This morning Ionis Pharmaceuticals announced that it has completed enrollment of PrProfile, its Phase 1/2a trial of ION717, a PrP-lowering ASO for prion disease (NCT06153966). The study’s status is now listed as “Active, not recruiting” on ClinicalTrials.gov.

This trial opened enrollment at its first site just over a year ago, on December 21, 2023, with a target enrollment of 56 participants. The ClinicalTrials.gov entry now confirms 56 as the “actual” (as opposed to “expected”) enrollment, meaning capacity has been reached.

What does this mean?

For patients newly diagnosed and looking to enroll, it’s bad news: there are no more spots in the trial, and indeed, there are currently no experimental therapies for prion disease being tested clinically anywhere in the world. This morning, I had to send my first email reply in a while to someone looking to enroll their sick loved one, saying that I’m sorry, but there’s no experimental drug trial I can refer them to. I haven’t had to send an email like that for a while now, and it’s very sad. And as the Ionis statement today reiterates, the company is not currently providing the drug for compassionate use, Right to Try, or Expanded Access requests.

For all of us pinning hopes on this trial and waiting to hear results, today’s news is another small step forward. Of course, all the enrolled patients still have to continue to undergo treatment, so there is no news today, nor will there be for a while, on how the trial is going. The randomized treatment period is 30 weeks, so if the last participant is receiving their first injection today, then the last study visit would be in July 2025. That’s when Ionis will likely have all of the clinical data from the trial — though analysis of biofluids, such as measuring whether the drug has lowered PrP in spinal fluid, may yet take a bit longer. Often, drug companies sponsoring trials will choose after the study is completed to issue a press release announcing top-line results of the trial, but there’s no guarantee that this will happen on any particular timeline. All in all, we may hope to have some idea in 2025 of how the trial worked out, but exact timing and level of detail to be disclosed remain uncertain. And remember: this is a Phase 1/2a trial with a primary outcome of safety and a secondary outcome of lowering PrP — it’s not designed to tell whether the drug “works” in the sense of slowing disease progression.

Just as I blogged in March, almost any outcome remains possible for this trial. The fact that the trial has remained open and fully enrolled rules out the worst outcomes — if the drug had proven acutely toxic, the trial would have been halted by now — but the outcome could still be anything from bad to medium to good to very good, or even just “hard to say”.

Also included in this morning’s announcement: Ionis has added a 70-week open label extension (OLE) to the trial. This means that all people who were in the trial and who survived through the end of their 30-week randomized period — no matter which arm they were assigned to, meaning in what order they received drug and placebo — will have the opportunity to go on to receive active drug. Of course, this is a rapidly progressive disease and many patients will likely have died before reaching the OLE.

OLEs are common in clinical trials and have been a feature of several recent trials of Ionis drugs, including tofersen for SOD1 ALS. Ionis didn’t share too much of its reasoning in adding this OLE to the trial, saying only that OLEs are “done for many reasons. In the case of PrProfile, the OLE will enable researchers to collect additional, longer-term data associated with exposure to ION717.” It’s certainly true in the case of tofersen that the longer-term data from the OLE ended up being crucial to the ultimate evidence supporting the drug’s efficacy and to its receiving Accelerated Approval from FDA.

Another view, not officially espoused by Ionis, is that OLEs may serve as a gesture of compassion or gratitude to patients who participated in the trial. This point of view was articulated in an HDBuzz Q&A about tominersen, in which one purpose of an OLE was described (by a third party, not by the drug company) as “To thank them for taking the risk of being among the first humans to receive this drug”. That makes sense in that of course people enroll in these trials in the hopes that the drug works and may benefit them, so receiving additional doses of drug is a bonus. But tominersen is also a dark reminder that many drugs turn out not to work, and may even do harm. Remember that we don’t know the outcome of the randomized trial of ION717 yet, and we certainly don’t know whether the drug benefits patients, since this trial wasn’t even designed to determine that outcome. Still, it makes sense that any patient who was hopeful enough about the drug to enroll in the trial would likely also choose to enroll in the OLE, and it’s a benefit to the research community to get longer-term data on this drug.

It’s worth reflecting that out of the 372 days from the date the trial opened to when it closed, it was paused for 132 days from April 5 to August 14. In 240 days of active recruitment, then, they enrolled 56 patients — an average of 1 every 4.3 days. This was at just 1 site in the beginning, ramping up to 11 by the time the pause happened in April, and finally 16 sites by the end. The rapid enrollment of this trial proves that the prion disease community shows up, and that it is easy to quickly enroll trials in this disease.