The Birth of ICOTYDE (3): 1898 Da—Why Can It Still Be Taken Orally?
icotrokinra still has difficulty crossing the intestinal epithelium, but its gastrointestinal stability, 200 mg dose, and picomolar-level potency allow even limited absorption to generate effective systemic exposure.
The Birth of ICOTYDE · Part 3
Previous article: From Peptide 1185 to PN-235: Why Keep Modifying It?
The previous article discussed how a cyclic peptide scaffold capable of tolerating the gastrointestinal environment was advanced to picomolar activity. At this point, researchers still had to face the most difficult hurdle: how can a cyclic peptide consisting of 13 residues, with a molecular weight of 1898.17 Da, cross the intestinal wall, enter the blood, and exert effects throughout the body?
From the perspective of traditional oral drug experience, icotrokinra is unconventional in almost every respect. It contains many peptide bonds, has high polarity, and has a highly complex three-dimensional structure. The solution researchers ultimately found was not to transform it into a readily absorbed small molecule, but rather to make the small fraction of drug that enters the circulation sufficient to produce efficacy, even while absorption remains very low.
The Fact That It Is Difficult to Absorb Has Not Changed
The FDA’s chemistry review places icotrokinra in the biopharmaceutics context of BCS Class IV, meaning that both solubility and permeability present challenges. Although substantial structural optimization had already been performed in earlier stages, the molecule itself still has great difficulty crossing the intestinal epithelium.
Animal experiments clearly reflect this limitation: the absolute oral bioavailability is approximately 0.11%–0.32% in rats and approximately 0.25%–0.30% in cynomolgus monkeys, and the vast majority of intact drug entering the gastrointestinal tract ultimately does not enter the systemic circulation. Because human studies did not include an intravenous dosing control, the absolute oral bioavailability of ICOTYDE in humans is currently unknown; therefore, the approximately 0.2% result from animal experiments cannot be directly applied to humans.
Figure 1. Complete structure of icotrokinra. This figure reuses the structural version from Figure 2 of the first article in this series. The two Pen residues form a disulfide macrocycle, but the molecule still retains a high molecular weight, high polarity, and numerous peptide bonds.
Why Low Absorption Can Still Produce Pharmacological Effects
Whether a drug can be used orally cannot be judged only by its absorption fraction; one must also consider whether the amount entering the circulation reaches an effective concentration. If a drug requires a very high plasma concentration to be effective, absorption of only a few parts per thousand is, of course, far from sufficient. What is distinctive about icotrokinra is that medicinal chemistry optimization reduced its effective concentration against IL-23R to a very low level. In SPR experiments at 37°C, the KD for binding of JNJ-77242113 (PN-235 / icotrokinra) to the extracellular domain of human IL-23R was 7.1 pM; in human PBMCs, its IC50 for inhibiting IL-23-induced STAT3 phosphorylation was 5.6 pM.
The recommended dose of the final product is 200 mg orally once daily. After healthy adults took a single 200 mg tablet under fasting conditions, the mean Cmax was 3.62 ng/mL, AUC∞ was 44.8 ng·h/mL, and median Tmax was 2 hours. Converted using the free-base molecular weight of 1898.17 Da, 3.62 ng/mL is approximately 1.91 nM, indicating that nanomolar levels of intact drug did indeed appear in plasma after oral administration.
The 1.91 nM value here is the total plasma concentration; it is neither the free drug concentration nor the target-site concentration in skin tissue, and therefore it cannot be directly divided by the KD to calculate receptor occupancy. Nevertheless, this set of data is sufficient to illustrate the developability logic of icotrokinra: it did not enable a large amount of drug to cross the intestinal wall, but instead reduced the systemic exposure required to produce efficacy through picomolar activity.
What 200 mg Increases Is the Amount Entering the Body, Not the Absorption Rate
Phase I studies and FDA materials show that, within the dose range studied, plasma exposure to icotrokinra increases approximately in proportion to the oral dose. The significance of 200 mg per day is that it provides a sufficient starting amount of drug for this absorption process with limited efficiency; it does not make the drug’s absorption rate higher. For a highly active molecule, whether the intact drug that ultimately enters the circulation can exceed the efficacy threshold is more meaningful than discussing the bioavailability percentage alone.
This strategy, of course, comes at a cost. Icotrokinra is a 13-mer peptide containing multiple non-natural or modified residues, and a daily dose of 200 mg means higher active pharmaceutical ingredient consumption; it also increases the costs of large-scale synthesis, quality control, and manufacturing. Low bioavailability has not become an advantage; rather, the problems it creates are jointly compensated for by activity, stability, and dose.
Gastrointestinal Stability Leaves Time for Low-Probability Absorption
Human studies found that, at different oral doses, approximately 37%–81% of the dose was recovered from feces as unchanged icotrokinra within 24 hours after dosing, while unchanged drug in urine was approximately 0.001% or lower. These results come from different studies and dosing conditions than the animal bioavailability data discussed earlier, and they cannot be assembled into mass-balance data totaling 100%; however, they do demonstrate an important fact: much of the drug that does not enter the circulation is not rapidly degraded in the gastrointestinal tract, but instead passes through the digestive tract in intact form.
The gastrointestinal stability discussed in the first article shows its value here. Stability does not directly increase permeability, but it can prolong the residence time of intact drug in the gastrointestinal tract, allowing absorption that originally has a very low probability to continue during this period and ultimately accumulate into measurable systemic exposure. The original PK study also noted that these exposures do not depend on a dedicated absorption enhancer; the final product likewise does not use a permeation-enhancing platform such as SNAC or a co-formulated protease inhibitor.
The Food Effect Shows That the Absorption Window Remains Narrow
ICOTYDE needs to be taken under fasting conditions. When the final 200 mg tablet was taken with a high-fat, high-calorie meal, Cmax decreased by 59% and AUC decreased by 43%; therefore, the FDA requires patients to take the drug with water on an empty stomach after waking and to wait at least 30 minutes before eating. Such a pronounced food effect indicates that its absorption still depends strongly on the gastrointestinal environment. Food may affect dissolution, gastric emptying, intestinal transport, the intraluminal environment, or the effective absorption window, but the currently available public information is not sufficient to determine which mechanism predominates.
Once the drug enters the circulation, it also does not disappear immediately. The FDA prescribing information gives a median elimination half-life of approximately 12 hours, which is compatible with once-daily dosing. Of course, dosing frequency is not determined by half-life alone; it must also be judged in combination with PK, PD, the exposure–response relationship, and clinical efficacy.
A Narrow but Feasible Oral Pathway
Icotrokinra has not overturned the principle that macromolecules are difficult to absorb orally. Looking back at its development process, each step compensates for another shortcoming: gastrointestinal stability gives the intact molecule time to await absorption, the 200 mg dose compensates for the low absorption rate, an approximately 12-hour half-life prolongs the residence of the drug in the circulation, and picomolar activity lowers the exposure required for efficacy.
If any one of these elements were missing, this route would be very difficult to make work. If the drug were degraded before it had a chance to be absorbed, the subsequent design considerations would have no basis; if its activity remained at the nanomolar or micromolar level, limited exposure would also have difficulty producing efficacy; if absorption were another order of magnitude lower, or if the drug were rapidly cleared after entering the circulation, increasing the dose might not be enough to solve the problem. The value of ICOTYDE lies precisely in the fact that researchers ultimately made these originally less-than-ideal properties work together, forming a narrow but feasible oral pathway.
Subsequent clinical trials demonstrated that the systemic exposure obtained in this way is sufficient to produce efficacy in patients with psoriasis. The story of FRONTIER, ICONIC, and the final FDA review will be covered in the next article.
Next article: The Birth of ICOTYDE (4): From PN-235 to the FDA—How an Oral Cyclic Peptide Became a Drug