Laboratory and field studies to investigate the efficacy of a novel, orally administered combination product containing moxidectin, sarolaner and pyrantel for the prevention of heartworm disease (Dirofilaria immitis) in dogs.

BACKGROUND: Dirofilaria immitis is a filarial parasite of dogs that can cause serious or fatal cardiopulmonary disease. Three studies were conducted to evaluate the efficacy and safety of monthly treatment with moxidectin in a chewable tablet product in combination with sarolaner and pyrantel to prevent heartworm disease in dogs after experimental challenge and in a clinical field study in the USA. METHODS: In two laboratory studies, dogs (8 per group) that had been inoculated 30 days prior with 50 third-stage D. immitis larvae were randomized to treatment on Day 0 with placebo or combination product, at the minimum dose of 24 µg/kg moxidectin, 2 mg/kg sarolaner and 5 mg/kg pyrantel (as pamoate salt). Study 2 also included groups treated with tablets containing moxidectin-alone (24 µg/kg) or sarolaner-alone (2 mg/kg). Efficacy was evaluated ~ 5 months after inoculation by adult heartworm counts at necropsy. In the field study, 410 dogs ≥ 8 weeks-old from 23 USA veterinary clinics were treated for 11 months with either combination product at 24-48 µg/kg moxidectin, 2-4 mg/kg sarolaner and 5-10 mg/kg pyrantel (n = 272) or Heartgard® Plus (ivermectin/pyrantel) at the label recommended dose rate (n = 138). Efficacy was evaluated on Day 330 using antigen and microfilaria testing to assess adult heartworm infection. RESULTS: In the laboratory studies, there were no heartworms recovered from any dog treated with the combination product or moxidectin alone and all dogs treated with placebo or sarolaner-alone were infected with 20-44 adult heartworms. In the field study, all dogs treated with the combination product tested negative for heartworm infection on Day 330, whereas two dogs treated with Heartgard® Plus tested positive. The Heartgard® Plus-treated dogs that tested heartworm positive were from the lower Mississippi River Valley region, where heartworm resistance has been confirmed to occur. The combination product was well tolerated in all studies. CONCLUSIONS: In laboratory studies, no heartworms were recovered from dogs treated with a single dose of the novel combination product containing moxidectin, sarolaner and pyrantel. Additionally, in the field study no dog tested positive for adult heartworm infection when dosed with the combination product monthly for 11 months, while two dogs treated with Heartgard® Plus tested positive.

A blinded, randomized, placebo-controlled trial of the safety of lokivetmab (ZTS-00103289), a caninized anti-canine IL-31 monoclonal antibody in client-owned dogs with atopic dermatitis.

BACKGROUND: Lokivetmab (ZTS-00103289) is a caninized anti-canine IL-31 monoclonal antibody that has demonstrated efficacy in reducing pruritus associated with atopic dermatitis (AD) in dogs in field trials. HYPOTHESIS/OBJECTIVES: This study evaluated the safety of lokivetmab in a randomized, double blind, placebo-controlled trial in client owned dogs with AD with minimal restrictions on concomitant medications and co-morbidities. ANIMALS: Clinicians at 14 veterinary clinics enrolled client owned dogs (n = 245) with chronic AD. METHODS: Dogs were randomized at a 2:1 ratio to receive either lokivetmab (1.0-3.3 mg/kg) or placebo administered subcutaneously on days 0 and 28. Clinicians examined dogs, and collected blood and urine for assessment of clinical pathology and immunogenicity (days 0, 28 and 42). RESULTS: There were no immediate hypersensitivity reactions (e.g. wheals, vomiting). Discomfort at administration occurred in 5.1% of dogs and was similar in frequency and severity between lokivetmab- and placebo-treated groups. Pruritus was reported as an adverse event during the study less frequently in the lokivetmab-treated group (4.9% and 19.3%, respectively); otherwise, adverse events occurred at a similar frequency between treatment groups. There were no clinically important differences between groups in clinical pathology results. Treatment-induced immunogenicity was found in 2.5% of lokivetmab treated dogs. A wide variety of concomitant medications were used with no clinically apparent adverse interactions. CONCLUSIONS AND CLINICAL IMPORTANCE: Among a diverse population of 162 client owned dogs with a clinical diagnosis of AD, treatment with two monthly doses of lokivetmab was safe, based on observed adverse events and clinical pathology results over a 42 day period.

A blinded, randomized, placebo-controlled, dose determination trial of lokivetmab (ZTS-00103289), a caninized, anti-canine IL-31 monoclonal antibody in client owned dogs with atopic dermatitis.

BACKGROUND: Pruritus is the hallmark clinical sign of atopic dermatitis (AD) in dogs. Lokivetmab, a caninized anti-canine IL-31 monoclonal antibody, reduced pruritus and associated inflammatory skin lesions in a proof-of-concept study in dogs with AD. HYPOTHESIS/OBJECTIVES: The objective was to describe lokivetmab dose response in a randomized, double blind, placebo-controlled trial. ANIMALS: Clinicians at 15 referral clinics enrolled 211 client owned dogs with a history of chronic AD. METHODS: Dogs were randomized to treatment with lokivetmab (0.125, 0.5 or 2.0 mg/kg) or placebo administered subcutaneously once on Day 0. Dog owners assessed visual analog scale (VAS) scores of pruritus on days 0, 1, 2, 3, 7, 14, 21, 28, 35, 42, 49 and 56. Clinicians assessed Canine AD Extent and Severity Index (CADESI-03) scores on days 0, 7, 14, 28, 42 and 56. RESULTS: Treatment with lokivetmab (2 mg/kg) resulted in a greater percentage reduction from baseline in owner assessed pruritus (days 1-49) and clinician assessed CADESI-03 scores (days 7-56) compared to placebo (P < 0.05); differences were achieved in lower dose groups but at later time points and for shorter duration for both owner assessed pruritus (0.5 mg/kg, days 2-35; 0.125 mg/kg, days 7-21) and clinician assessed CADESI-03 scores (0.5 mg/kg and 0.125 mg/kg, Day 14). CONCLUSIONS AND CLINICAL IMPORTANCE: Lokivetmab (0.5, 2.0 mg/kg) reduced pruritus compared to placebo for at least 1 month. Level and duration of response increased with increasing dose. Further studies are needed to better understand variability in individual responses across a broader population of dogs with AD.

Efficacy and safety of oclacitinib for the control of pruritus and associated skin lesions in dogs with canine allergic dermatitis.

BACKGROUND: Oclacitinib (Apoquel(®) ) inhibits the function of a variety of pro-inflammatory, pro-allergic and pruritogenic cytokines that are dependent on Janus kinase enzyme activity. Oclacitinib selectively inhibits Janus kinase 1. HYPOTHESIS/OBJECTIVES: We aimed to evaluate the safety and efficacy of oclacitinib for the control of pruritus associated with allergic dermatitis in a randomized, double-blinded, placebo-controlled trial. METHODS: Client-owned dogs (n = 436) with moderate to severe owner-assessed pruritus and a presumptive diagnosis of allergic dermatitis were enrolled. Dogs were randomized to either oclacitinib at 0.4-0.6 mg/kg orally twice daily or an excipient-matched placebo. An enhanced 10 cm visual analog scale (VAS) was used by the owners to assess the severity of pruritus from day 0 to 7 and by veterinarians to assess the severity of dermatitis on days 0 and 7. Dogs could remain on the study for 28 days. RESULTS: Pretreatment owner and veterinary VAS scores were similar for the two treatment groups. Oclacitinib produced a rapid onset of efficacy within 24 h. Mean oclacitinib Owner Pruritus VAS scores were significantly better than placebo scores (P < 0.0001) on each assessment day. Pruritus scores decreased from 7.58 to 2.59 cm following oclacitinib treatment. The day 7 mean oclacitinib Veterinarian Dermatitis VAS scores were also significantly better (P < 0.0001) than placebo scores. Diarrhoea and vomiting were reported with similar frequency in both groups. CONCLUSIONS AND CLINICAL IMPORTANCE: In this study, oclacitinib provided rapid, effective and safe control of pruritus associated with allergic dermatitis, with owners and veterinarians noting substantial improvements in pruritus and dermatitis VAS scores.

A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis.

BACKGROUND: Pruritus is the hallmark clinical sign of atopic dermatitis (AD) in dogs. Preliminary study results suggest that oclacitinib, a selective Janus kinase inhibitor, could reduce pruritus and associated inflammatory skin lesions in dogs with AD. HYPOTHESIS/OBJECTIVES: The objective was to evaluate efficacy and safety of oclacitinib (Apoquel®) for the control of AD in a randomized, double-blind, placebo-controlled trial. ANIMALS: Clinicians at 18 specialty clinics enrolled client-owned dogs (n = 299) with a history of chronic AD. METHODS: Dogs were randomized to receive either oclacitinib (0.4-0.6 mg/kg twice daily for 14 days and then once daily for up to 112 days) or an excipient-matched placebo. Owners assessed visual analog scale (VAS) scores of pruritus on days 0, 1, 2, 7, 14, 28, 56, 84 and 112. Clinicians assessed Canine AD Extent and Severity Index (CADESI-02) scores on days 0, 14, 28, 56, 84 and 112. RESULTS: On days 1, 2, 7, 14 and 28, oclacitinib-treated dogs had a 29.5, 42.3, 61.5, 66.7 and 47.4% reduction from baseline in owner-assessed pruritus scores, respectively, compared with a 6.5, 9.1, 6.5, 3.9 and 10.4% reduction in placebo-treated dogs. On days 14 and 28, dermatologists recorded a 48.4% reduction in CADESI-02 scores in oclacitinib-treated dogs compared with a 1.7% reduction and a 3.6% increase in placebo-treated dogs. After day 28, >86% of all placebo-treated dogs had moved to an open-label study, making between-group comparisons biased. Differences were significant at all time points assessed (P < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Oclacitinib provided rapid, effective and safe control of AD, with substantial improvement in VAS and CADESI-02 scores.