This blog post is a call to action. Patients newly diagnosed with prion disease in the U.S. have an opportunity to make a meaningful contribution to research by participating in Brian Appleby’s Teleneurology Assessment Program in CJD, or TAPCJD for short. In this post, I’ll talk about this moment in prion disease research, what we need, and how participating in TAPCJD can help.

this moment in the quest for a cure

We’ve entered a new era in the quest for a cure for prion disease. With the launch of PrProfile (NCT06153966) in 2024 and PRiSM (NCT07444580) in 2026, we now have 2 clinical trials, recruiting patients right now, of drug candidates designed to lower PrP, the protein that causes prion disease. As I opined shortly after PrProfile launched, this is the end of the beginning. For the first time ever, we are doing experiments in humans where the mechanism (lowering PrP) and the modalities (ASO and siRNA) have been shown in animal models to delay and slow prion disease.

At the same time, a long road still lies ahead to get us to a first safe and effective approved drug for prion disease. And an even longer road to a last drug. Because even after we have a first drug, we will still need more clinical trials, better drugs, and better combinations. To do all these clinical trials and do them right, we need more and better data describing the natural history of prion disease. That’s where TAPCJD comes in.

why we need natural history data

We do lots of animal studies in prion disease, but ultimately, only clinical data — data from human beings — can determine whether a drug is safe and effective. In the U.S., FDA’s mandate from Congress is to approve drugs based on “evidence consisting of adequate and well-controlled investigations” [21 U.S.C. §355(d)], so that only once a drug has been shown safe and effective in clinical trials will it be approved and widely available to patients who need it. The key term here is “well-controlled.” Who or what are the controls to which we compare data from patients in a trial?

There are a few options here, all of which need natural history data.

Many clinical trials are randomized and placebo-controlled. Some patients get the investigational drug, while others get a mock injection, or sugar pills. This is considered the gold standard, the strongest form of evidence for a drug. But all things being equal, patients would usually rather not get placebo, especially in a fatal and incurable disease, and the people running the trial would rather generate data about their drug from more people, rather than wasting a third or half of them on a placebo group. Moreover, even designing a placebo-controlled trial is hard to do right. You have myriad decisions to make: which patients to include (which subtypes of disease, how advanced can their disease be, what diagnostic criteria do they have to meet), how long to follow them, what assessments to perform to quantify their disease severity. If you get any of those parameters wrong, your trial results could easily appear null — meaning no difference between placebo and drug — regardless of how good the drug is. If you want to get all those parameters right — enroll the right patients for the right amount of time and measure the right things — you need natural history data, defined as data that describes what the disease “naturally” looks like, without attempted interventions. Those data allow you to run simulations and power calculations and figure out what trial design can get you the most definitive answer the most quickly, with a reasonable number of patients.

In some cases, FDA will accept a clinical trial that is open-label, meaning all patients knowingly receive the investigational drug, compared to natural history data. Here, you’re not just using the natural history data to design your experiment, the natural history data are part of your experiment. Thus, the bar for the quality of those data is much higher. FDA has outlined when, and how, natural history can form a control arm, in its 2018 Real-World Evidence Program Framework. We call these external control arms (ECAs), and understanding the opportunities and pitfalls of ECAs would be a whole separate blog post, if not a whole separate career. If it can be done right, an ECA means that all patients in a trial get drug, instead of needing to have a placebo group. There are multiple examples where this approach has failed, and multiple other examples where this approach has succeeded and been accepted by FDA for drug approval.

No matter what disease and what approach sponsors end up using, natural history data always plays a critical role in designing and conducting clinical trials.

what is TAPCJD

Dr. Brian Appleby, director of the U.S. prion surveillance center, launched TAPCJD in 2017 with the initial goal of determining whether telehealth visits could be used to gather clinical data for prion disease research and surveillance. TAPCJD has become our best source of publicly accessible data on how prion disease progresses clinically over time.

Prion disease is not nearly as rare as people think. These days there are nearly 600 new patients diagnosed each year in the U.S. Cross-sectionally, there exist a lot of data on prion disease. Yet it’s rarer to have access to longitudinal data, meaning data on how patients progress over time across the entirely of the illness. Remembering my mother-in-law’s illness, it’s not hard to see why. She spent months bouncing around from hospital to hospital seeking a diagnosis. She was declining rapidly, but the hope that it might turn out to be something treatable kept everyone searching for answers. When prion disease — for which there was no treatment — was finally suspected, that was the cue to pivot to hospice care. Thus, when we look at routinely collected data from the health care system, we often find that there are not many data points after a diagnosis of prion disease is reached. Yet for designing clinical trials, what we need to know is what happens after diagnosis, after the point when a patient could be referred to trial or go on a drug. Even with all the progress in AI-based data mining, it’s impossible to glean the right types of data from retrospective analysis of medical records, because usually, the data were never captured in the first place, and are never collected in a standardized manner. To do this right, we need to collect the data we want, prospectively.

TAPCJD collects exactly those kind of data — disease progression after diagnosis. Patients generally get referred to TAPCJD by the surveillance center or by CJD Foundation after receiving their diagnostic test results for prion disease. Patients at all different stages of disease are eligible; there is no cutoff saying the diagnosis has to be early enough in the disease process for the patient ot qualify. The whole study is done via a secure, clinical-grade teleconference platform. Patients and/or their caregivers connect with the study team once a month initially, then every 2 months, then every 3 months. By getting the patient and caregiver’s answers to simple questions over the course of about an hour, the study team can tabulate scores on a variety of metrics that quantify disease severity. A key outcome is the MRC Prion Disease Rating Scale (MRC-PDRS), a clinically validated metric that measures impairment in tasks of daily living. Data from TAPCJD have already been used to establish the validity of the MRC-PDRS [Leidy 2025], and the scale is now being used in both the PrProfile and PRiSM trials. Patients also consent to allow the data from their diagnostic tests to be integrated with TAPCJD, so that we can correlate their outcomes with potential risk factors.

using the data from TAPCJD

The best data in the world are of no use if people can’t access and analyze the data. Critically, Dr. Appleby has agreed to share de-identified data with people designing clinical trials, so that they can make the right decisions. We had access to the TAPCJD data while designing our PRiSM trial, and I have shown analyses of TAPCJD data in my talk at the Prion2025 conference and at the Investigator Meeting for PRiSM. The disease progression data from TAPCJD played an important role in our choice of inclusion criteria and clinical trial duration.

At a minimum, TAPCJD data will be critical in designing clinical trials. Data from TAPCJD will also help us determine whether an external control arm could be a viable approach in prion disease. By gathering data from more patients, it may be possible to figure out how well different risk factors, such as prion protein gentype, and subtype of prion disease, predict progression. Depending on the answer, we might be able to see clinical trials with no placebo group, or fewer patients on placebo.

call to action

Even with trials enrolling, TAPCJD is more important than ever. At a moment when trials are enrolling and it feels like we’re finally nearing a meaningful treatment, it would be easy and understandable to feel discouraged about participating in natural history data. People might feel disappointed if and when they learn that they don’t qualify for a trial, or that a trial is full, or paused awaiting safety reviews — all of which are things that happen all the time. But remember, we are not at a stage where we have clinical evidence that these investigational drugs are beneficial. A clinical trial is still an experiment. In fact, in our consent form, we advise people that the only benefit to participating in our trial is the opportunity to contribute to research. Even if you cannot participate in a trial, you still have the ability to make an incredibly valuable contribution to research by participating in a natural history study. Participation in TAPCJD is a valuable gift to the people who will be diagnosed next year, and the year after that.