JNJ-61803534: A Comprehensive Report on an Investigational RORγt Inverse Agonist

I. Introduction to JNJ-61803534

A. Overview and Origin

JNJ-61803534 is an investigational small molecule, developed as an orally active RORγt (Retinoic Acid Receptor-Related Orphan Receptor gamma t) inverse agonist. Its primary therapeutic aim was the treatment of autoimmune and inflammatory diseases, with a particular focus on psoriasis.[1] The oral route of administration is a significant feature, potentially offering advantages over biologic treatments for similar conditions which often require parenteral administration.

The development of JNJ-61803534 was a collaborative effort. The primary entities involved were Phenex Pharmaceuticals AG, based in Heidelberg, Germany, and Janssen Research & Development, LLC, a subsidiary of Johnson & Johnson Innovative Medicine, headquartered in the USA.[6] This partnership structure is common in the pharmaceutical industry, leveraging the specialized discovery and medicinal chemistry expertise often found in smaller biotechnology firms like Phenex Pharmaceuticals with the extensive resources for preclinical testing, large-scale clinical trials, and regulatory navigation typically possessed by large pharmaceutical corporations like Janssen. The contributions from Phenex Pharmaceuticals appear significant in the early discovery and chemical optimization phases, while Janssen likely led the broader preclinical characterization and clinical development program.

B. Chemical Properties

JNJ-61803534 belongs to the chemical class of thiazole bisamide derivatives. This specific structural class was the result of targeted medicinal chemistry efforts aimed at overcoming limitations, particularly CYP450 autoinduction in rats, which had hampered the development of earlier-generation thiazole amide RORγt inverse agonists.[6]

Key chemical identifiers and properties include:

CAS Number: 1917306-14-9 [1]
Molecular Formula: C23H23Cl2F6N3O4S [1]
Molecular Weight: 622.404 g/mol (often reported as 622.41 g/mol) [1]
Physical Appearance: The compound is described as a white to off-white solid powder.[1]
Structure: The chemical structure of JNJ-61803534 was publicly disclosed, notably in Figure 1a of the Scientific Reports publication by Xue et al. in 2021. It is important to note that an author correction was subsequently issued in April 2022 for this paper, rectifying an error in the depicted methyl stereochemistry on the pyrrolidine ring of the compound.[9] This correction underscores the critical importance of precise structural elucidation and representation in chemical and pharmacological research.

The progression from thiazole amides to thiazole bisamides reflects a deliberate and iterative drug design strategy. The issue of CYP450 autoinduction can lead to unpredictable drug exposure levels in vivo, potentially diminishing efficacy over time or complicating dosing regimens. By successfully designing JNJ-61803534 to avoid this metabolic liability, the development team achieved a significant improvement in its drug-like properties, making it a more viable candidate for clinical progression compared to its predecessors.

C. Rationale for Development

The fundamental rationale for the development of JNJ-61803534 was to create an orally administered small-molecule therapeutic that could effectively modulate the IL-23/IL-17 inflammatory pathway by targeting RORγt.[2] This pathway is well-established as a critical driver in the pathogenesis of numerous autoimmune and inflammatory disorders, with psoriasis and psoriatic arthritis being prominent examples. Biologic therapies, such as monoclonal antibodies targeting IL-17 or IL-23, have demonstrated considerable efficacy in these conditions, but they typically require parenteral administration and can be associated with high costs. JNJ-61803534 was envisioned as a means to provide a more convenient oral treatment option, potentially with a comparable or improved therapeutic profile.[4]

Table 1: Summary of JNJ-61803534 Key Properties

Property	Detail	Source(s)
Chemical Class	Thiazole bisamide	6
CAS No.	1917306-14-9	1
Molecular Formula	C23H23Cl2F6N3O4S	1
Molecular Weight	622.404 g/mol	1
Developer(s)	Phenex Pharmaceuticals AG & Janssen Research & Development, LLC (Johnson & Johnson Innovative Medicine)	6
Drug Class (Pharmacological)	RORγt Inverse Agonist	1
Primary Molecular Target	Retinoic Acid Receptor-Related Orphan Receptor gamma t (RORγt)	2

II. Mechanism of Action

A. Primary Molecular Target: Retinoic Acid Receptor-Related Orphan Receptor Gamma t (RORγt)

JNJ-61803534 exerts its pharmacological effects through direct modulation of Retinoic Acid Receptor-Related Orphan Receptor gamma t (RORγt).[2] RORγt is a nuclear receptor that functions as a ligand-regulated transcription factor. It is an isoform of RORγ, generated by differential promoter usage or exon splicing, and its expression is predominantly restricted to cells of the immune system.[11] Notably, RORγt is highly expressed in T helper 17 (Th17) cells, a subset of CD4+ T cells, and also found in other immune cell types such as γδ T cells and innate lymphoid cells (ILCs).[2]

The significance of RORγt in immunology stems from its established role as the "master regulator" or "key transcription factor" governing the differentiation of naive CD4+ T cells into the pro-inflammatory Th17 lineage.[2] It directly drives the expression of genes encoding hallmark Th17 cytokines, including IL-17A, IL-17F, and IL-22, as well as the IL-23 receptor (IL-23R), which is crucial for Th17 cell maintenance and expansion.

B. Pharmacological Profile: Inverse Agonist

JNJ-61803534 is characterized as an inverse agonist of RORγt.[1] This classification is distinct from that of a neutral antagonist. Nuclear receptors, including RORγt, can exhibit a degree of constitutive (basal) activity even in the absence of an endogenous ligand. An inverse agonist, upon binding to the receptor, not only blocks the binding of potential agonists but also actively reduces this basal level of receptor activity.[1] In the context of RORγt, this leads to a more profound suppression of its transcriptional output compared to what might be achieved by a simple antagonist. This enhanced suppression could contribute to the observed potency of JNJ-61803534.

C. Downstream Effects on the Th17 Pathway and Cytokine Production

The inverse agonism of RORγt by JNJ-61803534 translates into significant downstream immunological consequences. By diminishing RORγt activity, the drug effectively curtails the differentiation and expansion of Th17 cells.[1] This, in turn, leads to a marked reduction in the production of key pro-inflammatory cytokines that are characteristic of the Th17 immune response. These include, most notably, IL-17A and IL-17F, and also IL-22.[1] The IL-23/IL-17 signaling axis, critically dependent on RORγt function, is a well-validated pathogenic pathway in numerous autoimmune and inflammatory conditions, particularly psoriasis.[2] Thus, JNJ-61803534 aims to ameliorate these conditions by dampening this specific inflammatory cascade.

The targeting of RORγt, a "master regulator," presents both high therapeutic potential and inherent risks. Its central role in Th17 cell biology means that its inhibition can profoundly suppress a major inflammatory pathway, which is desirable for treating Th17-mediated diseases. However, master regulators often exert pleiotropic effects. RORγt, for instance, is also involved in the development of lymphoid tissues and thymocyte survival.[11] Systemic inhibition of such a fundamental transcription factor, even if highly selective for the RORγt isoform over RORα and RORβ, carries the risk of disrupting other essential physiological processes that are also dependent on RORγt. This consideration is particularly pertinent to understanding the potential for on-target toxicities, such as the embryo-fetal effects that ultimately led to the discontinuation of JNJ-61803534's development. The drug's potent inverse agonist activity, while beneficial for suppressing inflammation, might have inadvertently interfered with critical developmental roles of RORγt.

III. Preclinical Evaluation

The preclinical assessment of JNJ-61803534 encompassed a range of in vitro and in vivo studies to characterize its potency, selectivity, mechanism of action, efficacy in disease models, and initial safety profile.

A. In Vitro Studies

Potency against RORγt: JNJ-61803534 demonstrated high potency in inhibiting RORγt-driven transcriptional activity. In a 1-hybrid reporter assay utilizing HEK-293 T cells transfected with a vector encoding RORγt fused to a GAL4 DNA binding domain, JNJ-61803534 exhibited an IC50 (half-maximal inhibitory concentration) of 9.6±6 nM.[1] This low nanomolar value is indicative of a potent interaction with the target receptor.
Selectivity Profile:
ROR Isoform Selectivity: A critical aspect of RORγt modulator development is selectivity against other ROR family members, RORα and RORβ, due to their distinct physiological roles. JNJ-61803534 was shown to selectively inhibit RORγt-driven transcription over that of RORα and RORβ.[1] Specifically, in cellular GAL4 reporter assays, JNJ-61803534 displayed approximately 35-fold greater potency for RORγt compared to other tested nuclear receptors.[9]
Broad Off-Target Selectivity: To assess broader off-target potential, JNJ-61803534 was screened against a panel of 18 other human nuclear receptors (including thyroid hormone receptor α (TRα), retinoic acid receptor α (RARα), peroxisome proliferator-activated receptors (PPARα, PPARβ, PPARγ), liver X receptor β (LXRβ), farnesoid X receptor (FXR), vitamin D receptor (VDR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), retinoid X receptor α (RXRα), estrogen receptors (ERα, ERβ), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR)) and estrogen-related receptor γ (ERRγ). The compound showed minimal activity against these receptors. Furthermore, evaluations against a panel of 52 other receptors, ion channels, and transporters, 28 G protein-coupled receptors (GPCRs) (in both agonist and antagonist modes), and 46 kinases did not reveal significant binding or functional activity. Minor activities were noted against the adenosine A3 receptor, neurokinin 2 (NK2) receptor, Na+-channel, and Cl--channel, though the therapeutic relevance of these findings was not extensively detailed in the available information.[9]
Functional Effects on Human Immune Cells:
Th17 Cytokine Inhibition: Consistent with its mechanism as a RORγt inverse agonist, JNJ-61803534 demonstrated a dose-dependent inhibition of key Th17 cytokine production. In human CD4+ T cells cultured under Th17-polarizing conditions, the compound significantly reduced the secretion of IL-17A, IL-17F, and IL-22. These effects were observed at concentrations ranging from 1 nM to 1 μM.[1]
Specificity for Th17 Pathway: A crucial finding was the compound's specificity for the Th17 pathway. While potently inhibiting Th17 cytokine production, JNJ-61803534 did not inhibit the production of interferon-gamma (IFNγ) by human CD4+ T cells cultured under Th1-polarizing conditions.[1] This suggests that the drug's immunomodulatory effects are targeted towards Th17 cells, without broadly suppressing other important T helper cell responses like Th1 immunity.
No Impact on Regulatory T cells (Tregs): The development and function of regulatory T cells (Tregs) are vital for maintaining immune homeostasis and preventing autoimmunity. Preclinical in vitro studies indicated that JNJ-61803534 had no impact on the differentiation of Tregs from naive CD4+ T cells, nor did it affect the suppressive activity of natural Tregs.[1] This sparing of Treg function is a desirable characteristic for an immunomodulatory agent aimed at treating autoimmune diseases.

B. In Vivo Animal Model Studies

Mouse Collagen-Induced Arthritis (CIA) Model: The efficacy of JNJ-61803534 was evaluated in the CIA model, a well-established preclinical model of rheumatoid arthritis, which shares Th17-mediated pathology. Oral administration of JNJ-61803534, at doses ranging from 3 to 100 mg/kg twice daily (BID) or 60 mg/kg once daily (QD), resulted in a dose-dependent attenuation of inflammation. A maximum inhibition of the clinical arthritis score of approximately 90% was achieved.1 Furthermore, treatment with JNJ-61803534 led to reductions in cartilage damage and bone destruction, key pathological features of arthritis.1
Imiquimod-Induced Psoriasis Model (Mouse Skin Inflammation): To assess efficacy in a model more directly relevant to psoriasis, JNJ-61803534 was tested in mice with imiquimod-induced skin inflammation. Oral administration of the compound at doses of 30 and 100 mg/kg significantly inhibited the psoriatic-like skin inflammation disease score.1 This clinical improvement was correlated with molecular changes in the inflamed skin tissue; JNJ-61803534 dose-dependently inhibited the expression of RORγt-regulated genes, including those for IL-17A, IL-17F, IL-22, and the IL-23 receptor (IL-23R).1 These findings provided strong preclinical evidence for the therapeutic potential of JNJ-61803534 in psoriasis by demonstrating both clinical efficacy and target engagement in vivo.
Pharmacokinetics/Drug Metabolism Improvement: A notable aspect of JNJ-61803534's development was its chemical design as a thiazole bisamide. This structural modification was specifically aimed at addressing a significant pharmacokinetic challenge encountered with earlier thiazole amide-based RORγt inverse agonists, namely, CYP450 autoinduction in rats. JNJ-61803534 successfully avoided this autoinduction phenomenon, which was a critical improvement for its drug-like properties and further development.6
Initial Toxicology Assessment: Prior to human trials, JNJ-61803534 underwent 1-month Good Laboratory Practice (GLP) toxicology studies in rats and dogs. These studies identified dose levels that were well-tolerated in these species, providing the necessary safety data to support the progression of the compound into Phase 1 clinical studies.2

The collective preclinical data for JNJ-61803534 painted a promising picture. The compound exhibited potent and selective RORγt inverse agonism, translated this molecular activity into functional inhibition of the Th17 pathway in vitro, and demonstrated significant efficacy in animal models of both arthritis and psoriasis. The successful circumvention of the CYP450 autoinduction issue, coupled with an acceptable initial safety profile in standard toxicology studies, provided a solid foundation for advancing JNJ-61803534 into clinical development. The specificity of its immunomodulatory action, by primarily targeting Th17 responses while sparing Th1 and Treg functions, was a particularly encouraging finding, suggesting the potential for a targeted therapy with a favorable therapeutic window.

Table 2: Overview of In Vitro Preclinical Findings for JNJ-61803534

Assay Type	Target/System	Key Metric	Result	Effect on Cytokines	Effect on Treg	Source(s)
1-hybrid reporter assay	Human RORγt	IC50	9.6±6 nM	N/A	N/A	1
GAL4 reporter assays	Human RORα, RORβ, 18 other NRs	Selectivity	>35-fold selective for RORγt vs other NRs	N/A	N/A	9
Human CD4+ T cell Th17 differentiation	IL-17A, IL-17F, IL-22 production	Inhibition	Dose-dependent inhibition (1 nM - 1 μM)	↓IL-17A, ↓IL-17F, ↓IL-22	N/A	1
Human CD4+ T cell Th1 differentiation	IFNγ production	Inhibition	No inhibition	No change IFNγ	N/A	1
Human CD4+ T cell Treg differentiation/suppression	Differentiation & Suppressive Activity	Impact	No impact	N/A	No impact	2

Table 3: Overview of In Vivo Preclinical Efficacy for JNJ-61803534

Animal Model	Condition Modeled	Route of Administration	Dosage Range	Key Efficacy Endpoints	Key Findings	Source(s)
Mouse Collagen-Induced Arthritis (CIA)	Rheumatoid Arthritis	Oral (p.o.)	3-100 mg/kg BID or 60 mg/kg QD	Clinical arthritis score, cartilage/bone damage	Dose-dependent attenuation of inflammation (~90% max inhibition), reduced joint damage	1
Imiquimod-Induced Skin Inflammation	Psoriasis	Oral (p.o.)	30 and 100 mg/kg	Skin inflammation score, gene expression (IL-17A, IL-17F, IL-22, IL-23R)	Significant inhibition of disease score, dose-dependent inhibition of RORγt-regulated gene expression	1

IV. Clinical Development and Human Studies

Following the promising preclinical evaluation, JNJ-61803534 advanced into Phase 1 clinical trials to assess its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in humans.

A. Phase 1 Clinical Trial in Healthy Volunteers

A Phase 1, randomized, double-blind, single ascending dose (SAD) study was conducted with an oral formulation of JNJ-61803534 in healthy human volunteers.[2] This type of study represents the first human exposure to an investigational drug and is primarily designed to evaluate its safety profile across a range of doses and to gather initial human PK and PD data.

Safety and Tolerability Profile: The compound was reported to be well-tolerated in single ascending doses up to 200 mg.2 This finding suggested that, at least in the context of single administrations to healthy individuals, JNJ-61803534 did not elicit immediate or severe dose-limiting adverse events.
Pharmacokinetics (PK): The study revealed several key pharmacokinetic characteristics of JNJ-61803534:
Dose-Dependent Exposure: Oral administration resulted in dose-dependent increases in plasma exposure, indicating predictable absorption and systemic availability with increasing doses.[2]
Half-Life (T1/2): JNJ-61803534 exhibited a notably long plasma half-life, reported to be in the range of 164 to 170 hours. One source further specified mean T1/2 values of approximately one week (163.8 to 169.9 hours).[2] Such a long half-life is advantageous as it supports the potential for less frequent dosing regimens (e.g., once daily or even less often), which can enhance patient adherence, particularly for chronic conditions.
Time to Maximum Concentration (Tmax): The median Tmax was observed to be 6 hours post-dose for the 30 mg, 100 mg, and 200 mg doses, and slightly later at 10 hours post-dose for the 10 mg dose.[15]
Food Effect: For the 100 mg dose, mean plasma concentrations of JNJ-61803534 were generally similar following administration under fed or fasted conditions. Absorption appeared to be marginally faster under fasted conditions.[15] The lack of a significant food effect is beneficial as it simplifies dosing instructions for patients.
Pharmacodynamics (PD): A critical outcome of the Phase 1 study was the demonstration of in vivo target engagement and pharmacodynamic activity in humans.2 This was evidenced by a dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood samples taken from the healthy volunteers who received JNJ-61803534.2 This finding confirmed that the drug not only achieved systemic exposure but also exerted its intended biological effect (suppression of a key Th17 cytokine) at the doses administered in humans, providing an early indication of potential therapeutic activity. This successful translation of PK/PD from preclinical models to humans is a significant positive milestone in early-phase drug development.
Clinical Trial Registration: While standard practice, a specific ClinicalTrials.gov identifier (NCT number) for the JNJ-61803534 Phase 1 SAD study is not explicitly provided in the summarized research materials.4 Such identifiers are crucial for tracking clinical trial information publicly.

The initial Phase 1 data were encouraging, suggesting that JNJ-61803534 possessed a manageable safety profile in single doses for healthy individuals and a pharmacokinetic profile amenable to convenient oral dosing. The clear pharmacodynamic evidence of IL-17A suppression further supported its mechanism of action in humans. However, these SAD studies in healthy volunteers, while essential, are not designed to uncover all potential toxicities, especially those that might manifest with chronic dosing, in patient populations, or those specific to developmental stages, as was later discovered.

Table 4: Summary of Phase 1 Clinical Trial Results for JNJ-61803534 in Healthy Volunteers

Parameter	Detail	Source(s)
Study Population	Healthy Human Volunteers	2
Study Design	Randomized, Double-Blind, Single Ascending Dose (SAD)	2
Maximum Tolerated Single Dose	Well-tolerated up to 200 mg	2
Key Pharmacokinetic Findings	Dose-dependent increases in exposure; Plasma half-life (T1/2): 164-170 hours; Median Tmax: 6-10 hours	2
Key Pharmacodynamic Findings	Dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood (demonstrating in vivo target engagement)	2

V. Therapeutic Rationale and Potential Indications

The mechanism of action of JNJ-61803534, centered on the inhibition of RORγt and subsequent suppression of the Th17 inflammatory pathway, provided a strong rationale for its development in a range of autoimmune and inflammatory diseases.

A. Primary Target Indication: Psoriasis

Psoriasis was the primary therapeutic indication for which JNJ-61803534 was being developed.[2] This focus was based on the well-established role of the IL-23/IL-17 axis in the immunopathogenesis of psoriasis. The preclinical efficacy demonstrated in the imiquimod-induced mouse skin inflammation model, which mimics key features of human psoriasis, further solidified this rationale.[1] An effective and convenient oral therapy for psoriasis remains a significant unmet need, and JNJ-61803534 aimed to fill this gap.

B. Other Potential Autoimmune and Inflammatory Diseases

Given the central role of Th17 cells and IL-17 in various autoimmune conditions, JNJ-61803534 held potential for a broader range of indications beyond psoriasis. These included:

Psoriatic Arthritis (PsA): Often co-occurring with psoriasis, PsA also has a strong Th17-mediated inflammatory component.[4]
Rheumatoid Arthritis (RA): The significant efficacy observed in the mouse collagen-induced arthritis (CIA) model suggested potential applicability in RA.[1]
Inflammatory Bowel Disease (IBD): Conditions like Crohn's disease and ulcerative colitis involve Th17-driven inflammation in the gut mucosa.[2]
Multiple Sclerosis (MS): Th17 cells are known contributors to the neuroinflammation characteristic of MS.[2]
Other IL-17 Mediated Conditions: The drug was also considered for other diseases where IL-17 plays a pathogenic role.[21]

The development of an oral RORγt inhibitor like JNJ-61803534 can be seen as an endeavor to create an "oral biologic"—a small molecule capable of achieving the targeted efficacy of injectable biologic drugs (such as anti-IL-17 or anti-IL-23 antibodies) but with the added benefit of oral administration. This would represent a significant advancement in patient convenience and potentially accessibility. However, for chronic, generally non-life-threatening inflammatory diseases such as psoriasis, the threshold for safety is exceptionally high. Any new therapy must demonstrate a very favorable risk-benefit profile, especially when existing, albeit less convenient, treatments are available. The eventual emergence of significant safety concerns, such as embryo-fetal toxicity, would therefore pose a substantial barrier to continued development for these indications.

VI. Discontinuation of Development

Despite the promising early-stage preclinical and Phase 1 clinical data, the development of JNJ-61803534 was ultimately terminated.

A. Reason for Termination

The decision to halt the development program for JNJ-61803534 was based on adverse findings from a rabbit embryo-fetal development (EFD) study.[5] This type of study is a standard component of nonclinical safety testing, specifically designed to assess the potential for a drug to cause harm to a developing fetus when administered to a pregnant animal. The EFD study revealed that treatment with JNJ-61803534 impacted fetal development in rabbits.[5] While the specific nature of the fetal impact (e.g., particular malformations, growth inhibition, or lethality) is not detailed in the provided source materials, the finding was evidently significant enough to warrant discontinuation of the drug's development.

B. Implications of Embryo-fetal Toxicity

The observation of embryo-fetal toxicity raises substantial safety concerns regarding the potential use of JNJ-61803534 in humans, particularly in women of childbearing potential, who represent a significant portion of the patient population for diseases like psoriasis. For non-life-threatening conditions, the risk of inducing developmental abnormalities would almost certainly outweigh the potential therapeutic benefits.

The underlying cause of this toxicity could be related to the on-target mechanism of RORγt inhibition. RORγt is known to play roles in normal developmental processes, including the development of secondary lymphoid tissues and thymopoiesis (the development of T cells in the thymus).[11] Interference with such fundamental developmental pathways by an RORγt inverse agonist during critical periods of embryogenesis could plausibly lead to adverse developmental outcomes. This possibility underscores the challenge of targeting transcription factors that have pleiotropic roles, including essential functions during development.

The JNJ-61803534 program serves as an example of a drug candidate that successfully navigated early discovery challenges (such as optimizing for metabolic stability and demonstrating target engagement) and showed positive initial human safety and pharmacodynamic signals in Phase 1. However, it ultimately failed due to toxicity identified in specialized, later-stage preclinical safety studies (specifically, developmental and reproductive toxicology, or DART studies). This is a common juncture in the drug development pipeline where promising candidates can falter, often referred to as the "valley of death." The discrepancy between the good tolerability in adult healthy human SAD studies and the adverse findings in the rabbit EFD study highlights that different types of toxicity assessments are designed to uncover different risks, and results from one do not always predict outcomes in another, especially when considering sensitive developmental windows or species-specific effects.

VII. Summary and Conclusion

JNJ-61803534 was an orally bioavailable, potent, and selective RORγt inverse agonist developed through a collaboration between Phenex Pharmaceuticals AG and Janssen Research & Development, LLC. The compound was designed to treat autoimmune and inflammatory diseases, primarily psoriasis, by inhibiting the Th17 cell pathway and the production of pro-inflammatory cytokines such as IL-17.

Preclinical studies demonstrated that JNJ-61803534 effectively inhibited RORγt in vitro, showed selectivity over related ROR isoforms and a broad panel of other targets, and reduced Th17 cytokine production without adversely affecting Th1 or Treg cells. In vivo, it showed significant efficacy in animal models of psoriasis and rheumatoid arthritis, correlating with the inhibition of RORγt-regulated gene expression. A key medicinal chemistry achievement was overcoming the CYP450 autoinduction issues that had plagued earlier RORγt inhibitors of a similar chemical class.

Phase 1 single ascending dose studies in healthy human volunteers indicated that JNJ-61803534 was well-tolerated up to 200 mg. It exhibited a favorable pharmacokinetic profile characterized by dose-dependent exposure and a long plasma half-life (164-170 hours), supporting the potential for convenient oral dosing. Importantly, clear pharmacodynamic evidence of target engagement was observed in humans, with dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood.

Despite these promising early findings, the development of JNJ-61803534 was discontinued. The termination was due to adverse findings in a rabbit embryo-fetal development study, which indicated that the drug impacted fetal development.[5] This significant safety concern, particularly for a drug intended for chronic conditions like psoriasis where many patients are of reproductive age, ultimately outweighed its therapeutic potential.

The journey of JNJ-61803534 underscores the complexities and high attrition rates inherent in pharmaceutical R&D. It highlights the critical importance of comprehensive toxicological evaluations, including specialized developmental and reproductive toxicology studies, which can reveal risks not apparent in initial adult safety studies. While JNJ-61803534 itself will not advance, the research conducted provides valuable insights into the pharmacology of RORγt inhibition and the challenges associated with developing small-molecule modulators for nuclear receptors involved in critical physiological and developmental processes. The strong scientific rationale for targeting RORγt in autoimmune diseases persists, but future efforts will need to meticulously navigate the fine balance between achieving therapeutic efficacy and ensuring an impeccable safety profile, particularly concerning developmental effects.

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JNJ-61803534 Advanced Drug Monograph

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