Trial Outcomes & Findings for Proof-of-Concept Study of a Selective p38 MAPK Alpha Inhibitor, Neflamapimod, in Subjects With Mild Alzheimer's Disease (NCT NCT03402659)

Last Updated: 2021-10-27

Results Overview

Combined change from baseline in z-scores of total and delayed recall on the Hopkins Verbal Learning Test - Revised (HVLT-R) in neflamapimod-treated subjects compared to placebo. The primary endpoint was analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. For baseline total and delayed recall, a z-score for each subject is defined by z=(x-m)/s where x is the subject's recall at baseline, and m and s are the overall mean and overall standard deviation of recall at baseline across all subjects. A composite baseline z-score for each subject is calculated using equal weighting in the following way: Z=0.5\*z-score for total recall at baseline + 0.5\*z-score for delayed recall at baseline. For HVLT-R, higher score indicates improvement.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

161 participants

Primary outcome timeframe

Baseline and 24 weeks

Results posted on

2021-10-27

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Arm Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Overall Study STARTED	83	78
Overall Study COMPLETED	78	73
Overall Study NOT COMPLETED	5	5

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Proof-of-Concept Study of a Selective p38 MAPK Alpha Inhibitor, Neflamapimod, in Subjects With Mild Alzheimer's Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Arm n=83 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=78 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).	Total n=161 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Age, Categorical >=65 years	69 Participants n=5 Participants	62 Participants n=7 Participants	131 Participants n=5 Participants
Age, Continuous	72.6 years n=5 Participants	70.8 years n=7 Participants	71.8 years n=5 Participants
Sex: Female, Male Female	43 Participants n=5 Participants	37 Participants n=7 Participants	80 Participants n=5 Participants
Sex: Female, Male Male	40 Participants n=5 Participants	41 Participants n=7 Participants	81 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	79 Participants n=5 Participants	77 Participants n=7 Participants	156 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Netherlands	10 participants n=5 Participants	10 participants n=7 Participants	20 participants n=5 Participants
Region of Enrollment United States	38 participants n=5 Participants	35 participants n=7 Participants	73 participants n=5 Participants
Region of Enrollment Czechia	3 participants n=5 Participants	6 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Denmark	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment United Kingdom	29 participants n=5 Participants	23 participants n=7 Participants	52 participants n=5 Participants
Weight	74.4 Kg n=5 Participants	75.6 Kg n=7 Participants	75 Kg n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants who had analyzable results at Baseline and Week 24

Outcome measures

Outcome measures
Measure	Placebo Arm n=72 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=71 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R)	-0.09679 Z-score Standard Error 0.074840	-0.15776 Z-score Standard Error 0.085805

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants who had analyzable results at Baseline and Week 24

Change from baseline in Wechsler Memory Scale(WMS) immediate and delayed recall composites in neflamapimod-treated subjects compared to placebo. WMS scores were analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. Composite scores for immediate and delayed recall are the combination of all immediate and delayed recall task raw scores and ranges from 0-228. A higher score indicates improvement. The following tests in WMS are done both for immediate and delayed recall: Logical Memory test, in which subject is read a story; Verbal-Paired Associates, in which subject is given pairs of words and asked remember which words go together; and Visual Reproduction, in which subject is given drawings of specific shapes

Outcome measures

Outcome measures
Measure	Placebo Arm n=77 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=71 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Wechsler Memory Scale (WMS) Immediate and Delayed Recall	16.6 Scores on a scale Standard Error 2.09	16.0 Scores on a scale Standard Error 2.07

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants who had analyzable results at Baseline and Week 24

Change from baseline in total score of Clinical Dementia Rating Scale - Sum of Boxes (range 0-18) in neflamapimod-treated subjects compared to placebo. CDR-SB scores were analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. CDR-SB score is calculated by adding the individual scores from 6 domains, Memory, Orientation, Judgement and Problem Solving, Community Affairs, Home and Hobbies, and Personal Care. CDR-SB scores range from 0-18, where a lower score indicates improvement. The scale is administered in a semi-structured interview format with both the patient and the caregiver/informant.

Outcome measures

Outcome measures
Measure	Placebo Arm n=78 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=74 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)	1.0 Scores on a scale Standard Error 0.20	1.1 Scores on a scale Standard Error 0.21

SECONDARY outcome

Timeframe: Baseline and 26 Weeks (Follow-up visit, 2 weeks from end of dosing)

Population: All participants who had analyzable results at Baseline and Follow-up Visit (2 weeks post-treatment)

Changes from baseline in Mini-Mental State Examination (MMSE) scores were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value. The MMSE is scored from 0-30 with a higher score indicating improvement. The MMSE includes questions that test orientation, attention, memory, language and visual-spatial skills.

Outcome measures

Outcome measures
Measure	Placebo Arm n=79 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=70 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Mini-Mental State Examination (MMSE)	-0.5 Scores on a scale Standard Error 0.31	-0.8 Scores on a scale Standard Error 0.33

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants with analyzable results at Baseline and Week 24

Change from, baseline in Total Tau (t-tau) were compared using an ANCOVA with treatment group, background ADspecific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.

Outcome measures

Outcome measures
Measure	Placebo Arm n=68 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=62 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Cerebrospinal Fluid Total Tau	10.0 pg/mL Standard Error 6.83	-8.6 pg/mL Standard Error 7.36

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants who had analyzable results at Baseline and Week 24

Change from baseline in Phospho-Tau (p-tau181) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.

Outcome measures

Outcome measures
Measure	Placebo Arm n=68 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=62 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Cerebrospinal Fluid Phospho-tau	0.9 pg/mL Standard Error 0.63	-1.1 pg/mL Standard Error 0.68

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants who had analyzable results at Baseline and Week 24

Change from baseline in Amyloid beta (AB1-40) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.

Outcome measures

Outcome measures
Measure	Placebo Arm n=68 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=62 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Cerebrospinal Fluid Amyloid Beta 1-40	399.7 pg/mL Standard Error 249.18	282.3 pg/mL Standard Error 268.58

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants who had analyzable results at Baseline and Week 24

Change from baseline in Amyloid beta (AB1-42) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.

Outcome measures

Outcome measures
Measure	Placebo Arm n=68 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=62 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Cerebrospinal Fluid Amyloid Beta 1-42	31.1 pg/mL Standard Error 12.70	10.0 pg/mL Standard Error 13.75

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants with analyzable results at Baseline and Week 24

Change from baseline in Neurogranin were compared using an ANCOVA with treatment group, background ADspecific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.

Outcome measures

Outcome measures
Measure	Placebo Arm n=68 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=62 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Cerebrospinal Fluid Neurogranin	11.1 pg/mL Standard Error 9.16	-9.9 pg/mL Standard Error 9.82

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants with analyzable results at Baseline and Week 24

Change from baseline in Neurofilament Light Chain (NFL) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.

Outcome measures

Outcome measures
Measure	Placebo Arm n=68 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=62 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Cerebrospinal Fluid Neurofilament Light Chain	231.9 pg/mL Standard Error 61.31	121.7 pg/mL Standard Error 66.92

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All participants with analyzable results at Baseline and Week 24

Changes in the ratio of Phospho-Tau/Amyloid Beta (p-tau181/AB1-42) were compared using an ANCOVA with treatment group, background AD-specific therapy, CDR-Global Score as main effects and the baseline assessment as the covariate. The results of the ANCOVA are summarized using the treatment groups' least square means, the difference between the treatment groups' least square means, the 95% confidence interval for the treatment group difference and the p-value.

Outcome measures

Outcome measures
Measure	Placebo Arm n=68 Participants Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=62 Participants Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Cerebrospinal Fluid P-tau/AB1-42 Ratio	-0.0 ratio Standard Error 0	-0.0 ratio Standard Error 0

Adverse Events

Placebo Arm

Serious events: 3 serious events

Other events: 16 other events

Deaths: 0 deaths

Neflamapimod Arm

Serious events: 2 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo Arm n=83 participants at risk Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=78 participants at risk Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Multiple Myeloma	0.00% 0/83 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	1.3% 1/78 • Number of events 1 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.
Metabolism and nutrition disorders Hypokalemia	0.00% 0/83 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	1.3% 1/78 • Number of events 1 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.
General disorders Non-Cardiac Chest Pain	1.2% 1/83 • Number of events 1 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	0.00% 0/78 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.
Infections and infestations Pneumonia	1.2% 1/83 • Number of events 1 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	0.00% 0/78 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.
Injury, poisoning and procedural complications Fall	1.2% 1/83 • Number of events 1 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	0.00% 0/78 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.

Other adverse events

Other adverse events
Measure	Placebo Arm n=83 participants at risk Arm of trial including the 83 subjects that were randomly assigned (1:1) to take placebo	Neflamapimod Arm n=78 participants at risk Arm of trial including the 78 subjects that were randomly assigned (1:1) to take neflamapimod (active study drug).
Infections and infestations Upper Respiratory Tract Infection	8.4% 7/83 • Number of events 8 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	5.1% 4/78 • Number of events 4 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.
Injury, poisoning and procedural complications Fall	3.6% 3/83 • Number of events 3 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	6.4% 5/78 • Number of events 5 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.
Nervous system disorders Headache	4.8% 4/83 • Number of events 6 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	6.4% 5/78 • Number of events 6 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.
Gastrointestinal disorders Diarrhea	2.4% 2/83 • Number of events 2 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.	5.1% 4/78 • Number of events 4 • Up to 29 weeks. AEs occurring from when the subject signed the ICF until up to 30 days after the last dose were collected. Any AEs occurring before the start of treatment (i.e., before the first dose of the investigational product) were recorded in the medical history. Any sign, symptom, or disease present before starting the treatment period were only considered AEs if they worsen after starting the treatment period.

Additional Information

Jennifer Conway, Associate Director of Clinical Development

EIP Pharma

Phone: (617) 744-4400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place