Alzheimer Disease
Conditions
Brief summary
This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients.
Detailed description
This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients. A total of sixty (60) patients will be enrolled in the study. Patients will receive Placebo, 50 mg or 100 mg b.i.d. of PTI-125. The objective of this study are to investigate the safety, and biomarkers of PTI-125 following 28-day repeat oral administration.
Interventions
DRUGPlacebo oral tablet
Oral placebo tablet
DRUGSimufilam 100 mg tablet
Simufilam 100 mg oral tablet
DRUGSimufilam 50 mg oral tablet
Simufilam 50 mg oral tablet
Sponsors
National Institute on Aging (NIA)
Cassava Sciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The sponsor, participant, care provider, investigator including sub-investigators and outcomes assessors will be blinded to throughout the study which includes using an Integrated Web Response System (IWRS) and electronic data capture (EDC) to ensure blinding during the study.
Intervention model description
Approximately sixty (60) patients will be enrolled into the study and randomized to one of three cohorts. Cohorts will receive placebo or PTI-125 at 50 or 100 mg b.i.d. (n=20 per group)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Ages \>= 50 and \<= 85 years * Informed consent form (ICF) signed by the subject or legally acceptable representative. * Clinical diagnosis of dementia due to possible or probable Alzheimer's disease * Mini-Mental State Examination score \>= 16 and \<= 26 at screening * If female, postmenopausal for at least 1 year * Patient living at home, senior residential setting, or an institutional setting without the need for continuous (i.e. 24-h) nursing care * General health status acceptable for participation in the study * Fluency (oral and written) in English or Spanish * If receiving memantine, rivastigmine, galantamine or an AChEI, receiving a stable dose for at least 3 months. If receiving donepezil, any dose lower than 23 mg once daily. * The patient is a non-smoker for at least 3 years. * The patient or legal representative must agree to comply with the drawing of blood samples and with a lumbar puncture and the drawing of cerebrospinal fluid samples. * The patient has a ratio of total tau/Aβ42 in cerebrospinal fluid \>= 0.28. * Patient has a caregiver or legal representative responsible for administering the drug and recording the time.
Exclusion criteria
* Exposure to an experimental drug, experimental biologic or experimental medical device within the longer of 5 half-lives or 3 months before screening * Enrollment in the previous PTI-125 trial * A medical condition that would interfere with a lumbar puncture * Residence in a skilled nursing facility and requiring 24 h care. * Clinically significant laboratory test results * Clinically significant untreated hypothyroidism * Insufficiently controlled diabetes mellitus * Renal insufficiency (serum creatinine \> ULN) * Malignant tumor within 3 years before screening (except squamous and basal cell carcinoma or cervical carcinoma in situ or localized prostate cancer or localized stage 1 bladder cancer) * History of ischemic colitis or ischemic enterocolitis * Unstable medical condition that is clinically significant in the judgment of the investigator * Alanine transaminase (ALT) or aspartate transaminase (AST) \> ULN or total bilirubin \> ULN. * History of myocardial infarction or unstable angina within 6 months before screening * History of more than 1 myocardial infarction within 5 years before screening * Clinically significant cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are acceptable) * Symptomatic hypotension, or uncontrolled hypertension * Clinically significant abnormality on screening electrocardiogram (ECG), including but not necessarily limited to a confirmed corrected QT interval value \>= 450 msec for males or \>= 470 msec for females. * Stroke within 18 months before screening, or history of a stroke concomitant with onset of dementia * History of brain tumor or other clinically significant space-occupying lesion on CT or MRI * Head trauma with clinically significant loss of consciousness within 12 months before screening or concurrent with the onset of dementia * Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or resuscitation * Specific degenerative Central Nervous System disease diagnosis other than Alzheimer's disease (eg, Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease) * Wernicke's encephalopathy * Active acute or chronic Central Nervous System infection * Donepezil 23 mg quaque die currently or within 3 months prior to randomization * Discontinued AChEI \< 30 days prior to randomization * Antipsychotics; low doses are allowed only if the subject has received a stable dose for at least 3 months before randomization * Tricyclic antidepressants and monoamine oxidase inhibitors * Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses for benign tremor); low doses of benzodiazepines and zolpidem are allowed * Immunosuppressants, including systemic corticosteroids, if taken in clinically immunosuppressive doses (Steroid use for allergy or other inflammation is permitted.) * Antiepileptic medications if taken for control of seizures * Chronic intake of opioid-containing analgesics * Sedating H1 antihistamines * Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or similar therapeutic agent within 30 days before screening * Clinically significant illness within 30 days of enrollment * History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease * Positive serum hepatitis B surface antigen (HBsAg) or positive hepatitis C virus HCV antibody test at screening * Positive HIV test at screening * Positive urine drug test at screening * Loss of a significant volume of blood (\> 450 mL) within 4 weeks prior to the study * Suicidality on C-SSRS at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CSF YKL-40 | Screening to Day 28 | Change from Baseline (screening) in cerebrospinal fluid YKL-40 |
| Change From Baseline in CSF Abeta42 | Screening to Day 28 | Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid levels of Amyloid beta42 |
| Change From Baseline in CSF Total Tau. | Screening to Day 28 | Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid total tau. |
| Change From Baseline in CSF P-tau181 | Screening to Day 28 | Change from Baseline (screening) to Day 28 in cerebrospinal fluid P-tau181 |
| Change From Baseline in CSF Neurogranin | Screening to Day 28 | Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurogranin |
| Change From Baseline in CSF Neurofilament Light Chain | Screening to Day 28 | Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurofilament light chain |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Paired Associates Learning Test | Day 1 to Day 28 | Cognitive test assessing episodic memory. Boxes are displayed on the screen and are opened in a randomized order. One or more of them contains a pattern. The patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located. If the participant makes an error, the boxes are opened in sequence again to remind the participant of the locations of the patterns. The number of boxes increases progressively to a total of 8. |
| Spatial Working Memory Test | Day 1 to Day 28 | Cognitive assessment of spatial working memory: A number of colored squares (boxes) are shown on the screen. By selecting the boxes and using a process of elimination, the subject should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The number of boxes is gradually increased to a total of 8 for the subjects to search. The colors and positions of the boxes are changed from trial to trial to discourage stereotyped search strategies. |
| CSF IL-6, sTREM2, HMGB1, Albumin, IgG | Screening to Day 28 | Change from Baseline (screening sample) to Day 28 in secondary CSF biomarkers of neuroinflammation and blood-brain barrier integrity |
Other
| Measure | Time frame | Description |
|---|---|---|
| Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | Day 1 to Day 28 | FLNA linkages to these two receptors were assessed by densitometric quantitation of immunoblot bands of each receptor (detected by a specific antibody) in anti-FLNA precipitates. The measure is noted as a ratio to total FLNA. |
| Plasma P-tau181 | Day 1 to Day 28 | Percent change in plasma P-tau181 |
| Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker | Day 1 to Day 28 | SavaDx is a novel plasma biomarker |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Cohort Subjects administered matching placebo tablets twice daily for 28 days. | 22 |
| Simufilam (PTI-125), 100 mg Tablets Cohort Subjects administered 100 mg simufilam tablets twice daily for 28 days. | 21 |
| Simufilam (PTI-125), 50 mg Tablets Cohort Subjects administered 50 mg simufilam tablets twice daily for 28 days. | 21 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Cohort | Simufilam (PTI-125), 100 mg Tablets Cohort | Simufilam (PTI-125), 50 mg Tablets Cohort | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 12 Participants | 15 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 9 Participants | 6 Participants | 19 Participants |
| Age, Continuous | 71.3 years STANDARD_DEVIATION 6.68 | 69.3 years STANDARD_DEVIATION 5.47 | 67.1 years STANDARD_DEVIATION 8.76 | 69.2 years STANDARD_DEVIATION 6.97 |
| CSF Aβ42 | 125 pg/mL STANDARD_DEVIATION 152 | 117 pg/mL STANDARD_DEVIATION 51.4 | 108 pg/mL STANDARD_DEVIATION 54.8 | 111 pg/mL STANDARD_DEVIATION 86.1 |
| CSF HMGB1 | 424 pg/mL STANDARD_DEVIATION 48 | 446 pg/mL STANDARD_DEVIATION 67.3 | 454 pg/mL STANDARD_DEVIATION 70.6 | 441 pg/mL STANDARD_DEVIATION 62 |
| CSF IL-6 | 32.5 pg/mL STANDARD_DEVIATION 1.2 | 33.6 pg/mL STANDARD_DEVIATION 1.8 | 33.6 pg/mL STANDARD_DEVIATION 1.7 | 33.2 pg/mL STANDARD_DEVIATION 1.6 |
| CSF Neurofilament Light Chain | 161 pg/mL STANDARD_DEVIATION 42.8 | 219 pg/mL STANDARD_DEVIATION 95.3 | 181 pg/mL STANDARD_DEVIATION 64.4 | 187 pg/mL STANDARD_DEVIATION 67.5 |
| CSF neurogranin | 1200 pg/mL STANDARD_DEVIATION 365 | 1551 pg/mL STANDARD_DEVIATION 751 | 1352 pg/mL STANDARD_DEVIATION 614 | 1368 pg/mL STANDARD_DEVIATION 577 |
| CSF/plasma albumin ratio | 0.24 ratio STANDARD_DEVIATION 0.03 | 0.25 ratio STANDARD_DEVIATION 0.08 | 0.25 ratio STANDARD_DEVIATION 0.05 | 0.25 ratio STANDARD_DEVIATION 0.05 |
| CSF/plasma IgG ratio | 0.200 ratio STANDARD_DEVIATION 0.07 | 0.217 ratio STANDARD_DEVIATION 0.11 | 0.227 ratio STANDARD_DEVIATION 0.07 | 0.215 ratio STANDARD_DEVIATION 0.08 |
| CSF P-tau181 | 28.5 pg/mL STANDARD_DEVIATION 0.73 | 29.7 pg/mL STANDARD_DEVIATION 1.5 | 29.0 pg/mL STANDARD_DEVIATION 1 | 29.1 pg/mL STANDARD_DEVIATION 1.3 |
| CSF sTREM2 | 878 pg/mL STANDARD_DEVIATION 435 | 861 pg/mL STANDARD_DEVIATION 421 | 882 pg/mL STANDARD_DEVIATION 476 | 874 pg/mL STANDARD_DEVIATION 444 |
| CSF total tau | 104 pg/mL STANDARD_DEVIATION 32 | 106 pg/mL STANDARD_DEVIATION 27.9 | 101 pg/mL STANDARD_DEVIATION 17.6 | 103.7 pg/mL STANDARD_DEVIATION 25.8 |
| CSF total tau/Aβ42 ratio | 1.20 ratio STANDARD_DEVIATION 0.55 | 1.08 ratio STANDARD_DEVIATION 0.5 | 1.17 ratio STANDARD_DEVIATION 0.58 | 1.15 ratio STANDARD_DEVIATION 0.54 |
| CSF YKL-40 | 206 pg/mL STANDARD_DEVIATION 29.5 | 203 pg/mL STANDARD_DEVIATION 22.7 | 194 pg/mL STANDARD_DEVIATION 26 | 201 pg/mL STANDARD_DEVIATION 26.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 11 Participants | 11 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 10 Participants | 10 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Heterozygous APOE4 | 12 Participants | 14 Participants | 9 Participants | 35 Participants |
| Homozygous APOE4 | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Lymphocyte filamin A - TLR4, Ratio to total filamin A | 0.55 ratio STANDARD_DEVIATION 0.1 | 0.60 ratio STANDARD_DEVIATION 0.07 | 0.58 ratio STANDARD_DEVIATION 0.11 | 0.58 ratio STANDARD_DEVIATION 0.09 |
| Lymphocyte filamin A - α7nAChR, Ratio to total filamin A | 0.59 ratio STANDARD_DEVIATION 0.1 | 0.69 ratio STANDARD_DEVIATION 0.11 | 0.66 ratio STANDARD_DEVIATION 0.12 | 0.65 ratio STANDARD_DEVIATION 0.11 |
| Mini-Mental State Exam (MMSE) | 23.1 units on a scale STANDARD_DEVIATION 2.78 | 23.0 units on a scale STANDARD_DEVIATION 2.66 | 22.7 units on a scale STANDARD_DEVIATION 2.67 | 22.9 units on a scale STANDARD_DEVIATION 2.7 |
| Paired Associates Learning total errors | 35.5 errors STANDARD_DEVIATION 19.65 | 31.0 errors STANDARD_DEVIATION 20.74 | 36.1 errors STANDARD_DEVIATION 18.76 | 34.2 errors STANDARD_DEVIATION 19.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 19 Participants | 17 Participants | 55 Participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 9 Participants | 29 Participants |
| Spatial Working Memory total errors | 19.0 errors STANDARD_DEVIATION 7.49 | 22.1 errors STANDARD_DEVIATION 5.88 | 22.3 errors STANDARD_DEVIATION 6.64 | 21.1 errors STANDARD_DEVIATION 6.67 |
| Taking cholinesterase inhibitor or memantine | 8 Participants | 7 Participants | 5 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 12 / 22 | 9 / 21 | 4 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 | 0 / 21 |
Outcome results
Primary
Change From Baseline in CSF Abeta42
Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid levels of Amyloid beta42
Time frame: Screening to Day 28
Population: As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Change From Baseline in CSF Abeta42 | 4.8 pg/mL | Standard Deviation 30.9 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Change From Baseline in CSF Abeta42 | 12.5 pg/mL | Standard Deviation 11.9 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Change From Baseline in CSF Abeta42 | 16.2 pg/mL | Standard Deviation 21.1 |
Comparison: This primary analysis includes two 100 mg subjects who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.087ANCOVA
Comparison: This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.01ANCOVA
Primary
Change From Baseline in CSF Neurofilament Light Chain
Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurofilament light chain
Time frame: Screening to Day 28
Population: As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Change From Baseline in CSF Neurofilament Light Chain | -10.0 pg/mL | Standard Deviation 45 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Change From Baseline in CSF Neurofilament Light Chain | -76.3 pg/mL | Standard Deviation 50.6 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Change From Baseline in CSF Neurofilament Light Chain | -49.7 pg/mL | Standard Deviation 35.5 |
Comparison: This primary analysis includes two 100 mg subjects who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.0003ANCOVA
Comparison: This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.0058ANCOVA
Primary
Change From Baseline in CSF Neurogranin
Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurogranin
Time frame: Screening to Day 28
Population: As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Change From Baseline in CSF Neurogranin | -50.5 pg/mL | Standard Deviation 434 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Change From Baseline in CSF Neurogranin | -648 pg/mL | Standard Deviation 491 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Change From Baseline in CSF Neurogranin | -527 pg/mL | Standard Deviation 361 |
Comparison: This primary analysis includes two 100 mg subjects who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.0002ANCOVA
Comparison: This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.0005ANCOVA
Primary
Change From Baseline in CSF P-tau181
Change from Baseline (screening) to Day 28 in cerebrospinal fluid P-tau181
Time frame: Screening to Day 28
Population: As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Change From Baseline in CSF P-tau181 | -0.63 pg/mL | Standard Deviation 1.8 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Change From Baseline in CSF P-tau181 | -3.1 pg/mL | Standard Deviation 1.7 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Change From Baseline in CSF P-tau181 | -2.4 pg/mL | Standard Deviation 1.6 |
Comparison: This primary analysis includes two 100 mg subjects who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.005ANCOVA
Comparison: This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.002ANCOVA
Primary
Change From Baseline in CSF Total Tau.
Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid total tau.
Time frame: Screening to Day 28
Population: As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Change From Baseline in CSF Total Tau. | -3.2 pg/mL | Standard Deviation 14.8 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Change From Baseline in CSF Total Tau. | -18.7 pg/mL | Standard Deviation 10.4 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Change From Baseline in CSF Total Tau. | -14.6 pg/mL | Standard Deviation 9.6 |
Comparison: This primary analysis includes two 100 mg subjects who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: <0.0001ANCOVA
Comparison: This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.0012ANCOVA
Primary
Change From Baseline in CSF YKL-40
Change from Baseline (screening) in cerebrospinal fluid YKL-40
Time frame: Screening to Day 28
Population: As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample. This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Change From Baseline in CSF YKL-40 | -0.96 pg/mL | Standard Deviation 24.2 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Change From Baseline in CSF YKL-40 | -22.3 pg/mL | Standard Deviation 11.7 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Change From Baseline in CSF YKL-40 | -20.4 pg/mL | Standard Deviation 17.4 |
Comparison: This primary analysis includes two 100 mg subjects who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.0001ANCOVA
Comparison: This primary analysis includes one 50 mg subject who showed no detectable simufilam in plasma at return visits (their exclusion was not prespecified in the Statistical Analysis Plan).p-value: 0.0001ANCOVA
Secondary
CSF IL-6, sTREM2, HMGB1, Albumin, IgG
Change from Baseline (screening sample) to Day 28 in secondary CSF biomarkers of neuroinflammation and blood-brain barrier integrity
Time frame: Screening to Day 28
Population: Three subjects who had no detectable simufilam in plasma at return visits were removed from analyses (two in the 100 mg arm and one in the 50 mg arm). As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. One additional subject in the 50 mg arm was missing a Day 28 CSF sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF albumin | -240 pg/mL; optical density for albumin & IgG | Standard Deviation 1620 |
| Placebo Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF HMGB1 | 19.4 pg/mL; optical density for albumin & IgG | Standard Deviation 172.3 |
| Placebo Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF IL-6 | -1.1 pg/mL; optical density for albumin & IgG | Standard Deviation 2 |
| Placebo Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF sTREM2 | -77.3 pg/mL; optical density for albumin & IgG | Standard Deviation 510 |
| Placebo Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF IgG | -574.8 pg/mL; optical density for albumin & IgG | Standard Deviation 2518 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF HMGB1 | -143 pg/mL; optical density for albumin & IgG | Standard Deviation 51.3 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF IL-6 | -3.7 pg/mL; optical density for albumin & IgG | Standard Deviation 1.8 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF sTREM2 | -426 pg/mL; optical density for albumin & IgG | Standard Deviation 274 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF albumin | -2292 pg/mL; optical density for albumin & IgG | Standard Deviation 1760 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF IgG | -2350 pg/mL; optical density for albumin & IgG | Standard Deviation 2517 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF IgG | -2444 pg/mL; optical density for albumin & IgG | Standard Deviation 2097 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF albumin | -1245 pg/mL; optical density for albumin & IgG | Standard Deviation 1735 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF IL-6 | -3.3 pg/mL; optical density for albumin & IgG | Standard Deviation 1.9 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF HMGB1 | -152 pg/mL; optical density for albumin & IgG | Standard Deviation 50.1 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | CSF IL-6, sTREM2, HMGB1, Albumin, IgG | CSF sTREM2 | -424 pg/mL; optical density for albumin & IgG | Standard Deviation 386 |
Comparison: This analysis is for IL-6.p-value: 0.0078ANCOVA
Comparison: This analysis is for IL-6.p-value: 0.019ANCOVA
Comparison: This analysis is for sTREM2.p-value: 0.0002ANCOVA
Comparison: This analysis is for sTREM2.p-value: 0.0007ANCOVA
Comparison: This analysis is for HMGB1.p-value: 0.0001ANCOVA
Comparison: This analysis is for HMGB1.p-value: 0.0001ANCOVA
Comparison: This analysis is for albumin.p-value: 0.0001ANCOVA
Comparison: This analysis is for albumin.p-value: 0.046ANCOVA
Comparison: This analysis is for Immunoglobulin G.p-value: 0.012ANCOVA
Comparison: This analysis is for Immunoglobulin G.p-value: 0.014ANCOVA
Secondary
Paired Associates Learning Test
Cognitive test assessing episodic memory. Boxes are displayed on the screen and are opened in a randomized order. One or more of them contains a pattern. The patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located. If the participant makes an error, the boxes are opened in sequence again to remind the participant of the locations of the patterns. The number of boxes increases progressively to a total of 8.
Time frame: Day 1 to Day 28
Population: The least impaired patients (11 or fewer errors, representing a ceiling effect) and patients with 54 or more errors (very poor performance suggesting not understanding the task) were removed from the analysis. Also removed were the 3 patients with no detectable drug in plasma, 2 patients with ≥25% non-compliance by pill counts, one patient with no baseline test and one who did not understand instructions per rater notes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Paired Associates Learning Test | -1.5 Change from Day 1 in total errors | Standard Deviation 8.5 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Paired Associates Learning Test | -4.5 Change from Day 1 in total errors | Standard Deviation 17.7 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Paired Associates Learning Test | -5.7 Change from Day 1 in total errors | Standard Deviation 13.6 |
Comparison: This study was not powered for statistical significance on cognitive measures.
Comparison: This study was not powered for statistical significance on cognitive measures.
Secondary
Spatial Working Memory Test
Cognitive assessment of spatial working memory: A number of colored squares (boxes) are shown on the screen. By selecting the boxes and using a process of elimination, the subject should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The number of boxes is gradually increased to a total of 8 for the subjects to search. The colors and positions of the boxes are changed from trial to trial to discourage stereotyped search strategies.
Time frame: Day 1 to Day 28
Population: Removed from analysis were the 3 patients with no detectable drug in plasma, 2 patients with ≥25% non-compliance by pill counts, one patient with no baseline test and one who did not understand instructions per rater notes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Spatial Working Memory Test | -0.41 Change from Day 1 in total errors | Standard Deviation 7.54 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Spatial Working Memory Test | -2.31 Change from Day 1 in total errors | Standard Deviation 7.45 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Spatial Working Memory Test | -3.35 Change from Day 1 in total errors | Standard Deviation 4.86 |
Comparison: This study was not powered for statistical significance on cognitive measures.
Comparison: This study was not powered for statistical significance on cognitive measures.
Other Pre-specified
Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker
SavaDx is a novel plasma biomarker
Time frame: Day 1 to Day 28
Population: One subject in the 50 mg arm and two subjects in the 100 mg arm were omitted because these subjects showed no detectable plasma simufilam at any return visit. Two additional subjects in the 50 mg group were missing baseline plasma samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker | -3.2 Percent change | Standard Deviation 62 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker | -47.8 Percent change | Standard Deviation 19 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker | -44.1 Percent change | Standard Deviation 35 |
p-value: 0.003ANOVA
p-value: 0.016ANOVA
Other Pre-specified
Plasma P-tau181
Percent change in plasma P-tau181
Time frame: Day 1 to Day 28
Population: For plasma p-tau181 only: 4 subjects (1 in placebo, 2 in 50 mg and 1 in 100 mg arms) were removed because Coefficients of Variation (CVs) between duplicate measurements for either Day 1 or Day 28 samples were \>15% on repeat assay (both Day 1 \& Day 28 for a subject were repeated if CVs of either Day 1 or Day 28 were \>11%). Two outliers were removed (1 in placebo \[1.2 to 4.8 pg/ml\] and 1 in 100 mg \[2.1 to 5.1 pg/ml\] arms) for increases \>150% \& \> 2.5 pg/mL. Missing Day 1 blood samples: 2 in 50 mg.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort | Plasma P-tau181 | 20.7 Percent change | Standard Deviation 49 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Plasma P-tau181 | -16.5 Percent change | Standard Deviation 29 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Plasma P-tau181 | -15.1 Percent change | Standard Deviation 36 |
p-value: 0.01ANOVA
p-value: 0.02ANOVA
p-value: 0.009ANOVA
Other Pre-specified
Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes
FLNA linkages to these two receptors were assessed by densitometric quantitation of immunoblot bands of each receptor (detected by a specific antibody) in anti-FLNA precipitates. The measure is noted as a ratio to total FLNA.
Time frame: Day 1 to Day 28
Population: Three subjects who had no detectable simufilam in plasma at any return visit were removed from analyses (two in the 100 mg arm and one in the 50 mg arm). As noted in the Participant Flow, one subject in the 50 mg arm did not complete the study. Two additional subjects in the 50 mg arm were missing Day 1 blood samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Cohort | Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA - alpha7nAChR linkage | -0.07 ratio to total FLNA | Standard Deviation 0.19 |
| Placebo Cohort | Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA - TLR4 linkage | -0.05 ratio to total FLNA | Standard Deviation 0.18 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA - alpha7nAChR linkage | -0.24 ratio to total FLNA | Standard Deviation 0.16 |
| Simufilam (PTI-125), 100 mg Tablets Cohort | Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA - TLR4 linkage | -0.19 ratio to total FLNA | Standard Deviation 0.14 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA - alpha7nAChR linkage | -0.23 ratio to total FLNA | Standard Deviation 0.13 |
| Simufilam (PTI-125), 50 mg Tablets Cohort | Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes | FLNA - TLR4 linkage | -0.19 ratio to total FLNA | Standard Deviation 0.11 |
Comparison: Change from baseline in FLNA linkage to alpha7nAChR in subject lymphocytes. FLNA linkage to alpha7nAChR was expressed as the ratio of densitometric units of immunoblot bands of alpha7nAChR (probed with a specific antibody) to densitometric units of total FLNA.p-value: 0.005ANOVA
Comparison: Change from baseline in FLNA linkage to alpha7nAChR in subject lymphocytes. FLNA linkage to alpha7nAChR was expressed as ratios of densitometric units of immunoblot bands of alpha7nAChR (probed with a specific antibody) to densitometric units of total FLNA.p-value: 0.009ANOVA
Comparison: Change from baseline in FLNA linkage to TLR4 in subject lymphocytes. FLNA linkage to TLR4 was expressed as the ratio of densitometric units of immunoblot bands of TLR4 (probed with a specific antibody) to densitometric units of total FLNA.p-value: 0.01ANOVA
Comparison: Change from baseline in FLNA linkage to TLR4 in subject lymphocytes. FLNA linkage to TLR4 was expressed as the ratio of densitometric units of immunoblot bands of TLR4 (probed with a specific antibody) to densitometric units of total FLNA.p-value: 0.01ANOVA