Everybody is excited about TEV-408.
I’m interested.
I’m not excited yet.
And the reason is two letters and two numbers:
IL-15.
TEV-408, also known as TEV-53408, is an investigational monoclonal antibody designed to block interleukin-15, or IL-15, an immune signaling molecule involved in the intestinal inflammation and damage of celiac disease.
And the Phase 2a results Teva released last week are legitimately interesting.
The TEV-408 Results Are Good News
The study included 50 adults with celiac disease who were already following a gluten-free diet and had minimal intestinal damage at baseline.
Participants received a single subcutaneous injection of TEV-408 or placebo. Two weeks later, they began a six-week daily gluten challenge.
TEV-408 met its primary endpoint.
People receiving the drug had significantly less deterioration in villous-height-to-crypt-depth ratio than people receiving placebo.
The results involving intraepithelial lymphocytes, or IELs, were particularly interesting. The placebo group experienced a substantial increase in IEL density during the gluten challenge, while the TEV-408 group barely changed.
Participants receiving TEV-408 also reported lower gastrointestinal symptom scores.
Teva says there have been no emerging safety signals to date.
THAT’S GREAT NEWS.
And I mean that.
There is currently no FDA-approved drug that replaces the gluten-free diet for celiac disease, and I want researchers pursuing multiple approaches to treating this disease.
I’ve written before about the very different ways researchers are trying to develop medications for celiac disease. TEV-408 is particularly interesting because instead of doing something to the gluten itself, it is attempting to interfere with part of the immune response that follows.
But TEV-408 isn’t our first trip down this particular road.
We’ve Tried Blocking IL-15 Before
If you’ve been reading Fat Celiac for a really long time, this may sound familiar.
Meet AMG 714.
AMG 714 was the first anti-IL-15 monoclonal antibody investigated as a treatment for celiac disease. The Phase 2a randomized, placebo-controlled gluten-challenge trial included 64 adults with celiac disease.
And I’ve been writing about it since 2019.
I wrote about AMG 714 and IL-15 in July 2019, before the complete study results were published.
Then came the results.
AMG 714 showed some interesting effects on IELs and symptoms, particularly at the higher dose.
But it didn’t meet its primary endpoint. It did not significantly prevent the gluten-induced deterioration in intestinal architecture compared with placebo.
I wrote about those AMG 714 study results in September 2019.
And that still wasn’t the end of AMG 714.
The drug eventually became PRV-015 and researchers continued investigating whether blocking IL-15 might be useful in different celiac populations and circumstances. I wrote about AMG 714 returning in 2020 and later about the PRV-015 clinical trial.
AMG 714 was also studied separately in refractory celiac disease type 2. That Phase 2a trial likewise did not meet its primary endpoint of reducing aberrant IELs, although investigators reported some potentially interesting secondary findings.
So when I see another anti-IL-15 antibody producing positive celiac results, my reaction isn’t:
We’ve finally found it!
It’s:
Wait. What’s different this time?
Why Did TEV-408 Succeed Where AMG 714 Didn’t?
That’s the question I really want answered.
Both drugs are monoclonal antibodies targeting IL-15.
Yet TEV-408 met its Phase 2a primary endpoint while AMG 714 did not.
So what changed?
Is TEV-408 a better antibody?
Does it bind differently?
Is it more potent?
Does it remain active in the body longer?
Was the dose more effective?
Did differences in the study populations or gluten challenges matter?
Is it some combination of those things?
I don’t know yet.
And that’s why this result is interesting.
A disappointing clinical trial doesn’t necessarily mean the underlying biological target was wrong. Sometimes researchers learn something from the first attempt that allows them to build a better second attempt.
Science isn’t a straight line.
Then There’s My Bigger IL-15 Question
There’s another reason I’m not ready to jump up and down yet:
What does long-term IL-15 blockade look like?
IL-15 isn’t something scientists invented for celiac disease. It’s a cytokine involved in normal immune biology, including the development, survival and activity of natural killer cells and certain T-cell populations.
That doesn’t mean blocking IL-15 is inherently dangerous.
It means long-term safety matters.
And there’s an important limitation here.
We don’t currently have years of real-world experience with an approved direct anti-IL-15 drug being routinely used in another disease that allows us to simply look at that population and see what prolonged IL-15 blockade does.
AMG 714 provides some human experience with the approach, but it remained investigational. TEV-408 itself is also being developed for vitiligo, so I’ll be paying attention to that program as well.
There have been other investigational attempts to interfere with IL-15 or its signaling pathways, but that’s different from having years of post-approval, real-world exposure to a selective anti-IL-15 antibody.
That’s why a 50-person Phase 2a study can make me interested.
It can’t give us long-term experience we don’t have yet.
That Doesn’t Mean I Think TEV-408 Is Dangerous
This distinction matters.
I’m not arguing that blocking IL-15 is dangerous.
I’m not arguing that TEV-408 shouldn’t move forward.
And I’m certainly not arguing that these results aren’t important.
I’m saying:
We don’t know yet.
That’s not a criticism of a Phase 2a trial.
That’s what Phase 2a is for.
Drug development happens in stages because different stages answer different questions.
Early studies can tell us whether a biological idea appears to work in humans and begin establishing a safety profile.
Larger and longer trials give us considerably more information about efficacy, dosing and less-common or longer-term adverse effects.
That’s also why reading a headline announcing that a celiac drug “worked” isn’t enough. I’ve written before about how clinical-trial design can affect what we’re actually measuring in celiac research.
The details matter.
So Where Am I on TEV-408?
I’m watching.
I’m encouraged that TEV-408 met its primary endpoint.
I’m fascinated that researchers are revisiting an immune pathway that has been studied in celiac disease for years — and apparently getting a different result.
And I really want to see the complete data.
Right now, we’re working from topline results released by Teva. More analyses are still to come.
That’s enough for me to say:
This matters.
It’s not enough for me to say:
This is it.
So I’m not quite at:
YEAH TEV-408 — THIS IS IT!
Yet.
I’m at:
Okay, TEV-408. You have my attention. Now show me more.
Cheering is easy.
I want to know what happens next.
That’s the part of celiac research I find most interesting anyway.
Not just what happened?
But:
What came before it?
What’s different now?
And what question should we be asking next?
External reading
- TEV-408 Phase 2a results from Teva — current topline celiac results.
- AMG 714 Phase 2a celiac gluten-challenge study in The Lancet Gastroenterology & Hepatology — the key predecessor trial and best link for the “we’ve been here before” argument.
- AMG 714 Phase 2a refractory celiac disease trial on PubMed — useful for the broader IL-15/AMG 714 history.
Leave a Reply