Canine atopic dermatitis (CAD) affects 3 to 15% of the canine population. The arrival of atinvicitinib (NUMELVI, MSD Animal Health), a second-generation selective JAK1 inhibitor authorized in Europe in July 2025, has transformed the therapeutic landscape of this condition. This review details updated data, from the molecular mechanism to management strategies.
1. Background and Therapeutic Positioning
1.1 Epidemiology of canine atopic dermatitis
Canine atopic dermatitis is a chronic inflammatory, immunologically mediated skin disease whose prevalence in the general canine population has been estimated at between 3 and 15%, although the ACVD Task Force has acknowledged that these figures are not based on reliable epidemiological data (Hillier 2001). Pruritus accounts for more than 20% of consultation reasons in general veterinary practice, and CAD is the leading identifiable cause in dogs under three years of age (Drechsler 2024). Predisposed breeds worldwide include the Labrador Retriever, English Bulldog, Boxer, Pug, and West Highland White Terrier, with significant geographic variations in prevalence rates (Hensel 2024). In Hungary, a retrospective study of 600 atopic dogs confirmed these breed predispositions with local particularities (Tarpataki 2006).
A recent Chinese epidemiological study (Dong 2024) modeling CAD incidence in 14 major cities highlighted the critical role of climatic factors, confirming a strong positive correlation with summer temperature and humidity. Interestingly and counter-intuitively compared to human atopic models, this same study reported a negative correlation between CAD incidence and atmospheric pollutant concentrations, suggesting complex environmental and behavioral dynamics (such as a strictly indoor lifestyle during pollution peaks) affecting allergen exposure in companion dogs.
In the Labrador Retriever, the clinical phenotype is characterized by erythematous pruritus predominantly affecting the concave surfaces of the ear pinnae, interdigital spaces, and ventral trunk, with recurrent pododermatitis and external otitis as cardinal markers of cutaneous barrier dysfunction (Gentry 2025). The French Bulldog frequently presents facial manifestations with periocular and perilabial erythema, while the German Shepherd develops predominantly axillary and inguinal lesions with more pronounced secondary infection (Hensel 2024). In contrast to ichthyosis in the Golden Retriever, where the PNPLA1 gene mutation has been clearly identified, no major susceptibility gene has been formally characterized for CAD to date.
The French Bulldog is predisposed to canine atopic dermatitis
1.2 Pathophysiology: central role of the JAK-STAT pathway
Canine atopic dermatitis results from three mutually reinforcing mechanisms: a defective skin barrier that allows allergens to penetrate, an allergy-oriented immune response (Th2 polarization), and progressive sensitization to environmental allergens (Santoro 2015, Drechsler 2024). Atopic skin is both a gateway and an amplifier of inflammation. Faced with this complexity, ICADA recommends a management approach combining the elimination of triggering factors, restoration of the skin barrier, and pharmacological control of immunity (Olivry 2015). Olivry (2019) updated this algorithm to incorporate the new molecular targets identified since then, notably the Janus kinase (JAK) pathway (Olivry 2019).
Many cytokines responsible for pruritus and inflammation in CAD transmit their signal inside the cell via these enzymes. Blocking JAKs is equivalent to interrupting the transmission of the inflammatory message before the cell even reacts. Among these cytokines, IL-31 is the most directly pruritogenic. Produced by activated Th2 lymphocytes, it binds to a specific receptor (IL-31RA/OSMR) located on the surface of cutaneous sensory neurons, which activates JAK1 and JAK2 and directly triggers the scratching signal at the neuronal level (Gonzales 2014). TSLP, released by damaged keratinocytes, and IL-33 also use the JAK1 pathway to sustain inflammation and amplify pruritus.
The intracellular sequence unfolds as follows. The cytokine binds to its membrane receptor, which modifies the receptor conformation on the intracellular side and activates the associated JAKs through mutual phosphorylation. These JAKs in turn phosphorylate the receptor, creating docking sites for proteins called STATs (Signal Transducers and Activators of Transcription). The STATs bind to these sites, are phosphorylated on a tyrosine residue, then associate in pairs to migrate into the cell nucleus where they activate the transcription of genes encoding pro-inflammatory mediators, cell proliferation factors, and pruritogenic molecules (Gonzales 2014). JAK inhibitors block this cascade at the enzymatic activation step, before the signal reaches the nucleus, which explains their rapid onset of action on pruritus.
1.3 History of JAK inhibitors in veterinary medicine
Oclacitinib (APOQUEL® ND, Zoetis), the first JAK inhibitor authorized in veterinary medicine, received its marketing authorization in the United States in May 2013 for the control of pruritus associated with allergic dermatitis and the control of atopic dermatitis in dogs at least 12 months of age. In isolated enzyme systems, oclacitinib inhibits JAK1, JAK2, JAK3, and TYK2 with respective IC50 values of 10, 18, 99, and 84 nM, representing a selectivity of only 1.8-fold for JAK1 over JAK2 (Gonzales 2014). This modest selectivity necessitates a two-phase dosing regimen: 0.4–0.6 mg/kg twice daily for 14 days, then once daily for maintenance, in order to keep plasma concentrations below the inhibition threshold of JAK2-dependent cytokines involved in hematopoiesis (Nederveld 2025). Ilunocitinib (ZENRELIA, Elanco), authorized by the FDA in September 2024, is a non-selective JAK inhibitor with high affinity for JAK1, JAK2, and TYK2, administered at a dose of 0.6–0.8 mg/kg once daily (Patterson 2025). In a randomized clinical trial involving 268 atopic dogs, 83% of animals treated with ilunocitinib achieved therapeutic success (≥50% reduction in PVAS or CADESI-04 score) at day 28, compared to 31% in the placebo group (p < 0.001) (Forster 2025a). Atinvicitinib (NUMELVI, MSD Animal Health), authorized by the European Commission on July 24, 2025, represents the first and only second-generation JAK inhibitor in veterinary medicine, with a selectivity for JAK1 at least 10 times greater than that of the other members of the JAK family (EMA 2025).
On June 12, 2025, the Committee for Medicinal Products for Veterinary Use (CVMP) of the European Medicines Agency (EMA) issued a positive opinion for the granting of a marketing authorization for NUMELVI. The applicant for this marketing authorization is Intervet International B.V., a subsidiary of Merck & Co., Inc. (known as MSD outside the United States and Canada). The European Commission granted the marketing authorization on July 24, 2025, with effective market launch in Europe in the third quarter of 2025. Since February 2026, NUMELVI (atinvicitinib) has also received authorization in the United States for the control of pruritus associated with allergic dermatitis, including atopic dermatitis in dogs.
2. Presentation and Pharmaceutical Data
2.1 International nonproprietary name on the label and ATCvet code
The international nonproprietary name (INN) of the active substance is atinvicitinib. The assigned ATCvet code is QD11AH93, classifying this drug in the category of dermatological agents for the treatment of dermatitis, excluding corticosteroids, within the veterinary drug classification system (EMA 2025). The designation “not applicable” appears in the product labeling for sections relating to withdrawal periods, major incompatibilities, and environmental precautions.
2.2 Qualitative and quantitative composition
Each tablet contains 4.8 mg, 7.2 mg, 21.6 mg, or 31.6 mg of atinvicitinib as the active substance, respectively. Excipients include: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate (type A), tocofersolan, hydroxypropylcellulose, anhydrous colloidal silica, and magnesium stearate (EMA 2025).
Numelvi presentations
2.3 Pharmaceutical forms and available dosage strengths (S, M, L, XL)
NUMELVI is presented as oblong, white to off-white tablets, breakable along a score line on each face. Four dosage strengths are available: S (4.8 mg), M (7.2 mg), L (21.6 mg), and XL (31.6 mg). Each dosage strength is identified by an alphabetical marking (“S”, “M”, “L”, or “XL”) printed on each half-tablet on the upper face. The tablets may be divided into two equal halves along the score line (EMA 2025).
2.4 Commercial packaging and storage
Two types of primary packaging are available: aluminum/PVC/polychlorotrifluoroethylene thermoformed blister packs containing 30 tablets per strip (boxes of 1 or 3 strips, i.e., 30 or 90 tablets), and high-density polyethylene (HDPE) bottles containing 30 or 90 tablets. Not all pack sizes may be marketed in every member state. Marketing authorization numbers range from EU/2/25/351/001 to EU/2/25/351/016. This veterinary medicinal product requires no special storage conditions. Any remaining half-tablet must be replaced in the opened blister pack or bottle (EMA 2025).
2.5 Legal status and dispensing conditions
NUMELVI is a veterinary medicinal product subject to prescription. Its dispensing requires a prescription from a veterinarian (EMA 2025).
3. Molecular Mechanism of Action and Pharmacodynamics
3.1 Fundamentals of the JAK-STAT pathway
The JAK-STAT signaling pathway constitutes the primary transduction mechanism for more than 50 cytokines and growth factors. Four Janus kinases (JAK1, JAK2, JAK3, TYK2) and seven STAT proteins (STAT1 through STAT4, STAT5a, STAT5b, STAT6) orchestrate this cascade. JAK1 is recruited by virtually all pro-inflammatory type I and type II cytokine receptors, making it a central hub of immune and pruritogenic signaling (Gonzales 2014). JAK2, in contrast, is predominantly recruited by homodimeric receptors of hematopoietic cytokines such as erythropoietin (EPO) and GM-CSF, whose JAK2/JAK2 pairs ensure signal transduction necessary for bone marrow cell proliferation. JAK3, with expression restricted to hematopoietic cells, associates exclusively with the common γc chain of receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, playing a role in lymphocyte development and homeostasis. TYK2 participates in type I interferon and IL-12/IL-23 signaling, involved in antiviral defense and Th1/Th17 polarization (Patterson 2025). The specificity of JAK pairs recruited by each cytokine receptor determines the pharmacological and toxicological profile of each inhibitor: a molecule preferentially inhibiting JAK1 will target pruritogenic and pro-inflammatory cytokines, while non-selective inhibition also targeting JAK2 may compromise erythropoiesis (via the EPO/JAK2/JAK2 receptor) and granulopoiesis (via the GM-CSF/JAK2 receptor), and inhibition of JAK3 may impair T and NK lymphopoiesis. Understanding this molecular architecture is a prerequisite for comparative analysis of the three JAK inhibitors available in veterinary medicine in 2026.
3.2 Mechanism of competitive and selective JAK1 inhibition
Atinvicitinib acts as a reversible competitive inhibitor of the catalytic site of the JAK1 kinase, binding to the ATP-binding site in the JH1 kinase domain. Its chemical structure, distinct from the pyrrolopyrimidine core of oclacitinib, confers a selectivity at least 10 times greater for JAK1 compared to JAK2, JAK3, and TYK2 (EMA 2025). This second-generation selectivity allows targeted inhibition of JAK1-dependent cytokines involved in pruritus and allergic inflammation, while preserving the functions of other JAKs involved in hematopoiesis and host defense. By comparison, oclacitinib exhibits a JAK1/JAK2 selectivity of only 1.8-fold in isolated enzyme systems (IC50 of 10 nM for JAK1 vs. 18 nM for JAK2) (Gonzales 2014), which represents a limiting factor for the therapeutic window of this first-generation agent.
3.3 Targeted cytokines involved in pruritus and inflammation (IL-31, IL-4, IL-13, TSLP, IL-33)
Inhibition of JAK1 by atinvicitinib blocks signal transduction of multiple pathogenic cytokines in CAD. IL-31, the major pruritogenic cytokine produced by Th2 lymphocytes, signals via the IL-31RA/OSMR complex which recruits JAK1/JAK2; selective inhibition of JAK1 is sufficient to interrupt this pruritogenic cascade without significantly affecting JAK2-dependent functions at the target dose (EMA 2025). IL-4, a central mediator of Th2 polarization and IgE isotype switching, signals through the IL-4Rα/γc complex recruiting JAK1/JAK3. IL-13, involved in goblet cell hyperplasia and barrier dysfunction, uses the JAK1/JAK2/TYK2 pairs. TSLP, a keratinocyte alarmin released in response to barrier damage and allergenic stimuli, activates a receptor recruiting JAK1/JAK2 (Wichtowska 2025). All of these cytokine targets converge on the JAK1 pathway, justifying the selective inhibition approach for multiaxial control of the disease (Gonzales 2014).
3.4 JAK1 vs. JAK2, JAK3, TYK2 selectivity: biochemical data
Biochemical data from Intervet International B.V. indicate that atinvicitinib exhibits at least a 10-fold selectivity (factor ≥10) for JAK1 relative to each of the three other members of the JAK family (JAK2, JAK3, TYK2) in isolated enzyme systems (EMA 2025). Consequently, atinvicitinib exerts little to no effect on cytokines involved in hematopoiesis (EPO, GM-CSF, JAK2-dependent) or host defense (IL-12, IL-23, JAK2/TYK2-dependent). A poster presented at the 35th European Congress of Veterinary Dermatology (ECVD) in Bilbao in September 2025 confirmed that atinvicitinib behaves as a potent and highly selective inhibitor of JAK1 (MSD Animal Health 2025). By contrast, oclacitinib requires adjustment of administration frequency (switching from BID to SID after 14 days) to avoid prolonged inhibition of JAK2-dependent cytokines at supra-therapeutic plasma concentrations (Nederveld 2025).
3.5 Mechanism of action on pruritus: speed of effect and neurobiological basis
Atopic pruritus results from stimulation of cutaneous sensory nerve endings by pruritogenic mediators, primarily IL-31, but also IL-4, IL-13, and TSLP, which directly activate neuronal receptors via JAK1-dependent pathways. Inhibition of JAK1 by atinvicitinib interrupts this pruritogenic transmission within the first hours following oral administration. A presentation at the ECVD 2025 congress demonstrated that atinvicitinib significantly reduces pruritus in a canine IL-31 allergy model as early as 2 to 4 hours after administration (MSD Animal Health 2025). This rapid onset of action, clinically perceptible from the first dose, is based on the rapid absorption of the molecule (Tmax ≈ 1 hour) and its immediate inhibition of JAK1-dependent transduction at the level of sensory neurons and keratinocytes (EMA 2025).
3.6 Impact on skin barrier regulation
Atinvicitinib did not induce immunosuppressive effects at the target dose in preclinical and clinical studies (EMA 2025). The reduction in allergic inflammation dependent on JAK1 enzymatic activity leads to a decrease in white blood cell counts associated with inflammation (eosinophils, neutrophils, monocytes) while maintaining these parameters within reference intervals, indicating immune modulation rather than immunosuppression (Jirjis 2025). This property is compatible with preservation of skin barrier function, since attenuation of the Th2 inflammatory cascade reduces the degradation of intercorneocyte lipids and epidermal junction proteins induced by pro-inflammatory cytokines.
4. Pharmacokinetics in Dogs
4.1 Absorption: oral bioavailability, food effect
Following oral administration, atinvicitinib is rapidly and well absorbed, with a mean observed peak plasma concentration (Cmax) of 190 ng/mL, reached approximately 1 hour (Tmax) after administration (EMA 2025). Absolute bioavailability, evaluated after once-daily administration for four days, is approximately 65%. Bioavailability is higher in fed dogs, which justifies the recommendation to administer the drug with or around mealtime. This pharmacokinetic characteristic is directly integrated into the product labeling: “the veterinary medicinal product should be administered once daily, with or around mealtime” (EMA 2025).
4.2 Distribution: volume of distribution, plasma protein binding
The apparent volume of distribution at steady state is 1651 mL/kg body weight, indicating moderate to extensive tissue distribution (EMA 2025). Atinvicitinib shows moderate plasma protein binding, with 82.3% of bound substance in canine plasma at a concentration of 1802 ng/mL (5 µM). This moderate binding, lower than that of many anti-inflammatory agents, favors the pharmacologically active free fraction at cutaneous and neuronal sites of action.
4.3 Hepatic metabolism: enzymatic pathways involved (CYP450)
Atinvicitinib undergoes extensive metabolism in dogs, generating multiple metabolites. The primary clearance pathway is hepatic metabolism, although the specific cytochrome P450 isoenzymes involved have not been detailed in the published product labeling. Total body clearance from plasma is 1074 mL/h/kg body weight (17.9 mL/min/kg), placing atinvicitinib in the category of high hepatic clearance molecules (EMA 2025).
4.4 Elimination: elimination half-life, excretion routes
The terminal elimination half-life (t1/2, or terminal half-life) is 2 hours after oral administration, which is markedly shorter than that of oclacitinib (approximately 4 to 5 hours) (EMA 2025). Excretion occurs primarily via the fecal route through metabolites, with renal elimination and urinary excretion constituting a minor pathway. This short half-life implies that plasma concentrations rapidly fall below inhibition thresholds for cytokines after each administration, which may contribute to the favorable safety profile by limiting prolonged exposure to inhibitory concentrations.
4.5 Population pharmacokinetics: inter-individual variability according to body weight
The pharmacokinetics of atinvicitinib are linear and exposure increases proportionally to dose within the tested range. The weight-band dosing regimen (0.8–1.2 mg/kg) is designed to cover inter-individual variability within each weight band. In a 6-month study conducted with doses up to 5 times the maximum recommended dose, slight accumulation was observed in some individuals, with steady state reached after 7 weeks (EMA 2025).
4.6 Pharmacokinetics in special populations (renal/hepatic insufficiency)
No specific pharmacokinetic studies have been conducted in dogs with renal or hepatic insufficiency. However, the primarily metabolic (fecal) elimination pathway and the minor contribution of renal excretion suggest a limited risk of accumulation in cases of moderate renal insufficiency. Use in animals with significant hepatic insufficiency should be subject to an individual benefit/risk assessment by the responsible veterinarian.
5. Indications, Dosage, and Route of Administration
NUMELVI is indicated for the treatment of pruritus associated with allergic dermatitis, including atopic dermatitis, in dogs. It is also indicated for the treatment of clinical manifestations of atopic dermatitis in dogs (EMA 2025). These two distinct indications cover both symptomatic control of pruritus regardless of the allergic etiology (including food allergy, flea bite allergy, contact allergy) and the treatment of skin lesions specific to CAD.
5.2 Recommended dosage according to weight bands
The recommended dose is 0.8 to 1.2 mg of atinvicitinib/kg body weight, administered once daily by oral route, with or around mealtime (EMA 2025). The once-daily dosing regimen from the start of treatment represents a simplification compared to oclacitinib, which requires a twice-daily induction phase for 14 days.
5.3 Dosage selection guide (weight/tablet table)
The choice of dosage is made according to the following weight bands: dogs weighing 3.0 to 4.3 kg: ½ tablet of 4.8 mg (i.e., 2.4 mg); dogs weighing 4.4 to 6.0 kg: 1 tablet of 4.8 mg; dogs weighing 6.1 to 9.0 kg: 1 tablet of 7.2 mg; dogs weighing 9.1 to 13.5 kg: ½ tablet of 21.6 mg (i.e., 10.8 mg); dogs weighing 13.6 to 19.3 kg: ½ tablet of 31.6 mg (i.e., 15.8 mg); dogs weighing 19.4 to 26.5 kg: 1 tablet of 21.6 mg; dogs weighing 26.6 to 39.5 kg: 1 tablet of 31.6 mg; dogs weighing 39.6 to 54.0 kg: 1½ tablets of 31.6 mg; dogs weighing 54.1 to 79.0 kg: 2 tablets of 31.6 mg. Dogs outside these weight bands may receive a combination of whole and/or half-tablets to achieve the target dose of 0.8–1.2 mg/kg. The available dosage strengths do not allow precise dosing in dogs weighing less than 2 kg (EMA 2025).
5.4 Route and method of administration, management of scored tablets
Administration is exclusively oral. The tablets are scored along the score line and can be divided into two equal halves. Any unused half-tablet must be replaced in the opened blister pack or bottle (EMA 2025).
5.5 Treatment duration and clinical reassessment
The intensity and duration of signs of allergic dermatitis, including atopic dermatitis, are variable. The need for long-term treatment must be based on an individual benefit/risk assessment. It is recommended to identify and treat complicating factors such as bacterial, fungal, or parasitic infections (for example: fleas, Demodex mites), as well as underlying causes (flea allergy, contact allergy, food allergy) (EMA 2025).
5.6 Management of missed doses or overdose
The product labeling does not specify a specific course of action in cases of missed dose. In cases of overdose, the high JAK1 selectivity limits the potential for adverse effects mediated by the other JAK enzymes. The veterinary medicinal product was well tolerated when administered orally to healthy 6-month-old puppies treated with overdoses up to 5 times the maximum recommended dose, once daily for 6 months. At significant overdoses, treatment may result in greater susceptibility to the development of bacterial, fungal, and/or parasitic skin diseases. Symptomatic treatment is recommended in cases of adverse effects resulting from overdose (EMA 2025).
6. Precautions for Use, Contraindications, and Interactions
6.1 Absolute contraindications
NUMELVI is contraindicated in cases of hypersensitivity to the active substance or to any of the excipients (EMA 2025).
6.2 General precautions for use
No special warnings have been identified beyond the precautions for use detailed below (EMA 2025).
6.3 Use in puppies, pregnant or lactating females
The safety of NUMELVI has not been evaluated in dogs under 6 months of age or weighing less than 3 kg. Use in animals that are younger or of lower weight must be based on a benefit/risk assessment. This is the only JAK inhibitor authorized in dogs from the age of 6 months, which represents an advantage over oclacitinib (reserved for dogs 12 months and older) and ilunocitinib (Patterson 2025). Use is not recommended during gestation, lactation, or in breeding animals. Laboratory studies in rats and rabbits showed effects on prenatal development, inherent to the class of JAK inhibitors. Studies in male rats demonstrated an effect on sperm count and sperm motility (EMA 2025).
6.4 Precautions in immunocompromised or infected animals
The safety of the veterinary medicinal product has not been evaluated in dogs showing signs of immunosuppression such as uncontrolled primary hypothyroidism or rickettsiosis, nor in animals with progressive malignant neoplasia. Use in these cases must be based on a benefit/risk assessment by the responsible veterinarian (EMA 2025).
6.5 Known or potential drug interactions
No drug interactions are known. No interactions were observed in field studies when NUMELVI was administered concomitantly with other veterinary drugs such as antimicrobials (including topical), ecto- and endoparasiticides (isoxazolines, milbemycins, avermectins, pyrethroids), nutritional supplements, topical ear and skin cleansers not containing glucocorticoids, and medicated shampoos (EMA 2025). The absence of known drug interactions constitutes a practical advantage for the multimodal management of CAD.
A major differentiating point is the absence of impact on the vaccine immune response. A dedicated study demonstrated that an adequate serological response to modified live vaccines for canine adenovirus type 2 (CAV-2), canine distemper virus (CDV), canine parvovirus (CPV), and the inactivated rabies virus (RV) vaccine was achieved in 6-month-old vaccine-naive puppies receiving atinvicitinib at 3.6 mg/kg/day (i.e., 3 times the maximum recommended dose) for 84 days (EMA 2025). This poster, presented at the ECVD 2025 congress in Bilbao under the title “Protective antibody response to core vaccine antigens in dogs treated with high dose atinvicitinib,” constitutes a significant argument for the use of NUMELVI in young dogs during primary vaccination, where oclacitinib is contraindicated in animals under 12 months of age and where data on ilunocitinib under conditions of concomitant vaccination are more limited.
6.6 Special precautions for the human user
Persons administering the drug should wash their hands thoroughly with soap and water immediately after use (EMA 2025).
6.7 Adverse effects: frequency, nature, and clinical management
Adverse effects observed in dogs are classified as common when they affect 1 to 10 animals out of 100 treated and include: vomiting, diarrhea, lethargy, and anorexia (decreased appetite). In the clinical trial involving 289 allergic dogs, reported side effects were mild and transient: vomiting (2.1% atinvicitinib vs. 1.4% placebo), diarrhea (2.1% vs. 4.9%), anorexia (0.7% vs. 2.1%), and lethargy (2.8% vs. 1.4%) (Jirjis 2025). No papillomas or skin masses were reported in this study.
7. Clinical Efficacy Data
7.1 Preclinical studies (in vitro and experimental animal models)
In vitro pharmacodynamic studies confirmed the potency and high selectivity of atinvicitinib for JAK1 compared to other members of the JAK family. A poster presented at the ECVD 2025 congress in Bilbao, titled “The second-generation Janus kinase inhibitor atinvicitinib is a potent and highly selective inhibitor of JAK1,” detailed the biochemical selectivity profile of the molecule (MSD Animal Health 2025). In a canine model of pruritus induced by IL-31, a presentation at the same congress demonstrated that atinvicitinib significantly reduces pruritus within 2 to 4 hours following oral administration, confirming the correlation between JAK1 inhibition and rapid control of scratching behavior (MSD Animal Health 2025).
7.2 Pivotal efficacy study — multicenter randomized controlled trial (CADESI, PVAS)
The pivotal trial presented at the ECVD 2025 congress under the title “The Second-Generation Janus Kinase 1 Selective Inhibitor Atinvicitinib is a Safe and Effective Once-Daily Treatment For Dogs with Atopic Dermatitis” evaluated the safety and efficacy of NUMELVI in client-owned dogs diagnosed with CAD according to Favrot’s criteria and presenting significant pruritus. The animals were randomized to receive either two different dosing regimens of atinvicitinib or a placebo over a defined duration. The primary efficacy endpoint was based on the proportion of dogs achieving a ≥50% reduction in pruritus score (owner-assessed PVAS) or skin lesion severity index. Results showed that 87.5% of dogs receiving 0.8–1.2 mg of atinvicitinib/kg once daily throughout the study achieved this therapeutic success criterion, compared to only 23.1% in the placebo group (MSD Animal Health 2025). Treatment was well tolerated with no treatment-related adverse effects in this study. This response rate of 87.5% with atinvicitinib is among the highest reported for a JAK inhibitor in CAD, although the specific methodology of this trial (inclusion criteria, duration, assessment modalities) must be taken into account before any indirect comparison with trials conducted on other molecules. The absence of treatment-related adverse effects in the atinvicitinib group reinforces the hypothesis that second-generation JAK1 selectivity improves the benefit/risk ratio compared to first-generation inhibitors.
7.3 Field study on allergic pruritus — randomized controlled trial (289 dogs)
A second large-scale, randomized, placebo-controlled clinical trial involving 289 client-owned dogs suffering from allergic dermatitis was presented at the same congress under the title “The Second-Generation Janus Kinase 1 Selective Inhibitor Atinvicitinib: A Safe and Effective Once-Daily Treatment for Pruritus in Dogs with Allergic Dermatitis” (Jirjis 2025). This field study included dogs presenting severe pruritus associated with allergic dermatitis of any etiology, thus providing a population representative of daily clinical practice, including cases of food allergy, flea bite allergy, and atopic dermatitis. Administered once daily at the recommended dose of 0.8–1.2 mg/kg, NUMELVI was well tolerated with mild and transient side effects. At day 7, 81.8 ± 3.8% (least squares mean ± SEM) of dogs treated with atinvicitinib showed a ≥2 cm reduction in PVAS score, compared to 46.5 ± 5.3% in the placebo group (p < 0.0001). Significantly more dogs treated with atinvicitinib showed a 50% reduction in PVAS on at least 5 of the first 7 days of treatment (p = 0.0109) (Jirjis 2025). With regard to hematological tolerance, no notable changes in red blood cell parameters or clinical biochemistry were observed. Eosinophil, neutrophil, monocyte, and total white blood cell counts decreased in the treated group but remained within physiological limits, confirming reduction of allergic inflammation without immunosuppression. Safety information showed that papillomas and skin masses, signals of concern with other JAK inhibitors, were not reported in this study. Post-marketing pharmacovigilance data are being collected in accordance with EMA requirements (EMA 2025).
7.4 Studies on short-term antipruritic effect (Day 1–Day 7)
The short-term efficacy of atinvicitinib on pruritus has been demonstrated within the first hours of administration. The canine IL-31 allergy model showed a significant reduction in pruritus 2 to 4 hours after the first dose (MSD Animal Health 2025). In the clinical trial involving 289 dogs, the proportion of dogs showing a ≥50% reduction in PVAS was already significantly higher in the atinvicitinib group compared to placebo from day 3 of treatment (Jirjis 2025). NUMELVI is described by the marketing authorization holder as “clinically effective from the first dose.”
7.5 Studies on long-term efficacy (3–6 months)
The pivotal CAD study evaluated dogs over the full duration of the protocol, with 87.5% of animals treated at the recommended dose achieving the therapeutic success criterion (≥50% reduction in pruritus or skin lesions) (MSD Animal Health 2025). The high-dose tolerance study (up to 5 times the maximum dose) conducted over 6 months in 6-month-old puppies revealed no dose-limiting toxicity, with good long-term tolerance (EMA 2025). Additional data on efficacy beyond 6 months are expected in post-marketing publications.
7.6 Data on quality of life of animals and owners
A study using a 3D accelerometer for remote assessment of activity and behavior in healthy and atopic dogs was presented at the ECVD 2025 congress, providing objective data on the impact of treatment on quality of life (MSD Animal Health 2025). The reduction in pruritus and inflammation translates clinically into improved sleep, decreased scratching and licking behaviors, and restoration of social interaction with the owner.
8. Safety and Tolerability Data
8.1 Tolerance studies at target dose and high doses (5x, 10x)
The multiple-dose tolerance study was conducted in healthy 6-month-old puppies receiving atinvicitinib at doses up to 5 times the maximum recommended dose (i.e., up to 6.0 mg/kg/day), once daily for 6 months. The drug was well tolerated at these high doses, without major clinical adverse effects (EMA 2025). This safety margin must be considered in the context of the short 2-hour half-life, which limits cumulative systemic exposure despite high doses.
8.2 Hematological and biochemical profile: longitudinal monitoring
In the clinical study involving 289 dogs, no notable changes or abnormal trends in red blood cell parameters, clinical biochemistry, or urinalysis were observed in dogs treated with atinvicitinib (Jirjis 2025). Mean counts of eosinophils, neutrophils, monocytes, and total white blood cells decreased in treated dogs but remained within reference intervals, indicating a reduction in allergic inflammation rather than immunosuppression. This favorable hematological profile contrasts with the precautions required during prolonged use of oclacitinib at twice-daily dosing, where plasma concentrations may approach the inhibition thresholds of JAK2-dependent cytokines involved in hematopoiesis (Nederveld 2025).
8.3 Impact on immune surveillance: intercurrent infections
At the recommended dose, atinvicitinib did not induce immunosuppressive effects (EMA 2025). Rates of secondary infections (bacterial, fungal, parasitic) were not significantly increased in treated groups compared to placebo in clinical trials. At significant overdoses, increased susceptibility to the development of bacterial, fungal, and/or parasitic skin diseases was mentioned as a potential risk (EMA 2025).
8.4 Oncological data: neoplastic risk signals
The question of neoplastic risk is a matter of vigilance for the entire class of JAK inhibitors, given the role of the JAK-STAT pathway in tumor signaling and anti-tumor immune surveillance. In human medicine, JAK1/JAK2 inhibitors such as ruxolitinib have been associated with an increased incidence of basal cell and squamous cell carcinomas (17.1% vs. 2.7% with other therapies) (Marsella 2023). Tofacitinib, a JAK1/JAK3 inhibitor, has been subject to regulatory warnings regarding thromboembolic and neoplastic risk in patients with rheumatoid arthritis. In veterinary medicine, retrospective analyses of long-term use of oclacitinib in atopic dogs have not confirmed a significant increase in neoplastic risk (Nederveld 2025), although pharmacovigilance signals have been reported (papillomas, histiocytomas).
Although no papillomas or skin masses were reported in the initial 28-day clinical trial involving 289 dogs treated with atinvicitinib (Jirjis 2025), it is methodologically imperative to emphasize that a trial of such short duration possesses neither the statistical power nor the temporal follow-up required to assess the neoplastic risk of a new molecule. Any direct comparison with oclacitinib must be nuanced: while the latter has been the subject of isolated papilloma reports over its 13 years of commercialization, large recent retrospective epidemiological studies (Nederveld 2025) have formally demonstrated that the overall incidence of neoplasias is not statistically greater with oclacitinib compared to other systemic therapies. The increased selectivity of atinvicitinib for JAK1 offers an appealing mechanistic safety rationale, but only the rigorous accumulation of pharmacovigilance data over several years will confirm this theoretical oncological advantage.
The high JAK1 selectivity (factor ≥10) should theoretically reduce the risk of interference with JAK2/JAK3/TYK2 pathways involved in tumor immune surveillance, since host defense functions dependent on JAK2 (NK cells, macrophages activated by IL-12/IL-23) and JAK3 (cytotoxic T lymphocytes) are preserved. However, a longer post-marketing follow-up period, with systematic oncological monitoring across cohorts of several thousand dogs treated for more than 12 months, will be necessary to confirm the absence of an oncological signal and to durably establish the long-term safety profile of atinvicitinib on this point.
8.5 Comparative tolerability with other JAK inhibitors and conventional immunosuppressants
The increased selectivity of atinvicitinib for JAK1 (factor ≥10 vs. JAK2) compared to oclacitinib (factor 1.8 vs. JAK2) constitutes the pharmacological basis for an expected better tolerability profile, particularly from a hematological and immunological standpoint (EMA 2025, Gonzales 2014). The absence of a need for a twice-daily induction phase (unlike oclacitinib) and the possibility of use from 6 months of age (vs. 12 months for oclacitinib) further reinforce the differential safety profile.
9. Positioning Relative to Other JAK Inhibitors: Atinvicitinib / Oclacitinib / Ilunocitinib
9.1 Comparison of JAK selectivity profiles (IC50 and relative selectivity)
Oclacitinib exhibits enzymatic IC50 values of 10, 18, 99, and 84 nM for JAK1, JAK2, JAK3, and TYK2, respectively, representing a JAK1/JAK2 selectivity of 1.8-fold (Gonzales 2014). Ilunocitinib has high affinity for JAK1, JAK2, and TYK2, classifying it as a non-selective inhibitor (Patterson 2025). Atinvicitinib displays at least a 10-fold selectivity (factor ≥10) for JAK1 compared to each of the three other members of the JAK family (EMA 2025). This gradation of selectivity — ilunocitinib < oclacitinib < atinvicitinib — positions atinvicitinib as the most selective JAK inhibitor currently available in veterinary dermatology.
9.2 Pharmacokinetic comparison: onset of action, half-life, dosing frequency
Atinvicitinib has a Tmax of 1 hour and a half-life of 2 hours, oclacitinib a Tmax of approximately 1 hour and a half-life of 4 to 5 hours, and ilunocitinib a half-life of approximately 4 hours. All three molecules provide a rapid antipruritic effect within the first hours. The dosing frequency is once daily for atinvicitinib and ilunocitinib, versus twice daily for 14 days then once daily for oclacitinib (EMA 2025, Patterson 2025).
9.3 Efficacy comparison: CADESI-04, PVAS scores, indirect meta-analysis
In the absence of a published direct comparative (head-to-head) trial between atinvicitinib and the two other JAK inhibitors, only an indirect comparison is possible. Atinvicitinib at 0.8–1.2 mg/kg/day demonstrated a ≥50% reduction in pruritus or lesion rate in 87.5% of atopic dogs compared to 23.1% with placebo (MSD Animal Health 2025). Ilunocitinib at 0.6–0.8 mg/kg/day showed a therapeutic success rate of 83% at day 28 compared to 31% with placebo (Forster 2025). For oclacitinib, historical data from the pivotal Australian trial reported efficacy comparable to prednisolone in controlling pruritus and clinical signs of allergic dermatitis in dogs in private practice (Cosgrove 2013). These indirect comparisons must be interpreted with caution due to differences in design, inclusion criteria, and study duration.
9.4 Comparison of tolerability profile and adverse effects
The most common adverse effects are similar for all three JAK inhibitors: vomiting, diarrhea, anorexia, and lethargy. However, atinvicitinib has the theoretical advantage of less interference with JAK2-dependent cytokines involved in hematopoiesis, owing to its 10-fold selectivity. The absence of papillomas and skin masses in the trial involving 289 dogs treated with atinvicitinib (Jirjis 2025) contrasts with historical pharmacovigilance signals reported for oclacitinib, although long-term retrospective analyses have not confirmed a significant increase in neoplastic risk with oclacitinib (Nederveld 2025).
9.5 Specific advantages of atinvicitinib over oclacitinib
Atinvicitinib differs from oclacitinib in: a JAK1/JAK2 selectivity at least 5 times greater (factor ≥10 vs. 1.8), a simplified once-daily dosing regimen from day one (vs. BID for 14 days then SID), the possibility of use from 6 months of age (vs. 12 months), demonstrated absence of impact on the vaccine immune response at 3 times the maximum dose, and no known drug interactions (EMA 2025).
9.6 Specific advantages of atinvicitinib over ilunocitinib
Compared to ilunocitinib, atinvicitinib offers markedly superior JAK1 selectivity (factor ≥10 vs. the non-selective JAK1/JAK2/TYK2 profile of ilunocitinib), a shorter half-life (2 h vs. ~4 h), and authorization for use from 6 months of age. The increased selectivity should theoretically translate into less impact on hematopoiesis and long-term immune surveillance (EMA 2025, Patterson 2025).
9.7 Advantages and disadvantages compared to other treatments in atopic dogs: corticosteroids, cyclosporine, and lokivetmab
Systemic corticosteroids (prednisolone, 0.5–1 mg/kg/day orally in the attack phase; methylprednisolone, 0.4–0.8 mg/kg/day) provide rapid control of pruritus in more than 80% of cases but are accompanied by well-documented dose-dependent and duration-dependent side effects: polyuria-polydipsia (in 50 to 85% of cases depending on the study), polyphagia, skin atrophy, cutaneous calcinosis, increased infection risk (secondary pyoderma, demodicosis, dermatophytosis), suppression of the hypothalamic-pituitary-adrenal axis, and risk of iatrogenic diabetes mellitus during prolonged use. Atinvicitinib, with its selective targeting of the JAK1 pathway, avoids these pleiotropic glucocorticoid effects while providing comparable speed of pruritus control. As such, systemic corticosteroids retain their place in acute flares requiring broad and rapid anti-inflammatory action, but atinvicitinib constitutes a first-line alternative for long-term treatment.
Cyclosporine, a calcineurin inhibitor administered at 5 mg/kg/day per os, acts on T lymphocyte activation via inhibition of the NFAT pathway, with demonstrated efficacy in CAD (approximately 50% reduction in CADESI-03 after 4 to 6 weeks of treatment in pivotal trials). However, it presents a longer onset of action (4 to 6 weeks for maximum effect), frequent gastrointestinal effects at the start of treatment (vomiting in 25 to 30% of cases), and requires monitoring of renal and hepatic parameters. Atinvicitinib offers control of pruritus from the first hours after the first dose, a major temporal advantage in clinical practice.
Lokivetmab (CYTOPOINT, Zoetis), a subcutaneous injectable anti-IL-31 monoclonal antibody, specifically neutralizes IL-31 with excellent tolerance and a safety profile comparable to placebo in clinical trials. Its advantage lies in perfect compliance (single clinic injection) and the absence of systemic immunosuppression. Lokivetmab differs from JAK inhibitors by neutralizing the cytokine directly in systemic circulation before its binding to the receptor, rather than inhibiting intracellular transduction. Although atinvicitinib offers multiaxial inhibition that simultaneously blocks the signaling of multiple cytokines (IL-31, IL-4, IL-13, TSLP), particularly relevant for phenotypes with severe cutaneous inflammatory components, lokivetmab retains a decisive advantage in terms of compliance (single injection) and absolute safety (no hepatic metabolism and no systemic immunosuppression). Thus, these two approaches are not strictly hierarchical but integrate into a therapeutic continuum where patient characteristics (age, hepatic comorbidities, lesional phenotype) dictate the first-line choice. In dogs whose clinical phenotype involves a marked cutaneous inflammatory component (diffuse erythema, lichenification, papulocrustous lesions), the multiaxial inhibition of atinvicitinib may prove more suitable than the mono-cytokine neutralization of lokivetmab. The combination of lokivetmab + atinvicitinib has not been evaluated in controlled trials, but the absence of known drug interactions for atinvicitinib allows consideration of this possibility in refractory cases, subject to individual clinical assessment.
10. Perspectives and Practical Conclusions
10.1 Place of Numelvi in the overall therapeutic strategy for CAD
The arrival of atinvicitinib enriches the therapeutic arsenal available for the management of CAD. As an authorized first-line treatment, administrable from 6 months of age in a once-daily dose without an induction phase, NUMELVI is positioned as a preferred option for rapid control of pruritus and skin lesions of atopic dermatitis and allergic dermatitis more broadly. Second-generation JAK1 selectivity constitutes a pharmacological argument in favor of a better long-term safety profile, although post-marketing pharmacovigilance data will need to confirm this theoretical advantage. Veterinarians now have access to three oral JAK inhibitors, one anti-IL-31 monoclonal antibody, and conventional options (corticosteroids, cyclosporine, allergen-specific immunotherapy), enabling therapeutic personalization based on clinical phenotype, animal age, comorbidity conditions, and individual response to treatment.
10.2 Possible therapeutic combinations (allergen-specific immunotherapy, topical treatment)
The absence of known drug interactions opens the door to multimodal strategies combining atinvicitinib with allergen-specific immunotherapy (ASIT), emollient and ceramide-based topicals for skin barrier restoration, antiseptic shampoos for controlling secondary staphylococcal and yeast infections, and ectoparasiticides for elimination of fleas and Demodex mites as triggering or aggravating factors. The demonstrated absence of impact on vaccine response, even at 3 times the maximum dose in vaccine-naive 6-month-old puppies (EMA 2025), allows concomitant vaccination without the need for a treatment window.
10.3 Remaining open questions and ongoing research on this new veterinary drug
Several questions remain and represent priority research avenues.
Direct comparative efficacy (head-to-head trials) between atinvicitinib, oclacitinib, and ilunocitinib in homogeneous canine populations constitutes the most pressing need to guide therapeutic choices in practice. The review article by Noli (Noli 2025) emphasizes that differences in kinase selectivity and pharmacokinetic profiles among JAK inhibitors could translate into differential clinical advantages depending on disease phenotype, but only direct comparative trials will confirm this (Noli 2025). The very long-term safety profile (>12 months) under real-world use conditions, with longitudinal hematological monitoring (quarterly complete blood count), immunological monitoring (immunoglobulin levels, booster vaccine responses), and systematic oncological follow-up (incidence of papillomas, histiocytomas, lymphomas, and other tumors), will be decisive for durably positioning atinvicitinib within the hierarchy of therapeutic options.
The impact of atinvicitinib on the cutaneous microbiome and colonization by *Staphylococcus pseudintermedius*, a frequent complicating factor in CAD, warrants specific investigation, especially since the reduction of JAK1-dependent inflammation could modify the cutaneous micro-ecological environment. The potential interest of atinvicitinib in other canine immune-mediated dermatoses (pemphigus foliaceus, cutaneous lupus, vasculitis) and in other species (feline atopic dermatitis, for which no JAK inhibitor is currently authorized) constitutes a promising field of investigation. Complete characterization of the CYP450 metabolic pathways involved in the metabolism of atinvicitinib would allow anticipation of potential drug interactions with azole antifungals or other CYP substrates. The assessment of predictive biomarkers of therapeutic response — serum cytokine profile (IL-31/IL-10 ratio), cutaneous gene expression (Th2 transcriptomic signature), barrier dysfunction score (transepidermal water loss measurement, TEWL) — also constitutes a development axis for precision medicine in veterinary dermatology.
10.4 Practical recommendations in veterinary dermatology
Prescribing NUMELVI fits within a structured diagnostic approach: identification and treatment of triggering and aggravating factors (fleas, Demodex, bacterial and fungal infections, food allergy, contact allergy) remain a prerequisite or an indispensable complement to any immunomodulatory therapy. A dietary elimination trial of at least 8 weeks should be proposed to rule out or confirm a food allergy component before initiating long-term treatment. Strict parasite control (regular ectoparasiticide treatment against fleas and ticks, skin scrapings to exclude demodicosis caused by Demodex canis or *Demodex injai*) is imperative, as concomitant flea bite allergy is frequent.
Clinical follow-up should include regular reassessment of the pruritus score (PVAS) and skin lesions (CADESI-04), periodic hematological and biochemical workup, and monitoring for signs of intercurrent infections (superficial pyoderma, Malassezia pachydermatis otitis, dermatophytosis). Keeping up-to-date with available therapeutic options and integrating post-marketing pharmacovigilance data into daily practice are professional responsibilities of the dermatologist and the general practitioner.
Communication with the owner must emphasize the chronic nature of CAD, the necessity of long-term treatment in the majority of cases, and the importance of therapeutic compliance. The dosing simplification provided by NUMELVI (once-daily administration, without an induction phase) constitutes an advantage for compliance, a determining factor for long-term therapeutic success. The decision for long-term treatment is based on an individual and ongoing benefit/risk assessment, taking into account clinical response, tolerability, animal age, comorbidities, and owner expectations.
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