ION717 for Prion Diseases

Not currently recruiting at 16 trial locations

Overseen By Ionis Pharmaceuticals, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ionis Pharmaceuticals, Inc.

Disqualifiers: Hydrocephalus, Brain disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 30 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called ION717 to assess its safety and behavior in the body for people with prion diseases, which affect the brain. Participants will receive doses of ION717 and a placebo over 30 weeks, with the option to continue using ION717 for an additional 70 weeks. Individuals with early-stage prion disease who have a caregiver to assist them throughout the trial might be suitable candidates. As a Phase 1, Phase 2 trial, this research aims to understand how ION717 works in people and measure its effectiveness in an initial group, offering participants the chance to contribute to groundbreaking advancements in prion disease treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications.

Do I need to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ION717 is still under testing and has not been approved as safe or effective by health authorities. As a result, solid safety information for ION717 remains limited. Ongoing studies aim to determine its safety when administered as an injection near the spinal cord.

Since the study is in an early phase, researchers closely monitor the treatment for any side effects. This phase typically involves gathering detailed safety information in humans.

Participants in early studies help scientists understand how well people tolerate ION717 and identify any major side effects. Until more data is collected and shared, safety information remains limited. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ION717 for prion diseases because it offers a new approach to treating these difficult conditions. Unlike current treatments that mainly focus on alleviating symptoms, ION717 targets the underlying cause by specifically aiming at the prion proteins themselves. This targeted mechanism could potentially slow or stop the progression of the disease, which is a significant advancement over existing therapies. Additionally, ION717's regimen involves a double-blind period followed by an open-label extension, providing both immediate and longer-term insights into its effectiveness and safety.

What evidence suggests that ION717 might be an effective treatment for prion diseases?

Research has shown that ION717 is designed to reduce the amount of prion protein in the brain. These abnormal proteins cause prion diseases and can harm the brain. By lowering these proteins, ION717 aims to slow down or prevent this harm. Although human studies have not yet proven its effectiveness, its mechanism suggests it could help manage prion diseases. If ION717 proves effective, it might also aid in treating other conditions involving abnormal proteins. During the trial, participants will receive ION717 with a placebo in the double-blind treatment period, followed by ION717 alone in the open-label extension period. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with early-stage prion disease, confirmed as probable or definite. Participants need to commit to the study schedule and travel requirements. They must have a caregiver willing to support their involvement throughout the trial.

Inclusion Criteria

I am willing to follow all study requirements, including traveling.

I have been diagnosed with prion disease.

The main requirements for participating in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

up to 6 weeks

Treatment

Participants receive multiple doses of ION717 and placebo during the 30-week double-blind treatment period

30 weeks

Open-label extension

Participants receive multiple doses of ION717 during the 70-week open-label extension period

70 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

32 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ION717

Trial Overview The study is testing ION717, delivered directly into the spinal fluid (intrathecal delivery), against a placebo. It aims to assess how safe it is, how well tolerated by patients, its movement in the body (pharmacokinetics), and its effects on prion disease (pharmacodynamics).

How Is the Trial Designed?

Group I: ION717 + Placebo, Regimen 2 Experimental Treatment 2 Interventions

Participants will receive multiple doses of study drug (ION717 and placebo) during the 30-week double-blind treatment period; the order of doses is blinded. Participants will then receive multiple doses of ION717 during the 70-week open-label extension period.

Group II: ION717 + Placebo, Regimen 1 Experimental Treatment 2 Interventions

Participants will receive multiple doses of study drug (ION717 and placebo) during the 30-week double-blind treatment period; the order of doses is blinded. Participants will then receive multiple doses of ION717 during the 70-week open-label extension period.

Who Is Running the Clinical Trial?

Ionis Pharmaceuticals, Inc.

Lead Sponsor

Trials

151

Recruited

27,800+

Dr. Brett P. Monia

Ionis Pharmaceuticals, Inc.

Chief Executive Officer since 2020

PhD in Pharmacology from the University of Pennsylvania, BSc in Molecular Biology and Analytical Chemistry from Stockton State College

Dr. Eric Bastings

Ionis Pharmaceuticals, Inc.

Chief Medical Officer

MD

Published Research Related to This Trial

In a 156-week phase III study involving 417 patients with psoriatic arthritis (PsA), ixekizumab demonstrated a consistent safety profile with treatment-emergent adverse events occurring in 38% of patients, similar to other treatments.

Efficacy results showed that ixekizumab maintained significant improvements in PsA symptoms and low rates of radiographic progression, with response rates for ACR ≥20% at 62.5% for the every 2 weeks dosing and 69.8% for the every 4 weeks dosing by week 156.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1). Chandran, V., van der Heijde, D., Fleischmann, RM., et al.[2021]

In a phase I study involving 133 hypercholesterolemic subjects, RN317 was found to be well tolerated with no treatment-related discontinuations, demonstrating its safety profile.

RN317 effectively reduced LDL cholesterol levels by up to 52.5% after a single dose, and sustained reductions of approximately 50% were observed with multiple doses over an 85-day period, indicating its efficacy in managing cholesterol levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Randomized Study of a Specifically Engineered, pH-Sensitive PCSK9 Inhibitor RN317 (PF-05335810) in Hypercholesterolemic Subjects on Statin Therapy. Levisetti, M., Joh, T., Wan, H., et al.[2021]

The polymorphism at codon 129 of the human prion gene (PRNP) significantly affects the conformation and aggregation rates of the prion protein, with the methionine variant (rPrP(C(129M))) showing a more exposed helix 1 region compared to the valine variant (rPrP(C(129V))).

rPrP(C(129M)) aggregates faster and forms more aggregates than rPrP(C(129V)), suggesting that the methionine variant may contribute to a higher risk of prion disease due to its enhanced aggregation properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate. Pham, N., Yin, S., Yu, S., et al.[2021]

Creutzfeldt-Jakob disease (CJD) and related disorders are now classified as prion diseases, caused by the abnormal conversion of the normal prion protein (PrP) into a disease-causing form (PrP(Sc)), which leads to neurodegeneration.

The review highlights the infectious nature of prions and discusses the emergence of a new variant of CJD linked to a virulent form of bovine spongiform encephalopathy, emphasizing the need for understanding the molecular mechanisms behind these diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fundamentals of prion biology and diseases. DeArmond, SJ., Bouzamondo, E.[2019]

The novel ionizable lipid nanoparticle (244cis) demonstrated enhanced protein expression of human erythropoietin while significantly reducing immunogenicity compared to conventional lipid nanoparticles, making it safer for therapeutic use.

In a study involving tdTomato transgenic mice with pulmonary fibrosis, 244cis LNP achieved high levels of transfection in lung endothelial cells and fibroblasts, indicating its potential for effective mRNA delivery in chronic lung diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel piperazine-based ionizable lipid nanoparticles allow the repeated dose of mRNA to fibrotic lungs with improved potency and safety. Kim, M., Jeong, M., Lee, G., et al.[2023]

A systematic review of 10 randomized controlled trials with 4198 participants found that PCSK9 monoclonal antibodies (PCSK9-mAbs) had a minimal effect on reducing high-sensitivity C-reactive protein (hs-CRP) levels, with a change of -0.04 mg/L that was not statistically significant.

The analysis indicated that PCSK9-mAbs did not significantly impact hs-CRP levels regardless of the type of antibody used, treatment duration, or participant characteristics, suggesting that their primary benefit may not involve reducing inflammation as measured by hs-CRP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: a systematic review and meta-analysis of randomised controlled trials. Cao, YX., Li, S., Liu, HH., et al.[2019]

PCSK9 inhibitors are effective in significantly lowering LDL cholesterol levels, especially in patients who do not achieve satisfactory results with statins alone, highlighting their role in managing high cardiovascular risk.

Recent large-scale clinical trials have shown that PCSK9 monoclonal antibodies not only lower cholesterol but also reduce the rates of cardiovascular events, indicating their potential as a critical treatment option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The New Face of Hyperlipidemia and the Role of PCSK9 Inhibitors. Nicholls, SJ.[2021]

Lipid nanoparticles (LNPs) containing ALC-0315 demonstrated significantly greater efficacy in knocking down coagulation factor VII and ADAMTS13 in liver cells compared to those containing MC3, achieving up to 10-fold greater knockdown at a dose of 1 mg/kg in mice.

However, at a higher dose of 5 mg/kg, ALC-0315 LNPs showed increased liver toxicity markers, while MC3 LNPs did not, suggesting that while ALC-0315 is more effective, it may pose a risk of hepatotoxicity at elevated doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells. Ferraresso, F., Strilchuk, AW., Juang, LJ., et al.[2023]

The study identified a new prion protein species, PrP*20, which is detectable in uninfected human and animal brains and may indicate early stages of human prion diseases.

As prion diseases progress, there is a transition from increased levels of PrP*20 to the accumulation of the more pathogenic PrP27-30, suggesting that monitoring PrP*20 could be important for early diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accessibility of a critical prion protein region involved in strain recognition and its implications for the early detection of prions. Yuan, J., Dong, Z., Guo, JP., et al.[2020]

Ionizable lipids are essential for the effective delivery of mRNA in lipid nanoparticle (LNP) formulations, as demonstrated by the FDA approval of the first siRNA drug and two COVID-19 vaccines that utilized unique ionizable lipids.

The review highlights recent advancements in the design and function of ionizable lipids, emphasizing their critical role in enhancing the efficiency of RNA delivery systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rational design and combinatorial chemistry of ionizable lipids for RNA delivery. Xu, Y., Golubovic, A., Xu, S., et al.[2023]

Solid-contact ion-selective electrodes (SC-ISEs) made with different silicones showed excellent performance in detecting potassium ions, maintaining stable responses and selectivity even after 41 hours in porcine plasma, indicating their potential for use in physiological samples.

Among the tested silicones, the commercial silicone (Dow 3140) demonstrated the lowest signal drift in porcine plasma, suggesting it may be the most effective material for long-term applications in wearable sensors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of the Composition of Plasticizer-Free Silicone-Based Ion-Selective Membranes on Signal Stability in Aqueous and Blood Plasma Samples. Spindler, BD., Graf, KI., Dong, XIN., et al.[2023]

Incorporating propyl sulphonate groups into a polytetramethylene oxide-based polyurethane improved its mechanical properties and significantly reduced platelet deposition during short blood-contacting times, indicating better biocompatibility.

The presence of propyl sulphonate was more influential on the polymer's blood-contacting response than ethyl carboxylate, as it enhanced fibrinogen deposition while reducing platelet activation, suggesting potential for safer medical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of carboxylate and/or sulphonate ion incorporation on the physical and blood-contacting properties of a polyetherurethane. Okkema, AZ., Cooper, SL.[2019]

In a study involving 2181 patients over 24-104 weeks, most patients (73.7%) on alirocumab 75 mg Q2W plus statins reached LDL cholesterol (LDL-C) goals by week 8.

For the 26.3% of patients who had their dose increased to 150 mg Q2W, 60.9% achieved LDL-C goals by week 24, along with an additional 14.2% reduction in LDL-C, indicating effective dose-response management without increased adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of alirocumab dose increase on LDL lowering and lipid goal attainment in patients with dyslipidemia. Kastelein, JJ., Kereiakes, DJ., Cannon, CP., et al.[2019]

The study found that prions associated with Gerstmann-Sträussler-Scheinker disease (GSS-A117V) are highly infectious, with a significant infectivity level of 109.3 ID50 U/g, despite having a small protease-resistant core that lacks the C-terminus, suggesting that this part of the protein is not necessary for infectivity.

Purified 7 kDa PrPres aggregates, which are non-fibrillar and small, were shown to be highly infectious and capable of encoding the strain characteristics of the original prion sample, supporting the idea that non-fibrillar prion particles are effective in propagating neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolation of infectious, non-fibrillar and oligomeric prions from a genetic prion disease. Vanni, I., Pirisinu, L., Acevedo-Morantes, C., et al.[2023]

Prion diseases, caused by infectious agents known as prions, include serious conditions like Creutzfeldt-Jakob disease and 'mad cow' disease, and while significant research progress has been made in understanding their pathogenesis, effective diagnostic methods and treatments remain inadequate.

Despite advancements in prion disease research, current diagnostic procedures lack sensitivity, and no therapies have been proven to reliably alter the progression of these neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress and problems in the biology, diagnostics, and therapeutics of prion diseases. Aguzzi, A., Heikenwalder, M., Miele, G.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06153966?term=AREA%5BConditionSearch%5D(%22Spongiform%20encephalopathy%22)&rank=3

NCT06153966 | PrProfile: A Study to Assess the Safety, ... The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal (IT) delivery of ION717. Detailed ...

2. science.org science.org/content/article/can-new-drugs-stop-deadly-set-brain-eating-diseases

Can new drugs stop a deadly set of brain-eating diseases? ... trial. If ION717 works, the payoff might extend beyond prion diseases. It has become clear in the past 2 decades that abnormal proteins ...

3. cjdfoundation.org cjdfoundation.org/wp-content/uploads/2023/12/PrProfile-ION717-Study-Initiation-Community-Statement-12.21.23.pdf

PrProfile-ION717-Study-Initiation-Community- ... ION717 is an investigational drug designed to lower the amount of prion protein in the brain. Additional information, including key eligibility ...

4. neurology.ionis.com neurology.ionis.com/sites/default/files/2024-10/Prion%20Disease%20Clinical%20Trial%20Handout.pdf

Prion Disease Clinical Trial Handout.pdf - Ionis Pharmaceuticals ION717 has not been evaluated for safety and efficacy by any regulatory authorities and is not indicated for the treatment of any disease. Proposed ION717- ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11352000/

Perspectives on CRISPR Genome Editing to Prevent Prion ... In this perspective article, we summarize our current understandings of the origin, risk factors, and clinical manifestations of prion diseases.

6. cjdfoundation.org cjdfoundation.org/wp-content/uploads/2024/12/December-2024-Community-Statement-PrProfile-enrollment-completed-US.pdf

MED-US-PRNP-2400024 v1 11/2024 Page 1 of 2 ... Evaluation of the safety and efficacy of ION717 ... clinical trials necessary to evaluate ION717 in individuals with symptomatic prion disease.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06153966

NCT06153966 | PrProfile: A Study to Assess the Safety, ... The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal (IT) delivery of ION717.

8. withpower.com withpower.com/trial/phase-2-prion-diseases-11-2023-42adc

ION717 for Prion Diseases · Info for Participants What safety data exists for ION717 treatment for Prion Diseases? The provided research does not contain specific safety data for ION717 or its evaluation ...

9. cureffi.org cureffi.org/2024/12/27/ion717-trial-fully-enrolled/

ION717 trial fully enrolled Ionis Pharmaceuticals announced that it has completed enrollment of PrProfile, its Phase 1/2a trial of ION717, a PrP-lowering ASO for prion disease.