A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ION717.

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal (IT) delivery of ION717.

Detailed Description
-----------------
This is a first-in-human, randomized, multi-center study in participants with prion disease. Eligible participants will receive ION717 and placebo. The order of doses will be randomized and blinded to participants, study sites and the Sponsor. The study will consist of a screening period of up to 6 weeks, a 24-week double-blind treatment period and a 36-week post-treatment period. Multiple dose levels will be tested.

Official Title
-----------------
A Phase 1/2a Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION717 in Patients With Prion Disease

Conditions
-----------------
Prion Disease

Intervention / Treatment
-----------------
* Drug: ION717
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria A confirmed diagnosis of probable or definite prion disease. Early-stage prion disease at the time of Screening. Willing to meet all study requirements, including travel to Study Center, procedures, measurements and visits. Patients must have a caregiver who is ≥ 18 years old and who is able and willing to facilitate the patient's involvement, to the best of their ability, for the duration of the trial; caregivers must also be able and willing to provide information about themselves and the patient for the duration of the trial. Aged ≥ 18 at the time of informed consent. Key Exclusion Criteria Clinically significant abnormalities in medical history, laboratory tests or physical examination that would render a patient unsuitable for inclusion. Any contraindication or unwillingness to undergo an MRI. Obstructive hydrocephalus, presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter. Known brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment. Have any other condition, which, in the opinion of the Investigator would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ION717 + Placebo, Regimen 1<br>Participants will receive multiple doses of study drug (ION717 and placebo) during the 24-week treatment period. The order of doses is blinded. | Drug: ION717<br>* ION717 will be administered by IT injection.<br>Drug: Placebo<br>* Placebo-matching ION717 will be administered by IT injection.<br>|
| Experimental: ION717 + Placebo, Regimen 2<br>Participants will receive multiple doses of study drug (ION717 and placebo) during the 24-week treatment period. The order of doses is blinded. | Drug: ION717<br>* ION717 will be administered by IT injection.<br>Drug: Placebo<br>* Placebo-matching ION717 will be administered by IT injection.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events. |  | Baseline up to Week 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of ION717 |  | on Day 1 and Week 9 | 
| Area Under the Plasma Concentration-time Curve (AUC) of ION717 |  | on Day 1 and Week 9 | 
| Half-life (t1/2λz) of ION717 in Plasma |  | on Day 1 and Week 9 | 
| Cerebrospinal fluid (CSF) Concentration of ION717 |  | Pre-dose and at multiple points post-dose up to Week 25 | 
| Amount of ION717 Excreted in Urine |  | Post-dose on Day 1 | 
| Percent Change from Baseline in Prion Protein (PrP) Concentration in CSF |  | Pre-dose and at multiple points post-dose up to Week 25 |