Issue 03: The fatigue nobody measured

If you have Sjögren's, you already know the thing nobody writes headlines about. It isn't the dry eyes. It's the fatigue. The kind where you've slept eight hours and still can't make it through the afternoon, and the appointment you finally got spends four minutes on your tear film and none on that.

So this issue goes deep on Sjögren's, starting where you'd start. We also promised to give the CAR-T news a proper look, and it turns out to be part of the same story.

Don't have Sjögren's? Stay anyway. A long-ignored disease suddenly getting several new treatment approaches at once is happening across autoimmune medicine, and the CAR-T part applies to a lot of us.

First, the two scorecards

This is the one piece of jargon worth learning, because it explains why a drug can be called a success and still not touch the thing bothering you.

The doctor's scorecard (ESSDAI). A clinician goes through your body system by system (joints, lungs, kidneys, glands, blood) and rates how active the disease looks. You could feel terrible and score low. You could feel okay and score high.

Your scorecard (ESSPRI). You rate three things from 0 to 10: dryness, pain and fatigue. This is the one that reflects your Tuesday.

When you see "met its primary endpoint," the first question is: which scorecard?

A drug moved the fatigue number. Here's the honest version.

A few years ago, a mid-stage trial of a drug called dazodalibep enrolled people specifically because their symptoms were bad, not because their organs looked inflamed, and it measured the three things you actually feel.

Fatigue dropped 1.7 points on the drug and 0.3 on placebo. Dryness fell 1.9 against 0.8, and pain 1.8 against 0.4. On a 0 to 10 scale, a 1.7-point move on fatigue is not a cure, and it's not nothing. It's the kind of change people notice in their week.

Now the part most coverage skips. On 22 September, Amgen announced that dazodalibep succeeded in a large late-stage trial. Good news, genuinely. But that trial used the doctor's scorecard, in people with organ involvement. The matching late-stage trial in people whose main problem is symptoms, the one that would confirm the fatigue result, is expected to finish late this year.

So the fatigue signal is real and promising, and it is still a mid-stage result waiting to be confirmed. Both halves of that sentence matter.

How it works: T cells flip a switch (a protein called CD40 ligand) that turns B cells on. Dazodalibep covers that switch. It interrupts one specific conversation rather than suppressing the whole immune system.

Why it matters: Today's Sjögren's treatments mostly manage dryness. A drug that moves fatigue would be a different kind of thing, and this is the best evidence so far that one might.

Stage: fatigue result is Phase 2 (mid-stage). The September announcement is a Phase 3 topline on the doctor's scorecard, not yet published in full. · Source: Phase 2 trial (PMC); Amgen

The drug with the FDA right now, and what it did not show

Ianalumab is the one we've flagged in both previous issues. It's under FDA review with two designations meant to speed things up: Breakthrough Therapy and priority review. No decision date has been announced. If it's approved, it would be the first targeted therapy approved for Sjögren's disease. We'll tell you the moment there's a decision, either way.

The numbers are more modest than the headlines. In the two big trials, the doctor's scorecard improved by 6.4 and 6.5 points on the drug, and by 5.1 and 5.5 on placebo. So the drug's edge over placebo was around one point.

Look at how much the placebo groups improved. That happens a lot in Sjögren's trials: careful monitoring, attention and hope make people feel and score better. Any real drug has to beat that, not just beat nothing.

On dryness, pain and fatigue, the improvements were described as "numerical." In trial language, that means the numbers leaned the right way but the study couldn't prove the effect. If fatigue is your main problem, this one hasn't answered your question yet.

How it works: it clears out B cells and blocks a survival signal they depend on.

Why it matters: a first approval changes what can be prescribed, even if it's imperfect. First drugs usually are. They open the door for better ones.

Stage: two Phase 3 trials completed; under FDA review. · Source: Rheum Live; Novartis

The CAR-T pause, and where Sjögren's fits

CAR-T in one sentence: doctors take your own immune cells, re-engineer them in a lab to hunt down the cells driving your disease, and give them back. The hope is a reset rather than a lifelong medication, and early autoimmune results were striking.

On 24 August, Novartis paused its autoimmune trials of a CAR-T therapy called rap-cel after three participants developed a rare reaction and very sadly, passed away from the complications.

The paused trials cover conditions including lupus, lupus nephritis, systemic sclerosis, myositis, ANCA-associated vasculitis, rheumatoid arthritis, myasthenia gravis and some forms of MS. One of them is a small, early-stage study in rheumatoid arthritis and Sjögren's, run outside the US.

Separately, Bristol Myers Squibb paused new enrollment in its own autoimmune CAR-T trials as a precaution. People already enrolled will continue.

It's very sad and sobering to hear this type of news. Three people volunteered for research so the rest of us would know more. They were hoping for a cure. I hope one day we can achieve that safely.

A pause is also the safety system doing its job: stopping early, before more people are dosed, while the data is reviewed with regulators. It's why every item in this briefing carries a stage label. Promising and proven are different words.

If you're in one of these trials or were considering one, your trial team is the right place to ask what this means for you.

Stage: early-stage trials, paused for safety review. · Source: CGTLive; BioPharma Dive

On the horizon

Three Sjögren's treatment studies are enrolling in the US right now, all aimed at the disease rather than the dryness:

• CLN-978 (early stage): a shot under the skin that points your own T cells at the B cells driving the disease. Same goal as CAR-T, with no cell harvesting.
• AlloNK with rituximab (mid stage): donor immune cells that help rituximab clear B cells more thoroughly.
• Tofacitinib (mid stage): a pill already approved for rheumatoid arthritis, being studied for safety in Sjögren's by the NIH.

The trial registry shows more hits than this, but several are registries, a tissue bank and a cancer study. We check them by hand. The full list, with what each one is: constellate.health/sjogrens/clinical-trials

Save for your next clinic visit

Try this one: "Is my fatigue being tracked anywhere in my chart, or only my dryness?" If your fatigue has never been written down and scored, it can't show up as better or worse, and the treatments in late-stage trials are aiming squarely at it.

Help us build something for Sjögren's

Sjögren's doesn't get nearly the attention it deserves. We're starting a small community of people with Sjögren's to change that: more visibility for the disease, and support that's actually specific to it, from what we cover here to the tools we build.

It's early, and the first members will shape what it becomes. If you'd like to be one of them, just email me "count me in". That's all it takes.

Not Sjögren's? Email me and tell us your condition. It decides which community comes next.

Close

We went deep on one disease this time because the news earned it, not because we're narrowing. If you've spent years being told there was nothing to follow for Sjögren's, this issue is the argument that it changed while nobody was announcing it.

If this was useful, forward it to someone who needs it.

Meredith

For information only. Not medical advice. Talk to your doctor before changing anything.