ilunocitinib

For the control of pruritus associated with allergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age.

Zenrelia™

Zenrelia is indicated for control of pruritus associated with allergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age.

FDA application 141-585

Mechanism of Action Ilunocitinib is a non-selective JAK inhibitor which inhibits the function of a variety of pruritogenic, pro-inflammatory and allergy related cytokines that are dependent upon JAK enzymes. Ilunocitinib has a high potency for JAK1, JAK2, and tyrosine kinase 2 (TYK2) inhibition. Ilunocitinib is not a corticosteroid or an antihistamine. Pharmacokinetics Ilunocitinib is rapidly and well absorbed and excreted via the biliary/fecal route after oral administration in dogs. Following a single oral or intravenous administration of ilunocitinib at 0.8 mg/kg, the oral bioavailability based on area under the curve from the time of dosing to the last quantifiable plasma concentration (AUClast) was 80% in the fed state and 60% in the fasted state. The systemic clearance following intravenous administration was 399 mL/hour(h)/kg with a terminal half-life of 3.6 h. The volume of distribution was 1390 mL/kg (n=8). The maximum plasma concentration (Cmax) and AUClast were 120% and 45% higher, respectively, in the fed state as compared to the fasted state (n=16). In a laboratory margin of safety study, healthy adult dogs (see Target Animal Safety ) received daily oral administration of Zenrelia at 0.8 mg/kg, 1.6 mg/kg, 2.4 mg/kg, or 4.0 mg/kg for 182 consecutive days. Dogs were dosed in the fed state, the prandial state of maximum bioavailability. At 0.8 mg/kg, the ilunocitinib mean (coefficient of variation %) Cmax was 310 ng/mL (20.6%) with a median time to Cmax of 2 h (range 1 – 2 h), and the AUClast and half-life were 1360 h*ng/mL (25.1%) and 3.3 h (11.9%), respectively. Minimal accumulation was observed between Days 1 and 182 with geometric mean accumulation ratios for Cmax and AUClast between 1.1 and 1.6. After the first dose, Cmax increased in a linear but less than proportional manner where a 5-fold increase in dose resulted in a 3.4-fold (90% confidence limit: 2.9 – 4.0) increase in Cmax. There was a non-linear relationship between dose and AUClast where a 5-fold increase in dose resulted in a 4.2-fold (90% confidence limit: 3.4 – 5.1) increase in AUClast. Pharmacokinetic parameters are presented as geometric means.

FDA application 141-585

User Safety Warnings Not for use in humans. Keep this drug out of the reach of children. Wash hands immediately after handling tablets. In case of accidental ingestion, seek medical attention immediately. Animal Safety Warnings Due to the risk of infections, dogs should be up to date on vaccinations prior to starting Zenrelia (see Target Animal Safety ). Due to the risk of an inadequate immune response to vaccines, do not administer vaccines to a dog receiving Zenrelia. Discontinue Zenrelia for at least 28 days to 3 months prior to vaccination and withhold Zenrelia for at least 28 days after vaccination (see Target Animal Safety ). Dogs should be monitored for the development of infections because Zenrelia may increase susceptibility to infections, including adenoviral hepatitis and pancreatitis, demodicosis, interdigital furunculosis, coccidiosis, and pneumonia, and exacerbation of subclinical or uncomplicated infections (see Target Animal Safety and Adverse Reactions). Zenrelia is not for use in dogs with serious infections. Zenrelia may cause a progressive or persistently decreased hematocrit, hemoglobin, and/or red blood cell count without a corresponding increase in absolute reticulocyte count (see Target Animal Safety ). New neoplastic conditions (benign and malignant) were observed in dogs treated with Zenrelia during clinical studies (see Adverse Reactions ). Consider the risks and benefits of treatment prior to initiating Zenrelia in dogs with a history of recurrent serious infections or recurrent demodicosis or neoplasia (see Adverse Reactions and Target Animal Safety ). Zenrelia modulates the immune system. Zenrelia is not for use in dogs less than 12 months of age (see Target Animal Safety ). Keep Zenrelia in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

FDA application 141-585

Control of Atopic Dermatitis In a masked field study assessing effectiveness and safety of Zenrelia for the control of atopic dermatitis in dogs, 181 Zenrelia-treated dogs and 87 placebo-treated dogs diagnosed with atopic dermatitis were evaluated for safety up to 112 days. By Day 112, 66.7% of placebo-treated dogs and 22.1% of Zenrelia-treated dogs exited the study. Adverse reactions seen during the field study are summarized in Table 1 below. Table 1. Adverse Reactions through Day 112 N = number of dogs Adverse Reaction Zenrelia N = 181 Number of Dogs (%) Placebo N = 87 Number of Dogs (%) Vomiting or nausea 40 (22.1 %) 14 (16.1 %) Diarrhea 36 (19.9 %) 9 (10.3 %) Lethargy 22 (12.2 %) 9 (10.3 %) Otitis externa 19 (10.5 %) 20 (23.0 %) Anorexia 17 (9.4 %) 7 (8.0 %) Dermal growth (e.g., cyst, papilloma) 16 (8.8 %) 4 (4.6 %) Epiphora or ocular discharge 14 (7.7 %) 1 (1.1 %) Coughing or wheezing, including respiratory infections 12 (6.6 %) 2 (2.3 %) Bacterial skin infection 10 (5.5 %) 9 (10.3 %) Elevated liver enzyme(s) 10 (5.5 %) 2 (2.3 %) Urinary tract infection 10 (5.5 %) 2 (2.3 %) Upset stomach, including flatulence and abdominal pain 10 (5.5 %) 0 Leukopenia 9 (4.9 %) 1 (1.1 %) Sneezing 8 (4.4 %) 1 (1.1 %) Lipoma 7 (3.9 %) 1 (1.1 %) Weight gain 7 (3.9 %) 0 Increased water intake 4 (2.2 %) 2 (2.3 %) Gingivitis (occurrence or worsening) 4 (2.2 %) 0 Blood in stool 4 (2.2 %) 0 Elevated total bilirubin 4 (2.2 %) 0 Elevated triglyceride 4 (2.2 %) 0 Histiocytoma 3 (1.7 %) 0 Increased appetite 3 (1.7 %) 0 Fungal skin infection 3 (1.7 %) 2 (2.3 %) Weight loss 2 (1.1 %) 1 (1.1 %) Metastatic neoplasia (i.e., hemangiosarcoma) 1 (0.6 %) 0 Systemic fungal infection 1 (0.6 %) 0 Mast cell tumor 1 (0.6 %) 0 Abnormal hematology results likely related to Zenrelia treatment included thrombocytopenia, leukopenia, neutropenia, lymphopenia, eosinopenia, monocytopenia, and decreased red blood cell count. Abnormal serum chemistry results likely related to Zenrelia treatment included increased hepatobiliary parameters (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin), increased blood urea nitrogen (concurrently with an increase in creatinine for one dog), hypertriglyceridemia, hypercholesterolemia, hypoalbuminemia (without a concurrent hyperglobulinemia), and hypoglobulinemia (with or without a decrease in total protein). Twelve Zenrelia-treated dogs withdrew from the study early due to an adverse reaction, nine of which were considered likely related to Zenrelia treatment. These reactions included repeated episodes of vomiting, leukopenia, neutropenia, worsening of pre-existing lymphocytosis, enlargement of a non-resolving histiocytoma, eyelid mass with bacterial blepharitis, otitis interna with vestibular disease, urinary tract infection, and upper respiratory infection. Five placebo dogs withdrew from the study early due to an adverse reaction (i.e., lethargy, worsening of pre-existing lymphocytosis, occurrence of nystagmus, skin infection, and teat infection). One Zenrelia-treated dog was diagnosed with splenic and liver masses on Day 112. Histopathologic diagnosis after euthanasia one month later confirmed metastatic splenic and hepatic hemangiosarcoma. Another Zenrelia-treated dog experienced traumatic tendonitis and a puncture wound four days prior to study completion, which progressed to a serious infection. The owner elected amputation after study completion. A third Zenrelia-treated dog experienced a moderate neutropenia on Day 28 associated with a pre-existing subclinical urinary tract infection (UTI) that had progressed into a clinical UTI. The neutrophil count normalized seven days later while still receiving Zenrelia, prior to exiting the study to receive antibiotics. Control of Pruritus Associated with Allergic Dermatitis In a masked field study assessing effectiveness and safety of Zenrelia for the control of pruritus associated with allergic dermatitis in dogs, 206 Zenrelia-treated dogs and 100 placebo-treated dogs diagnosed with allergic dermatitis were evaluated for safety up to 112 days. By Day 112, 84% of placebo-treated dogs and 49.5% of Zenrelia-treated dogs exited the study. Adverse reactions seen during the field study are summarized in Table 2 below. Table 2. Adverse Reactions through Day 112 N = number of dogs Adverse Reaction Zenrelia N = 206 Number of Dogs (%) Placebo N = 100 Number of Dogs (%) Vomiting or nausea 32 (15.5%) 11 (11.0 %) Diarrhea 26 (12.2 %) 5 (5.0 %) Lethargy 25 (12.1 %) 7 (7.0 %) Urinary tract infection 13 (6.3 %) 2 (2.0 %) Anorexia 10 (4.9 %) 3 (3.0 %) Coughing, wheezing, or difficulty breathing 9 (4.4 %) 0 Elevated liver enzyme(s) 8 (3.9 %) 0 Otitis externa 8 (3.9 %) 5 (5.0 %) Increased water intake 7 (3.4 %) 2 (2.0 %) Upset stomach, including flatulence, retching, and abdominal pain 5 (2.4 %) 4 (4.0 %) Ocular discharge 5 (2.4 %) 1 (1.0 %) Elevated triglyceride 5 (2.4 %) 0 Dermal or subcutaneous growth (e.g., cyst, nodule) 3 (1.5 %) 2 (2.0 %) Sneezing 3 (1.5 %) 0 Blood in stool 3 (1.5 %) 0 Increased urination 3 (1.5 %) 0 Bacterial skin infection 2 (1.0 %) 4 (4.0 %) Weight gain 2 (1.0 %) 0 Neurological disorder (e.g., tremors, ataxia) 2 (1.0 %) 0 Increased appetite 1 (0.5 %) 0 Fungal skin infection 1 (0.5 %) 0 Fever 1 (0.5 %) 0 Hematuria (without urinary tract infection) 1 (0.5 %) 0 Abnormal hematology results likely related to Zenrelia treatment included thrombocytosis, leukopenia, neutropenia, eosinopenia, and monocytopenia. Abnormal serum chemistry results likely related to Zenrelia treatment included increased hepatobiliary parameters (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin), increased blood urea nitrogen, increased creatinine, hypertriglyceridemia, hypercholesterolemia, hypoproteinemia, and hypoglobulinemia (with or without a decrease in total protein). Seven Zenrelia-treated dogs withdrew from the study early due to an adverse reaction, four of which were considered likely related to Zenrelia treatment. These reactions included vomiting, lethargy, soft stool, neutropenia, increased liver enzymes, fever, abdominal discomfort, coughing, and wheezing. Four placebo treated dogs also withdrew from the study early due to an adverse reaction (i.e., splenic hemangiosarcoma, restlessness, abdominal pain, lethargy, and vomiting).

FDA application 141-585

Administer orally 0.27 to 0.36 mg ilunocitinib/lb (0.6 to 0.8 mg ilunocitinib/kg) body weight, once daily, with or without food.

Oral

Zenrelia™

The dose of Zenrelia (ilunocitinib tablets) is 0.27 to 0.36 mg ilunocitinib/lb (0.6 to 0.8 mg ilunocitinib/kg) body weight, administered orally, once daily, with or without food. Dosing Chart Weight Range (in lb) Weight Range (in kg) Number of Tablets to be Administered 4.8 mg tablets 6.4 mg tablets 8.5 mg tablets 15 mg tablets 6.6 – 8.8 3.0 - 4.0 0.5 8.9 – 11.8 4.1 – 5.3 0.5 11.9 – 14.3 5.4 – 6.5 0.5 14.4 – 17.7 6.6 – 8.0 1 17.8 – 23.6 8.1 – 10.6 1 23.7 – 31.1 10.7 – 14.1 1 31.2 – 35.4 14.2 – 16.0 1.5 35.5 – 43.1 16.1 – 19.5 1.5 43.2 – 55.0 19.6 – 24.9 1 55.1 – 62.5 25.0 – 28.3 2 62.6 – 83.3 28.4 – 37.4 1.5 83.4 – 110.0 37.5 – 49.9 2 110.1 – 137.5 50.0 – 62.4 2.5 137.6 – 166.0 62.5 – 74.9 3 ≥ 166.1 ≥ 75 Administer the appropriate combination of tablet strengths

ORAL

FDA application 141-585