Evaluation of the Safety and Efficacy of AMX0035 (Phenylbutyrate and Ursodoxicoltaurine) in Patients with Progressive Supranuclear Palsy: A Phase 2b/3 Study
- Trial ID
- 2023-505893-14-00
- Protocol
- A35-009
- Sponsor
- Amylyx Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the impact of **AMX0035** compared to placebo on the disease progression rate in individuals with **Progressive Supranuclear Palsy** (PSP), as measured by the total Progressive Supranuclear Palsy Rating Scale (PSPRS). This is clinically relevant as it aims to determine the potential of AMX0035 in slowing the progression of PSP, a neurodegenerative disorder characterized by motor and cognitive impairments.
Secondary objectives include:
- Assessing the impact of AMX0035 compared to placebo on the disease progression rate as measured by the PSPRS.
- Evaluating the efficacy of AMX0035 compared to placebo on motor aspects of activities of daily living, as measured by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II.
- Evaluating the safety and tolerability of AMX0035 in participants with PSP.
Participants
The clinical trial involves a total of **641 participants** diagnosed with **Progressive Supranuclear Palsy**. The study population includes both male and female subjects, aged between **40 to 80 years**. Participants were selected based on specific criteria, including the ability to provide informed consent and a stable dosing regimen of anti-Parkinsonian drugs. The trial population is characterized by individuals who are able to walk independently or with minimal assistance and have a score of less than 40 on the total Progressive Supranuclear Palsy Rating Scale. Participants are required to reside outside skilled nursing or dementia care facilities, although residence in assisted living facilities is permitted. The study includes individuals who have experienced PSP symptoms for less than five years. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with scheduled visits and treatment requirements. The trial includes a vulnerable population, ensuring comprehensive monitoring and adherence to ethical standards.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **efficacy** of AMX0035 in individuals diagnosed with **Progressive Supranuclear Palsy**. This is a Phase 2b/3 study, employing a **randomized**, **double-blind**, and **controlled** methodology to ensure the reliability and validity of the results. Participants will be randomly assigned to receive either the investigational product, AMX0035, or a placebo that matches AMX0035 in appearance. The trial is expected to span approximately 104 weeks, with the primary endpoint being the change from baseline at Week 52 in the total Progressive Supranuclear Palsy Rating Scale (PSPRS) score.
The study will commence with an inclusion (screening) visit, where potential participants will be assessed against the inclusion criteria, such as age between 40 to 80 years, a score of ≥24 on the Mini Mental State Examination, and the ability to walk independently or with minimal assistance. Following successful screening, participants will be enrolled and begin the treatment phase. The trial will include regular follow-up visits to monitor the participants' health, adherence to the treatment regimen, and any adverse events. These visits will also involve laboratory tests, MRI scans, and assessments of the PSPRS score.
The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the long-term impact of the treatment. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial's design ensures that all participants, including their study partners, are willing and able to comply with the study's requirements, thereby maintaining the integrity of the data collected.
Treatment
The clinical trial involves the administration of **AMX0035**, an experimental medication formulated as a **powder**. This investigational product is a fixed-dose combination of two active chemical substances: **phenylbutyrate** and **ursodoxicoltaurine**. The medication is administered **orally**. The maximum daily dose is set at **8 grams**, with a total maximum dose of **5824 grams** over the course of the treatment period, which spans up to **104 weeks**. The trial aims to evaluate the safety and efficacy of AMX0035 in patients with Progressive Supranuclear Palsy. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
In addition to the experimental treatment, a **placebo** matching AMX0035 is utilized as a comparator in the study. The placebo is designed to mimic the appearance and administration route of the active treatment, ensuring blinding of participants and investigators. The placebo does not contain any active substances and serves as a control to assess the true efficacy of AMX0035. The use of a placebo is critical in determining the impact of the investigational drug on disease progression as measured by the Progressive Supranuclear Palsy Rating Scale (PSPRS).
Efficacy
The efficacy of AMX0035 in the treatment of **Progressive Supranuclear Palsy** will be assessed through a Phase 2b/3 clinical trial. The primary endpoint for evaluating efficacy is the change from baseline at Week 52 in the total Progressive Supranuclear Palsy Rating Scale (PSPRS) score. This endpoint is designed to meet evidentiary requirements both in the United States and internationally, with specific regional adaptations: a 10-item PSPRS for the USA and a 28-item PSPRS for other regions.
Secondary endpoints include the change from baseline at Week 52 in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II score, as well as the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). These measures will provide additional insights into the efficacy and safety profile of AMX0035.
The PSPRS and MDS-UPDRS are validated scales used to quantify disease progression and symptom severity in patients with Progressive Supranuclear Palsy. Efficacy assessments will be conducted at baseline and at Week 52, with data collection and analysis performed according to the trial protocol to ensure consistency and reliability of results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provides a signed informed consent form (ICF) and has the mental capability to understand the ICF. If participant is unable to sign the ICF, the ICF must be signed by a representative in accordance with local regulatory requirements.
- Is willing and able to comply with the scheduled visits, treatment schedule, laboratory tests, and other requirements of the study, including MRI scans.
- Participant’s study partner is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study. The participant’s study partner is defined as a caregiver, family member, social worker, or friend who has frequent contact with the participant (approximately 10 hours per week), will accompany the participant to study visits to provide information as to the participant’s functional abilities, and will speak the local language fluently to ensure comprehension of informed consent and informant-based assessments of the participant.
- Is male or female 40 to 80 years of age, inclusive.
- Participant must reside outside a skilled nursing facility or dementia care facility at the time of Screening and admission to such a facility must not be planned. Residence in an assisted living facility is allowed.
- Meets the following criteria for possible or probable PSP (Steele-Richardson-Olszewski Syndrome) according to MDS 2017 criteria (Höglinger 2017): a. Gradually progressive disorder, with age at disease onset ≥ 40 years. b. Either or both of the following two criteria are met: i. Vertical supranuclear gaze palsy OR slow velocity of vertical saccades AND postural instability with repeated unprovoked falls within 3 years, OR tendency to fall on the pull-test within 3 years. ii. Slow velocity of vertical saccades AND postural instability with more than two steps backward on the pull-test within 3 years.
- Presence of PSP symptoms for <5 years (as determined by the best judgement of the Investigator). For the purpose of this inclusion criterion, a PSP symptom is defined as any neurological, cognitive, or behavioral symptom consistent with known symptoms of PSP, occurring newly and subsequently progressing during the clinical course in the absence of another identifiable cause.
- Score of <40 on the total (28-item) PSPRS Score.
- Is Able to walk independently or with minimal assistance, defined as the ability to walk 5 steps with minimal assistance (stabilization of one arm).
- Score of ≥24 on the Mini Mental State Examination (MMSE).
- Dosing of anti-Parkinsonian drugs (coenzyme Q10, levodopa/carbidopa, levodopa/benserazide, fava bean extract, a dopamine agonist, catechol-O-methyltransferase inhibitor, amantadine, or other Parkinson’s disease medications) should be stable for 60 days before enrollment and anticipated to remain stable for the double-blind phase of the Phase 2b or Phase 3 study portion, as applicable to the participant, at the discretion of the Investigator.
- All female participants must have a negative serum pregnancy test at Screening.
- Female participants of childbearing potential (women of childbearing potential [WOCBP]) who engage in heterosexual intercourse must have a negative urine pregnancy test on Day 1 prior to the first dose of study drug.
- WOCBP must agree to abstain from heterosexual intercourse or use a highly effective birth control method for the duration of the study and for 6 months after the last dose of study drug. Female participants who are two years postmenopausal or surgically sterile are not considered be of childbearing potential.
- Female participants must not be planning to become pregnant for the duration of the study and for 6 months after the last dose of study drug.
- Female participants must not be planning to breastfeed or be breastfeeding for the duration of the study and for 6 months after the last dose of study drug.
- Male participants must agree to abstain from heterosexual intercourse or use a highly effective birth control method for the duration of the study and for 6 months after the last dose of study drug.
- Male participants must not be planning to father a child or provide sperm for donation for the duration of the study and for 6 months after the last dose of study drug.
Exclusion Criteria
- Has exposure to AMX0035 or has a known hypersensitivity to AMX0035, either of its components, any of its excipients, or bile salts. Note that under this exclusion criterion, participants in the Phase 2b study portion are not eligible to take part in the Phase 3 portion.
- Requires use of a feeding tube.
- Evidence of any neurological disorder that could explain signs of PSP, including any of the following: a. Signs of idiopathic Parkinson's disease (e.g., severe asymmetric Parkinsonian signs, clinically significant tremor at rest, or prominent and sustained response to levodopa therapy or other medications that are used to treat Parkinson’s disease). b. Signs of multiple system atrophy (MSA) (e.g., prominent early cerebellar limb ataxia or unexplained symptomatic autonomic dysfunction). c. Signs of Lewy body disease (e.g., hallucinations or delusions unrelated to dopaminergic therapy or other illness). d. Probable Alzheimer’s (AD) disease according to National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical criteria for mild cognitive impairment due to AD or AD dementia. e. History of repeated strokes with stepwise progression of Parkinsonian features. f. History of major stroke. g. History of severe or repeated head injury. h. History of encephalitis. i. History of neuroleptic use within the past 6 months. Clozapine or quetiapine may be permitted if at a stable dose for 60 days prior to Screening. j. History of oculogyric crises. k. History of street-drug–related Parkinsonism.
- Any contraindication to MRI or abnormal findings evidenced by MRI including any of the following: a. Severe leukoencephalopathy. b. Relevant structural abnormalities (normal pressure or obstructive hydrocephalus) including basal ganglia, diencephalic, mesencephalic, pontine, or medullary infarctions, hemorrhages, hypoxic-ischemic lesions, tumors, or malformations. c. Arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). d. Severe cerebral amyloid angiopathy.
- History of autosomal dominant PSP due to a Microtubule Associated Protein Tau (MAPT) mutation.
- History of an autosomal dominant mutation associated with Frontotemporal Lobar Degeneration (FTLD) (e.g., an autosomal dominant mutation in C9ORF72 or GRN)
- Abnormal clinical laboratory results including any of the following findings (at Screening only): a. Abnormal liver function defined as aspartate transaminase (AST) and/or alanine transaminase (ALT) > 3× the upper limit of normal (ULN). b. Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. c. Ongoing anemia with hemoglobin concentration < 10.0 g/dL.
- Current biliary disease which may lead to biliary obstruction or impaired biliary flow, including active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gallbladder polyps, gangrene of the gallbladder, or abscess of the gallbladder.
- History of Class III/IV heart failure per New York Heart Association (NYHA) criteria.
- Clinically significant infection, inflammation, or medical condition other than PSP that would pose a risk to the participant if they were to participate or impair their ability to participate in the study, in the judgment of the Investigator, including any of the following: a. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) at time of Screening or on Day 1 prior to study drug dosing. b. Presence of pathologies that can alter the enterohepatic circulation of bile acids (e.g., ileal resection and stoma, regional ileitis). c. Severe salt restriction, where added salt intake due to treatment with study drug would put the participant at risk in the judgment of the Investigator.
- Evidence of any clinically significant neurological disorder other than PSP, including significant cerebrovascular abnormalities, vascular dementia, motor neuron disease or ALS, Huntington’s disease, normal pressure hydrocephalus, brain tumor, seizure disorder, multiple sclerosis, or known structural brain abnormalities. Evidence of disease may be provided by MRI.
- Prior or current diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) or International Classification of Diseases (ICD)-10 criteria
- Presence of unstable psychiatric disease, cognitive impairment (e.g., major cognitive dysfunction), dementia, major depression, or substance abuse that would impair ability of the participant to provide informed consent and follow instructions, in the judgment of the Investigator.
- Significant suicidal ideation within 1 year prior to Screening as evidenced by answering “yes” to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening or history of suicidal attempts within the last 2 years.
- Participation in any other clinical investigation using an experimental drug within 5 half-lives or within 6 weeks (small molecules) or 6 months (monoclonal antibodies, antisense oligonucleotides, or other biologics), whichever is longer, prior to Day 1.
- Exposure to gene or cell therapy prior to Screening or during study.
- Exposure to any prohibited therapy within 30 days prior to Screening.
- Any factor which, in the opinion of the Investigator, precludes the participant’s full compliance with or completion of this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Apr 2024 | 12 |
 Belgium | Not Recruiting | 01 Apr 2024 | 12 |
 Bulgaria | Not Recruiting | 01 Apr 2024 | 11 |
 France | Not Recruiting | 01 Apr 2024 | 53 |
 Germany | Not Recruiting | 01 Apr 2024 | 54 |
 Italy | Not Recruiting | 01 Apr 2024 | 40 |
 The Netherlands | Not Recruiting | 01 Apr 2024 | — |
 Poland | Not Recruiting | 01 Apr 2024 | 18 |
 Spain | Not Recruiting | 01 Apr 2024 | 45 |
 Sweden | Not Recruiting | 01 Apr 2024 | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo matching AMX0035 | Placebo | N/A | — | — | — | N/A |
AMX0035 | Test | POWDER | ORAL | 8 | 104 | PRD9452980 |