Laboratory safety evaluation of lokivetmab, a canine anti-interleukin-31 monoclonal antibody, in dogs.

Lokivetmab (Cytopoint®, Zoetis) is a canine monoclonal antibody that specifically binds and neutralizes interleukin (IL)-31. Lokivetmab is approved for use in dogs for the treatment of atopic dermatitis (AD) and allergic dermatitis. The laboratory safety of lokivetmab was evaluated in 2 studies by adapting the science-based, case-by-case approach used for preclinical and early clinical safety evaluation of human biopharmaceuticals. The main objectives were to demonstrate the safety of lokivetmab in healthy laboratory Beagle dogs by using integrated clinical, morphologic, and functional evaluations. In Study 1, dogs were treated s.c. with saline or lokivetmab at 3.3 mg/kg (1X, label dose) or 10 mg/kg (3X intended dose) for 7 consecutive monthly doses, with terminal pathology and histology assessments. In Study 2, the functional immune response was demonstrated in naïve dogs using the T-cell dependent antibody response (TDAR) test with 2 different dose levels of unadjuvanted keyhole limpet hemocyanin (KLH) as the model immunogen. The primary endpoint was anti-KLH IgG antibody titer, and secondary endpoints were ex vivo IL-2 enzyme-linked immunospot (ELISpot) and peripheral blood mononuclear cell lymphoproliferation assays. Both studies included monitoring general health, periodic veterinary clinical evaluations, serial clinical pathology and toxicokinetics, and monitoring for anti-drug antibodies. In both studies, the health of dogs receiving lokivetmab was similar to controls, with no treatment-related changes uncovered. Extensive pathology evaluations of immune tissues (Study 1) revealed no lokivetmab-related morphologic changes, and in dogs treated at 10 mg/kg lokivetmab, immunization with the model antigen KLH did not impair the functional antibody or T-cell recall responses. There were no immunogenicity-related or hypersensitivity-related responses observed in either study. These studies in healthy laboratory dogs showed that lokivetmab was well-tolerated, did not produce any treatment-related effects, and had no effect on immune system morphology or its functional response. These studies also demonstrated the utility of a science-based case-by-case approach to the safety evaluation of a veterinary biopharmaceutical product.

Experimental veterinary SARS-CoV-2 vaccine cross neutralization of the Delta (B.1.617.2) variant virus in cats.

SARS-CoV-2 has exhibited varying pathogenesis in a variety of Mammalia family's including Canidae, Mustelidae, Hominidae, Cervidae, Hyaenidae, and Felidae. Novel SARS-CoV-2 variants characterized by spike protein mutations have recently resulted in clinical and epidemiological concerns, as they potentially have increased infectious rates, increased transmission, or reduced neutralization by antibodies produced via vaccination. Many variants have been identified at this time, but the variant of continuing concern has been the Delta variant (B.1.617.2), due to its increased transmissibility and infectious rate. Felines vaccinated using an experimental SARS-CoV-2 spike protein-based veterinary vaccine mounted a robust immune response to the SARS-CoV-2 spike protein. Using a reporter virus particle system and feline serum, we have verified that vaccinated felines produce antibodies that neutralize the SARS-CoV-2 Wuhan strain and variant B.1.617.2 at comparable levels.

VANGUARD®crLyme: A next generation Lyme disease vaccine that prevents B. burgdorferi infection in dogs.

Lyme disease, a public health threat of significance to both veterinary and human medicine, is caused by the tick (Ixodes) transmitted spirochete, Borreliella burgdorferi. Here we report on the immunogenicity and efficacy of VANGUARD®crLyme (Zoetis), the most recent canine Lyme disease vaccine to be approved by the United States Department of Agriculture. VANGUARD®crLyme is a subunit vaccine consisting of outer surface protein A (OspA) and a recombinant outer surface protein C (OspC) based-chimeric epitope protein (chimeritope) that consists of at least 14 different linear epitopes derived from diverse OspC proteins. The combination of OspA and the OspC chimeritope (Ch14) in the vaccine formulation allows for the development of humoral immune responses that work synergistically to target spirochetes in both ticks and in mammals. Immunogenicity was assessed in purpose-bred dogs. A two-dose vaccination protocol resulted in high antibody titers to OspA and Ch14 and vaccinal antibody reacted with 25 different recombinant OspC variants. Efficacy was demonstrated using an Ixodes scapularis -purpose bred dog challenge model. Vaccination with VANGUARD®crLyme provided protection against infection and prevented the development of clinical manifestations and histopathological changes associated with Lyme disease.

Field safety study of VANGUARD®crLyme: A vaccine for the prevention of Lyme disease in dogs.

Here we report the results of a large-scale pre-license safety study in which two serials of VANGUARD®crLyme, a vaccine for canine Lyme disease, were tested in its target population (dogs) under the conditions of its intended use. Six-hundred and twenty dogs, from three distinct geographic regions of the United States were enrolled in this study with each receiving two doses of vaccine by subcutaneous injection 3 to 4 weeks apart. Approximately one-third of the dogs were of minimum age (≤8 weeks of age) to meet regulatory requirements. Safety was evaluated by observation of local and systemic reactions for at least 10 days after each vaccination. Abnormal health events (AHEs) occurred at low frequencies and no serious AHEs were observed. The results demonstrated that VANGUARD®crLyme is safe for use in healthy dogs 8 weeks of age or older.

Comparative efficacy of topical treatments with Revolution® Plus (selamectin and sarolaner) and Bravecto® for Cats (fluralaner) against Ixodes scapularis ticks on cats.

The efficacy of three consecutive monthly treatments with a novel topical product (Revolution® Plus/Stronghold® Plus, Zoetis) containing selamectin in combination with the isoxazoline, sarolaner, was compared with that of another topical isoxazoline, fluralaner [Bravecto® (fluralaner topical solution) for Cats, Merck] against Ixodes scapularis ticks on cats. Twenty-four cats were ranked by pre-treatment tick counts to form groups of three and were randomly allocated to be treated with placebo, the minimum label dosage of Revolution® Plus (6 mg/kg selamectin plus 1 mg/kg sarolaner) or the minimum label dosage of Bravecto® for Cats (40 mg/kg fluralaner) within the groups. On Days 0, 30, and 60, each cat in the placebo and Revolution® Plus-treated groups was treated topically, whereas cats in the Bravecto® for Cats-treated group were treated topically once on Day 0 with fluralaner and, subsequently, these animals were treated with the placebo on Days 30 and 60 to maintain masking. Doses were calculated based on weight to provide the minimum label dosage for each product; the calculated volume of product to be administered was rounded off to the nearest 0.1 mL. The selamectin plus sarolaner-treated cats received effective dosages of 5.29-7.12 mg/kg selamectin and 0.88-1.19 mg/kg sarolaner, while the fluralaner cats received dosages of 35.21-43.16 mg/kg fluralaner. Cats were infested with approximately 50 unfed viable adult I. scapularis ticks on Days 5, 12, 26, 40, 54, 68, 82, and 88. Efficacy was assessed at 48 h after each infestation. There were no adverse reactions to any treatment during the study. The placebo-treated cats maintained adequate tick infestations throughout the study. Three monthly treatments with selamectin plus sarolaner (Revolution® Plus) resulted in high and consistent efficacy against I. scapularis for up to 30 days after each treatment. Based on geometric means, efficacy was ≥99.1% at all time points assessed. Treatment with fluralaner (Bravecto® for Cats) provided high and consistent efficacy of ≥99.3% up to Day 70. On Day 84, efficacy was 90.1%; however, cats from which ticks were recovered on Day 84 had received approximately 4%-12% less than the minimum dosage of 40 mg/kg fluralaner. Three consecutive monthly treatments with Revolution® Plus or a single treatment with Bravecto® for Cats provided >90% control of I. scapularis ticks over a 12-week time period.

Efficacy of three consecutive monthly doses of a topical formulation of selamectin and sarolaner (Revolution® Plus/Stronghold® Plus) compared with a single dose of fluralaner (Bravecto® for Cats) against induced infestations of Ctenocephalides felis on cats.

In a controlled laboratory study, the efficacy against fleas, Ctenocephalides felis, of a single treatment of fluralaner topical solution (Bravecto® for Cats, Merck) was compared with that of three consecutive monthly topical treatments with selamectin and sarolaner (Revolution® Plus, Zoetis). Twenty-four domestic short hair cats were ranked based on host suitability flea counts to form groups of three and were randomly assigned within group to one of three treatments. The first group received a topical treatment with (a) placebo (vehicle control for Revolution® Plus) on Days 0, 30, and 60, (b) 6 mg/kg selamectin and 1 mg/kg sarolaner on Days 0, 30, and 60, or (c) 40 mg/kg fluralaner on Day 0 and placebo (vehicle control for Revolution® Plus) on Days 30 and 60. Because doses were rounded off, the selamectin plus sarolaner-treated cats received effective dosages of 5.25-6.60 mg/kg selamectin and 0.88-1.10 mg/kg sarolaner, while the fluralaner-treated cats received dosages of 34.71-43.08 mg/kg fluralaner. All cats were infested with 100 (±5) fleas on Day -1 and at biweekly intervals after that, from Day 13 to Day 89. Flea comb counts were conducted 24 hours after treatment or after re-infestation. There were no adverse events related to treatment during the study. Except for a single cat from which 20 fleas were recovered on Day 90, all other placebo-treated cats had at least 48 fleas at each count, indicating adequacy of infestation of the controls. Based on geometric mean live flea counts, three consecutive monthly treatments with Revolution® Plus resulted in consistent and high efficacy of ≥98.6% compared with placebo throughout the study. A single treatment with Bravecto® for Cats provided consistent and high efficacy of ≥94.6% on all count days during a period of 12 weeks, the approved duration of efficacy for the product. Based on the efficacy results of the study, both products were equivalent in their ability to control fleas on cats. Use of Bravecto® for Cats every 12 weeks or the consecutive monthly use of Revolution® Plus is expected to provide extended high residual kill over the respective labeled durations of efficacy of the two products.

Efficacy of a new topical formulation containing selamectin plus sarolaner against three common tick species infesting cats in the United States.

The efficacy of a single topical application of a combination product containing selamectin and sarolaner (selamectin/sarolaner; Revolution® Plus/Stronghold® Plus) was evaluated in seven laboratory studies against Ixodes scapularis (three studies), Dermacentor variabilis (two studies), or Amblyomma maculatum (two studies). In each study, cats were randomly allocated to treatment groups based on pre-treatment host-suitability tick counts. On Days -2, 5, 12, 19, 26 and 33, the cats were infested with unfed adult ticks. On Day 0, cats were treated with either a placebo (vehicle control) or with the spot-on solution at the minimum dose of 6.0 mg selamectin and 1.0 mg sarolaner/kg bodyweight. In one study with I. scapularis and one with D. variabilis an additional group of cats was treated with selamectin alone (Revolution®, Zoetis) at 6.0 mg/kg bodyweight. Tick counts were conducted after treatment and after each weekly re-infestation and efficacy determined relative to placebo-treated animals. There were no treatment-related adverse reactions in any of the studies. Geometric mean live tick counts were significantly (P < 0.05) lower in the selamectin/sarolaner-treated groups compared to the geometric mean tick counts in the placebo-treated groups at all time-points in all studies. For all species, a single topical administration of the selamectin/sarolaner combination resulted in>90% efficacy against existing infestations based on geometric means. Efficacy against weekly re-infestations was >90% based on geometric means for at least 5 weeks for I. scapularis and D. variabilis, and for at least 4 weeks against A. maculatum. Selamectin alone had no efficacy against I. scapularis, where counts on selamectin-treated cats were not significantly different from placebo at all time points (P > 0.05), and for D. variabilis, counts were not significantly different from placebo at 2, 3 and 5 weeks after treatment (P > 0.05) and efficacy was never greater than 85%. Thus, the activity of the sarolaner against three common tick species found on cats in the US is complementary to the existing broad-spectrum parasite control of selamectin. The inclusion of sarolaner with selamectin in a combination product (Revolution® Plus/Stronghold® Plus) provides for the treatment of existing tick infestations and gives at least one month of control against re-infestation following a single topical application.

Efficacy and safety of a new topical formulation of selamectin plus sarolaner in the treatment and control of natural infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States.

A new topical formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) was evaluated in the treatment and control of naturally occurring infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States. Three thousand three hundred three (3303) cats were screened in 25 veterinary practices in 15 states and 153 hookworm-positive cats (A. tubaeforme and/or A. braziliense), mainly from Alabama, Mississippi, Texas, and Hawaii, were identified; 135 cats met all the criteria for enrollment and were included on study. The cats were randomly assigned to treatment with Revolution® (at the label dosage, to provide a minimum dosage of 6 mg/kg selamectin) or selamectin plus sarolaner (at a dosage of 6-12 mg/kg plus 1-2 mg/kg, respectively). Treatments were administered at the time of enrollment and repeated 30 days later. Fecal samples were collected for differential fecal egg count prior to the first treatment (Day 0), prior to the second treatment (Day 30), and approximately 30 days later (Day 60). Efficacy was based on the percentage reductions in geometric mean fecal egg count for A. tubaeforme on Day 30 and Day 60 compared with Day 0. Where cats were co-infected with T. cati, efficacy against this species was also evaluated. Efficacy data were evaluated for A. tubaeforme for 40 cats on both Day 30 and Day 60 for the group treated with the selamectin/sarolaner combination and reductions in geometric mean fecal egg counts of 99.4% and 99.7% were demonstrated for Day 30 and Day 60, respectively. For the group treated with selamectin alone, 44 and 40 cats were evaluated and percent reductions for Day 30 and Day 60 were 99.5% and 99.9%, respectively. For T. cati, 14 cats were evaluated in the selamectin/sarolaner-treated group for Day 30 and for Day 60, and the reduction in geometric mean fecal egg count was 100% for both days. There were 11 and 9 cats evaluated for Day 30 and Day 60, respectively, for the selamectin-treated group and the reduction was again 100% for both days. The geometric mean fecal egg counts post-treatment were significantly lower than pre-treatment for both A. tubaeforme and T. cati, for both treatments, and for both periods of interest (P < 0.0001). No serious adverse events related to treatment with either product occurred during the study. Thus, both selamectin alone and the combination product of selamectin/sarolaner were safe and effective when administered on a monthly basis for the treatment and control of natural infections of A. tubaeforme and T. cati. The addition of sarolaner to the formulation did not interfere with the efficacy of selamectin against these nematodes.

Efficacy of a topical formulation of selamectin plus sarolaner against induced infestations of Amblyomma americanum on cats and prevention of Cytauxzoon felis transmission.

Cytauxzoonosis, caused by infection with Cytauxzoon felis, is the most severe tick-borne disease of cats. The purpose of our study was to determine the efficacy of selamectin (6.0 mg/kg) plus sarolaner (1.0 mg/kg) formulated in combination (Revolution® Plus / Stronghold® Plus, Zoetis) applied topically once a month on cats for three months against induced infestations of Amblyomma americanum adults and to evaluate the effectiveness of the product in preventing the transmission of C. felis. This study was conducted in two phases. Sixteen cats were dosed with selamectin/sarolaner or a placebo (vehicle control) on Days 0, 28, and 56. In phase 1, each cat was infested with 50 (±5) unfed adult A. americanum on Day 4 and tick counts were conducted on Day 6 (48 h post infestation) and Day 7 (72 h post infestation) to evaluate acaricidal efficacy. In phase 2, to confirm acaricidal efficacy and evaluate prevention of C. felis transmission, each cat was infested on Day 60 with 50 (±5) adult A. americanum acquisition fed as nymphs on two C. felis-infected donor cats. Tick counts were conducted on Day 62 (48 h post infestation) and Day 63 (72 h post infestation). Blood samples were collected on Days -9, 60, 70, 76, and 90 and tested for infection with C. felis. Placebo cats were adequately infested on all count days, with least squares (geometric) mean live tick counts ranging from 34.0 (28.8) to 46.1 (46.0). Treatment reduced the least squares (geometric) mean counts compared to placebo by 27.1 (32.1)% and 90.4 (96.8)% on Days 6 and 7, respectively. The corresponding percent reductions were 56.4 (60.6)% and 94.7 (97.3)% on Days 62 and 63, respectively. Least squares mean counts were significantly lower in the treated group compared with the placebo group on all count days (P ≤ 0.0286). All cats were negative for C. felis by PCR prior to study start. In phase 2, seven cats in the control group and no cats in the selamectin/sarolaner group became infected with C. felis (P = 0.0017). Topical treatment with selamectin/sarolaner was >90% effective in reducing A. americanum tick counts 72 h after infestation and prevented the transmission of C. felis from infected ticks following the third of three monthly treatments. Revolution® Plus / Stronghold® Plus offers an option for the control of A. americanum infestations on cats and for preventing the transmission of C. felis to cats.

The efficacy of a novel topical formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) in preventing the development of Dirofilaria immitis in cats.

Three controlled studies were conducted to investigate the efficacy of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) in preventing feline heartworm disease in cats. In all studies, cats were inoculated with 100 Dirofilaria immitis third stage larvae on Day -30. In the first study, cats were treated with selamectin plus sarolaner as a single dose on Day 0 or as three consecutive monthly doses on Days 0, 28 and 56. In the second and third studies, cats were treated with either sarolaner alone on Day 0, selamectin plus sarolaner on Day 0 or selamectin plus sarolaner as three consecutive monthly doses on Days 0, 28 and 56. In all three studies, dosages were 6 mg/kg selamectin plus 1 mg/kg sarolaner or 1 mg/kg sarolaner alone. Control cats were given a placebo containing inert formulation ingredients (vehicle). All treatments were administered at a single site topically to the skin cranial to the scapulae. Cats were humanely euthanized on Day 145/146 (i.e., 175/176 post-inoculation), and adult D. immitis worms were recovered and enumerated. Across the three studies, adult heartworms were recovered from 87 to 100% of control cats, with geometric mean worm counts ranging from 2.1 to 5.4. No adult D. immitis worms were recovered from cats treated with selamectin plus sarolaner. Cats treated with sarolaner alone were not protected against D. immitis infection, showing geometric mean worm counts of 1.9 to 2.4. In these studies, selamectin (6 mg/kg) plus sarolaner (1 mg/kg) was 100% effective in preventing heartworm development in cats when administered topically as one dose 30 days after inoculation or as three consecutive monthly doses starting 30 days post-inoculation. These studies demonstrated that a single topical administration of selamectin plus sarolaner at the recommended dosage was completely effective in preventing the development of D. immitis in cats.

The speed of kill of a topical combination of selamectin plus sarolaner against induced infestations of Ixodes scapularis ticks on cats.

The speed of kill of a novel, topical product containing selamectin in combination with sarolaner (selamectin/sarolaner; Revolution® Plus/Stronghold® Plus) was evaluated against Ixodes scapularis ticks on cats. Sixteen cats were randomly allocated to a treatment group and treated topically on Day 0 with either placebo (vehicle control) or 6 mg/kg selamectin plus 1 mg/kg sarolaner. Cats were infested with approximately 50 unfed viable adult I. scapularis ticks on Days -2, 7, 14, 21, 28 and 35. Efficacy was assessed at 4, 8, 12, 24, 48 and 72 h after treatment on Day 0 and at 4, 8, 12 and 24 h after post-treatment re-infestations. There were no adverse reactions to the topical treatment with selamectin/sarolaner. Placebo-treated cats maintained tick infestations throughout the study. Treatment with selamectin/sarolaner significantly reduced tick counts within 12 h (P < 0.0001) and resulted in 100% efficacy by 24 h. For subsequent re-infestations, live tick counts were significantly reduced by 12 h after infestation on Day 7 (P = 0.0120) and by 24 h for Days 14-35 (P < 0.0001). At 24 h after the post-treatment re-infestations, efficacy based on geometric (arithmetic) means was ≥96.1% (94.5%) through Day 21, 75.3% (67.7%) on Day 28 and 66.4% (56.4%) on Day 35. Thus, a single topical dose of Revolution® Plus/Stronghold® Plus at the recommended minimum dose started killing ticks within 12-24 hours after treatment and re-infestations for up to 5 weeks. High acaricidal efficacy (≥90% reduction in tick burden) was achieved within 24 h after treatment and subsequent re-infestations for at least three weeks.

Efficacy and safety of a combination of selamectin plus sarolaner for the treatment and prevention of flea infestations and the treatment of ear mites in cats presented as veterinary patients in the United States.

Two randomised, single-masked, multi-center field studies were conducted in the United States in cats presented as veterinary patients. The first study evaluated the efficacy and safety of a topically applied formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) against natural flea infestations; the second study evaluated its efficacy against natural ear mite infestations. The product was administered topically by the cats' owners at the dose range provided in the market product of 6.0-12.0 mg selamectin and 1.0-2.0 mg sarolaner per kg bodyweight. Imidacloprid plus moxidectin (Advantage® Multi for Cats, Bayer) was used as a positive control in both studies at the label dosage. In the flea study, treatments were administered on Days 0, 30, and 60. Efficacy was calculated based on the mean percent reduction of live flea counts on Days 30, 60, and 90 relative to the pre-treatment count. In the ear mite study, a single treatment was applied on Day 0 and efficacy was determined on Days 14 and 30 based on the presence or absence of ear mites. In both studies, patients were randomly allocated to treatments in the ratio of 2:1, selamectin plus sarolaner: imidacloprid plus moxidectin. In the two studies, 405 cats received treatment with selamectin plus sarolaner; of these, 256 cats received three monthly treatments in the flea study. There were no serious adverse reactions to treatment with selamectin plus sarolaner; health issues noted were typical of the normal ailments or minor traumatic injuries expected in the general cat population and were similar in both treatment groups. Efficacy against fleas based on geometric (arithmetic) means was 97.2% (95.9%), 99.5% (99.4%), and 99.8% (99.8%) in the selamectin plus sarolaner group and was 79.7% (70.5%), 91.4% (77.3%), and 95.5% (87.4%) in the imidacloprid plus moxidectin group on Days 30, 60, and 90, respectively. Flea counts for the selamectin plus sarolaner group were significantly lower than the counts for the imidacloprid plus moxidectin group at all time-points after treatment administration on Day 0 (P < 0.001). Treatment reduced the clinical signs of flea allergy dermatitis (alopecia, dermatitis/pyodermatitis, erythema, pruritus, scaling, and papules) in affected cats by 86.7%-100% in the selamectin plus sarolaner group and by 66.7%-100% in the imidacloprid plus moxidectin group. In the ear mite study, a single application of selamectin plus sarolaner resulted in the clearance of mites from 87.5% of cats within 14 days and 94.4% of cats within 30 days of treatment. The respective percentages of mite-free cats in the imidacloprid plus moxidectin group were 64.0% and 72.0%. There were significantly more cats with no mites noted in the selamectin plus sarolaner group than in the imidacloprid plus moxidectin group on Day 14 and Day 30 (P ≤ 0.018). Selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) administered topically at monthly intervals for three months was well tolerated and highly effective for the treatment and prevention of natural infestations of fleas on cats presented as veterinary patients. Clinical signs of flea allergy dermatitis improved in affected cats following treatment administration. A single topical treatment was also safe and highly effective for the treatment of ear mite infestations in naturally infested cats.

Vaccination against porcine reproductive and respiratory syndrome virus (PRRSV) reduces the magnitude and duration of viremia following challenge with a virulent heterologous field strain.

Forty PRRS-negative, three week-old weaned pigs were randomized into two groups in separate rooms and inoculated with a modified live PRRS vaccine (Fostera® PRRS) or control (PBS). Four weeks after vaccination pigs were rehoused in a single room and challenged intranasally and intramuscularly with virulent PRRSV strain NADC20. Timed serum samples were collected and titrated for PRRS virus and anti-PRRS virus antibodies. The study concluded when ≥80% of the pigs in the control group were determined to be virus negative (27days post-challenge). Mean duration of viremia was significantly lower (p=0.0327) for vaccinated pigs compared to non-vaccinated pigs. A significant reduction (p≤0.0053) in mean post-challenge viremia titer was seen in vaccinates compared to non-vaccinates from days 8 through 22 post-challenge. At the individual pig level, no pigs in the vaccinated group had detectible PRRSV in serum at the end of the study (27days post-challenge), while 15% of non-vaccinated pigs remained positive for virus.

Efficacy and speed of kill of a new spot-on formulation of selamectin plus sarolaner against flea infestations in cats.

The efficacy of a new spot-on formulation of selamectin plus sarolaner against induced flea infestations in cats was confirmed in three placebo-controlled, blinded studies. Purpose-bred adult cats (n=8/group) were blocked by pre-treatment flea counts and randomly allocated to treatment with either a placebo or with the spot-on formulation at the minimum dose of 6.0mg selamectin and 1.0mg sarolaner per kg bodyweight. Treatments were applied topically once on Day 0. All cats were infested with approximately 100 unfed, adult Ctenocephalides felis prior to treatment and at weekly intervals for 5 weeks. In Studies 1 and 2 comb counts were conducted to determine the numbers of viable fleas 24h after treatment and subsequent weekly infestations. In Study 3, flea counts were conducted at 6, 12, 24 and 48h after treatment and 3, 6, 12 and 24h after subsequent weekly infestations to evaluate the speed of kill against fleas. Cats in the placebo-treated groups maintained flea infestations throughout all studies. In Study 1, no live fleas were found on any of the treated cats, resulting in 100% efficacy for 5 weeks after a single treatment (P≤0.0001). In Study 2, selamectin/sarolaner reduced flea counts by 92.4% immediately after treatment and by 97.7%-100% after re-infestations for five weeks (P≤0.0001). In the speed of kill study, selamectin/sarolaner started killing fleas within 12h after treatment administration and within 6h following re-infestation for at least 28days. Efficacy was 98.1% by 24h after treatment and 100% within 24h after re-infestations for 5 weeks. A single topical administration of a new spot-on formulation of selamectin plus sarolaner at the minimum dose rapidly and consistently kills fleas on cats for at least 5 weeks.

Efficacy of a new spot-on formulation of selamectin plus sarolaner in the treatment of Otodectes cynotis in cats.

The efficacy of a new spot-on formulation of selamectin/sarolaner was evaluated against induced Otodectes cynotis infestations in cats in two randomized, blinded studies. Fourteen and 16 cats were randomly assigned to treatment groups in Studies 1 and 2, respectively. On Day 0, animals were either treated with placebo or with the spot-on formulation at the minimal dose of 6.0mg selamectin and 1.0mg sarolaner per kg bodyweight. Treatments were administered topically at the base of the neck. Presence of live mites was evaluated 14days after treatment administration by otoscopic examination and total live mite counts (adults plus immature) were conducted on Day 30 by ear lavage. Efficacy was calculated based on the reduction of mean total live mite counts on Day 30 in the selamectin/sarolaner-treated group versus the placebo-treated group. There were no treatment-related adverse reactions during the studies, apart from one cat in each treatment group with alopecia at the administration site. In both studies combined, live mites were present on Day 14, in 14 out of 15 cats in the placebo-treated groups and in 2 out of 15 cats in the selamectin/sarolaner-treated groups. On Day 30, the arithmetic mean live mite counts were 576.9 and 875.8 in the placebo-treated groups and 5.8 and 4.7 in the selamectin/sarolaner-treated groups, in Studies 1 and 2, respectively. The live mite counts were significantly (P≤0.0021) lower in the selamectin/sarolaner-treated groups compared to the placebo-treated groups with efficacies of 99.2% and 99.3%, in Studies 1 and 2 respectively. A single administration of a new spot-on formulation of selamectin/sarolaner at the minimum dose was safe and highly efficacious in the treatment of ear mite infestations in cats.

Efficacy of a new spot-on formulation of selamectin plus sarolaner for cats against adult Ctenocephalides felis, flea egg production and adult flea emergence.

A new spot-on formulation of selamectin plus sarolaner was evaluated against fleas for adulticidal efficacy, and for the effect on egg production and hatching when applied to flea-infested cats. Ten male and ten female adult domestic shorthair cats were randomly assigned to one of two treatment groups based on pre-treatment flea counts. Cats received topical treatment on Day 0 in a single spot to the dorsal scapular area with either a placebo formulation or with the combination formulation at the minimal dose of 6.0mg selamectin plus 1.0mg sarolaner per kg bodyweight. On Days -1, 5, 12, 19, 26 and 33, cats were infested with approximately 100 (±5) unfed Ctenocephalides felis fleas. At 24h after treatment or 48h after subsequent flea infestation, cats were housed for a 20-h period in a cage to allow collection of flea eggs. At the end of this period, flea eggs were collected from the cages and cats were combed to remove and count live fleas. Emerged viable larvae and emerged adult fleas were counted 3days and 35days, respectively, after egg collection. The new spot-on formulation of selamectin plus sarolaner provided 100% efficacy against adult fleas up to Day 36 following a single application. Fleas on placebo-treated cats produced large numbers of eggs throughout the study, with individual counts ranging from 110 to 1256 eggs. Following treatment, four flea eggs were collected from a single selamectin/sarolaner-treated cat on Day 29, but there were no eggs collected from any other selamectin/sarolaner-treated animal during the study. No larvae or adult fleas developed from these four eggs. From the eggs collected from the placebo-treated cats, the mean percentage of live larvae and adults that emerged ranged from 67.3% to 84.2% and from 50.7% to 81.8%, respectively. A single topical treatment with a new spot-on formulation of selamectin plus sarolaner at the minimum label dose thus controlled fleas on cats and was 100% effective in preventing flea reproduction for over one month after treatment.

Efficacy of a new spot-on formulation of selamectin plus sarolaner against four common tick species infesting cats in Europe.

A single application of a new spot-on formulation of selamectin plus sarolaner (Stronghold®Plus, Zoetis) was evaluated for efficacy against the most common tick species infesting cats in Europe. In each of the seven laboratory studies, 16 adult and purpose-bred cats were randomly allocated to one of two treatment groups based on pre-treatment tick counts. Weekly infestations with 50 unfed adult Ixodes ricinus (2 studies), Ixodes hexagonus (1 study), Dermacentor reticulatus (2 studies), or Rhipicephalus sanguineus (2 studies) were scheduled on Days -2, 5, 12, 19, 26 and 33. Cats were treated on Day 0 with the spot-on formulation at the minimum recommended label dose of 6.0mg selamectin and 1.0mg sarolaner per kg bodyweight or with a placebo. Ticks were counted 48h after treatment and after each re-infestation. No treatment-related adverse reactions were recorded in any of the studies. Geometric mean live tick counts were significantly (P≤0.0012) lower in the selamectin/sarolaner-treated group compared to the placebo-treated group at all time-points. Against I. ricinus and I. hexagonus, efficacy was ≥97.2% against existing infestations and ≥97.4% against weekly re-infestations for at least 5 weeks. Treatment was 100% effective against existing R. sanguineus infestations and was ≥95.8% for at least 4 weeks. Against D. reticulatus treatment resulted in ≥94.4% efficacy for at least 4 weeks. Thus, a single application of the new spot-on formulation of selamectin plus sarolaner at the minimum dose provides rapid treatment of existing infestations and is at least one month effective against re-infestation by all relevant European tick species in cats.

Efficacy of a new spot-on formulation of selamectin plus sarolaner against Ancylostoma tubaeforme and Toxocara cati in cats.

The efficacy of a new spot-on formulation of selamectin plus sarolaner for cats was evaluated against induced infections with Ancylostoma tubaeforme (hookworm) and Toxocara cati (roundworm). Five laboratory studies were conducted using adult, purpose-bred cats. Four of the studies were designed to evaluate efficacy of the combination against A. tubaeforme, the dose-limiting gastrointestinal nematode species for selamectin. In two of these studies non-interference between selamectin and sarolaner was also evaluated. The fifth study evaluated efficacy of the combination against mixed infections of A. tubaeforme and T. cati. The hookworm isolates in three studies were of US origin, as was the roundworm isolate. In the two remaining studies, cats were inoculated with a hookworm isolate of European origin. Cats were inoculated with 150 (±50) to 200 (±50) infective hookworm larvae 30-42days prior to treatment and with 400 infective roundworm eggs 60days prior to treatment. Cats were ranked by pre-treatment faecal egg counts and randomly allocated to different treatment groups. In all studies, cats were treated at the minimum label dose to provide 6.0mg selamectin per kg bodyweight. All animals were euthanized 7-10days after treatment for worm counts. Efficacy was calculated based on the reduction of the geometric mean worm counts in the treated groups versus the placebo-treated control groups. The efficacy against adult hookworms was 99.2%, 94.3% and 100% in three of these studies, and was lower in the remaining two studies. The efficacy against T. cati was 100%. Furthermore, non-interference between sarolaner and selamectin was demonstrated. Thus, a single topical application of the new spot-on formulation of selamectin plus sarolaner at the minimum label dose is effective in the treatment of adult hookworm and roundworm infections in cats.

Long-term compassionate use of oclacitinib in dogs with atopic and allergic skin disease: safety, efficacy and quality of life.

BACKGROUND: Oclacitinib is safe and effective for treating dogs with pruritus associated with allergic and atopic dermatitis, based on randomized clinical trials of up to 4 months duration. HYPOTHESIS/OBJECTIVES: This study assessed long-term safety, efficacy and quality of life of oclacitinib-treated dogs enrolled in a compassionate use programme. ANIMALS: Two hundred and forty-seven client-owned dogs with allergic skin disease that had previously benefited from oclacitinib therapy. METHODS: Dogs were enrolled in an open-label study at 26 veterinary clinics. Dogs received 0.4-0.6 mg/kg oclacitinib twice a day for 14 days, then once a day for up to 630 days. Assessments were performed at ~90 day intervals. Owners completed a quality-of-life survey and assessed pruritus using a Visual Analog Scale (VAS) at each clinic visit. Veterinarians assessed dermatitis using a similar VAS. Abnormal health events, concomitant medication and clinical pathology results were summarized. RESULTS: Visual Analog Scale scores showed improvement from baseline at all time points. The percentage of dogs showing ≥50% reduction from baseline on day 90 was 63.9% for pruritus and 66.4% for dermatitis. Owners saw a positive impact on quality of life in >91% of all dogs. Urinary tract infection/cystitis, vomiting, otitis, pyoderma and diarrhoea were the most frequently reported (>5% of dogs) abnormal clinical signs. Haematology and serum chemistry means remained within the normal reference ranges. Concomitant medications were well tolerated. CONCLUSIONS AND CLINICAL IMPORTANCE: Results indicated that oclacitinib was safe and efficacious for long-term use and improved the quality of life for dogs in this study.

A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs.

BACKGROUND: Ciclosporin is approved for the treatment of atopic dermatitis (AD) in dogs and has been shown to be safe and effective. Placebo-controlled studies suggest that oclacitinib is a safe and effective alternative therapy. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy and safety of oclacitinib, in comparison to ciclosporin, for the control of AD in a blinded, randomized clinical trial, incorporating a noninferiority test at day 28. ANIMALS: A total of 226 client-owned dogs with a history of AD from eight sites were enrolled. METHODS: Enrolled animals were randomized to receive oral oclacitinib (0.4-0.6 mg/kg twice daily for 14 days, then once daily) or oral ciclosporin (3.2-6.6 mg/kg once daily) for 12 weeks. Owners assessed pruritus using an enhanced visual analog scale (VAS), and veterinarians assessed dermatitis using the Canine Atopic Dermatitis Extent and Severity Index (CADESI)-02. RESULTS: On days 1, 2, 7, 14, 28, 56 and 84, the percentage reduction from baseline for owner-assessed pruritus changed from 25.6 to 61.0% in the oclacitinib group compared with 6.5 to 61.5% in the ciclosporin group; differences were significant at all time points up to day 28. On day 56, ciclosporin-treated dogs showed a similar decrease in pruritus to oclacitinib-treated dogs. On day 14, the percentage reduction from baseline CADESI-02 was significantly greater in the oclacitinib group (58.7%) than in the ciclosporin group (43.0%). Three times as many adverse events attributed to gastrointestinal signs were reported in the ciclosporin group compared with the oclacitinib group. CONCLUSIONS AND CLINICAL IMPORTANCE: In this study of treatment for canine AD, oclacitinib had a faster onset of action and a lower frequency of gastrointestinal side effects compared with ciclosporin.