A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double-Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia Followed by an Open-Label Extension

FTD-GRN is caused by mutations in GRN, primarily resulting in
haploinsufficiency and deficient levels of PGRN in CSF, blood, and tissues.
PGRN is known to promote lysosomal function, in addition to having neurotrophic
and anti-inflammatory effects. Patients with FTD-GRN have notable abnormalities
in lysosomal, glial, and inflammation biomarkers. This includes an accumulation
of lipofuscin in the brain and retina, and elevated expression of ionized
calcium-binding adaptor molecule 1 (IBA1) and complement component 1q (C1Q),
markers of microglial activation, in the frontal cortex. There is currently no
effective therapy for FTD-GRN. There are no approved medications for FTD, and
current therapy consists of off-label medication management for symptoms
associated with FTD or behavioral and/or physical therapy with limited effects
(Tsai and Boxer 2016). Because the impacts of FTD on both patient and caregiver
health are profound, and disease progression is unrelenting until death, there
is an unmet medical need for treatments that provide meaningful symptomatic
benefit, improve survival, and/or delay progression of the disease.
Based on the proposed disease mechanism and data from in vitro and in vivo
nonclinical models, increasing PGRN levels via a CNS-penetrant recombinant PGRN
biologic such as DNL593 may be a successful therapeutic mechanism to correct
the PGRN deficiency and thus treat FTD-GRN.

This study has been transitioned to CTIS with ID 2023-508697-28-00 check the CTIS register for the current data.

This Phase 1/2 study will enable clinical development of DNL593 in FTD-GRN.
This is the first time DNL593 will be administered to humans. The principal aim
of this study is to obtain safety and tolerability data of DNL593, administered
via IV infusion or SC injection or infusion, in healthy participants and
participants with FTD-GRN. This information, together with the PK and PD data,
will help establish the doses and dosage regimen suitable for efficacy studies
and inform the design of future studies. The PD effect of DNL593 will be
explored by measuring relevant biomarkers, including CSF biomarkers.

This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind
study to evaluate the safety, tolerability, PK, and PD of single and multiple
doses of DNL593 in two parts (Part A and Part B [for Part B, investigator,
participants, and Sponsor medical monitor will remain blinded]) followed by an
optional OLE period. Part A will evaluate the safety, tolerability, PK, and PD
of single doses of DNL593 in approximately 64 healthy male participants and
healthy female participants of nonchildbearing potential. Part B will evaluate
the safety, tolerability, PK, and PD of multiple doses of DNL593 over 24 weeks
in up to 42 participants (minimum of 30 participants) with FTD-GRN. Part B will
be followed by Part C, an optional OLE period for up to 18 months of treatment.

Study Interventions, Dose, and Mode of Administration
• Study interventions: DNL593 and DNL593 placebo, both provided as a sterile
lyophilisate. On the label, the drug product may be described as *lyophilisate*
or *powder* per local requirements.
• Proposed doses for part B: Proposed doses for Part B: For Cohort B1, 9 mg/kg
(based on most recently recorded weight) via IV infusion every 2 weeks (Q2W)
for 3 months, followed by every 4 weeks (Q4W) for 3 months. For Cohort B2, no
more than 2 × dose escalation from Part A or Cohort B1 via Q4W IV or SC
administration. For Cohort B3, no more than 2 × dose escalation from Part A or
from Cohort B1 or B2; route of administration and dosing interval will be
selected based on emerging safety, PK, and PD data from previous cohorts.

Main procedures (BURDEN):
- B1: 9-10 ward visits and 3 hospitalisations
- B2: 6 ward visits and 3 hospitalisations. A hospitalisation consists of 2-3
study visits.
- B1 in OLE study (part C): 21 visits, incl. 7 overnight stays
- B2 in OLE study (part C): 21 visits, incl. 3 overnight stays
- ward visits last 4-8 hours.
- checks to be carried out (not during all visits):
- drug review
- Check to see if you can join the study.
- The investigator will take some blood from you.
- Urine test
- Physical examination.
- ECG
- A neurological exam
- CSF collection
- Brain MRI
- A neuropsychological test
- Speech and language test
- Short questions/questionnaires

ASSOCIATED RISKS:
While participating in this study, you may have side effects from the study
drug. You may experience all, some, or no side effects, and the side effects
may vary in severity. The severity may be mild, moderate, severe, life
threatening, or fatal.
Many side effects may go away shortly after the drug is stopped, but in some
cases, side effects can last longer or be permanent.
No clinical studies with DNL593 have been conducted to date. Important
potential risks have been identified based on established class effects and the
nonclinical (studies done in animals) safety findings observed with DNL593 and
they are

• Anemia, or low blood cells
• Immunogenicity (ability of a foreign substance to provoke an immune response
in the body)
• Infusion related reactions (IRRs) are any signs or symptoms you may
experience during drug infusion.

+ risks associated to the procedures (like collection of CSF, blood draws etc)
risks to (un)born child or pregnant women yet unknown.

BENEFIT:
protocol page 20:
FTD-GRN is a rare, uniformly fatal neurodegenerative disease caused by GRN
mutations with no effective treatments towards the symptoms or progression of
the disease. The mean age of onset of 61 years often affects people in the
prime of life and results in substantial socioeconomic difficulties (Moore et
al. 2020). Therefore, there is an unmet medical need for participants with
FTD-GRN. Based on the disease mechanism and data from the nonclinical studies
with DNL593, increasing PGRN levels via a CNS-penetrant recombinant PGRN
biologic such as DNL593 may be a therapeutic mechanism to correct the PGRN
deficiency and thus treat FTD-GRN.
This is the first clinical evaluation of DNL593, and clinical benefit has not
yet been established. Participants with FTD-GRN in the current study may not
receive any therapeutic benefit.

The treatment hypothesis of DNL593 is targeted towards the assumed cause of
FTD-GRN, decreased PGRN levels due to the GRN mutation. Therefore, development
of DNL593 is only possible within this specific population. The assessments
included in this study are typical of standard neurological diagnosis for
neurodegnerative disease (history, exam, MRI, lumbar puncture). As described
above, there are currently no effective symptomatic or disease modifying
therapies for FTD caused by GRN mutations. FTD-GRN is rapidly progressive, with
substantial cognitive, behavioral and motor symtoms that greatly affect quality
of life in the patient and his/her caregiver. Even in patients with advanced
disease stage without cognitive or behavioral capacity for consent, it is
possible that improvements in symptoms associated with FTD-GRN may lead to
benefits in patient and/or caregiver quality of life.