Does Blocking IL-17F Actually Matter?

What IL-17A and IL-17F are

IL-17A and IL-17F are close relatives. They are about half identical, they signal through the same receptor — a two-part complex of the proteins IL-17RA and IL-17RC — and they both switch on inflammation. The difference is strength and amount: IL-17A is the more powerful signal molecule for molecule (it binds IL-17RA more tightly), while IL-17F is weaker but more plentiful in inflamed tissue.

They also come in three forms: two IL-17A molecules paired together, two IL-17F molecules paired together, and a mixed A-plus-F pair. A drug that blocks only IL-17A, like secukinumab (Cosentyx) or ixekizumab (Taltz), clears the A pair and part of the mixed pair, and leaves the F pair active. A dual A/F drug catches all three.

How bimekizumab and sonelokimab block both cytokines

Bimekizumab takes the simple road. It is an ordinary Y-shaped antibody, and it works because the two cytokines look so alike. A patch on their surface is nearly identical on both, and bimekizumab's single binding site grips that shared patch, as its crystal structure with IL-17F confirms. Because the same patch sits on IL-17A, on IL-17F, and on the mixed A/F pair, one antibody neutralises all three. One binding site, three targets.

Sonelokimab takes the modular road, and does not rely on the two cytokines looking alike. It is a Nanobody, a much smaller molecule about a quarter the size of a normal antibody, built from three tiny single-domain binders strung together by flexible links. One grabs IL-17F, one grabs both IL-17A and F, and the third grabs albumin, an abundant, long-lived blood protein. That albumin grip does two jobs: it gives the drug a long half-life, and because albumin leaks into inflamed, swollen tissue, it helps the drug gather where the inflammation is. It is also small, so it slips into tissue more easily. Those two things are its pitch for doing more than a bigger antibody can.

Both end in the same place, blocking the A/A, A/F and F/F pairs alike. But bimekizumab gets there by making one arm that fits both, while sonelokimab bolts separate arms together and adds a delivery trick.

What the genetics say about IL-17

The target is also genetically real, which not every drug can claim: genome-wide studies of psoriasis and psoriatic arthritis keep flagging this pathway, including TRAF3IP2 — the gene for Act1, the adaptor that carries the IL-17 receptor's own signal — and IL23R one step upstream. The genetics even predict the trade-off. People born with a broken IL-17F gene or a missing IL-17 receptor get lifelong thrush (Puel et al., Science 2011), which showed the two cytokines are essential against Candida but otherwise largely redundant. Redundant enough to add little on the joints; essential enough to cost antifungal defence.

The idea behind the dual drugs is simple: if you also switch off IL-17F, you should get more. Whether that is true is something the trials can answer, and the answer turns out to depend on whether you look at the skin or the joints.

ACR50 and PASI90: the joint and skin scores

Psoriatic arthritis attacks the joints and, in most patients, the skin, so its trials report two kinds of result:

• ACR50 is the share of patients whose joint disease improved by at least 50%. Think of it as the joint score.
• PASI90 is the share of patients whose psoriasis cleared by at least 90%. Think of it as the skin score.

Here are the four drugs, with both scores side by side.

Blocking IL-17F adds no proven joint benefit

On the joint score, the two dual drugs sit a little higher. Bimekizumab reached an ACR50 of about 44% in its trials, and sonelokimab reported about 42%. The two IL-17A-only drugs land around 35 to 40%. At first glance the extra target looks worth a few points.

But we cannot compare these numbers, because the trials differ in three ways:

• The measure. Bimekizumab and sonelokimab report ACR50 at week 16. Secukinumab and ixekizumab report their headline as ACR20 (a 20% improvement) at week 24, and their ACR50 is a secondary figure at a later point.
• The timing. Week 16 and week 24 are different checkpoints.
• The patients. Each trial enrolled a slightly different mix.

No trial has put a dual drug directly against an IL-17A-only drug in psoriatic arthritis. So that joint lead is only a guess from numbers that do not quite line up, not something a trial has shown. For now, treat the dual drugs as sitting in the same joint range as the ones they aim to replace.

Blocking IL-17F clears more skin

The skin score is cleaner. Among patients who also had psoriasis, bimekizumab cleared 90% of skin disease in roughly 61 to 69% of them, and sonelokimab reported 61%. Secukinumab, the class leader, reaches 33 to 49% depending on the dose. That gap is wider and steadier than anything on the joints.

The skin also has something the joints do not: a direct comparison. It comes from a psoriasis trial rather than a psoriatic arthritis one, but in the head-to-head BE RADIANT study, bimekizumab beat secukinumab on complete skin clearance (PASI100), the strictest bar there is. Two drugs in the same trial, and the dual one won on skin. That is the strongest evidence the IL-17F idea has so far, and it is a skin result.

This fits a broader pattern. The dual drugs help most in skin-driven disease — complete psoriasis clearance, and conditions such as hidradenitis suppurativa — while in the joint diseases, psoriatic arthritis and axial spondyloarthritis, their advantage over the IL-17A-only drugs is smaller.

Why IL-17F matters in skin but not joints

There is a concrete reason: where each cytokine is made. IL-17A is the more potent of the two, but in psoriatic skin IL-17F is the more abundantly expressed. A drug that blocks only IL-17A therefore leaves much of the skin's signal untouched; a dual drug removes IL-17F as well. In the joint the balance flips: IL-17A predominates in the synovium, where it has been measured at well over ten times the level of IL-17F. If we block IL-17F in the joint, it removes only a small fraction, so it makes little difference. But if we block IL-17F in the skin, it pays off the most, as IL-17F is relatively abundant.

The trade-off: more candidiasis (thrush)

The extra blockade is not free. IL-17A and IL-17F both help defend the moist surfaces of the body — the mouth, throat and skin folds — against Candida, a common yeast. Block both and you remove more of that defence than blocking IL-17A alone, so the dual drugs carry a higher rate of mild fungal infection, usually oral thrush, than the single-target drugs. In bimekizumab's psoriatic arthritis trials, Candida infections were more common than on placebo, though they were mild or moderate, none were systemic, and most cleared with antifungal treatment.

This is the cost side of the decision, and it is exactly why the joint-versus-skin split matters in practice. If a patient's psoriasis is severe, the deeper skin clearing can be well worth a manageable risk of thrush. If the joints are the main problem — where, as we saw, the dual drugs have no proven advantage — you have to ask whether blocking IL-17F buys enough to justify the added fungal risk at all.

Sonelokimab's real rival is bimekizumab

Because both make the same dual A/F bet, sonelokimab's real competitor is bimekizumab, not Cosentyx or Taltz. What separates them is the format we saw earlier: sonelokimab is the small, albumin-anchored Nanobody, bimekizumab the full-size antibody. IZAR-1 was built to start answering one question: does that smaller format deliver a better or longer-lasting response?

One caution about that result. MoonLake reported sonelokimab's 42% joint response on its own, without the placebo group, which stays hidden until the full programme finishes. Without the placebo number you cannot tell how much of the 42% is the drug and how much is the improvement every group in a trial tends to show. The figure is real, but it is not yet something you can line up against the others.

The takeaway: blocking IL-17F helps skin, not joints

Block IL-17F on top of IL-17A and, on today's evidence, the gain is mostly in the skin. It clears more psoriasis, and one head-to-head trial backs that up. On the joints, which are what define psoriatic arthritis, the dual drugs land in the same range as the drugs they mean to replace. The small edge in the numbers may be the difference between trials, not between drugs. And the extra blockade has a cost: a higher rate of mild fungal infection, easy to accept when the skin is the problem and harder to justify when it is the joints.