Oral cyclic peptides: solid form and formulation development

Scope and Evidence Grading

This report reviews publicly available information on drug-substance solid form, salt selection, drug-product composition, publicly described manufacturing examples and biopharmaceutics for two systemically active oral peptide products newly approved by the US FDA in 2026: Merck’s enlicitide decanoate (LIPFENDRA) and Johnson & Johnson’s icotrokinra (ICOTYDE). It is not a complete review of all previously marketed oral peptide or cyclic-peptide products.

The governing principle is the separation of established fact from inference. Every statement carries a source tag. Where this report draws a conclusion of its own, the conclusion is tagged as an inference and the reasoning is given. Where public information is absent, the gap is listed in Chapter 6 rather than filled by speculation.

Critical review required. This report was generated with AI assistance and is based exclusively on publicly available information. Every reader should independently assess the evidence, reasoning and source documents and should not assume that every statement, interpretation or conclusion is accurate or complete. The principal limitation is the absence of first-hand, non-public program knowledge from the Merck and Johnson & Johnson development teams, including internal CMC data, formulation rationale, failed approaches, decision records and commercial manufacturing details.

Source tags used throughout

1. Executive Summary

Both products were approved in 2026 and are notable new examples of systemically active oral peptides directed at extracellular protein targets. They are not the first marketed oral cyclic-peptide products; earlier examples include oral cyclosporine and voclosporin. LIPFENDRA is the first FDA-approved oral PCSK9 inhibitor, while ICOTYDE is the first FDA-approved targeted oral peptide antagonist of IL-23R. Their formulations differ materially, but the public record is insufficient to characterize them as opposite solid-form strategies because icotrokinra crystallinity is not disclosed.

Principal findings

The approved labels disclose no amorphous-solid-dispersion polymer, self-emulsifying vehicle, nanocrystal excipient system or enteric coating. However, qualitative excipient lists do not disclose particle engineering, drug-substance controls, quantitative composition or unit operations, and therefore cannot prove that either marketed product is a simple dry-blend tablet. Public data strongly support permeability as a major constraint, but do not justify the categorical conclusion that solubility is irrelevant [LABEL 1, 9; INFERENCE].

Enlicitide’s drug substance is amorphous, and all three candidate salts were amorphous. Merck’s patent records the chloride, caprate (used interchangeably with decanoate) and acetate salts as amorphous solids isolated by lyophilization. Salt selection was driven by chemical stability, not by solid-state physical performance [PATENT 3].

Icotrokinra’s crystallinity is not disclosed. The label describes the drug substance only as a white to almost white powder and gives a pH–solubility profile. No dedicated solid form or polymorph patent was found [LABEL 9, NOT DISCLOSED].

The two routes diverge on the use of a permeation enhancer. Merck incorporates sodium caprate (90/180/360 mg in clinical formulations), achieving approximately 1% oral bioavailability at a 20 mg daily dose [LABEL 1, PATENT 3, PAPER 4]. No dedicated permeation enhancer is identified in the ICOTYDE label. Animal absolute bioavailability was approximately 0.1–0.3%, whereas human absolute bioavailability has not been reported; the 200 mg clinical dose cannot be attributed solely to low bioavailability from public evidence [LABEL 9, PAPER 10].

Fasted dosing is a shared commercial limitation. Both labels require administration on an empty stomach with a minimum 30-minute interval before food [LABEL 1, 9]. Merck continues formulation bridging work after approval: MK-0616-044, initiated 31 August 2026, explicitly compares test formulations under fed and fasted conditions against the marketed reference tablet [TRIAL 8].

Analytical development and specification setting are important CMC considerations. Icotrokinra comprises 13 amino acids with 12 stereocenters; the studied material was reported as >95% pure with >95% enantiomeric excess, with potential epimers assessed by UHPLC [PAPER 10]. This does not establish that process-development work is less important [INFERENCE].

2. Enlicitide Decanoate (LIPFENDRA®)

2.1 Approval status and product identity

2.2 Drug substance properties

2.3 Solid form and salt selection

2.3.1 All three candidate salts are amorphous

This is the single most consequential solid-form finding in this report. Merck’s patent US20240238367A1 / WO2023023245A1 records three candidate salts and their solid forms [PATENT 3]:

The patent text states of each in turn that the compound is in an amorphous form of the chloride, caprate and acetate salt respectively, and notes that caprate and decanoate are used interchangeably. All three are isolated from solution by lyophilization; no crystallization step appears [PATENT 3].

2.3.2 Salt selection was driven by chemical stability

The patent gives the reason for moving away from the chloride. Preparation of the chloride salt requires acidification with hydrochloric acid following supercritical fluid chromatography and evaporation; hydrochloric acid is a strong acid, and an excess in a given batch leads to increased chemical degradation of the molecule. Figure 5 of the patent shows higher impurity levels for the amorphous chloride salt than for the amorphous acetate or amorphous caprate salts. The patent states that the stability of the chloride salt depends on the synthetic process used, whereas the acetate and caprate salts are not subject to that risk and are stable irrespective of the process [PATENT 3].

2.3.3 Independent corroboration from the clinical record

ClinicalTrials.gov registrations corroborate the patent account. Early studies are registered under the intervention name "Enlicitide Chloride" (for example MK-0616-007, -008, -012), while studies registered from 2024 onward use "Enlicitide Decanoate" (MK-0616-025, -023, -026, -028) [TRIAL 8]. The salt change therefore occurred mid-way through clinical development rather than during early candidate selection.

2.4 Drug product composition

2.4.1 Marketed formulation

The label records the following composition [LABEL 1]:

Note. In the clinical pharmacology section the label states that each LIPFENDRA tablet contains sodium caprate, which facilitates the oral absorption of enlicitide, and that the oral bioavailability of enlicitide is approximately 1% [LABEL 1]. It is unusual for a label to name the functional role of an excipient and to state an absolute bioavailability figure.

2.4.2 Tablet description and unit weight estimate

The label describes a 20 mg tablet, white to off-white with grey specks, oval, film-coated, debossed "119" on one side and the company logo on the other [LABEL 1]. A third-party database sourced from the FDA Structured Product Label records a longest dimension of 13 mm, unscored [3P 16].

2.4.3 Quantitative composition of clinical-phase formulations (patent examples)

The patent provides two worked preparation examples with stated masses, which are the closest available approximation to a quantitative composition [PATENT 3]. These are clinical-phase formulations and differ from the marketed product, which contains no macrogol and does contain croscarmellose sodium.

Example A — high-shear wet granulation tablet, target tablet weight 564.9 mg

Sodium caprate (1.5 kg) and macrogol (499.9 g) were dry-mixed in a 10 L high-shear granulator at 183 rpm for one minute, then granulated with water to a suitable endpoint. Wet granules were milled through a 2.0 mm screen on a conical mill, fluid-bed dried at an inlet temperature of 70 °C to a loss on drying below 3.00%, and milled through a 1.0 mm screen. Dried granules (1.275 kg) were blended with Compound 1 (26.96 g), lactose (150.4 g) and silicon dioxide (22.58 g) in a 10 L diffusion blender for 920 revolutions, milled through a 0.8 mm screen, then blended with magnesium stearate (22.58 g) for 460 revolutions and compressed on a rotary tablet press [PATENT 3].

The resulting composition, calculated by this report from the stated masses (the caprate-to-macrogol ratio within the granulation is taken as 1500:499.9) [INFERENCE — arithmetic conversion]:

This conversion is corroborated by the clinical record: the Phase 1 multiple-ascending-dose study used regimens described as 20 mg MK-0616 with 360 mg sodium caprate, 10 mg with 360 mg, and 10 mg with 180 mg [PAPER 4]. The agreement provides independent support for the calculation.

Example B — roller-compacted capsule, target fill weight 490 mg

Microcrystalline cellulose (179.7 g), sodium caprate (661 g), Compound 1 (41 g) and silicon dioxide (8.996 g) were blended in a 10 L diffusion blender for 375 revolutions; magnesium stearate (4.498 g) was added and blended for 250 revolutions; the blend was roller compacted at 21 bar with 2.0 mm coarse and 1.0 mm fine screens; the resulting granules (761.9 g) were lubricated with a further 3.8 g of magnesium stearate for 250 revolutions in a 5 L blender and hand-filled into capsules [PATENT 3]. This corresponds to approximately 74% sodium caprate, 20% microcrystalline cellulose and 4.6% active, or roughly 360 mg sodium caprate and 22 mg active per unit [INFERENCE — arithmetic conversion].

2.4.4 Composition ranges as claimed

All data in this table: [PATENT 3].

2.5 Biopharmaceutics

2.5.1 Enhancer dose and pharmacodynamic response (Phase 1)

The Phase 1 multiple-ascending-dose study published in Circulation provides direct evidence on the relationship between enhancer dose and effect [PAPER 4]:

All sodium caprate-containing formulations in that study, including the caprate-only placebo, were dry-filled enteric-coated HPMC capsules (Vcaps® Enteric, Capsugel®/Lonza). The authors note that the pharmacokinetics of the 10 mg / 180 mg regimen were similar to those of the 10 mg / 360 mg regimen, which supports the similarity of the LDL-C reductions [PAPER 4].

The same paper states that in preclinical studies, oral bioavailability required coformulation with a medium-chain fatty acid permeation enhancer such as sodium caprate to allow absorption of the peptide by the paracellular route [PAPER 4]. This is the primary-source statement on the route of absorption.

2.6 Formulation iteration and post-approval development

ClinicalTrials.gov records a sequence of relative bioavailability studies showing that formulation optimization continued through Phase 3 and beyond approval [TRIAL 8]:

2.7 Drug substance synthesis and starting materials

Merck published the large-scale synthesis of enlicitide decanoate in Science in 2026, using a tailored suite of enzymes for biocatalysis [COMPANY 6]. A third-party review describes the route as follows: the second-generation synthesis restructured the sequence by deferring macrocyclization to improve yield and reduce chromatographic purification; three crystalline intermediates were identified that allowed purification by crystallization rather than chromatography; the total step count was reduced to 43 with a longest linear sequence of 21; yield improved roughly 1000-fold over the first generation; and biocatalysis and chemoenzymatic methods were used to simplify the synthesis of key unnatural amino acids [3P 7].

The compound and its preparation were first disclosed in WO2019/246349 A1 [PATENT 18]. The discovery process and the structural design elements — a northern lactam staple, a southern N-benzyl amide spacer and a ring-closing metathesis-derived cross-link — are described in the 2026 J. Med. Chem. paper [PAPER 5].

2.7.1 External collaboration during discovery

The assignment record for US20230159592A1 / US12209145B2 shows a separate chain of title in which IRBM S.p.A. assigned the rights of Elisabetta Bianchi and Danila Branca to Merck Sharp & Dohme Corp. [PATENT 21].

IRBM S.p.A. is located in Pomezia, Rome, and was formerly Merck’s Italian research institute (IRBM Merck Research Laboratories Rome), operating as an independent contract research organization after Merck’s withdrawal in 2009. This indicates that the discovery phase involved external collaboration rather than being wholly internal [INFERENCE — based on the assignment record].

3. Icotrokinra (ICOTYDE™)

3.1 Approval status and product identity

3.2 Drug substance properties

3.2.1 Sequence and structural elements

The sequence given in Figure 1 of the ADME publication is [PAPER 10]:

Ac-cyclo[Pen-Asn-Thr-7MeTrp-Lys(Ac)-Pen]-Phe(2ae)-2Nal-ThpGly-Glu-Asn-3Pal-Sar-NH₂

The sequence itself is quoted from the source. The functional attribution of each residue below is this report’s reading [INFERENCE]:

The published sequence contains four unmodified canonical residues: two Asn residues, one Thr and one Glu. The other nine positions are non-canonical or chemically modified [INFERENCE — counting the published sequence; PAPER 10].

3.2.2 Solid form status

3.3 Drug product composition

The label records the following composition [LABEL 9]:

3.3.1 Tablet description and unit weight estimate

The label describes a 200 mg tablet, yellowish orange to yellowish brown, oval, film-coated, debossed "200" on one side and "JNJ" on the other [LABEL 9]. A third-party database sourced from the FDA Structured Product Label records a longest dimension of 19 mm, unscored [3P 16].

Tablet weight and quantitative drug loading are not publicly disclosed [NOT DISCLOSED]. The longest tablet dimension alone cannot support a reliable unit-weight or drug-loading estimate.

3.3.2 Administration and dispersion option

The label directs 200 mg orally once daily, taken upon waking with water on an empty stomach, with at least 30 minutes to elapse before eating; tablets are to be swallowed whole and not crushed, split or chewed [LABEL 9].

For patients with difficulty swallowing, the label provides an alternative: place one tablet in at least 120 mL of water; dispersion may take several minutes and may be incomplete; the mixture may appear yellow, milky or cloudy, and small visible pieces are safe to swallow; swirl gently and drink the entire mixture, then add at least a further 120 mL of water to rinse and drink it completely; administration must be completed within 15 minutes of dispersion [LABEL 9].

3.4 Biopharmaceutics and ADME

3.4.1 In vitro permeability — the pivotal dataset

In polarized LLC-PK1 monolayers expressing MDR1 (which encodes human P-glycoprotein), ¹⁴C-icotrokinra showed low, non-saturable permeability across 1–300 μM [PAPER 10]:

The authors conclude that efflux ratios remained below 2 across the concentration range with and without a P-gp inhibitor, with no directional difference, indicating that icotrokinra is not a P-gp substrate; efflux ratios in mock-transfected control monolayers were likewise below 2 [PAPER 10].

3.4.2 Stability — what the molecular design actually achieved

3.4.3 Animal and human pharmacokinetics

Sources: [PAPER 10] for animal and first-in-human solution data; [LABEL 9] for the tablet Tmax range. The first-in-human study used a solution formulation (50 mM sodium phosphate, pH 7.4) at single doses of 10, 25, 100, 300 and 1000 mg after an overnight fast.

3.4.4 Dose linearity, mass balance and local exposure

Dose proportionality: across 25–1000 mg, the slopes of the power model for Cmax and AUC0–24 on both day 1 and day 10 were close to 1 with 90% confidence intervals containing 1 [PAPER 10]. The label states dose-proportional increases across 0.05 to 5 times the recommended dosage [LABEL 9].

Accumulation: Cmax accumulation ratios of 0.70–1.65 and AUC accumulation ratios of 0.9–1.49 on once-daily dosing [PAPER 10]; the label states accumulation up to 1.6-fold for Cmax and up to 1.5-fold for AUC, with steady state reached in approximately 3 days [LABEL 9].

Urinary excretion of unchanged drug was negligible, below 0.001% [PAPER 10].

Fecal excretion of unchanged drug rose with dose, from 37.2% at 10 mg to 80.7% at 1000 mg [PAPER 10].

No metabolites were detected in plasma or urine; the only drug-related component in plasma was the parent [PAPER 10].

Measurable drug concentrations were detected in sigmoid colon and rectal biopsies following 25 mg and 100 mg doses [PAPER 10].

Cmax at the 200 mg dose is approximately 0.002 μM [PAPER 10].

3.4.5 Tissue distribution, with an antibody comparator

Following a 1 mg/kg intravenous dose in cynomolgus monkeys, icotrokinra distributed well into tissues relevant to psoriasis, psoriatic arthritis and inflammatory bowel disease, including skin, blister fluid, ileum, cecum, colon, rectum, patellar synovium, patellar tendon, intervertebral ligament, Achilles tendon and sacroiliac ligament, with tissue-to-plasma concentration ratios of 45.8%–156%. By comparison, the anti-IL-23 monoclonal antibody risankizumab gave tissue-to-serum ratios of 4.07%–32.1% at the same test facility using the same sampling procedures [PAPER 10].

3.4.6 Drug interaction profile

Not a substrate of P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K or BCRP; does not inhibit P-gp, OAT1, OAT3, OCT2, MATE1, MATE2-K, BCRP or BSEP [PAPER 10].

Inhibition of OATP1B1 and OATP1B3 of 43.9% and 48.0% respectively at the highest concentration tested; given a Cmax of approximately 0.002 μM at 200 mg, no interaction is expected at clinically relevant concentrations [PAPER 10].

CYP enzymes: IC50 ≥ 100 μM for all isoforms tested; at 100 μM most isoforms showed under 10% inhibition, with weak inhibition of CYP1A2 (19%) and CYP2E1 (30%); no mRNA induction of CYP1A2, CYP2B6 or CYP3A4 [PAPER 10]. The label states that no formal drug–drug interaction studies have been conducted and no clinically significant interactions have been identified [LABEL 9].

Plasma protein binding is low: 43.7%–56.0% in mouse, rat and monkey and 49.7%–55.2% in human, with higher binding in rabbit (70.3%–71.9%); preferential binding to human serum albumin over α-1 acid glycoprotein [PAPER 10].

Blood-to-plasma ratio below 1 in all species, 0.49–0.61 in human [PAPER 10].

3.4.7 Food effect and special populations

Section 12.3 of the label states that icotrokinra AUC decreased by 43% and Cmax decreased by 59% following administration with a high-fat meal (1000 calories, 50% fat), and that no clinically significant pharmacokinetic differences were observed following administration of caffeine [LABEL 9].

The same section records that no clinically relevant differences were observed between healthy subjects and patients with moderate-to-severe plaque psoriasis, or between pediatric patients 12 years and older weighing at least 40 kg and adults [LABEL 9].

3.5 Formulation bridging

Phase 2 used a 100 mg tablet; a 200 mg tablet was developed for Phase 3, and the two were bridged in a single-dose, open-label, randomized crossover study in 24 healthy subjects, of whom 23 completed. Under fasted conditions, the geometric mean ratios for one 200 mg Phase 3 tablet relative to two 100 mg Phase 2 tablets were 88.1% for Cmax, 94.2% for AUC0-last and 94.9% for AUC0-∞; median Tmax was 2 hours for both formulations and mean half-life was 12.4–13.0 hours [PAPER 10].

A clinical protocol additionally records that interim results from a healthy-subject crossover study showed the oral bioavailability and pharmacokinetic profile of the immediate-release tablet under fasted conditions to be similar to the oral solution used in the first-in-human study [TRIAL].

3.6 Patent landscape

The patent numbers below are taken from a published third-party patent analysis. The underlying documents were not individually reviewed for this report and should be verified before use in any freedom-to-operate assessment [3P 15]:

The last two related inventions are recorded in the conflict-of-interest disclosure of the Dermatology and Therapy publication and are therefore primary-source [PAPER 10].

4. Comparative Analysis

4.1 Side-by-side parameters

Sources: [LABEL 1, 9]; [PATENT 3]; [PAPER 4, 10]; [3P 16].

4.2 The economics of the two strategies

Both products face the same physical constraint — very low intestinal permeability of a peptide of this size — and adopt opposite responses [INFERENCE, based on the evidence assembled above]:

The Merck route uses sodium caprate to support oral absorption, with approximately 1% human bioavailability and a 20 mg daily dose [LABEL 1]. Clinical formulations studied 180–360 mg sodium caprate, and one patent example contains about 64% enhancer by mass [PATENT 3, PAPER 4]. The commercial enhancer quantity and its tablet mass fraction are not disclosed. Enhancer performance, gastrointestinal tolerability and manufacturing requirements remain relevant development considerations [INFERENCE].

The ICOTYDE label identifies no dedicated permeation enhancer and specifies a 200 mg daily dose [LABEL 9]. Absolute oral bioavailability of 0.1–0.3% was measured in animals; human absolute bioavailability was not reported [PAPER 10]. Public evidence does not establish that the human dose was selected solely to compensate for low absorption. Drug-substance demand, tablet size and the labeled dispersion option are relevant practical considerations [INFERENCE].

It should be emphasized that the fasted dosing requirement is common to both routes. Adding a permeation enhancer did not remove it [LABEL 1, 9].

4.3 Terminology: cyclic versus macrocyclic peptide

The two sponsors use systematically different language, which is worth noting in technical communication:

Merck consistently uses "macrocyclic peptide" for enlicitide in the label and press materials [LABEL 1, COMPANY 2], although earlier clinical protocols used "small molecule cyclic peptide inhibitor" [TRIAL 8].

J&J uses only "13-amino acid peptide" in the label and "targeted oral peptide" in corporate communications [LABEL 9, COMPANY 13], while the Dermatology and Therapy publication describes the molecule as a macrocyclic peptide [PAPER 10].

On definitions: a cyclic peptide is any peptide containing a ring, irrespective of the mode of cyclization or ring size. A macrocyclic peptide is a subset, conventionally defined by a ring of at least twelve atoms. For external technical materials, using "cyclic and macrocyclic peptides" together, or defining the chemical space as "beyond Rule of 5 (bRo5)", avoids the ambiguity [INFERENCE — terminology recommendation].

5. Methodological Conclusions

5.1 What product labels show about enabling technologies

The approved labels do not identify an amorphous-solid-dispersion carrier, a self-emulsifying vehicle or an enteric coating. However, qualitative excipient lists do not disclose particle engineering, drug-substance controls or manufacturing unit operations, so they cannot establish that either product is made by a simple conventional process [LABEL 1, 9].

Permeability and chemical stability are important development considerations in these cases. Their relative importance versus dissolution or solubility must be established for each molecule and formulation; public labels alone do not justify dismissing solubility-enabling approaches across the oral-peptide modality [INFERENCE].

5.2 Solid-form work centres on salt selection and amorphous stabilization

All three candidate salts of enlicitide were amorphous, and the selection criterion was chemical degradation risk rather than solid-state physical performance [PATENT 3]. It should also be noted that the three crystalline species in the synthetic route serve to replace chromatographic purification and bear no relation to the solid form of the final drug substance [3P 7].

The practical work content of solid-form development in this modality therefore comprises [INFERENCE]:

Counterion screening judged on chemical stability — residual acid, ion-pair compatibility — rather than on melting point or hygroscopicity ranking

Characterization of glass transition temperature, hygroscopicity and physical stability of the amorphous solid

Establishing an analytical criterion for the absence of crystallization where no crystalline reference pattern exists, including justification of the powder X-ray diffraction limit of detection

Compatibility and moisture migration studies for an amorphous drug substance coexisting with a high proportion of hygroscopic excipient

5.3 Distinguishing solubility-limited from permeability-limited absorption

For icotrokinra, low in vitro permeability and dose-proportional human exposure across 25–1000 mg support a permeability-related development hypothesis [PAPER 10, INFERENCE]. The 0.1–0.3% absolute bioavailability measurements are from animals, not humans. These observations alone do not establish the relative contributions of dissolution, intestinal permeability and other processes to human absorption, or predict the effect of an enhancer.

A pH–solubility profile alone cannot establish that intestinal precipitation makes an enhancer ineffective. Dissolved concentration, precipitation and redissolution kinetics, dose, luminal volume and membrane transport all need assessment. As an illustrative calculation only, 0.2% absorption of a 200 mg dose would correspond to 0.4 mg absorbed; 0.2% is not an established human bioavailability for icotrokinra [INFERENCE].

5.4 Evaluation checklist if a permeation enhancer were considered for a molecule of this type

The following is proposed by this report on the basis of the public information for both products; it is not a recommendation made by any cited source [INFERENCE]:

Measure the microenvironmental pH on disintegration in an enhancer-rich formulation. Sodium caprate is the sodium salt of capric acid (pKa approximately 4.9); the roughly 64% mass fraction belongs to a patent formulation example, not a verified commercial tablet composition [PATENT 3]. Icotrokinra is practically insoluble at pH 9 [LABEL 9]. The actual local pH and its effect on dissolution and absorption require measurement [INFERENCE].

Assess drug–enhancer ion-pair compatibility. Icotrokinra has an isoelectric point of 7.15 [LABEL 9] and therefore carries net positive charge in the stomach and upper small intestine, while caprate is an anionic surfactant. A cationic peptide and an anionic surfactant may form a poorly soluble complex, or the increased lipophilicity may favour membrane interaction. The direction cannot be predicted a priori.

Consider intestinal barrier safety. Sodium caprate and related permeation enhancers may act through multiple concentration- and formulation-dependent mechanisms, including epithelial-membrane effects and tight-junction-associated paracellular transport. For a product taken daily for life and intended for extension into inflammatory bowel disease, this warrants independent evaluation. Relevant comparators: ICOTYDE safety through 16 weeks was comparable to placebo in placebo-controlled trials [COMPANY 13], whereas the most common adverse reactions reported for LIPFENDRA in the HeFH study were diarrhea and dizziness [LABEL 1].

Account for the loss of luminal exposure. The unabsorbed fraction of icotrokinra remains as parent drug in the gut lumen, with human fecal recovery of unchanged drug reaching 80.7% [PAPER 10], and is detectable in colonic and rectal biopsies [PAPER 10]. Increasing systemic absorption would correspondingly reduce the quantity available for local action.

Do not assume that adding a permeation enhancer removes food effects. The LIPFENDRA label lists sodium caprate and requires fasted administration at least 30 minutes before food, but does not disclose the commercial sodium caprate quantity [LABEL 1]. The 180–360 mg amounts refer to clinical formulations [PAPER 4].

5.5 Commercial manufacturing establishments disclosed in the FDA SPL

The ICOTYDE SPL identifies Janssen Pharmaceutica NV for API manufacture and analysis; Janssen Cilag SpA for analysis, manufacture, packaging and labeling; Johnson & Johnson Private Limited and SGS India Private Limited for analysis; and JOM Pharmaceutical Services, LLC for packaging and labeling. These entries identify registered establishment functions, not the complete supply chain or the specific operations performed at each location [LABEL 9]. The LIPFENDRA SPL should be reviewed in the same way before making supply-chain conclusions.

6. Public Information Gaps

The following was not obtained within the scope of this search. No filling speculation is offered; the list is provided to guide targeted follow-up.

7. Sources

[1] [LABEL] LIPFENDRA® (enlicitide) tablets, US Prescribing Information. Merck Sharp & Dohme LLC, Rahway, NJ. Initial US approval 2026. DailyMed SPL set id 100ec543-fbd0-44fc-b740-db9cdff39145. Open source ↗

[2] [COMPANY] Merck press release: LIPFENDRA® (enlicitide) approved by the US FDA as the first once-daily oral PCSK9 inhibitor to lower LDL-C in adults with primary hypercholesterolemia. 15 July 2026.

[3] [PATENT] US20240238367A1 / WO2023023245A1, "Compounds for treating conditions related to PCSK9 activity." Applicant Merck Sharp and Dohme LLC. Priority 19 August 2021; published 18 July 2024. Family: EP4387645A1, JP2024532129A, CN118159281A, AU2022330007A1, CA3228604A1, KR20240050369A, MX2024002146A, IL310851A. Open source ↗

[4] [PAPER] Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor. Circulation, 2023. DOI 10.1161/CIRCULATIONAHA.122.063372 (open access). Open source ↗

[5] [PAPER] Nair AG, Rao AU, Lo MM-C, Tucker TJ, Embrey MW et al. Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR. J. Med. Chem. 2026;69(11):13473.

[6] [COMPANY] Merck press release: Merck scientists publish landmark Science paper on the large-scale biocatalytic synthesis of investigational oral PCSK9 inhibitor enlicitide decanoate. May 2026.

[7] [3P] American Peptide Society review of enlicitide decanoate (source for synthetic step counts, crystalline intermediates and yield improvement; verification against the primary publication is recommended).

[8] [TRIAL] ClinicalTrials.gov: NCT06691906 (MK-0616-025), NCT06880874 (MK-0616-035), NCT07481708 (MK-0616-041), NCT07776665 (MK-0616-044), NCT05261126 (MK-0616-008 full protocol), NCT05934292 (MK-0616-020 full protocol), NCT06008756 (CORALreef Outcomes).

[9] [LABEL] ICOTYDE™ (icotrokinra) tablets, US Prescribing Information. Janssen Biotech, Inc., Horsham, PA. Initial US approval 2026; NDA 220149. DailyMed SPL set id aee3c963-edc0-4252-8769-cdf6c7cdc21a. Open source ↗

[10] [PAPER] Knight B, Tammara B, Modi NB, Dallas S et al. Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling. Dermatol Ther (Heidelb) 2025;15:2495–2520. DOI 10.1007/s13555-025-01454-7; PMID 40629250 (open access, CC BY-NC). Open source ↗

[11] [PAPER] Fourie AM, Cheng X, Chang L et al. JNJ-77242113, a highly potent, selective peptide targeting the IL-23 receptor, provides robust IL-23 pathway inhibition upon oral dosing in rats and humans. Sci Rep. 2024;14:17515.

[12] [PAPER] Bissonnette R, Pinter A, Ferris LK et al. An oral interleukin-23-receptor antagonist peptide for plaque psoriasis. N Engl J Med. 2024;390:510–21.

[13] [COMPANY] Johnson & Johnson press release: FDA approves ICOTYDE™ (icotrokinra). 18 March 2026.

[14] [3P] European Medicines Agency, Icotyde summary of opinion; CHMP positive opinion adopted 23 July 2026; SmPC to be published following European Commission authorisation.

[15] [3P] Patsnap patent analysis article: Icotrokinra — first oral IL-23 inhibitor in Phase III, April 2026 (source of patent numbers; verification against original documents recommended).

[16] [3P] Third-party database records derived from FDA Structured Product Labels and the openFDA NDC directory (tablet dimensions, package configurations, NDC codes). LIPFENDRA: NDC 0006-5084-01 (30-count bottle), 0006-5084-59 (7-count). ICOTYDE: NDC 57894-201-30 (30-count bottle), 57894-201-07 (7-count blister).

[17] [PATENT] WO2025042927A2, "Sustained release formulations for poorly permeable cyclic peptides." Applicant Merck Sharp & Dohme LLC. Priority 24 August 2023; published 27 February 2025. Open source ↗

[18] [PATENT] WO2019/246349 A1, PCSK9 antagonist compounds (original disclosure of the compound and its preparation). Family: IL279363B2, US12178842B2. Related: US11306125B2, EP4021919A1. Open source ↗

[19] [3P] Icotrokinra (Icotyde) review. Amrita Journal of Medicine; DOI 10.4103/amjm.amjm_44_26. (Cited in earlier drafts for the food-effect figures; those figures have since been verified directly against the label and are cited here as [LABEL 9].)

[20] [COMPANY] Merck CORALreef press releases: CORALreef Lipids (November 2025), CORALreef HeFH (November 2025, published concurrently in JAMA), CORALreef AddOn (March 2026).

[21] [PATENT] US20230159592A1 / US12209145B2, "PCSK9 antagonist compounds." Merck Sharp & Dohme LLC. Inventor information taken from the assignment records recorded on Google Patents, including a separate chain of title from IRBM S.p.A. to Merck Sharp & Dohme Corp. Open source ↗

[22] [3P] Justia Patents inventor search records (source for the complete inventor listing order of US20240238367A1). Inventorship is a published bibliographic element, but the official USPTO Patent Center or WIPO Patentscope record should be treated as authoritative.

[23] [PATENT] US11484565B2, "PCSK9 antagonist compounds." Merck Sharp & Dohme LLC. Inventors as recorded in field (72) of the patent front page. Open source ↗

8. Appendix: Inventors on Enlicitide-Related Patents

This appendix records the inventor listings for enlicitide-related patents, taken from the bibliographic data published on Google Patents and Justia and from patent front pages. Inventorship is a published bibliographic element and is not confidential information.

8.1 Formulation and salt form patent

US20240238367A1 / WO2023023245A1 — "Compounds for treating conditions related to PCSK9 activity"

Applicant: Merck Sharp and Dohme LLC. Priority 19 August 2021. This filing covers the solid forms of the three salts (chloride, caprate, acetate), pharmaceutical compositions containing a permeation enhancer, and the two preparation examples reproduced in Section 2.4.3. Twenty-one inventors are listed, in the published order [PATENT 3, 3P 22]:

8.2 Composition of matter patents

US11484565B2 — "PCSK9 antagonist compounds"

Eight inventors recorded on the patent front page [PATENT 23]: Hubert Josien (Jersey City, NJ), Abbas Walji (Lansdale, PA), Harold B. Wood (Westfield, NJ), Fa-Xiang Ding (Staten Island, NY), Jian Liu (Edison, NJ), Thomas Joseph Tucker (North Wales, PA), Michael Man-Chu Lo (Bedminster, NJ), Liangqin Guo (Monroe, NJ).

US20230159592A1 / US12209145B2 — "PCSK9 antagonist compounds"

Inventors readable from the assignment records [PATENT 21]: Ling Tong, Sobhana Babu Boga, Fa-Xiang Ding, Sookhee Nicole Ha, Hubert B. Josien, Angela Dawn Kerekes, Jian Liu, Anilkumar G. Nair, Harold B. Wood, Thomas Joseph Tucker, Abbas M. Walji, Chengwei Wu, Yusheng Xiong; together with Elisabetta Bianchi and Danila Branca, assigned via IRBM S.p.A.

WO2019246349A1 / A8 — "PCSK9 antagonist compounds"

Applicants Merck Sharp and Dohme Ltd and Merck Sharp and Dohme LLC. Inventors visible in the Google Patents bibliographic record include Harold B. Wood, Hubert B. Josien, Abbas M. Walji and Anilkumar G. Nair; the retrieved listing was truncated and the complete roster requires review of the original document [NOT DISCLOSED — to be completed].

8.3 Limits of interpreting inventor overlap

Comparing the two sets of listings:

The available inventor lists show some overlap, but the composition-of-matter records reviewed here are not all complete. A definitive count of shared inventors is therefore not established.

Anilkumar Nair, first author of the 2026 J. Med. Chem. discovery paper, appears on the composition of matter filings but not on the formulation filing [PAPER 5, PATENT 21].

The lists identify named inventors on particular filings; they do not describe the complete discovery or formulation teams.

Patent inventor overlap alone cannot establish internal organizational boundaries, reporting lines or the roles of individuals. The technical distinction between chemistry discovery and formulation/process development remains an analytical observation, rather than a verified description of the project organization [INFERENCE].