The Generative Brain

PrP-lowering antisense oligonucleotide (ION717)

ION717 is an antisense oligonucleotide that lowers prion protein (PrP) production, given by lumbar puncture. It is the first PrP-lowering drug tested in people, in Ionis's Phase 1/2a PrProfile trial in symptomatic patients, which enrolled 56 people in 2024 and re-opened in March 2026 to test a third dosing regimen. No efficacy data are public.

Key facts

  • Ionis describes ION717 as an investigational RNA-targeted medicine designed to reduce CNS expression of PrP; it has not been evaluated for safety or efficacy by any regulator.
  • PrProfile is a Phase 1/2a first-in-human, randomized, multicenter study (Ionis study ION717-CS2, EudraCT 2023-503355-98); registry start 2024-01-04 (actual), primary completion estimated February 2027 and study completion June 2030 (estimated), registry status active not recruiting (last updated 17 August 2026), actual enrolment 85 after regimen 3 started.
  • Design: screening up to 6 weeks; a 30-week double-blind treatment period in which participants receive ION717 and placebo in a blinded order; a 142-week open-label extension; a 32-week post-treatment period; three regimens, of which regimens 1 and 2 are fully enrolled.
  • Outcomes include safety, plasma pharmacokinetics (Cmax, AUC and half-life on Day 1 and Week 9), CSF ION717 concentration and percent change from baseline in CSF PrP up to Week 33 (the December 2023 registry text said Week 25), and urinary excretion on Day 1.
  • Eligibility: confirmed probable or definite early-stage prion disease; excluded are obstructive hydrocephalus, a functioning CSF shunt or CNS catheter, and brain or spinal disease interfering with lumbar puncture.
  • 56 symptomatic patients enrolled over 2024 across 16 sites; a planned recruitment pause allowed data review and enrolment resumed in August 2024, not for safety reasons; full enrolment was announced in December 2024 with an open-label extension (70 weeks then, 142 weeks in the current registry text).
  • On 17 March 2026 Ionis announced a third dosing regimen after a preliminary analysis; regimen 3 adds about 20 more symptomatic participants without placebo and the open-label period grows from 70 to 142 weeks; dose levels were not disclosed; the statement says preliminary data are not sufficient to establish safety, tolerability or efficacy; data will be presented at future medical meetings, expected after primary completion (about February 2027), and an update was given at the Prion 2025 conference in Brazil.
  • Commentary from a Broad scientist who has worked with Ionis (an interpretation, unconfirmed by Ionis) is that the first two regimens looked safe but lowered PrP less than hoped, which is why a higher-dose regimen was added.
  • Preclinical basis: in prion-infected mice, ASOs extended survival 61 to 98 percent when started early and 55 percent when given near onset; efficacy held across five strains.
  • Origin: Vallabh and Minikel connected with Ionis in 2014; Holly Kordasiewicz of Ionis co-authored the ASO studies; ION717 is described as the first PrP-lowering drug ever tested in humans.
  • CSF PrP is reported as percent change from each person's own baseline, because baselines differ between people; this is the Broad group's argument (citing Mortberg 2022), not an Ionis statement.

Timeline

  1. 2014Ionis and the Broad team begin collaborating.
  2. 2019JCI Insight mouse study published.
  3. 2023Ionis first discloses the PrProfile design.
  4. 2024Registry start date.
  5. 2024Recruitment resumes after a planned pause.
  6. 2024Trial fully enrolled; open-label extension added.
  7. 2025Update presented at the Prion 2025 conference.
  8. 2026Ionis announces regimen 3 and re-opens the trial.
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