-*), as appropriate
• Tmax
• Terminal disposition rate constant (*z) with the respective t1/2
• Other parameters, including oral volume of distribution and oral clearance,
may be determined as appropriate.
• CSF-to-plasma ratios on Days 29 and 71
These parameters may also be determined for metabolites if appropriate.
Pharmacodynamics:
PD of SAR443060 is measured by RIPK1 pS166 in PBMCs from blood. Exploratory
biomarker assays for cytokines, lipids, and metabolomics may be explored in
PBMCs, plasma, urine, and CSF.
Exploratory Clinical:
• Clinical changes in the ALSFRS-R
Background summary
SAR443060 is a new experimental drug that is being developed as part of the
treatment for ALS. The purpose of this study is to investigate how safe and
tolerable the new experimental drug SAR443060 is, what its effects are when it
is administered to patients with ALS and how the new experimental drug is
absorbed and processed by the body.
Receptor-interacting protein kinase 1 (RIP1) is a serine/threonine kinase
involved in the regulation of inflammation and cell death. In response to tumor
necrosis factor (TNF)-alpha signaling, RIP1 is activated, and in turn regulates
activation of downstream targets, including RIPK3, mixed-lineage kinase
domain-like (MLKL) and NF-kB. This signaling cascade initiates a number of
cellular processes, including cytokine release, microglial activation, and
necroptosis, a regulated form of cell death.
RIPK1 inhibition has been shown to reduce necroptotic cell death in several
animal models, including a model of motor neuron cell death related to
amyotrophic lateral sclerosis. Immunoblotting analysis of human ALS spinal cord
samples has shown increased levels of RIPK1 to be present.
SAR443060 is a novel, potent and selective RIP1 kinase inhibitor that has
favorable pharmacokinetic properties and good penetration across the blood
brain barrier, allowing target inhibition in the central nervous system. As
such, it is a potential therapeutic candidate for neurodegenerative diseases
such as amyotrophic lateral sclerosis (ALS).
Study objective
Double-blinded part:
The primary objectives of the study are as follows:
• To investigate the safety and tolerability of 28 days of oral doses of
SAR443060 in subjects with ALS.
The secondary objectives of the study are as follows:
• To characterize the PK in plasma and CSF following oral doses of SAR443060.
• To characterize the PD and target engagement of SAR443060 using an assay for
RIPK1 pS166 in PBMCs.
The exploratory objectives of the study are as follows:
• To measure changes in cytokines (such as monocyte chemoattractant protein 1
[MCP-1]), neurofilament light chain (NF L), and other inflammatory and
neurodegenerative biomarkers in blood, urine, and CSF.
• To explore clinical changes in the revised Amyotrophic Lateral Sclerosis
Functional Rating Scale-Revised (ALSFRS R).
Open Label Extension:
The primary objective of the OLE is as follows:
• To investigate the safety and tolerability of up to 12 months of oral doses
of SAR443060 in subjects with ALS
The exploratory objectives of the OLE are as follows:
• To characterize the PD and target engagement of SAR443060 using an assay for
RIPK1 pS166 in PBMCs
• To measure changes in cytokines (such as MCP-1), NF-L, p75ECD and other
target- and disease-related (e.g., inflammatory and neurodegenerative)
biomarkers in blood, CSF, and urine
• To explore clinical changes in the ALSFRS-R
Study design
This is a (potentially multicenter) randomized, placebo-controlled,
double-blind, crossover design phase 1B study that will include up at least 16
and up to 26 subjects. There are two treatment periods. Subjects will be
randomized 1:1 to receive either active or placebo treatment for 28 days BID
for the first period and then cross over to the opposite treatment assignment
for 28 days BID for the second period. There will be a 14-day washout period
between the 2 treatment periods.
Subjects will be admitted to the research unit on days 1, 28, 42, and 70.
Subjects will be confined to the unit for up to 3 days/2 nights at each
admission. In between the subjects will visit the research unit once per week
and will administer the study medication at home.
Open-Label Extension:
In the Netherlands, subjects who complete the double-blind study period through
the FFU visit may be eligible to enter an OLE and receive dosing with SAR443060
for up to an additional 12 months.
Cumulative data from the ongoing safety review of 8 ALS subjects in the
double-blind part of this study and data from the completed 3-month nonclinical
toxicity support the initiation of the OLE.
Subjects who complete the double-blind study period more than 14 days before
enrolling in the OLE will undergo baseline safety assessments to reassess
eligibility prior to receiving SAR443060 in the OLE.
Intervention
SAR443060 (RIPK1 kinase inhibitor)
Study burden and risks
The burden for the participants includes the time investment for the briefing,
screening, the occasions, and the follow-up visit. The occasion will consist of
12 days and 8 nights of confinement to the research units. Additionally the
participants will visit the research unit 10 times for approximately 4 hour
visits.
Blood, urine, CSF (3x) and DNA (1x) samples will be collected during the
screening, the occasions and the follow-up visits. Participants will be
requested to complete several questionnaires concerning their mental, physical
and neurological status and will undergo physical examinations. Life-style
restrictions concerning prescription medication, smoking, alcohol intake,
strenuous activity and contraception will apply.
The risks of participation are primarily those associated with adverse
reactions to the study drug SAR443060 , which has been evaluated in over 57
healthy subjects (up to 400mg BID) and in 10 patients with ALS or Alzheimer's,
and in nonclinical studies to characterize its safety profile. There have been
no identified risks or adverse drug reactions to date from the evaluation of
SAR443060 in healthy volunteers in Study DNLI-D-0001. Preclinical studies
indicate that the immune system, red blood cells, platelets and skin are
potential target organs/cell populations in human subjects participating in
clinical studies. In nonclinical studies, these effects were observed in
monkeys at relatively high exposures (1000mg/kg/d) that exceed those to be
tested in human subjects (400mg/d) and are expected to be reversible and able
to be monitored in a clinical setting. In the ongoing 3-month nonclinical
toxicity study in cynomolgus monkeys, individual animals administered 40 and
200 mg/kg/d had moderate to severe reductions in both red cell mass and
platelets. These are also expected to be reversible and able to be monitored in
a clinical setting. The Phase 1b dose is 50 mg BID, and at this dose level, the
anticipated exposure is expected to provide at least a 6-fold margin to
potential risks for thrombocytopenia and anemia in the clinic.
Avenue Pierre Brossolette 1
Chilly Mazarin 91380
FR
Avenue Pierre Brossolette 1
Chilly Mazarin 91380
FR
Listed location countries
Age
Inclusion criteria
Double-blinded part:
6) Diagnosis of laboratory-supported probable, probable, or definite (sporadic
or familial) ALS according to the El Escorial World Federation of Neurology
revised research diagnostic criteria (Ludolph et al. 2015;)
7) Less than 3 years since symptom onset
8) Forced vital capacity (FVC) >50% predicted measured within 30 days of
screening
9) If subject is taking approved ALS treatments (riluzole and/or edaravone),
doses must be stable for >=2 months prior to screening and subject is expected
to stay on a stable regimen throughout the study.
11) Subjects must be able to swallow the study capsules.
Open Label Extension:
1) Successful completion of both periods of the double-blind, crossover part of
this study within 12 months of anticipated first dose of OLE
2) Body weight of at least 45 kg
6) Stable prescription medications including riluzole and/or edaravone for >= 1
month. New prescription medications or changes to existing medications during
this trial period are allowed with investigator discretion.
7) Subjects must either be able to swallow the study capsules (thickening
agents to assist in swallowing are permitted) or have a G-tube in place and are
able to administer study drug through G-tube either independently or with help
via a caregiver.
Exclusion criteria
Double-blinded part:
1) Unstable or poorly controlled comorbid disease process of any organ system
currently requiring active treatment or likely to require treatment adjustment
during the study, as assessed by the investigator or Sponsor
2) History of a clinically significant non-ALS neurologic disorder (other than
frontal temporal lobe dementia), including, but not limited to, muscular
dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, AD,
Parkinson*s disease, Lewy body dementia, vascular dementia, Huntington*s
disease, epilepsy, stroke, multiple sclerosis, brain tumor, or brain infection
or abscess
3) History of head trauma resulting in loss of consciousness or clinically
significant concussion within 1 year before screening, or any head trauma that
resulted in permanent neurologic deficit
4) Clinical laboratory test values outside the normal range at screening,
unless assessed by the investigator and CRO medical monitor as clinically
acceptable or as specified in other exclusion criteria below
21) Use of or intention to use any prohibited prescription or over-the-counter
(OTC) medication (including vitamin/mineral supplements and herbal medicines
such as St. John*s Wort) that is a moderate to strong CYP3A inducer or
inhibitor within 7 days or 5 half-lives (whichever is longer) of the first dose
administration or anticipated use through the follow-up visit. Note: other
medications are permitted if subject is on a stable regimen for at least 30
days before first dose administration. Nonsystemic medications (e.g., topical
medications unlikely to achieve meaningful plasma exposure), subcutaneous
lidocaine, paracetamol, and caffeine for treatment of post-LP headache, and
medications needed to treat AEs and medical emergencies are permitted. Other
medication may also be permitted if jointly agreed to by both investigator and
Sponsor.
22) Use of anticoagulation, daily aspirin >100 mg, or anti-platelet medications
within 5 half-lives before the first administration of study drug or
anticipated need for these medications through the final follow-up visit. Note:
the use of OTC nonsteroidal anti-inflammatory drugs (NSAIDs) at doses specified
in the OTC drug label for less than 3 consecutive days is permitted.
23) History of bleeding disorders included but not limited to thrombocytopenia
(defined as platelets <140,000/µL), von Willebrand disease, hemophilia, and
other factor deficiencies
Open Label Extension:
1) Presence of laboratory abnormalities, physical examination findings, or AEs
determined to be clinically significant by the investigator from the
double-blind part of the study that have not resolved by the FFU visit
2) For subjects who completed the double-blind part of the study >14 days prior
to start of OLE, presence of clinical laboratory test values outside the normal
range at OLE screening, significant physical examination abnormalities, or
persistent AEs from the double-blind part of the study, unless assessed by the
investigator as clinically acceptable
3) New diagnosis of a clinically significant non-ALS neurologic disorder (other
than frontal temporal lobe dementia), including, but not limited to: muscular
dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, AD,
Parkinson*s disease, Lewy body dementia, vascular dementia, Huntington*s
disease, epilepsy, stroke, multiple sclerosis, brain tumor, or brain infection
or abscess
4) Any diagnosis of new onset disease that was exclusionary in the randomized,
double-blind part of the study. New onset spinal cord disease or other lumbar
region abnormalities that may interfere with lumbar puncture (e.g., skin
infection, structural abnormalities) will be allowed at the investigator*s
discretion
10) Participation in any other investigational drug trial or use of
investigational drug within 7 days or 5 half-lives (whichever is longer) prior
to OLE initiation, or planned use of investigational drugs during the OLE
12) Use of or intention to use any prohibited prescription or over-the-counter
(OTC) medication (including vitamin/mineral supplements and herbal medicines
such as St. John*s Wort) that is a moderate to strong CYP3A4/5 inducer or
inhibitor within 7 days or 5 half-lives (whichever is longer) of the first dose
administration or anticipated use through the follow-up visit. Note: other
medications are permitted if subject is on a stable regimen for at least 30
days before first dose administration. Nonsystemic medications (e.g., topical
medications unlikely to achieve meaningful plasma exposure), subcutaneous
lidocaine, paracetamol, and caffeine for treatment of post-LP headache, and
medications needed to treat AEs and medical emergencies are permitted. Other
medication may also be permitted if jointly agreed to by both investigator and
Sponsor.
13) Use of anticoagulation, daily aspirin >100 mg, or anti-platelet medications
within 5 half-lives before the first administration of study drug or
anticipated need for these medications through the final follow-up visit. Note:
the use of OTC NSAIDs at doses specified in the OTC drug label for less than 3
consecutive days is permitted.
14) History of bleeding disorders included but not limited to thrombocytopenia
(defined as platelets <140,000/µL), von Willebrand disease, hemophilia, and
other factor deficiencies
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 | EUCTR2018-003623-11-NL |
| ClinicalTrials.gov | NCT03757351 |
| CCMO | NL67676.056.18 |