This morning Ionis Pharmaceuticals announced that PrProfile (NCT06153966), their Phase 1/2a trial of ION717, a PrP-lowering antisense oligonucleotide for symptomatic prion disease patients, has re-opened.

background

If you’re just tuning in now, here’s a bit of background. ION717 is the first PrP-lowering drug ever tested in humans. PrP lowering has a strong scientific foundation, because PrP is the protein that causes prion disease, and this therapeutic approach has been shown effective in various animal models of prion disease [Raymond 2019, Minikel 2020]. We all produce PrP in our brains, but in prion disease, this protien misfolds. By reducing the amount of PrP that the brain produces, we are reducing the fuel to the fire.

Over the course of 2024, PrProfile enrolled 56 symptomatic patients diagnosed with prion disease. The experimental drug is an antisense oligonucleotide (ASO), dosed intrathecally, which means by a lumbar puncture or spinal tap. Originally, patients were enrolled into two cohorts. Each cohort had patients randomized to either active drug or placebo. Ionis never disclosed the difference between the two cohorts, but I’ve speculated it was probably two different dose levels — let’s call them a low dose and a mid dose. The last patient made their last study visit in July 2025, and Ionis initially told the patient community at the CJD Foundation Conference that month that they planned to announce some study data in 2026. At a shareholder meeting on February 25, 2026, Ionis stated that they planned to instead add another cohort to PrProfile and extend the trial through 2027, but no official timeline was given until today.

the update

This morning, Ionis updated its clinical trial posting (NCT06153966) and notified patient groups that they are now recruiting again. Of the 16 trial sites that participated in the 2024 enrollment period, only 3 sites are active as of today: Cleveland, Tokyo, and Yamguchi. More sites may yet open, but Ionis’s announcement also says that not all sites will necessarily participate.

The nature of this third “dosing regimen” being added now has not been disclosed, but my speculation is that it’s most likely a third dose level. If the previous levels were low and mid, then let’s call this one high dose. (Another possibility I cannot rule out is that the new regimen involves a different dosing frequency rather than a different dose level in milligrams.) Unlike the previous two dosing regimens, this one is not randomized to placebo. All patients will receive the experimental drug. I speculate that this is because Ionis feels it has already collected enough placebo data to which to compare the patients on active drug. In addition, the open label extension (OLE), through which surviving participants in the first cohorts are still receiving experimental drug, will continue, and will also be offered to the new participants.

what does this mean?

Ionis has not shared any results from the trial, other than to say:

The preliminary data show an encouraging safety and tolerability profile that support expanding PrProfile to test an additional dosing regimen. These preliminary data are not sufficient to establish the safety, tolerability, or efficacy of ION717 as a treatment for prion disease.

My interpretation based on publicly disclosed information is that most likely, the first two dosing regimens looked safe enough (which does not mean perfectly safe), but did not lower PrP quite as much as hoped. Therefore, Ionis wishes to test a higher dose level in the hopes of lowering PrP more deeply. The first two dosing regimens tested in 2024 must not have been a disaster (if they had, development of ION717 would likely have been terminated) and must also not have been a home run (if they had, Ionis might have advanced straight to a pivotal trial designed to get the drug approved). All this is my interpretation, which has not been confirmed by Ionis.

For patients being diagnosed just now, and their families, this means there is a trial you can screen for and might be eligible to participate in. But remember, this is still research, and not treatment. We do not know whether ION717 is safe nor whether it is effective. These are questions that only clinical trials can eventually answer, but we don’t have the answers yet. And as before, pre-symptomatic people at risk of genetic prion disease are still not eligible for this trial.

Going forward, Ionis now says the primary completion date — the last patient visit — is estimated for February 2027. After that, the company will likely take time to run tests on the blood and CSF from the trial, then crunch the data. If we’re lucky, perhaps before the end of 2027 they might make some announcement at a conference or in a press release as to the top line results of the trial. Ionis has not committed to any timeline, that is just my speculation based on typical practices in the industry.

For now, we can be glad that the data from the first two dosing regimens of PrProfile looked good enough to support continued development of the drug, and we can be glad that research will continue.