Today Ionis Pharmaceuticals doubled down on its commitment to prion disease and announced a new timeline for a first-in-human clinical trial. Details are still limited but this blog post will unpack what we know and what we can expect.

background

For those just tuning in now: Sonia and I are not affiliated with Ionis Pharmaceuticals. We are patient-scientists trying to cure Sonia’s disease from our laboratory at the Broad Institute of MIT and Harvard.

Sonia and I announced in 2018 that we were collaborating with Ionis on a drug to lower PrP for prion disease. We had visited Ionis at their headquarters in Carlsbad, California in 2014 to make the case that their antisense oligonucleotide (ASO) technology was a perfect fit for prion disease: we have a bad actor protein we want to lower in the brain, they have a programmable drug modality deliverable to the brain and capable of lowering the RNA for most any gene. By 2018 our collaboration with them had yielded enough positive data that they were willing to commit to making a drug candidate to bring forward to clinical trials.

But then the timeline dragged for a few years. Drug development is an enormously complex and difficult undertaking, and any number of scientific and regulatory obstacles can result in setbacks. Ionis initially told the prion disease community that they planned to launch a first-in-human trial of a drug candidate called ION716 in 2021, but subsequently pivoted to a different drug candidate. In March 2022 they again said trials would begin by end of 2022, but the end of 2022 came and went without any public statement. Ionis was clearly still committed to prion disease — they continued to fund research in our lab and others, they sponsored the CJD Foundation’s 2023 conference, and they presented data at conferences. But the timeline to trials remained an unknown.

today’s announcement

This morning Ionis released an official statement for the prion disease community. They also discussed their plans at an investor event called Innovation Day held live in New York and available via webcast (press release, slide deck). Key points include:

  • The new drug candidate is named ION717
  • They intend to start a first Phase 1/2a clinical trial, called PrProfile (pronounced simply “profile”), by end of 2023.
  • That first trial will in symptomatic patients — they are not enrolling pre-symptomatic at-risk people at this time
  • They don’t plan to make the drug available outside of the clinical trial
  • ION717 will be developed solely by Ionis, without any big pharma partner

Here’s a screenshot of a slide presented today, showing the timeline and the logo they’ve designed for the upcoming trial:

It is worth briefly mentioning, the event today also highlighted a few technological advances at Ionis that, while not immediately relevant to prion disease, could be promising for the future. The company is betting on a new chemical backbone, mesyl phosphoramidate (MsPA), that they developed recently [Anderson 2021], to provide better potency and tolerability for future drugs. In a shift with decades of precedent, Ionis now says they’ll also be developing siRNAs, and not just ASOs — the two drug modalities are both oligonucleotide-based and lower a target RNA molecule, but act via different mechanisms inside the cell. Finally, they say they have “targeted delivery” technologies in the pipeline with progress in “delivering medicines across the blood-brain barrier with systemic dosing” — a hint that one day, a drug might be delivered by an intravenous or subcutaneous route rather than intrathecal (via a lumbar puncture). Again, none of these are likely to be relevant to the current drug. The timeline of drug development is such that anything ready to dose patients today is based on techology that is at least a few years old. Thus, while details have not yet been disclosed, we can assume that ION717 probably uses a more tried-and-true backbone chemistry without any new MsPA modifications, is an ASO, and will be delivered via lumbar puncture.

what this means

While details are limited so far, here’s a bit of what I think we can take away.

First: this sounds real and imminent. Granted, we’ve seen timelines slip before, and the slide deck does contain the caveat “Timing based on current estimates, subject to change.” But: the new drug candidate has a name, the trial has a name, the statement gives a specific short-term timeline and tells readers to expect more details on clinicaltrials.gov. That’s more detail than Ionis has given prion disease patients at any time up until now. Launching a clinical trial is a huge amount of work: a sponsor needs to file an Investigational New Drug (IND) application with FDA (and/or equivalent in other countries), get Institutional Review Board (IRB) ethical approval from the hospitals involved, sign contracts with the hospitals, train the clinical site personnel to run the trial, enlist clinical laboratories to analyze the samples, convene a data monitoring committee, and so on and so on. If Ionis believes that they will be starting the trial before 2023 — in under 3 months — we can infer that most of these activities are already well underway and some may already be complete. That makes this all seem more concrete than it has seemed up to now.

Second: only symptomatic patients will be eligible for now. Sonia and I have long advocated for preventive trials in pre-symptomatic people at risk for prion disease, such as Sonia. Apparently that won’t happen in this first trial. The rationale provided in the community statement is simply that “this pathway will enable the quickest opportunity to evaluate whether ION717 will help people with prion disease”. That implies that a trial in symptomatic patients either will be faster, or could launch sooner, or both. But Ionis hints that they still aspire to treat pre-symptomatic people eventually, perhaps in a future trial. The community statement says that “The information from this study and our additional research will help determine next steps in the program”, which may imply that pre-symptomatic trials are a possible next step depending on results from this trial and other ongoing research studies. In her presentation at Innovation Day, Holly Kordasiewicz, Senior Vice President of Neurology Research at Ionis, stated that ION717 “has the potential to treat all forms of the disease. This includes both presymptomatic patients with gene mutations as well as symptomatic patients. Our goal is to treat all patients.” Note that throughout its statement and investor slide deck, the company has always used the term “prion disease”. To me, this suggests that patients of all subtypes (CJD, FFI, GSS, etc.) will be eligible, since after all, they are all the same thing at the molecular level, and ION717 is designed to target the root molecular cause: PrP.

Third: the drug will only be available to patients enrolled in the clinical trial. There exist various legal mechanisms, in the U.S. and elsewhere, for a pharmaceutical company to provide an experimental, still-unapproved drug to patients outside of a trial. You may have heard terms such as Expanded Access Program (EAP), compassionate use, preapproval access, Treatment IND, and Right To Try. Some of these terms have an official definition in FDA parlance, while others are used more loosely. This is a good starting point if you want to understand the technical details and terminology. There are a lot of common misconceptions about many of these pathways, including the idea that Right To Try means the right to a drug, when in fact, it only means people have the right to ask, while the company has the right to say no. Regardless, the statement today indicates that Ionis will not be providing the drug through any such pathway. This is a fairly typical decision for pharma companies at this stage, for a variety of reasons. In some cases this is because the clinical trial is randomized (some percent of patients get placebo) and the company does not want to siphon potential patients away from the clinical trial by offering a different pathway by which patients are guaranteed to get the drug. In other cases it may be because companies fear it is harder to ensure the safety of patients receiving an experimental drug outside of a trial. Yet another possibility is the fear that any adverse events that occur outside of a trial may be held against them by FDA, though FDA says this is very rare: this says “it is extremely rare for FDA to place an IND on clinical hold due to adverse events observed in expanded access treatment. Review of >10,000 expanded access INDs invoking >1000 commercial INDs revealed only 2 clinical holds (0.2%).” By way of justification, Ionis’s community statement simply says that “evaluation of the safety and efficacy of ION717 in clinical trials is essential to establishing whether ION717 can help people diagnosed with prion disease”, which doesn’t give a ton of detail as to the thought process behind the decision.

Fourth: Ionis is developing the drug solo — it will be “wholly owned”. In contrast, many of Ionis’s recent drug development programs have been partnered with big pharma companies: tominersen for Huntington’s disease with Roche, tofersen for SOD1 ALS with Biogen. Ionis does still have drugs in development that are partnered — the press release also highlighted some data from a collaboration with AstraZeneca — but Ionis now seems to have a lot of enthusiasm for also taking some drugs forward on its own, including its ASOs against GFAP, MECP2, PLP1, and now the prion protein gene PRNP. My take is that this is probably good news: getting a second company involved could mean too many cooks in the kitchen, and sometimes big companies can be slow and bureaucratic. Ionis is a smaller, more nimble company, and my guess is that them moving this forward solo will mean a better alignment between our sense of urgency and their sense of urgency. Of course, the counter-argument would be that big companies can bring a lot of resources to bear, but if Ionis feels they can marshall those resources without a big pharma partner, so much the better.

what to expect next

I bet there will probably be a series of incremental updates over the next few months. The statement alludes to an upcoming clinicaltrials.gov posting. Once that goes live, we will know a lot more, possibly including: which hospitals nationwide and worldwide will be clinical trial sites, what criteria allow a patient to be eligible, how many patients they plan to enroll, and for how long they plan to treat them. Until then, there’s a lot of guesswork.

One important question that, sadly, many families will be grappling with is whether to keep a loved one alive on life support in the hopes that they’ll eventually be able to enroll in this clinical trial. The Ionis statement does not any provide guidance on this question, but we can find a few precendents to help guide an educated guess.

All prior trials of Ionis’s ASOs in other neurological diseases have excluded patients who were too advanced. The VALOR trial of tofersen in SOD1 ALS (NCT02623699) and the trial of ION363 in FUS ALS (NCT04768972) both restricted enrollment to patients with forced/slow vital capacity (FVC or SVC, each being measures of respiratory function) ≥50%. This criterion may have been designed to ensure that patients still had sufficient quality of life left to preserve, or, that patients would live long enough for the drug’s potential benefits to kick in — FVC is a predictor of survival in ALS [Czaplinski 2006]. Similarly, the GENERATION-HD1 study of tominersen in Huntington’s (NCT03761849) required an independence score ≥70, the trial of a MAPT ASO in Alzheimer’s (NCT03186989) was restricted to people with “mild Alzheimers disease”, and so on. And Ionis isn’t alone in this: our retrospective analysis of 20 years of clinical trials in neurodegenerative diseases found that a majority of trials used some kind of disease severity rating scale as an inclusion/exclusion criterion, and over the past two decades, the number of such criteria per trial has doubled and the strictness of the maximum severity cutoff has gotten tighter [Mortberg 2022]. All told, my guess is that it’s very unlikely that the upcoming Ionis trial would enroll patients who are already on a feeding tube or a ventilator.

Indeed, given that prion disease progresses so quickly and that our mouse studies found that ASOs take at least few weeks to yield benefit [Minikel 2020], my guess is that Ionis will have a fairly strict cutoff, trying to restrict enrollment to patients who were only just recently diagnosed and/or still have substantial cognitive capacity, in part to ensure that patients will live long enough for the drug to kick in. Mechanistically, we believe that lowering PrP, as ION717 is designed to do, can help to save neurons that are still hanging on, but is not going to bring back neurons that are already dead, so I would not expect a PrP-lowering drug to reverse existing symptoms in patients who are already advanced.

The above question, which I’m sure many families are grappling with right now, is just one example of the new problems we’re about to have as we enter a new era of rationally designed therapies for prion disease. PrP-lowering ASOs work in animal models and appear to be by far the most credible shot-on-goal for a prion disease drug that we’ve ever had yet. That such a therapy may soon enter trials is an incredibly hope-inspiring development. But until now the message of “there’s no hope for patients diagnosed today” was devastating but simple. Now things get more complicated. There will be both high hopes and dashed hopes, rage and regret. Not everyone who wants or needs the drug will get it. Trials will last years. People will die waiting. The drug may turn out to be safe and effective, or it may not. Even if the ultimate outcome is the best possible outcome, it’s not going to be easy getting there.

Sonia and I will continue to share updates, here on CureFFI.org and on PrionAlliance.org, as we hear them. Now that you’ve read this blog post, we don’t know more than you do. Please don’t write to us asking for the drug — we don’t have it either, and we don’t control what Ionis does with it. All anyone can say for now is, stay tuned.