A Double-Blind, Placebo-Controlled 16-Week Study of the Cognitive Effects of the Oral P38 Alpha Kinase Inhibitor Neflamapimod in Dementia with Lewy Bodies (DLB)

This is a double-blind, placebo controlled research study to compare any levels
of improvement in memory and attention in patients with mild to moderate DLB
after taking neflamapimod or placebo.

Patient will receive the study drug (neflamapimod or placebo) in the form of
capsules and will take them by mouth with food, twice a day if weigh less than
80 kg (176 lb) or 3 times a day if weigh 80 kg (176 lb) or more. The study
duration is 16 weeks.

The purpose of this study is to investigate how safe and effective the new
medicine neflamapimod is when it is administered to patients with Dementia with
Lewy Bodies (DLB). Doctors cannot prescribe neflamapimod yet outside of a study.
The efficacy of neflamapimod will be compared to the efficacy of a placebo.

The purpose of this study is to determine whether neflamapimod can improve
learning skills, problem solving skills, and memory loss in people diagnosed
with mild to moderate DLB. More specifically, the aim of this study is to find
out if you experience any improvement in your:
* Verbal learning, memory, and attention
* Cognitive and functional performance
In this research study, a new drug named neflamapimod will be tested for the
treatment of mild to moderate DLB. In other words, neflamapimod is not sold as
a drug yet in the US as it has not yet been approved for marketing by the US
Food and Drug Administration (FDA). Neflamapimod is an experimental drug;
*experimental* means that its efficacy has not yet been confirmed by clinical
trials in DLB, and therefore it has not been approved by the US FDA or European
Medicines Agency (EMA) or any other regulatory agency. This Phase 2 study is
being conducted for research purposes only and is required for a possible
marketing approval of neflamapimod by the regulatory agencies (like the FDA)
around the world.

The primary objective is to evaluate the effect of neflamapimod on cognitive
function as assessed in a study-specific Neuropsychological Test Battery (NTB)
comprised of:
*Cogstate Detection test (DET)
*Cogstate Identification test (IDN)
*Cogstate One Card Learning test (OCL)
*Cogstate One Back test (ONB)
*Letter Fluency Test
*Category Fluency Test (CFT)

The secondary objectives are to:
*Evaluate the effects of neflamapimod on informant/caretaker evaluation of
cognition and function, as assessed by the Clinical Dementia Rating Scale-sum
of Boxes (CDR-SB).
*Assess the effects of neflamapimod on general cognition, as assessed by the
Mini Mental State Examination (MMSE).
*Assess the effects of neflamapimod on episodic memory, as assessed by the
International Shopping List Test (ISLT).
*Assess the effects of neflamapimod on select domains of the 10-item
Neuropsychiatric Inventory (NPI-10), including depression (dysphoria), anxiety,
hallucinations, and agitation/aggression.
*Evaluate the effects of neflamapimod on motor function as assessed by the
Timed Up and Go Test (TUG).
*Evaluate the effects of neflamapimod on quantitative electroencephalography
(EEG) parameters.

This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled,
proof-of-principle study of neflamapimod versus matching placebo (randomized
1:1) administered with food for 16 weeks in subjects with DLB. Subjects
weighing <80 kg will receive 2 capsules per day (in divided doses) and those
weighing *80 kg will receive 3 capsules per day (in divided doses). Subjects
receiving two capsules per day will be administered 1 capsule, twice daily
(BID) with food (i.e., with the morning and evening meals), either neflamapimod
40 mg or placebo. Subjects receiving 3 capsules per day will be administered 1
capsule three times daily (TID) with food (i.e., with the morning, mid-day, and
evening meals), either neflamapimod 40 mg or placebo. Doses should be
administered at least 3 hours apart.
Following completion of informed consent procedures, subjects will enter the
Screening phase of the study.
One to two Screening visits are planned, during which safety screening measures
will be undertaken, a practice NTB will be performed, and the required
diagnosis and cognitive impairment will be confirmed. Screening will be
conducted within 21 days before Baseline (Day 1). If a DaTscan* is required to
determine study eligibility, Screening may be extended to 35 days.
Once eligibility is confirmed and before the first dose of study drug, subjects
will be randomly assigned on a 1:1 basis to placebo or neflamapimod for the
16-week treatment period. Investigators and subjects will be blinded to the
treatment assignment. Randomized subjects will be stratified by International
Shopping List Test (ISLT) Total Recall score at Baseline (< 21 vs. >21), i.e.
by wheter patients have an episodic memory defect at baseline or not.
Subjects will receive study drug for 16 weeks. Dosing will start on Day 1
following completion of all baseline procedures. During the 16-week treatment
period, subjects will return to the clinic every 2 weeks for the first month
and then every 4 weeks thereafter. A Final Study Visit (i.e. Follow-Up Visit)
will be conducted 2 weeks (+/-3 days) after completion of study drug or after
the Early Termination (ET) visit.
The NTB, ISLT, and NPI-10 will be conducted at Screening, Baseline (Day 1),
Week 4 (Day 28), Week 8 (Day 56), and Week 16 (Day 112) or ET if early
termination. The CDR-SB and TUG will be conducted at Baseline (Day 1), Week 8
(Day 56), and Week 16 (Day 112) or ET. The MMSE will be conducted at Screening,
Baseline (Day 1), Week 8 (Day 56), and Week 16 (Day 112) or ET. EEGs will be
conducted at Baseline (Day 1) and Week 16 (Day 112) or ET. Samples for plasma
biomarkers will be obtained at Screening, Baseline (Day 1) and Week 16 (Day
112) or ET.

Once eligibility is confirmed and before the first dose of study drug, subjects
will be randomly assigned on a 1:1 basis to placebo or neflamapimod for the
16-week treatment period. Investigators and subjects will be blinded to the
treatment assignment. Randomized subjects will be stratified by International
Shopping List Test (ISLT) Total Recall score at Baseline (< 21 vs. >21), i.e.
by wheter patients have an episodic memory defect at baseline or not.

Possible side effects of Neflamapimod
Neflamapimod may cause side effects.

To date, approximately 270 subjects have received neflamapimod at doses up to
750 mg twice a day, and for up to 6 months.
103 subjects with Alzheimer's disease were dosed in 3 different studies with
different treatment durations (up to 24 weeks) where neflamapimod doses of 40
and 125 mg twice a day were studied. Overall neflamapimod was well-tolerated
with 3 subjects who discontinued early, all other subjects completed their
scheduled dosing period.
The most common side effects seen in these 3 studies included:

* diarrhea (8%)
* headache (7%)
* sleepiness (5%)
* falling (5%)

This is the first study testing neflamapimod in patients with DLB. Even if you
are in the group that gets the active drug (neflamapimod, the medically active
substance) during the study, your DLB-related symptoms may not improve or may
worsen.
In clinical studies prior to those conducted in subjects with Alzheimer*s
disease, headache, common cold, gastroenteritis (nausea/vomiting), diarrhea,
and sleeplessness/insomnia have been the most common adverse events reported.
Nausea/vomiting and diarrhea, which have been primarily mold, appear to have
the strongest association with neflamapimod treatment.
In addition, abnormalities in blood tests of liver function have been seen in
subjects treated with neflamapimod. Elevations to 3 times the normal range was
seen in 1 of 95 subjects with earlyAlzheimer*s disease at doses of 40 mg twice
a day, and in 1 of 7 subjects with rheumatoid arthritis treated at a dose of
250 mg twice a day. You will have periodic blood tests during the study to
monitor liver function.

Neflamapimod, the study medicine may also have adverse effects/side effects
that are still unknown.


Risks to an Unborn child
The consequences of this study drug for an unborn child are not known.

Tests
Blood sampling
Drawing blood may be painful or cause some bruising.
The risks of taking blood include fainting as well as pain, bruising, swelling,
or infection where the needle was inserted. These discomforts are brief and
usually do not last long.

Placebo Risks
The DLB symptoms may not improve or may even worsen.

Allergic Reactions
As with taking any drug, there is a risk of allergic reaction. This reaction
can be mild, such as rash or hives, but also severe, such as breathing problems
due to swelling of the throat or shock, even risk of death.

DaTscan*
When a DaTscan* is performed, patient is exposed to radiation because of both
the Ioflupane I 123 chemical and the procedure. A DaTscan* can also cause
headache, nausea, vertigo, dry mouth, or dizziness. These reactions are
usually mild to moderate. In addition, reactions to the chemical injection,
usually redness of the skin, itching, and pain at the injection site, have been
reported. The chemicals from a DaTscan* are excreted into human milk;
therefore if patient is nursing a child it is recommended to interrupt nursing
and pumping and discarding breast milk for 6 days after the DaTscan*. If
patient is taking drugs that bind to a dopamine transporter, this may interfere
with the scan images.
The total amount of radiation each patient will be exposed to in this study is
approximately 12 mSv.
If patient participates in scientific research involving exposure to radiation
more often, the patient should discuss with the investigator whether
participation at this moment would be safe.
The radiation used during the study may lead to damage to patient's health.
However, this risk is small. We nevertheless advise you not to participate in
another scientific study involving exposure to radiation in the near future.
Examinations or procedures involving radiation for medical reasons are not a
problem.

MRI Scan
MRI scanners use a large magnet and radio waves to take pictures of the body.
The scanning takes about 30 to 60 minutes depending on what part of body is
scanned. The effects of the magnetic fields in an MRI scanner have been widely
studied. There are no known risks from being exposed to the magnetic fields.
Before an MRI scan, patient will be asked a series of questions by the MRI
staff to be sure that they do not have any medical reasons that stop you from
having an MRI. Patient should not have an MRI if you have a pacemaker,
metallic cardiac valve(s), or certain types of metallic aneurysm clips. Patient
should not have an MRI if have implanted electronic infusion pumps or other
metallic pieces in their body. For some MRI scans, patients may get an MRI
contrast material. This contrast material is given in patient's vein. Patient
will not get the MRI contrast material if patient have abnormal kidney
function. It is uncommon, but patient may feel warmth or pain in the area
where the needle was inserted. Patient may also have nausea, vomiting, or
headache. Serious allergic reactions that may be life threatening are very
rare.

Electrocardiogram (ECG)
An ECG is used to check any problems with the electrical activity of the
heart. Skin irritation from the ECG electrode pads or pain when removing the
pads are possible side effects.

Electroencephalogram (EEG)
An EEG is used to check any problems with electrical activity of the brain.
Skin irritation from the ECG electrode pads or pain when removing the pads are
possible side effects. It also takes a long time to connect someone to an EEG
machine, as dozens of electrodes have to be attached to patient's head and
various gels, salt solutions, and/or pastes will be used to keep the electrodes
in place.

Unknown Risks
There may be risks that are currently not known or cannot be predicted.
Subject's condition may worsen, remain the same, or improve as a result of
taking part in this research study.
Some side effects may not be known yet.