A Phase Ib/IIa Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Immunogenicity of Different Doses, Regimens and Combinations of Tau Targeted Vaccines in Subjects with Early Alzheimer*s Disease

A first generation of the vaccine called ACI-35 has been studied in animals as
well as in 24 subjects with mild to moderate Alzheimer*s disease and was safe
and well tolerated.
Subsequently, second generation vaccines have been developed to increase
further the production of antibodies against the abnormal Tau proteins. These
second generation vaccines, which include ACI-35.030 and JACI-35.054, have been
studied in animals. Both ACI-35.030 and JACI-35.054 have already been given to
the patients who participated earlier in this study.

The purpose of this research study is to evaluate the safety and tolerability
of two study vaccines, ACI-35.030 and JACI-35.054 in subjects with a mild form
of Alzheimer*s disease who are 50-75 years-old. Both study vaccines have been
designed to stimulate the body*s immune system to make proteins called
antibodies which remove an abnormal form of the Tau protein which accumulates
in the brain in Alzheimer*s Disease. It is hoped that the reduction of the
buildup of the abnormal Tau proteins will slow down the progression of
Alzheimer*s disease.
The aim of this research study is to find out if these new vaccines:
• are safe and tolerated by patients with early Alzheimer*s Disease
• increase the immune response against the abnormal form of the Tau protein

The study consists of 3 periods - screening period (up to 42 days); treatment
period (50 weeks) and safety follow-up period (24 weeks) and post-injection
period extension which is optional.

Your participation in the study will last up to 80 weeks (around 1.5 years) in
total. This should involve 18 visits to your study doctor in hospital. During
the 50-week treatment period you will receive 4 administrations of the study
vaccine. At the end of this time the study doctor will continue to monitor you
for 24 weeks. If the follow-up period is extended in a given sub-cohort by
another 24 weeks (6 months), the overall duration will be up to around 104
weeks.

All subjects will be kept under clinical observation for 24 hours after the
first administration of study vaccine and for 4 hours after subsequent
administrations of study vaccine. If the follow-up period is extended in a
given sub-cohort by another 24 weeks (6 months), the overall duration will be
up to around 104 weeks.I

Group 1 will receive either ACI-35.030 or a placebo. Group 2 will receive
either JACI-35.054 or a placebo. The placebo looks like ACI-35.030 or
JACI-30.054 but contains no medication and so it is not expected to have any
effect. This will allow the Sponsor to see if ACI-35.030 and JACI-30.054 work
as well as or better than the placebo. The administration schedule will be the
same in both groups, i.e. the study vaccine or placebo will be administered 4
times with an interval of 8, 16 and 24 weeks respectively between each dose.
Group 3 will receive ACI-35.030 and JACI-35.054 in sequential administration.

In group 1 and 2, the dose will be increased successively based on the
observations made during the study, as long as the treatment is considered
safe. At each dose level, the data obtained will be thoroughly assessed, for
example possible adverse reactions observed and results from tests performed,
before the decision is made whether to elevate the dose or not. In group 3 both
vaccines ACI-35.030 and JACI-35.054 will be administered in a sequence based on
non-human primate immunogenicity data and on data reviewed during the previous
sub-cohort interim analyses. Prior to starting any of the sub-cohorts 3.1, 3.2
and/or 3.3 the selected dosages will have been evaluated in cohorts 1 and 2 and
safety monitored for at least 10 weeks.

Due to the Covid-19 pandemic, local travel restrictions in Finland effective as
of 18 March 2020, and the need to preserve the safety of study participants,
modifications are made to the schedule of immunizations of sub-cohort 1.1
subjects not having received the 3rd injection at month 6 already:
immunizations at month 6 (week 24) will not be performed in 7 of 8 sub-cohort
1.1 subjects for whom the planned Visit 5 does not allow all assessments to be
done according to the protocol. In addition, Visits 5 (week 24), 6 (week 26)
and 7 (week 36) are replaced by remote visits in case these fall during the
at-risk period. Due to the resurgence of the Covid-19 pandemic in multiple
participating countries since September 2020, additional adjustments related to
the mode of administration of study assessments including study vaccine
administration may apply in Finland and other participating countries after the
above measures were implemented in Finland.

Group 1 (with ACI-35.030 or placebo) will have three sub-groups with different
doses of the vaccine:
• Sub-group 1.1: The participants of this sub-group have already been enrolled
and received 300 µg ACI-35.030 or placebo per administration.
• Sub-group 1.2: The participants of this subgroup have already been enrolled
and received 900 µg ACI-35.030 or placebo per administration.
• Sub-group 1.3: The participants of this subgroup have already been enrolled
and received 1800 µg ACI-35.030 or placebo per administration.
Group 2 (with JACI-35.054 or placebo) will have three sub-groups with different
doses of the vaccine:
• Sub-group 2.1: The participants have already been enrolled been enrolled and
received 15 µg JACI-35.054 or placebo per administration.
• Sub-group 2.2: The participants will receive up to 60 µg JACI-35.054 or
placebo per administration. This sub-group may or may not be opened dependent
on the assessment of results from the first sub-group.
• Sub-group 2.3: The participants will receive up to 150 µg JACI-35.054 or
placebo per administration. This sub-group may or may not be opened dependent
on the assessment of results from the second sub-group.
Group 3 with ACI-35.030 and JACI-35.054 in sequential administration:
• Sub-group 3.1: ACI-35.030 at 900 µg/dose and JACI-35.054 at a dose previously
evaluated in cohort 2 and found to be safe after a study treatment period of at
least 10 weeks will be administered sequentially
• Sub-group 3.2: This optional sub-cohort may include a different sequence of
administration than in sub-cohort 3.1 and/or different dosages of ACI-35.030
and/or JACI-35.054 based on available safety, tolerability and immunogenicity
data from previous sub-cohort interim analyses. Dosages of ACI-35.030 and of
JACI-35.054 will have been previously evaluated in cohorts 1, 2 and/or 3
without significant safety or tolerability concerns.
• Sub-group 3.3: This optional sub-cohort may include a different sequence of
administration than in sub-cohorts 3.1 and 3.2 and/or different dosages of
ACI-35.030 and/or JACI-35.054 based on available safety, tolerability and
immunogenicity data from previous sub-cohort interim analyses. Dosages of
ACI-35.030 and of JACI-35.054 will have been previously evaluated in cohorts 1,
2 and/or 3 without significant safety or tolerability concerns.

The study vaccine is in a research stage, so it may have adverse effects that
are not known in advance. As with any new drug there is a risk that rare or
unexpected adverse effects may occur.
Reaction at the Injection Site
It is possible that redness, pain, itching or swelling might be observed at the
site of the injection.
Meningoencephalitis (brain inflammation)
There is a small theoretical risk that ACI-35.030 and JACI-35.054 might lead to
inflammation in the brain, so-called meningoencephalitis. This was observed in
6% of subjects in a previous study with another vaccine targeting a different
protein, so-called beta-amyloid. No signs of meningoencephalitis have been
observed to date in animal studies with ACI-35.030 and JACI-35.054 or in the
study of the previous formulation in 24 subjects. The study physician will look
for any signs of this by examining you at the study visits. In addition, the
brain MRI and lumbar puncture will help to identify the cause and/or exclude
such an inflammation of the brain.
Placebo Risks
If you are in the group that is assigned to placebo (the medically inactive
substance), you will not be able to benefit from potential effect of the
vaccine.
Allergic or Other Immune Reactions
As with taking any drug, there is a risk of allergic reaction. You will be
asked to stay at least 24 hours in the clinic after receiving the first
injection of the study vaccine, and for 4 hours following each subsequent
injection to monitor any occurrence of acute reactions during this timeframe.
Please inform your study doctor if you notice any allergic reactions after the
visit. You will also be monitored with blood tests for any other unwanted
reactions of the immune system to the study vaccine.
Blood Sampling
The risks of taking blood include fainting and pain, bruising, swelling, or
rarely, infection where the needle was inserted. These discomforts are brief
and transient.
Electrocardiogram
Skin irritation from the ECG electrode pads or pain when removing the pads are
possible adverse effects.
Lumbar Puncture (spinal tap)
Lumbar puncture (also called spinal tap) involves insertion of a needle at the
bottom of the spinal canal to collect a cerebrospinal fluid. For most people,
spinal tap does not cause any serious problems; the most common side effect is
headache after the procedure which occurs in about 1-2% of people over 50 years
of age. This is usually short lasting (1-2 days), and you will be asked to lie
down and drink caffeinated fluids and then contact the study doctor. On rare
occasions if it continues (for up to 7 days) you may need to be treated with a
*blood patch* (a small amount of your blood injected into the puncture site).
Less common adverse effects include pain at the place where the needle was
inserted or a very brief sensation in the leg or in the buttocks, if the needle
has hit a nerve. These symptoms can be treated and usually improve over time.
Other complications such as low blood pressure, dizziness, bleeding into the
spinal canal or an infection in the brain are very uncommon and may require
hospital treatment.