Of every protein our radar tracks, one is pursued more than any other: TNF-alpha, the master switch of inflammation. On its own that's not surprising — anti-TNF biologics have been among the best-selling drugs on Earth for two decades. What is surprising is the chemistry now rising around it.
From the Knitify Pharma Demand Radar — our running read on where pharmaceutical demand is heading. We publish the observations; the method behind them stays in-house.
The climbers aren't antibodies
The inflammation zone is one of the densest on the board, and the molecules climbing through it aren't injectable antibodies. They're oral small molecules aimed at the surrounding inflammatory network from the inside — TYK2, the JAK family, the NLRP3 inflammasome, IL-6. A category built for twenty years on biologics is being re-fought with pills.
TNF-alpha's dominance itself is old news; anti-TNF antibodies proved that neutralizing a single cytokine could rewrite chronic diseases like rheumatoid arthritis, psoriasis and inflammatory bowel disease. What has changed is not the target's importance but the toolkit pointed at it — and the tool now gaining ground is chemistry you can swallow.
The clearest single signal is deucravacitinib — the first oral TYK2 inhibitor to win FDA approval, for plaque psoriasis and, more recently, psoriatic arthritis. [1] It's proof of concept that the most lucrative franchise in medicine — immunology — can be attacked with a small molecule you swallow instead of an antibody you inject.
The science: two ways into the same inflammation
To see why the modality is shifting, follow the wire. A cytokine like IL-6, IL-23 or the interferons is a message released by one immune cell and read by another, and many of those messages travel through a relay called the JAK–STAT axis. (TNF-alpha itself is the telling exception: it signals through a different route, the NF-kappaB pathway, which is why blocking it still takes an injected antibody rather than a pill.) In the JAK–STAT case: the cytokine docks onto a receptor on the cell surface, and on the inside face of that receptor sit Janus kinases — JAK1, JAK2, JAK3 and TYK2. When the receptor engages, these enzymes switch on, tag each other with phosphate groups, and recruit STAT proteins that carry the message to the nucleus and turn on the genes that sustain inflammation. Cytokine outside, receptor at the wall, JAK enzymes just inside, STATs to the nucleus.
Anti-TNF antibodies work at the very first step — outside the cell, mopping up the cytokine so it never reaches its receptor. The oral molecules take the other route — slipping inside the cell to silence the JAK–STAT switchboard that the neighbouring cytokines depend on: IL-23, IL-12, IL-6, the interferons. Same inflammatory network, attacked one node over from TNF.
That difference in location dictates the modality. An antibody is a large protein that acts outside cells and cannot easily cross the cell membrane. A JAK or TYK2 enzyme sits inside the cell, so the drug that blocks it has to get inside too — precisely what a small, membrane-permeable molecule can do and a biologic cannot. Intracellular target, small molecule; extracellular target, biologic. The chemistry and the biology are locked together.
The selectivity problem — and why allosteric TYK2 matters
The catch is right there in the name: the JAK family is a family. Its four members share very similar catalytic machinery, and different cytokines route through overlapping combinations of them. Block the family broadly and you dampen far more than the inflammation you aimed at — JAK2, for instance, also carries the signals that keep blood cell production running. Early JAK inhibitors bound the ATP pocket, the active site, which is highly conserved across the family, so hitting one member cleanly without brushing the others is genuinely hard.
Deucravacitinib is notable because it grips TYK2 somewhere else entirely — at an unusual regulatory site on the enzyme's pseudokinase domain rather than the crowded, conserved active site. Binding there locks the enzyme off without competing at the ATP pocket every kinase shares, and because that regulatory pocket is less conserved, it is easier to hit TYK2 alone. The result quiets the IL-23, IL-12 and interferon signals driving psoriasis while largely sparing the other JAK enzymes. [2] That selectivity is what turns an oral pill from a compromise into a credible rival to an injected antibody.
This is the deeper reason the field took decades. The idea of an oral drug that reaches inside the cell was never the obstacle; making one selective enough to be both effective and tolerable was. And because that is a chemistry problem, the demand it creates lands on people who make molecules, not people who grow proteins.
The demand: a hundred-billion-dollar category, up for grabs
Immunology is one of the largest prizes in medicine — a category worth well over a hundred billion dollars a year, long dominated by injected biologics. Two forces are now pushing demand toward oral chemistry. First, the biologics that built the category are losing patent protection: adalimumab biosimilars have arrived at prices roughly 85% below the originator, which collapses the economics of the old model and rewards genuinely differentiated mechanisms rather than more of the same.
Second, an oral small molecule is simply a different business. Biologics are grown, not synthesized — cultured in living cells inside bioreactors, purified through elaborate multi-step processes, kept cold from factory to pharmacy, and delivered by injection or infusion. A small molecule is built by chemical synthesis in ordinary plants, pressed into a shelf-stable tablet, and swallowed. That contrast cascades through cost of goods, distribution, and the size of the population you can realistically reach. A pill gets to patients — milder disease, markets without cold-chain infrastructure — that an injectable biologic never will.
When a category this large starts shifting from biomanufacturing to synthetic chemistry, the demand for that chemistry is the story, and it's early. The biosimilar wave sharpens the point. Once a biologic loses exclusivity, near-copies crowd in and price competition drives steep discounts. Because biosimilars are expensive to make and not automatically interchangeable the way small-molecule generics are, that erosion is messier than a patent cliff for a pill — but it is real, and it strips the pricing power out of the franchises that defined the category. The way to escape a commoditizing biologic is to offer what a biosimilar can't copy: a different mechanism, delivered a different way. Oral chemistry is that escape route.
Who feels the shift
For makers of small-molecule active ingredients and the contract manufacturers who serve them, this is the headline. Intracellular immunology targets mean demand for complex, often chiral synthesis, high-potency handling, and the kind of process chemistry the CDMO base built for oncology and neuroscience already knows. A modality shift toward oral immunology opens a new stream for that base.
For immunology drug developers, the strategic question changes shape. Franchises defended with better and better biologics now face a second axis of competition: answer biosimilar pressure with a next-generation injectable, or cross into oral chemistry. Differentiation moves from "which cytokine do you block" toward "which node do you hit, and how is it delivered" — and a selective oral option can defend a franchise precisely where a biosimilar cannot follow.
And for biosimilar makers, the shift cuts both ways. Their business is producing faithful copies of the biologics that built the category, and there is real, durable money in that. But if the growth and the pricing power are migrating toward an oral chemistry they don't manufacture, the volume they win sits in a maturing part of the market while the frontier moves elsewhere.
The nuance: pills aren't a free lunch
Oral convenience comes with genuine tradeoffs. The JAK class carries class-wide safety warnings from regulators — cautions around serious infections, blood clots, cardiovascular events and malignancy have been attached to oral JAK inhibitors as a group. Part of the appeal of a selective, allosteric approach like TYK2 inhibition is the hope of separating the benefit from those class-level risks by leaving the other JAK enzymes largely untouched — but the long-term safety of newer selective agents is still being established, and a clean early profile is not the same as a proven one.
Efficacy is the other tradeoff. For some patients and diseases, the best biologics set a high bar an oral may not fully clear; an injected antibody delivers a large, exquisitely targeted molecule the body can't easily match. The oral wave isn't a claim that pills beat biologics on every axis. It's that a differentiated, convenient, cheaper-to-make molecule can be good enough for a broad population — and can reach the large tier of milder disease for which an injection was never worth the trouble.
So the realistic near-term picture is not replacement but stratification: a two-tier world where oral small molecules expand the treated base and hold the milder end, while biologics keep their footing in severe disease. The demand is simply widening to include a chemistry that, until recently, immunology mostly left to other therapeutic areas.
Why the modality shift is the story
This is a manufacturing and market story as much as a scientific one. Oral small molecules are made and sold in a completely different world from biologics: different plants, different supply chains, no cold chain, no injection, and a far larger addressable population. When the most valuable target in medicine starts shifting modality, the demand for the underlying chemistry moves with it — and that shift is exactly what the radar is registering. For anyone who makes small-molecule APIs, "immunology" just stopped being someone else's biologics business.
Editorial commentary from the Knitify Pharma Demand Radar. Not investment, legal, regulatory, or medical advice.