Orismilast: A Comprehensive Profile of a Next-Generation Selective PDE4B/D Inhibitor for Immunological Diseases

Executive Summary

Introduction to Orismilast

Orismilast is an investigational, orally administered, new molecular entity poised to represent the next generation of treatments for a spectrum of chronic inflammatory and immunological diseases. It is classified as a small molecule inhibitor of the enzyme phosphodiesterase 4 (PDE4), a well-validated target in immunology. What distinguishes Orismilast from its predecessors is its high potency and specific selectivity for the PDE4B and PDE4D subtypes, which are understood to be the predominant drivers of the inflammatory cascade within immune cells.[1] This targeted mechanism has led to its positioning as a potential "best-in-class" or "first-in-class" therapy for conditions with significant unmet medical needs, including atopic dermatitis, psoriasis, and hidradenitis suppurativa.[3]

Core Value Proposition

The central therapeutic hypothesis for Orismilast is its ability to offer an "improved therapeutic window" compared to earlier, less selective pan-PDE4 inhibitors, such as apremilast. This concept is built on two foundational pillars: enhanced efficacy and a well-established safety profile. By selectively and potently inhibiting the PDE4B and PDE4D subtypes, Orismilast is designed to achieve a more profound anti-inflammatory effect and a deeper clinical response than has been previously observed with this drug class.[3] Simultaneously, it is expected to retain the manageable and well-characterized safety profile associated with PDE4 inhibition, which is notably free from the significant systemic risks that have led to black box warnings for other oral systemic therapies like Janus kinase (JAK) inhibitors.[6] This combination of attributes positions Orismilast as a potentially transformative oral treatment option—a convenient and patient-friendly alternative to injectable biologics and a safer alternative to other potent oral agents.

Key Clinical Findings Summary

The clinical development program for Orismilast has yielded promising data across multiple Phase 2 studies. In moderate-to-severe plaque psoriasis, the IASOS trial demonstrated statistically significant and clinically meaningful improvements in skin clearance, with a notable proportion of patients achieving 90% improvement in the Psoriasis Area and Severity Index (PASI90), suggesting a deeper response than seen with first-generation PDE4 inhibitors.[8] In moderate-to-severe atopic dermatitis, the ADESOS trial showed statistically significant improvements in investigator-assessed disease clearance and a rapid, significant reduction in pruritus, a key symptom for patients.[1] For hidradenitis suppurativa, a notoriously difficult-to-treat condition with limited options, the OSIRIS proof-of-concept study showed clinically relevant improvements in inflammatory lesion counts, pain, and quality of life, even in patients who had previously failed biologic therapies.[9] Across all studies, the safety profile has been consistent with the known effects of the PDE4 inhibitor class, dominated by transient, mild-to-moderate gastrointestinal events, with no new or unexpected safety signals emerging.

Strategic and Commercial Outlook

Orismilast is being developed by UNION Therapeutics, which acquired the asset from LEO Pharma. UNION is pursuing a broad, multi-indication strategy to maximize the drug's potential across immunology.[4] A key component of this strategy was the 2021 partnership with Innovent Biologics, which secured a development and commercialization pathway for Orismilast in the Greater China market, providing significant non-dilutive funding and external validation of the program.[10] The U.S. Food and Drug Administration (FDA) has recognized the drug's potential by granting Fast Track designation for both atopic dermatitis and hidradenitis suppurativa, signaling an expedited regulatory path.[4] With its unique profile as a safe, effective, and convenient oral therapy, Orismilast is strategically positioned to address the significant and persistent unmet need for new treatment paradigms in immunodermatology and beyond.[1]

Drug Profile and Chemical Characteristics

General Classification

Orismilast is classified as a new molecular entity (NME), a designation for a drug containing an active substance that has not previously been approved for marketing in a given jurisdiction.[13] As a small molecule drug, its relatively low molecular weight allows for oral bioavailability, a key feature that distinguishes it from large-molecule biologic therapies that require parenteral administration.[14] This characteristic is central to its value proposition as a convenient, patient-friendly systemic treatment for chronic inflammatory conditions.[3]

Nomenclature and Synonyms

Throughout its development lifecycle, Orismilast has been identified by several names and alphanumeric codes, reflecting its corporate history and formulation-specific development paths.

• International Nonproprietary Name (INN): Orismilast.[16]
• Development Codes and Synonyms:
• LEO-32731 / LEO32731: This code originates from LEO Pharma, the original developer of the molecule, before its acquisition by UNION Therapeutics.[10]
• UNI-50001 and UNI-50002: These codes are used by UNION Therapeutics to differentiate between the oral (UNI-50001) and topical (UNI-50002) formulations of Orismilast under investigation.[3]
• IBI353: This code is used by Innovent Biologics, the strategic partner for the development and commercialization of Orismilast in China.[13]

The existence of these various identifiers is common in pharmaceutical development and provides a traceable history of the asset's progression from discovery to late-stage clinical trials and regional partnerships.

Chemical Structure and Properties

Orismilast is a complex heterocyclic compound. Its precise chemical identity is defined by its structure, formula, and a series of unique registry numbers and codes used in scientific and regulatory databases.

• IUPAC Name: 2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxospiro[1,3-benzodioxole-2,4'-thiane]-4-yl]ethanone.[15]
• Molecular Formula: $C_{19}H_{15}Cl_{2}F_{2}NO_{7}S$.[15]
• Molecular Weight: Approximately 510.3 g/mol.[15]

A consolidated list of key chemical and database identifiers is provided in Table 1 for reference.

Identifier Type	Value	Source(s)
IUPAC Name	2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1',1'-dioxospiro[1,3-benzodioxole-2,4'-thiane]-4-yl]ethanone	15
Molecular Formula	$C_{19}H_{15}Cl_{2}F_{2}NO_{7}S$	15
Molecular Weight	~510.3 g/mol	15
CAS Number	1353546-86-7	15
SMILES String	C1CS(=O)(=O)CCC12OC3=C(C=CC(=C3O2)OC(F)F)C(=O)CC4=C(C=N+[O-])Cl
InChIKey	ZININGNRPUGNSL-UHFFFAOYSA-N
DrugBank ID	DB19042
ChEMBL ID	CHEMBL3654384
UNII	JH1CX8SG5V

The availability of both oral (UNI-50001) and topical (UNI-50002) development codes reveals a broader platform strategy for the Orismilast molecule. The development of two distinct formulations is enabled by the drug's "attractive physicochemical properties," which permit multiple routes of administration. This dual-formulation approach suggests a comprehensive lifecycle management and market segmentation strategy. In immunodermatology, topical agents are the cornerstone of treatment for mild-to-moderate disease, whereas systemic therapies are reserved for moderate-to-severe cases where topical treatment is impractical or insufficient. By developing a topical formulation, UNION Therapeutics can position Orismilast to compete in the large market for mild-to-moderate atopic dermatitis and psoriasis. Concurrently, the oral formulation is being developed to challenge established systemic therapies—including other oral agents and injectable biologics—in the high-value moderate-to-severe disease space. This strategy allows a single NME to address a wider spectrum of disease severity, potentially capturing a larger patient population and maximizing the commercial return on the asset.

Pharmacodynamics and Differentiated Mechanism of Action

The Role of PDE4 in Inflammation

The therapeutic activity of Orismilast is rooted in its function as an inhibitor of phosphodiesterase 4 (PDE4). The PDE superfamily of enzymes is responsible for regulating intracellular signaling by catalyzing the hydrolysis of cyclic nucleotides, primarily cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The PDE4 enzyme subfamily is specific for cAMP, breaking it down into its inactive form, adenosine monophosphate (AMP).

PDE4 is the predominant cAMP-degrading enzyme found within immune and inflammatory cells, such as T-cells, monocytes, macrophages, and neutrophils, as well as structural cells like keratinocytes. In chronic inflammatory diseases, the expression and activity of PDE4 are often upregulated, leading to lower levels of intracellular cAMP and a subsequent pro-inflammatory state.

By inhibiting the PDE4 enzyme, drugs like Orismilast prevent the degradation of cAMP, causing its intracellular levels to rise. This accumulation of cAMP triggers a critical downstream signaling cascade, primarily through the activation of Protein Kinase A (PKA). Activated PKA, in turn, phosphorylates various transcription factors, including the cAMP response element-binding protein (CREB). This process ultimately leads to a broad shift in the cellular inflammatory profile: the production of pro-inflammatory cytokines is suppressed, while the synthesis of anti-inflammatory cytokines, such as Interleukin-10 (IL-10), is increased. This fundamental mechanism—increasing intracellular cAMP to rebalance cytokine production—is the basis for the anti-inflammatory effects of the entire PDE4 inhibitor class.

The Next-Generation Advantage: Selective PDE4B/D Inhibition

The PDE4 enzyme family is not monolithic; it comprises four distinct gene subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. These subtypes are expressed differentially across various tissues and cell types and are associated with different physiological functions. A critical evolution in the understanding of PDE4 biology has been the identification of PDE4B and PDE4D as the key subtypes highly expressed in immune cells and primarily responsible for driving the inflammatory response in diseases like psoriasis and atopic dermatitis. In contrast, PDE4A and PDE4C are less prominent in these cells.

First-generation PDE4 inhibitors, most notably apremilast, are "pan-PDE4 inhibitors," meaning they inhibit all four subtypes with relatively similar potency. While this approach is effective, its clinical utility has been hampered by what is often described as "modest efficacy". The scientific rationale behind next-generation inhibitors like Orismilast is that this limited efficacy is a consequence of non-selective inhibition. The development strategy for Orismilast has been guided by the hypothesis that a more potent and targeted inhibition of only the key inflammatory subtypes, PDE4B and PDE4D, could yield a superior clinical response.

Orismilast is consistently defined as a potent and selective inhibitor of the PDE4B and PDE4D subtypes. This selectivity forms the scientific foundation for its "next-generation" and potential "best-in-class" status. By focusing its inhibitory action on the subtypes most relevant to inflammation, Orismilast is designed to maximize its anti-inflammatory effect. This targeted approach is intended to overcome the efficacy ceiling observed with pan-PDE4 inhibitors. The clinical data from the IASOS trial in psoriasis, which reported PASI90 response rates of 22-28%, are presented as early evidence supporting this hypothesis of a "deeper response". The overarching goal is to create an "improved therapeutic window," where higher efficacy can be achieved while maintaining the well-understood and generally manageable safety profile of the drug class, thereby offering a more favorable risk-benefit balance for patients.

Broad-Spectrum Immunomodulation

The selective inhibition of PDE4B and PDE4D by Orismilast translates into a broad-spectrum immunomodulatory effect, impacting multiple cytokine pathways that are central to the pathogenesis of various inflammatory diseases. This action occurs early in the inflammation cascade, upstream of the specific cytokine-receptor interactions targeted by many biologic therapies. Preclinical and clinical biomarker studies have confirmed Orismilast's ability to potently suppress key pro-inflammatory cytokines across the Th1, Th17, and Th2 axes.

• Th1 Pathway Modulation: Orismilast has been shown to inhibit the production of key Th1-related cytokines, including Tumor Necrosis Factor-alpha (TNF-α) and Interferon-gamma (IFN-γ). The clinical relevance of this was powerfully demonstrated in a biomarker sub-study of the IASOS psoriasis trial. Using minimally invasive tape strips to sample proteins directly from the skin of patients, researchers found that oral Orismilast treatment led to a significant reduction in TNF-α protein levels in psoriatic lesions, with reductions of 66% and 60% observed for the 20 mg and 30 mg BID doses, respectively.
• Th17 Pathway Modulation: The Th17 pathway, particularly the role of IL-17 and IL-23, is a cornerstone of psoriasis pathogenesis. Preclinical models showed Orismilast inhibits the secretion of IL-17, IL-22, and IL-23. The IASOS biomarker study provided compelling human data to support this. Treatment with Orismilast resulted in a significant reduction of IL-17A protein levels in the skin, with reductions of 52% and 51% for the 20 mg and 30 mg doses. This molecular effect was directly and strongly correlated with clinical outcomes; a clinical response of 75% improvement in PASI score (PASI75) was associated with a near-complete 98% reduction in IL-17A protein levels in the skin.
• Th2 Pathway Modulation: The Th2 pathway, characterized by cytokines such as IL-4, IL-5, and IL-13, is central to the pathophysiology of atopic dermatitis. Preclinical studies demonstrated that Orismilast inhibits the secretion of these key Th2 cytokines. This provides a strong mechanistic rationale for its development in atopic dermatitis.

This robust body of translational evidence, connecting the proposed mechanism of action in preclinical models to direct molecular changes in human tissue that correlate with clinical improvement, serves as a powerful de-risking element for the Orismilast development program. It establishes a clear, evidence-based link between target engagement (PDE4B/D inhibition), biological effect (cytokine reduction), and clinical outcome (disease improvement). For regulators, clinicians, and investors, this provides a high degree of confidence that the observed efficacy is a direct and reproducible consequence of the drug's intended mechanism, thereby increasing the perceived probability of success in pivotal Phase 3 trials.

Clinical Development, Corporate Strategy, and Regulatory Status

Development History and Corporate Ownership

The development of Orismilast began at LEO Pharma, a global company specializing in dermatology, where it was identified by the development code LEO-32731. In a strategic portfolio transaction in 2020, the rights to Orismilast were acquired by UNION Therapeutics A/S. UNION Therapeutics is a privately held, clinical-stage pharmaceutical company based in Hellerup, Denmark, with a focus on developing novel treatments for immunological and infectious diseases. Since the acquisition, UNION has taken charge of the global clinical development program, advancing Orismilast through multiple mid-to-late-stage clinical trials across a range of indications.

Strategic Partnership with Innovent Biologics

In a significant strategic move in September 2021, UNION Therapeutics entered into an exclusive collaboration and license agreement with Innovent Biologics, Inc.. This agreement grants Innovent the exclusive rights to research, develop, and commercialize Orismilast in Mainland China, Hong Kong, Macau, and Taiwan.

The financial terms of the deal were substantial, reflecting the perceived value of the asset. UNION Therapeutics received a non-refundable upfront payment of $20 million and is eligible to receive up to an additional $247 million in development, regulatory, and commercial milestone payments. Furthermore, UNION is entitled to receive tiered royalties on net sales of Orismilast within the licensed territory.

This partnership serves several strategic purposes. For UNION, it provides a significant infusion of non-dilutive capital to fund its ongoing global development efforts. It also serves as a strong external validation of Orismilast's potential from a major biopharmaceutical player and establishes a clear and well-funded pathway to access the large and growing Chinese market for inflammatory diseases. For Innovent, the agreement added a promising mid-stage, potential best-in-class oral therapy to its autoimmune pipeline, aligning with its strategic focus.

Broad-Spectrum Clinical Program

Leveraging Orismilast's broad anti-inflammatory mechanism, UNION Therapeutics is pursuing an ambitious multi-indication clinical development strategy targeting several major immunological diseases with high unmet needs. The current clinical pipeline status for oral Orismilast is as follows:

• Atopic Dermatitis (AD): The program is designated as "Phase 3 ready" following the successful completion of the ADESOS Phase 2b dose-finding study.
• Psoriasis (PsO): This program is also "Phase 3 ready" after positive results from the IASOS Phase 2b study.
• Hidradenitis Suppurativa (HS): Following encouraging proof-of-concept data from the OSIRIS study, this program is in preparation for a Phase 2b study.
• Ulcerative Colitis (UC): A Phase 2 Investigator-Initiated Trial (IIT), known as the UCORIS study, has been completed, providing initial exploratory data in this inflammatory bowel disease indication.

FDA Regulatory Trajectory

Orismilast has had a positive and productive regulatory trajectory with the U.S. Food and Drug Administration (FDA), marked by key approvals and designations that facilitate its development.

• Investigational New Drug (IND) Approval: In late 2020, the FDA approved UNION's IND application for oral Orismilast, granting permission to initiate Phase 2b clinical trials in patients with moderate-to-severe plaque psoriasis. This was a critical milestone that enabled the start of the IASOS trial in the United States.
• Fast Track Designation: The FDA has granted Fast Track designation to oral Orismilast for two separate indications. This designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. The benefits include more frequent meetings with the FDA and potential eligibility for Accelerated Approval and Priority Review. The two indications granted this status are:
• Moderate-to-severe Atopic Dermatitis.
• Moderate-to-severe Hidradenitis Suppurativa.

The granting of two distinct Fast Track designations is a significant regulatory endorsement of the Orismilast program. It formally acknowledges the FDA's view that both moderate-to-severe AD and HS are serious conditions with substantial unmet medical needs. For atopic dermatitis, this need is for a safe and effective oral therapy that avoids the black box warnings associated with JAK inhibitors. For hidradenitis suppurativa, the unmet need is even more acute, with only one approved biologic and no approved oral therapies for moderate-to-severe disease. These designations signal that the FDA finds the preliminary clinical data for Orismilast compelling and is committed to collaborating with UNION to streamline its development. This de-risks the regulatory pathway and potentially shortens the timeline to market approval.

EMA Regulatory Trajectory

The provided documentation does not contain specific details regarding regulatory filings, opinions, or designations from the European Medicines Agency (EMA). However, the inclusion of multiple European countries (Germany, Poland, United Kingdom) as clinical trial sites for both the ADESOS and IASOS Phase 2b studies indicates that the necessary clinical trial applications have been approved by national competent authorities within Europe and that regulatory engagement with European bodies is an active component of the global development strategy.

Clinical Efficacy and Safety Analysis by Indication

The clinical utility of Orismilast has been evaluated in a series of robust, indication-specific Phase 2 trials. A comparative summary of the key trials in dermatology is presented in Table 2, followed by a detailed analysis of each study.

Trial Name (Identifier)	Indication	Phase	Design	Patient Population (n)	Dosing Arms (BID)	Primary Endpoint	Key Efficacy Results	Source(s)
ADESOS (NCT05469464)	Atopic Dermatitis	IIb	Randomized, Placebo-Controlled, Dose-Ranging	233	Placebo, 20 mg, 30 mg, 40 mg	% change in EASI at Week 16	Not statistically significant vs. placebo (p>0.05). Statistically significant improvement in IGA 0/1 (20 mg, 40 mg) and itch reduction (PP-NRS ≥4) vs. placebo.
IASOS (NCT05190419)	Plaque Psoriasis	IIb	Randomized, Placebo-Controlled, Dose-Ranging	202	Placebo, 20 mg, 30 mg, 40 mg	% change in PASI at Week 16	Statistically significant improvement vs. placebo for all doses (p<0.001). PASI75: 39.5-49.0%. PASI90: 22.0-28.3%.
OSIRIS (NCT04982432)	Hidradenitis Suppurativa	IIa	Open-Label, Single-Arm, Proof-of-Concept	20	Individualized up to 40 mg	(Exploratory) Change in AN-count, HiSCR	In completers (n=9): 67% achieved HiSCR50, 44% HiSCR75. 33.1% mean reduction in AN-count. 48.2% reduction in pain.

Atopic Dermatitis: The ADESOS Trial (NCT05469464)

The ADESOS study was a pivotal Phase IIb trial designed to evaluate the efficacy, safety, and optimal dose of oral Orismilast in adults with moderate-to-severe atopic dermatitis.

• Trial Design: This was a comprehensive 16-week, multicenter study involving 48 sites across Europe and the USA. It employed a randomized, double-blind, placebo-controlled, parallel-group design, which is the gold standard for assessing therapeutic efficacy. A total of 233 adult patients were enrolled.
• Dosing Arms: Patients were randomized in a 1:1:1:1 ratio to receive one of four treatments: placebo, Orismilast 20 mg, Orismilast 30 mg, or Orismilast 40 mg. All treatments were administered orally twice daily (BID).
• Endpoints: The study assessed multiple domains of atopic dermatitis. The primary endpoint was the percentage change from baseline in the Eczema Area and Severity Index (EASI) score at week 16. Key secondary endpoints included the proportion of patients achieving an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-point improvement from baseline, and the proportion of patients achieving a 4-point or greater reduction in the Peak Pruritus Numerical Rating Scale (PP-NRS).
• Efficacy Results: The trial yielded a mixed but informative set of results.
• Primary Endpoint (EASI): While patients in all Orismilast groups experienced a reduction in their EASI scores, the study did not meet its primary endpoint. The difference in percentage change from baseline in EASI between the active treatment arms and the placebo arm was not statistically significant ($p > 0.05$). This outcome was largely attributed to an unexpectedly high placebo response rate, a known and persistent challenge in atopic dermatitis clinical trials, particularly among patients with moderate disease severity.
• Secondary Endpoints (IGA and Pruritus): In contrast to the primary endpoint, Orismilast demonstrated clear and statistically significant efficacy on key secondary measures. A significantly greater proportion of patients treated with the 20 mg and 40 mg doses achieved the IGA 0/1 endpoint compared to placebo ($p < 0.05$). Furthermore, the trial showed a rapid and significant effect on itch, one of the most burdensome symptoms of AD. A significantly greater proportion of patients across all Orismilast doses achieved a clinically meaningful reduction in itch (≥4-point PP-NRS reduction) as early as week 2 of treatment.

Plaque Psoriasis: The IASOS Trial (NCT05190419)

The IASOS study evaluated Orismilast in adults with moderate-to-severe plaque psoriasis, an indication where Th1 and Th17 pathways are dominant.

• Trial Design: IASOS was a 16-week, randomized, double-blind, placebo-controlled, Phase 2b dose-ranging study that enrolled 202 patients across sites in the US, UK, Germany, and Poland.
• Dosing Arms: Patients were randomized to receive placebo or one of three active doses of Orismilast (20 mg, 30 mg, or 40 mg) administered twice daily.
• Endpoints: The primary endpoint was the percentage change from baseline in the Psoriasis Area and Severity Index (PASI) score at week 16. Important secondary endpoints included the proportion of patients achieving 75% (PASI75) and 90% (PASI90) reductions in their PASI scores, as well as achieving an IGA score of 0 or 1.
• Efficacy Results: The results from IASOS were robust and highly positive.
• Primary Endpoint (PASI): The trial successfully met its primary endpoint with high statistical significance. All three Orismilast doses demonstrated superior PASI reduction compared to placebo ($p < 0.001$). Mean percentage reductions in PASI at week 16 were approximately 53%, 61%, and 64% for the 20 mg, 30 mg, and 40 mg arms, respectively, compared to just a 17% reduction in the placebo group. The onset of action was rapid, with statistically significant improvements observed as early as week 4.
• PASI75 and PASI90 Responses: The study demonstrated substantial rates of skin clearance. At week 16, between 39.5% and 49.0% of patients on Orismilast achieved PASI75. Critically, between 22.0% and 28.3% of patients achieved PASI90, a measure of near-complete skin clearance. This level of PASI90 response is a key point of differentiation, as it suggests a deeper and more profound clinical effect than has been typically associated with first-generation PDE4 inhibitors.
• Biomarker Corroboration: As discussed previously, the clinical improvements were strongly supported by molecular data from patients' skin, showing significant reductions in key psoriasis-driving proteins like IL-17A and TNF-α, confirming the drug's mechanism of action in vivo.

Hidradenitis Suppurativa: The OSIRIS Trial (NCT04982432)

The OSIRIS study was an exploratory trial designed to obtain the first clinical proof-of-concept for Orismilast in hidradenitis suppurativa (HS), a severe and debilitating inflammatory skin disease with very few effective treatment options.

• Trial Design: OSIRIS was a 16-week, open-label, single-arm, single-center, investigator-initiated Phase 2a study. Twenty adult patients with a spectrum of disease from mild to severe HS were enrolled.
• Dosing: The study explored an individualized dosing regimen where patients received Orismilast twice daily, with the dose adjusted up to a maximum of 40 mg BID based on tolerability and response.
• Endpoints: As an exploratory study, endpoints focused on established HS clinical response measures, including the Hidradenitis Suppurativa Clinical Response (HiSCR), the change in the total count of abscesses and inflammatory nodules (AN-count), and patient-reported outcomes such as pain (Global Pain Assessment) and quality of life (DLQI).
• Efficacy Results: Despite the small sample size and high discontinuation rate (11 of 20 patients did not complete 16 weeks), the results among the 9 completers were highly encouraging.
• HiSCR: A significant clinical response was observed, with 67% of completers achieving HiSCR50 (at least a 50% reduction in AN-count with no increase in abscesses or draining fistulas). Even higher response thresholds were met by a subset of patients, with 44% achieving HiSCR75 and 22% achieving HiSCR100 (complete clearance of abscesses and nodules). This level of response is particularly noteworthy as several of these patients had previously failed treatment with biologic therapies, indicating Orismilast may be effective in a treatment-refractory population.
• Lesion and Pain Reduction: Completers experienced a mean reduction in their AN-count of 33.1%. Perhaps most importantly for this patient population, there was a substantial mean reduction in skin-related pain of 48.2% and a corresponding 39.6% improvement in the DLQI score, demonstrating a meaningful impact on the most burdensome aspects of the disease.

The stark difference in the primary endpoint outcomes between the ADESOS (AD) and IASOS (psoriasis) trials warrants closer examination. Psoriasis is a classic Th1/Th17-mediated disease, and the IASOS trial delivered a clear, statistically robust, and dose-ordered efficacy signal on its primary endpoint of skin clearance (PASI). In contrast, atopic dermatitis is a more heterogeneous disease, classically driven by Th2 inflammation, and the ADESOS trial failed to show a significant separation from placebo on its primary skin clearance endpoint (EASI), largely due to a high placebo effect. While Orismilast does inhibit Th2 cytokines and demonstrated significant efficacy on other crucial AD measures like global assessment (IGA) and rapid itch reduction , the data suggest that its efficacy signal, when measured by traditional skin clearance metrics, is more pronounced and less ambiguous in the Th1/Th17-dominant environment of psoriasis. This does not negate its potential in AD. Instead, it highlights a strategic necessity for the Phase 3 program in AD to pivot its focus. UNION Therapeutics has indicated that the IGA score, which was a successful secondary endpoint in Phase 2, will become the primary endpoint for Phase 3, and the rapid, potent effect on itch will be a key secondary endpoint and marketing message. This pragmatic approach leverages the trial's strengths and reframes the value proposition for Orismilast in AD away from competing with biologics on maximal skin clearance and toward offering a safe, oral option that provides rapid symptomatic relief.

Ulcerative Colitis: The UCORIS Trial

Beyond dermatology, the UCORIS study provided the first exploratory data for Orismilast in ulcerative colitis (UC), an inflammatory bowel disease. This Phase 2a, open-label IIT provided preliminary evidence of potential efficacy. Among the nine patients enrolled, three (33%) achieved clinical remission. However, two of these three patients discontinued treatment due to adverse effects (headache and nausea). One patient successfully completed 12 weeks of treatment and met the primary endpoint of clinical remission. While very early and limited, these data suggest that the broad anti-inflammatory mechanism of Orismilast may have therapeutic potential outside of skin diseases, warranting further investigation.

Consolidated Safety and Tolerability Profile

Overview

Across the comprehensive Phase 2 clinical program spanning atopic dermatitis, psoriasis, and hidradenitis suppurativa, Orismilast has demonstrated a consistent and predictable safety profile. The observed adverse events are in line with the well-established safety experience of the broader PDE4 inhibitor drug class. Crucially, no new, unexpected, or major safety concerns have been identified during its clinical development to date.

Common Treatment-Emergent Adverse Events (TEAEs)

The most frequently reported TEAEs associated with Orismilast are dose-dependent and primarily affect the gastrointestinal (GI) system. This is a known class effect of PDE4 inhibitors.

• Specific Adverse Events: The most common TEAEs, consistently reported across all clinical trials, include diarrhea, nausea, and headache. Vomiting and dizziness have also been reported at a lower frequency. In the ADESOS trial, for example, the incidence of any GI disorder in the total Orismilast group was 63.5%, compared to 20.0% in the placebo group. Nausea was reported in 37.6% of Orismilast patients versus 9.1% of placebo patients, and diarrhea was reported in 35.4% versus 5.5%, respectively.
• Onset and Duration: These characteristic side effects are generally mild to moderate in severity. They typically have an early onset, occurring predominantly within the first four weeks of initiating treatment, and often resolve or diminish in intensity with continued administration as patients acclimate to the drug.

Serious Adverse Events (SAEs) and Discontinuations

Serious adverse events have been rare in the Orismilast clinical program. In the 233-patient ADESOS study, only two SAEs (1.1%) were reported across all Orismilast treatment arms, and no deaths occurred. Similarly, only three SAEs were reported in the 202-patient IASOS psoriasis trial.

While not medically serious, the tolerability of the common GI side effects is a key clinical management challenge and the primary driver of treatment discontinuation. In the ADESOS trial, 21.3% of patients in the combined Orismilast arms discontinued treatment due to a TEAE, compared to only 3.6% in the placebo arm. GI events, particularly nausea, were the leading cause of these discontinuations. The OSIRIS study also noted that an initial rapid dose-escalation strategy led to unacceptable tolerability and premature discontinuations, necessitating a switch to a slower, individualized titration schedule. This underscores that while the side effects are manageable, they are significant enough to impact patient adherence. The successful long-term use of Orismilast will depend heavily on optimizing the modified-release formulation and the initial dose-titration schedule to mitigate these early AEs and support patients through the initial treatment period.

Safety Events of Special Interest

A critical aspect of Orismilast's safety profile is its favorable comparison to other systemic therapies for inflammatory diseases.

• Mental Health Profile: First-generation PDE4 inhibitors, such as apremilast, carry warnings regarding depression and suicidal ideation, which can be a significant concern for both prescribers and patients, particularly in populations like psoriasis patients who have a higher baseline prevalence of depression. In stark contrast, the clinical data for Orismilast have shown a clean psychiatric safety profile. In the ADESOS trial, reported rates of depression were low and comparable to placebo, and, most importantly, there were no reported occurrences of suicidal behavior or ideation. Should this favorable psychiatric safety profile be maintained through Phase 3 trials, it would represent a major clinical advantage and a powerful point of differentiation from apremilast, potentially positioning Orismilast as a preferred first-line oral option for patients with or at risk for mood disorders.
• Infection Risk: Unlike many biologics and JAK inhibitors that carry warnings about increased risk of serious infections due to their immunosuppressive effects, Orismilast has not shown such a signal. In fact, in the ADESOS trial, the rate of infections was numerically lower in the Orismilast-treated groups compared to the placebo group.
• Comparison to Other Systemics: The safety profile of Orismilast appears free from the adverse events of special interest associated with other drug classes. For example, conjunctivitis and arthralgia, which are associated with IL-13-targeting biologics like dupilumab, were reported very infrequently. Most significantly, Orismilast is not associated with the risks of serious infections, malignancy, major adverse cardiovascular events (MACE), and thrombosis that have resulted in an FDA black box warning for the entire class of JAK inhibitors.

Strategic Analysis and Future Outlook

Competitive Landscape and Positioning

Orismilast is entering a dynamic and competitive therapeutic landscape for immunological diseases. Its success will depend on its ability to clearly differentiate itself from three major classes of established and emerging systemic therapies. The strategic positioning of Orismilast appears to be centered on occupying a unique niche as the "safe oral" option that balances efficacy and convenience.

• Versus Apremilast (Otezla): Orismilast is positioned for a direct, head-to-head challenge with apremilast, the incumbent oral PDE4 inhibitor. The competitive narrative is built on the premise of being a "next-generation" agent with superior efficacy. This claim is substantiated by the Phase 2b IASOS trial results, which demonstrated PASI90 response rates (22-28%) that suggest a deeper level of skin clearance than is typically achieved with apremilast. A second, equally critical point of differentiation is the potentially superior psychiatric safety profile. The absence of any signal for suicidal ideation in Orismilast's clinical program to date directly addresses a key safety concern associated with apremilast, which could make Orismilast a more attractive option for a broad range of patients, especially those with a history of depression. This dual advantage of enhanced efficacy and improved safety could enable Orismilast to displace apremilast as the preferred PDE4 inhibitor and effectively compete with future apremilast generics.
• Versus JAK Inhibitors: The primary competitive advantage of Orismilast over oral JAK inhibitors (e.g., upadacitinib, abrocitinib) is its markedly superior safety profile. The entire JAK inhibitor class is encumbered by an FDA-mandated black box warning regarding the risks of serious infections, malignancy, major adverse cardiovascular events, and thrombosis. Orismilast has shown no such safety signals. This allows it to be positioned as a much safer first-line oral systemic therapy. While JAK inhibitors may offer higher peak efficacy in some patients, the significant safety liabilities and associated monitoring requirements make them a less desirable option for many physicians and patients. Orismilast can be marketed as the oral therapy that provides meaningful efficacy without these serious risks.
• Versus Injectable Biologics: Against highly effective injectable biologics (e.g., TNF inhibitors like adalimumab or IL-4/13 inhibitors like dupilumab), the core value proposition of Orismilast is the convenience of oral administration. A significant segment of the patient population is needle-averse or prefers the simplicity and portability of a pill over a subcutaneous injection that requires refrigeration and proper disposal. While biologics may set the highest bar for efficacy in terms of complete skin clearance, Orismilast offers a compelling balance of meaningful efficacy, safety, and superior convenience. Furthermore, in atopic dermatitis, Orismilast demonstrated a faster onset of itch relief than is typically seen with biologics, a key patient-reported benefit that can be a strong driver of treatment choice.

Addressing Unmet Needs

The development of Orismilast is directly targeted at a well-defined and persistent unmet medical need across multiple chronic inflammatory diseases: the need for a treatment that is simultaneously effective, safe for long-term use, and orally administered. Currently, no single therapy class optimally satisfies all three criteria. Apremilast is oral and safe but offers only modest efficacy. JAK inhibitors are oral and effective but carry significant safety concerns. Biologics are effective and generally safe but require injections. Orismilast is uniquely positioned to fill this therapeutic gap, offering a novel option that combines the convenience of a pill, a safety profile that does not require extensive monitoring, and a level of efficacy that appears to be a significant improvement over the current oral standard of care.

Future Development and Phase 3 Considerations

With the atopic dermatitis and psoriasis programs now designated as "Phase 3 ready," the design of these pivotal trials will be critical for regulatory approval and commercial success.

• Atopic Dermatitis: Based on the Phase 2b ADESOS results, the Phase 3 program will likely pivot its primary endpoint from EASI to the IGA 0/1 response, where a statistically significant effect was demonstrated. The rapid and potent reduction in itch will be a key secondary endpoint, serving as a major part of the clinical and commercial narrative. The trial design may also incorporate stratification by baseline disease severity to better manage the high placebo response observed in patients with more moderate disease.
• Psoriasis: The primary goal of the Phase 3 psoriasis program will be to replicate and confirm the strong efficacy signals from the IASOS trial. The key objective will be to demonstrate statistically superior PASI75 and, most importantly, PASI90 response rates compared to placebo, thereby cementing the claim of enhanced efficacy over apremilast.
• Hidradenitis Suppurativa: Following the promising OSIRIS data, the next step is a larger, randomized, controlled Phase 2b study. This trial will need to establish a more definitive dose and confirm the encouraging signals on HiSCR and patient-reported outcomes like pain and quality of life, which are critical endpoints in this disease.

Conclusion: Projected Role in Therapy

Orismilast has established a compelling and differentiated profile as a potent, next-generation selective PDE4B/D inhibitor. The comprehensive Phase 2 data package provides a strong foundation of evidence supporting its potential to offer a superior therapeutic window compared to existing therapies. Its mechanism of action is well-defined and has been validated in human clinical trials through robust biomarker data.

If the promising efficacy and safety signals observed in Phase 2 are successfully replicated in pivotal Phase 3 trials, Orismilast is poised to become a significant new agent in the therapeutic armamentarium for immunodermatology. It has the potential to displace apremilast as the oral PDE4 inhibitor of choice and to capture a substantial portion of the market for patients seeking an effective oral therapy without the safety liabilities of JAK inhibitors. Its ultimate success will depend on three key factors: the confirmation of its superior efficacy profile in larger trials, the effective clinical management of its characteristic gastrointestinal tolerability to maximize patient adherence, and the ability to articulate its unique value proposition as a safe, effective, and convenient oral therapy in a competitive marketplace.

Works cited

1. Orismilast, a phosphodiesterase 4B/D inhibitor, in moderate-to-severe atopic dermatitis: efficacy and safety from a multicentre randomized placebo-controlled phase IIb dose-ranging study (ADESOS) - PubMed, accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/39847538/
2. UNION therapeutics A/S announces new paper on clinical potential of the emerging class of PDE4B/D inhibitors published in journal of Dermatology and Therapy, accessed October 17, 2025, https://uniontherapeutics.com/union-therapeutics-a-s-announces-new-paper-on-clinical-potential-of-the-emerging-class-of-pde4b-d-inhibitors-published-in-journal-of-dermatology-and-therapy/
3. UNION therapeutics A/S receives FDA approval for IND of oral next generation PDE4-inhibitor (orismilast) for investigation in plaque psoriasis, accessed October 17, 2025, https://uniontherapeutics.com/union-therapeutics-a-s-receives-fda-approval-for-ind-of-oral-next-generation-pde4-inhibitor-orismilast-for-investigation-in-plaque-psoriasis-2/
4. Orismilast - UNION Therapeutics, accessed October 17, 2025, https://uniontherapeutics.com/orismilast/
5. UNION therapeutics announces positive topline results from the IASOS Phase 2b study of oral orismilast in patients with moderate to severe psoriasis - PR Newswire, accessed October 17, 2025, https://www.prnewswire.com/news-releases/union-therapeutics-announces-positive-topline-results-from-the-iasos-phase-2b-study-of-oral-orismilast-in-patients-with-moderate-to-severe-psoriasis-301716683.html
6. One-on-one: TDD Chats with UNION Therapeutic's CO-CEO Kim Kjøller About the New RAVE Data on Orismilast in AD - The Dermatology Digest, accessed October 17, 2025, https://thedermdigest.com/one-on-one-tdd-chats-with-union-therapeutics-co-ceo-kim-kjoller-about-the-new-rave-data-on-orismilast-in-ad/
7. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions, accessed October 17, 2025, https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death
8. UNION therapeutics A/S announces publication of results from the ..., accessed October 17, 2025, https://uniontherapeutics.com/union-therapeutics-a-s-announces-publication-of-results-from-the-iasos-phase-2b-study-of-orismilast-in-psoriasis-in-journal-of-the-american-academy-of-dermatology/
9. UNION therapeutics announces publication of results from the ..., accessed October 17, 2025, https://uniontherapeutics.com/union-therapeutics-announces-publication-of-results-from-the-osiris-phase-2-study-of-orismilast-in-hidradenitis-suppurativa-in-the-journal-of-the-european-academy-of-dermatology-and-venereology/
10. Innovent and UNION Therapeutics Enter into Strategic Collaboration ..., accessed October 17, 2025, https://www.prnewswire.com/news-releases/innovent-and-union-therapeutics-enter-into-strategic-collaboration-and-license-agreement-for-orismilast-a-next-generation-pde4-inhibitor-for-inflammatory-dermatology-conditions-301385656.html
11. Union therapeutics signs deal with Innovent to develop orismilast in China, accessed October 17, 2025, https://www.pharmaceutical-technology.com/news/union-therapeutics-innovent-orismilast/
12. Oral Orismilast Shows Clinically Relevant Improvement In Patients With Moderate To Severe Hidradenitis Suppurativa | Dermatology Times, accessed October 17, 2025, https://www.dermatologytimes.com/view/oral-orismilast-shows-clinically-relevant-improvement-in-patients-with-moderate-to-severe-hidradenitis-suppurativa
13. UNION Therapeutics - Orismilast - AdisInsight - Springer, accessed October 17, 2025, https://adisinsight.springer.com/drugs/800033858
14. Orismilast - Drug Targets, Indications, Patents - Patsnap Synapse, accessed October 17, 2025, https://synapse.patsnap.com/drug/1f299aacad6748fd98a7273fc32783bc
15. Orismilast | C19H15Cl2F2NO7S | CID 54765967 - PubChem, accessed October 17, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Orismilast
16. ORISMILAST - gsrs, accessed October 17, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/JH1CX8SG5V
17. Orismilast | CAS NO.:1353546-86-7 | GlpBio, accessed October 17, 2025, https://www.glpbio.com/orismilast.html
18. Orismilast | Drug Information, Uses, Side Effects, Chemistry - PharmaCompass.com, accessed October 17, 2025, https://www.pharmacompass.com/chemistry-chemical-name/orismilast
19. Compound: ORISMILAST (CHEMBL3654384) - ChEMBL - EMBL-EBI, accessed October 17, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL3654384
20. Orismilast ( LEO-32731) | CAS 1353546-86-7 | AbMole BioScience, accessed October 17, 2025, https://www.abmole.com/products/orismilast.html
21. Orismilast - Cenmed Enterprises, accessed October 17, 2025, https://cenmed.com/orismilast-c007b-583634/
22. Pharmacology of orismilast, a potent and selective PDE4 inhibitor, accessed October 17, 2025, https://orbit.dtu.dk/files/329059779/Acad_Dermatol_Venereol_2022_Silverberg_Pharmacology_of_orismilast_a_potent_and_selective_PDE4_inhibitor.pdf
23. Orismilast, a Potent and Selective PDE4B/D Inhibitor, Reduces Protein Levels of Key Disease Driving Cytokines in the Skin of Patients With Plaque Psoriasis - PubMed Central, accessed October 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12447663/
24. Orismilast Tablets Significantly Clear Psoriasis Skin | HCPLive, accessed October 17, 2025, https://www.hcplive.com/view/orismilast-tablets-significantly-clear-psoriasis-skin
25. Pharmacology of orismilast, a potent and selective PDE4 inhibitor - PubMed, accessed October 17, 2025, https://pubmed.ncbi.nlm.nih.gov/36527389/
26. UNION therapeutics announces full-year results for 2024, accessed October 17, 2025, https://uniontherapeutics.com/union-therapeutics-announces-full-year-results-for-2024/
27. UNION therapeutics announces presentation of new data on orismilast at the EADV Congress 2023 - PR Newswire, accessed October 17, 2025, https://www.prnewswire.com/news-releases/union-therapeutics-announces-presentation-of-new-data-on-orismilast-at-the-eadv-congress-2023-301949284.html
28. Union plans Phase III trial for atopic dermatitis after Phase IIb win - Clinical Trials Arena, accessed October 17, 2025, https://www.clinicaltrialsarena.com/news/union-plans-phase-iii-trial-for-atopic-dermatitis-after-phase-iib-win/
29. P0942 Orismilast for the treatment of moderate to severe Ulcerative Colitis: Analysis of preliminary data from UCORIS, a phase 2a, open-label, single-arm exploratory clinical trial - Oxford Academic, accessed October 17, 2025, https://academic.oup.com/ecco-jcc/article/19/Supplement_1/i1766/7967814
30. UNION therapeutics A/S receives FDA approval for IND of oral next generation PDE4-inhibitor (orismilast) for investigation in plaque psoriasis - PR Newswire, accessed October 17, 2025, https://www.prnewswire.com/news-releases/union-therapeutics-as-receives-fda-approval-for-ind-of-oral-next-generation-pde4-inhibitor-orismilast-for-investigation-in-plaque-psoriasis-301202575.html
31. UNION therapeutics receives FDA Fast Track designation for oral orismilast for the treatment of moderate to severe hidradenitis suppurativa - PR Newswire, accessed October 17, 2025, https://www.prnewswire.com/news-releases/union-therapeutics-receives-fda-fast-track-designation-for-oral-orismilast-for-the-treatment-of-moderate-to-severe-hidradenitis-suppurativa-301718012.html
32. UNION therapeutics announces positive topline results from the ..., accessed October 17, 2025, https://uniontherapeutics.com/union-therapeutics-announces-positive-topline-results-from-the-osiris-investigator-initiated-proof-of-concept-study-of-oral-orismilast-in-patients-with-hidradenitis-suppurativa/
33. UNION therapeutics announces positive topline results from the OSIRIS investigator-initiated proof-of-concept study of oral orismilast in patients with hidradenitis suppurativa - PR Newswire, accessed October 17, 2025, https://www.prnewswire.com/news-releases/union-therapeutics-announces-positive-topline-results-from-the-osiris-investigator-initiated-proof-of-concept-study-of-oral-orismilast-in-patients-with-hidradenitis-suppurativa-301856308.html
34. UNION's orismilast enters Phase IIb and a crowded small molecule market, accessed October 17, 2025, https://www.clinicaltrialsarena.com/analyst-comment/orismilast-phase-iib-small-molecule-market/
35. Orismilast, a phosphodiesterase 4B/D inhibitor, in moderate-to-severe atopic dermatitis: efficacy and safety from a multicentre randomized placebo-controlled phase IIb dose-ranging study (ADESOS) | British Journal of Dermatology | Oxford Academic, accessed October 17, 2025, https://academic.oup.com/bjd/article/192/6/995/7976923
36. Efficacy and safety of orismilast, a potent PDE4B/D inhibitor, in adults with moderate-to-severe atopic dermatitis: a phase 2b randomized, double-blind, placebo-controlled clinical trial (ADESOS) | British Journal of Dermatology | Oxford Academic, accessed October 17, 2025, https://academic.oup.com/bjd/article-abstract/191/Supplement_2/ljae266.067/7728650
37. UNION therapeutics announces positive topline results from the IASOS Phase 2b study of oral orismilast in patients with moderate to severe psoriasis, accessed October 17, 2025, https://uniontherapeutics.com/union-therapeutics-announces-positive-topline-results-from-the-iasos-phase-2b-study-of-oral-orismilast-in-patients-with-moderate-to-severe-psoriasis/
38. Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, phase 2b trial (IASOS) - ResearchGate, accessed October 17, 2025, https://www.researchgate.net/publication/375593341_Orismilast_in_moderate-to-severe_psoriasis_Efficacy_and_safety_from_a_16-week_randomized_double-blinded_placebo-controlled_dose-finding_phase_2b_trial_IASOS
39. (PDF) Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open‐label, single‐centre, single‐arm, dose‐finding clinical trial - ResearchGate, accessed October 17, 2025, https://www.researchgate.net/publication/376842217_Orismilast_for_the_treatment_of_mild_to_severe_hidradenitis_suppurativa_Week_16_data_from_OSIRIS_a_Phase_2a_open-label_single-centre_single-arm_dose-finding_clinical_trial
40. Positive Results Seen in Orismilast Treatment of Patients with HS ..., accessed October 17, 2025, https://www.hcplive.com/view/positive-results-seen-in-orismilast-treatment-of-patients-with-hs
41. Should the Black Box Warning of Brodalumab and Apremilast Deter Prescribing in Psoriasis Patients with Depression? - ResearchGate, accessed October 17, 2025, https://www.researchgate.net/publication/348335918_Should_the_Black_Box_Warning_of_Brodalumab_and_Apremilast_Deter_Prescribing_in_Psoriasis_Patients_with_Depression
42. Psoriasis treatment: Apremilast - American Academy of Dermatology, accessed October 17, 2025, https://www.aad.org/public/diseases/psoriasis/treatment/medications/apremilast
43. Janus Kinase (JAK) inhibitors: Drug Safety Communication - FDA Requires Warnings about Increased Risk of Serious Heart-related Events, Cancer, Blood Clots, and Death, accessed October 17, 2025, https://www.fda.gov/safety/medical-product-safety-information/janus-kinase-jak-inhibitors-drug-safety-communication-fda-requires-warnings-about-increased-risk