Today we’re proud to announce that PRiSM (NN112), our first-in-human clinical trial of PrP-siRNA, has begun enrolling pre-symptomatic participants at high genetic risk of prion disease. Potential participants can learn more on the study’s ClinicalTrials.gov posting as well as official announcements on the Prion Alliance blog and our Community Statement. People interested in participating in the trial should contact a study site to ask to be screened for eligibility.

This blog post will review how we got here, what we hope to accomplish, and what might come next.

How PRiSM started

For years we’ve worked on multiple approaches to lower PrP, the protein that causes prion disease, in the brain. PRiSM, which launched in April, is a first-in-human clinical trial of a divalent siRNA drug (known as 2439-s4, 2439-exNA, or PrP-siRNA) [Gentile 2026]. The trial, sponsored by the Broad Institute and funded by NIH through the NeuroNEXT program, is a single ascending dose trial. The trial is designed to test the safety as well as potency (how much it lowers PrP) of just a single dose of the siRNA, administered intrathecally (through a lumbar puncture). We don’t yet know if PrP-siRNA is safe or effective in humans. Indeed, this early stage trial is not designed to determine whether the drug is effective — meaning whether it slows disease progression or increases survival. The trial is only a first step towards evaluating the drug’s potential in human patients.

Earlier this year, the trial began recruiting and dosing symptomatic patients diagnosed with prion disease. We chose to start testing the drug in symptomatic patients, because all drugs — especially brand new drugs never previously tested in humans — carry risks, and in symptomatic patients, who are typically declining rapidly, this risk is justified. Initially, we also only had clearance from FDA to test the drug in symptomatic patients.

Why we are able to now open a pre-symptomatic arm

When we first submitted our Investigational New Drug (IND) application to FDA to request permission to proceed to clinical trials, the Agency allowed us to proceed only in symptomatic patients. The FDA’s initial rationale was that our toxicology studies in animals hadn’t evaluated the safety of lowering PrP, because the drug, which targets a specific RNA sequence, does not match the PrP gene in any other species besides humans and monkeys. Before we could dose pre-symptomatic patients, FDA wanted us to do further toxicology studies in monkeys to discharge this risk. We submitted a response arguing that the safety of PrP lowering has been established through decades of animal studies, with some support from human genetic data as well. While these studies do not, and cannot, prove that PrP lowering is perfectly safe, we argued that a new study in monkeys would not prove that either, particularly because any potential side effects of PrP lowering might only emerge upon deeper lowering than this drug achieves, for a longer period of time than a toxicology study lasts. FDA’s initial response had cited [Wulf 2017], a comprehensive review of scientific literature about biological roles of PrP and potential consequences of its absence. In our response we included a letter of support generously provided by Adriano Aguzzi, the senior author of that paper, arguing that the overall read of the literature was that any effects of PrP lowering would be mild, and that available data supported proceeding to a trial in pre-symptomatic individuals. In her remarks to FDA at the Duke Margolis RISE Forum, Sonia emphasized that she, a pre-symptomatic carrier, is at high risk of a terrible, fatal disease, and that “we need to be having a serious conversation about when humans get the right… to cut the monkeys in line”.

As we’ve discovered on several occasions now, FDA are smart, reasonable scientists. They heard us. The Agency responded with a request for a very reasonable set of modifications to our protocol and consent form, and allowed the pre-symptomatic study to proceed. (Building on the public IND documentation we shared in 2025, we’ve now posted our updated regulatory interactions with FDA around the pre-symptomatic arm to our lab website for you to read). In the months since then, NIH generously added funding for the pre-symptomatic arm through a modification to the NeuroNEXT grant, and the IRB (the hospital ethics board) cleared the protocol as well. PRiSM is designed to proceed through 3 dose levels each tested in a separate group of participants: first 50 mg, then 100 mg, then 200 mg. The pre-symptomatic protocol that we wrote called for the opening of each dose level in pre-symptomatic people to be gated on an acceptable safety profile after testing that same dose level in symptomatic patients first. Therefore, our opening of the pre-symptomatic arm today is currently at a 50 mg dose level, and is thanks to the Data Safety Monitoring Board for our trial determining that the safety of 50 mg in symptomatic patients was acceptable. We do not yet have data on target engagement (PrP lowering), and PRiSM is not even designed to be statistically powered to assess clinical outcomes such as rate of disease progression. The current decision to open the pre-symptomatic trial does not mean that the drug was found to be potent or effective, only that it was deemed safe enough based on limited data from a few human patients.

What participants should know

We hope that participants who enroll will do so as a contribution to research, and not out of an expectation of direct health benefits. There are not yet any human data to demonstrate a benefit of PrP-siRNA, and this early stage trial is not designed to determine whether the drug benefits people.

Participants should know that even though PrP-siRNA has now been tested in a few symptomatic patients, it is still a very new drug. We have only a limited toxicology package in animals — less than FDA typically requires, and the consent form that participants sign will warn you of this. We have human data from very few patients, and for only a short period of time. People with high-risk PRNP genetic variants are at very high probability of developing a severe disease with a usually rapid decline that once it strikes, may be irreversible. For this reason, we believe it’s important to develop drugs for the pre-symptomatic population. At the same time, this clinical trial is an experiment, and participation carries risks.

A participant’s schedule in the pre-symptomatic arm looks almost exactly like the symptomatic arm of the trial, which I outlined in my previous post. If a pre-screening phone call suggests that a participant may be eligible, they will be invited to an in-person screening visit. Participants will need to have their genetic test report in hand confirming they have a PRNP variant, and only those genetic variants that cause a high risk of disease are eligible. This test report will be reviewed at screening, along with a host of tests and questionnaires to confirm eligibility. If the participant is deemed eligible, a trial site will schedule a baseline visit in which the investigational drug is administered. For the baseline visit, the participant is admitted to the hospital overnight for monitoring. Afterwards they will return for several in-person visits, at 1, 2, 4, 8, 12, and 24 weeks post-dose. This sequence of visits was designed to allow us to monitor whether the drug is safe and whether it is doing its job of lowering PrP. Each visit will involve a variety of activities, such lumbar puncture for CSF, blood draws, MRI scans of your brain, neurological and medical exams, cognitive testing, reviewing any adverse events and changes in medications, and more. Not all activities will occur at every visit.

This trial will have lots of built-in pauses for safety monitoring and reviews. At many times, it will not be recruiting at all, or will have only 1 or 2 trial slots open. For pre-symptomatic participants, we already have a lot of observational data from OBSERVE, our long-running biomarker study at Mass General, so PRiSM does not include an observational arm for this population. Pre-symptomatic people who contact a study site about enrolling at a time when a slot is not currently open, may be kept in a log and recontacted later when a spot opens up.

Goals for this arm of the trial

The goal, at this stage, is not to clinically benefit the individual participants in the trial. We’re administering just a single dose that may be active for some number of months but not forever, at a dose level that we don’t yet know how active it is. Even if the drug were to successfully lower PrP, and even if lowering PrP turns out to be the right thing to do, we don’t expect that to translate to benefit in this trial. Relative to the scheme of all the years of life that someone is living at risk, a single dose is not likely to move the needle on lifetime risk or age of onset. Instead, as with the symptomatic arm of this trial, the goal here is to gain initial human learnings that will guide further development of this drug. How much can we lower PrP? For how long? Using what dose levels? With what safety profile? The answers to these questions will determine whether, and exactly how — what dose level, what dose frequency, in what group of people — we evaluate PrP-siRNA for pre-symptomatic people in a future clinical trial.

As patient-scientists with a long term commitment to solving this disease, we also seek to make the learnings from this trial larger than this one drug. Already by opening this arm, we’ve charted new regulatory territory with FDA and established a precedent that we hope other sponsors can follow. By running this pre-symptomatic trial arm, we hope to learn who we can recruit, how quickly, how people and demonstrate to other sponsors that drug development for pre-symptomatic people is feasible. We’ve made a commitment to share individual-level patient data from the trial so that our data can help inform future trials. Whether or not we ultimately determine that divalent siRNA has a future in prion disease, we hope that running this trial will be step forward for clinical research in prion disease.

What to expect next

Drug development is painstakingly slow, and this is especially true at the clinical phase. To accommodate the new pre-symptomatic arm, NeuroNEXT has generously extended the funding for the PRiSM trial through November 2029. The plan is to recruit all the participants and complete all the study visits sooner, with the final stretch reserved for analyzing samples (blood, spinal fluid) and data collected in the trial. We’ve already seen that in our symptomatic trial arms, there are a lot of pauses, with generally only 1-2 slots open at any given time, and then lots of weeks in between to collect safety data before proceeding. That will be doubly true for pre-symptomatic, because proceeding in pre-symptomatic is gated on the safety data collected not only in the pre-symptomatic arm but also in the symptomatic arm. If we see something worrisome in either patient population, we could need to pause to learn more, or stop entirely. That’s true for symptomatic patients too, of course, but it’s especially true in pre-symptomatic because these are people with, on expectation, years of healthy life to live, and the level of risk acceptable for a new drug needs to be calibrated accordingly.

The good news is, we’re moving forward and blazing new territory — an immense privilege, and it’s with great gratitude to NeuroNEXT for funding this trial, the Broad Institute for sponsoring it, and our incredibly motivated patient population for showing up. Beyond that, we don’t expect to have any specific news on trial results for a while. We’ll just be running the best trial we can, and learning the most we can from it.