A Phase 3, Multicenter, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of AL001 in Individuals at Risk For or With Frontotemporal Dementia Due to Heterozygous Mutations in the Progranulin Gene

Frontotemporal dementia is a rare progressive disease that affects behavior,
language cognition, or movement, causing difficulty in planning activities,
communicating with others, or performing everyday tasks. The disorder is
identified by the presenting signs and symptoms such as behaving
inappropriately at work or in social settings, difficulty speaking and
understanding language, or problems with movement or daily activities. There
are no approved therapies to slow or halt the disease. However, the symptoms of
FTD may be managed with medications by the treating physician. The length of
progression of the disease may vary from 2 to 20 years once properly diagnosed
and may depend on the underlying cause of FTD. Some individuals have a family
history of FTD (familial or hereditary FTD) caused by a gene mutation that
affects the proteins essential for normal brain cell functioning and survival.
Mutations in the progranulin gene reduce the levels of progranulin in the body.
Progranulin is a protein involved in cell survival and regulating inflammation.
Normal levels of progranulin are required for the brain to work properly.
AL001 is being tested for the treatment of individuals who have a progranulin
gene mutation that causes FTD.
AL001 is an antibody, a molecule that can bind to other molecules or
receptors. AL001 attaches to a receptor called Sortilin, blocking the
destruction of the progranulin protein, leading to higher levels of progranulin
in the body.

This study has been transitioned to CTIS with ID 2023-506873-36-00 check the CTIS register for the current data.

The primary objective of this study is:
Part 1: To evaluate the efficacy of AL001 compared with placebo as measured by
CDR® plus NACC FTLD-SB.
Part 2: To assess the long-term safety and tolerability of AL001 in
participants who have completed 96 weeks of double-blinded treatment
on Part 1 of the study

Secondary Efficacy:
To evaluate the efficacy of AL001 compared with placebo as measured by CGI-S.
To evaluate the efficacy of AL001 compared with placebo as measured by CGI-I
To evaluate the efficacy of AL001 compared with placebo as measured by RBANS
Pharmacodynamic: To evaluate the Pharmacodynamic (PD) of AL001 compared with
placebo as measured by disease pathology biomarkers
Safety Objective: To evaluate the safety and tolerability of AL001 compared
with placebo as measured by safety assessments and ADAs

This is a multicenter Phase 3, randomized, double blind, placebo controlled,
Bayesian adaptive study to evaluate the efficacy and safety of AL001 compared
to placebo in participants who are carriers of heterozygous loss of function
GRN mutations causative of FTD.

Up to approximately 180 participants will be randomly assigned, in a double
blind fashion, to receive AL001 or placebo in a 2:1 ratio (AL001:placebo).

Part 1 of the study will include a screening period (within 6 weeks prior to
randomization), a treatment period and an 8 week safety follow up period
concluding with the Study Completion Visit. Upon completion of the double blind
study treatment period, participants who qualify are planned to be offered an
OLE study with AL001 (to be described in a separate protocol.

Part 2 is an optional 96-week OLE period for eligible participants who have
completed Part 1.

The study has two parts: A treatment period Part 1 (in total max. 96 weeks),
followed by an open-label extension (OLE) period Part 2 (in total max. 96
weeks) for eligible participants who have completed Part 1.

In another study, a total of 64 participants were enrolled. Of the 64
participants enrolled in the Phase 1 study, the most common discomforts
reported are: headache, headache after lumbar puncture, vomiting, lipase
increase (measure of an inflamed or injured pancreas), anaemia (low red blood
cell count), myalgia (muscle pain) and upper respiratory tract infection
(infection of the nasal passages or sinuses) For those who have decided to
participate in the optional lumbar puncture assessment, the potential side
effects are post lumbar puncture syndrome (e.g., headache after lumbar
puncture) and puncture site pain.

The side effects that were reported to be related to AL001 included:
Post-lumbar puncture syndrome (headache after lumbar puncture procedure),
Myalgia (muscle pain), Lipase increase (measure of an inflamed or injured
pancreas), Tachycardia (fast heartbeat), Murphy*s sign positive (physical
examination finding suggesting an inflamed gallbladder).

• Risk of developing Antidrug antibody (ADA): There is a chance that his/her
body will develop antibodies against AL001 or that a hypersensitivity reaction
(which can be severe and life threatening) will be induced. Theoretically this
means that if you should need AL001 as therapy in the future, your response to
treatment by this drug may be reduced or absent, and/or you may get a
hypersensitivity reaction. Of the Phase 1 participants, 16 showed positive
results for anti-drug antibodies. The impact of anti-drug antibodies on safety
or efficacy of AL001 is still unknown.
• Infusion Risks: Infection may occur causing redness and discharge at the
site with an elevated temperature. Infusion-related reactions include allergic
reactions reactions, which can be severe and life threatening. These reactions
are experienced by patients during the infusion of monoclonal antibody therapy
and/or within hours of an infusion. Symptoms can include flushing, difficulty
breathing, breathlessness (tightening of the muscles), reddening of the face,
changes in heart rate and blood pressure, sudden feeling of tightening thorax
(in the walls of your lungs), back pain, fever, hives, swelling, nausea, and
all types of rashes.
• Allergic Reactions: Allergic reactions can occur with any drug and this can
be in the form of itching, difficulty breathing, and a skin rash and/or drop in
blood pressure.
• Drawing blood may be painful or cause some bruising.