Solensia (Canada)

Company: Zoetis

frunevetmab injection

DIN 02518449

Veterinary Use Only

Feline anti-Nerve Growth Factor monoclonal antibody for cats

STERILE

Description

SOLENSIA^® is an injectable solution containing 7 mg/mL of frunevetmab in histidine buffer (sorbitol, L-histidine, polysorbate, sodium hydroxide, hydrochloric acid and water). Frunevetmab is a feline therapeutic monoclonal antibody that neutralizes Nerve Growth Factor (NGF). The product does not contain a preservative.

Solensia Indications

SOLENSIA is indicated for the alleviation of pain associated with osteoarthritis in cats.

Dosage and Administration

The nominal dose of SOLENSIA (frunevetmab injection) is 1.0 mg/kg body weight, administered subcutaneously once a month. The full content of each vial is for single use only and vial should be properly discarded after puncture.

Dosing Information: Cats should be dosed by weight range according to the Dosing Chart below. Cats are given the full content of 1 or 2 vials based on body weight. Aseptically withdraw the total dose into a single syringe and administer immediately.

Table 1. Dosing Chart

*1 mL frunevetmab injection per vial

For cats greater than 7 kg, the contents of more than one vial are required to administer a single dose. In those cases, withdraw the appropriate content from each required vial into the same syringe.

Contraindications

Do not use in case of hypersensitivity to the active substance or to any of the excipients.

Do not use in breeding, pregnant or lactating cats.

Do not use in cats less than 12 months or under 2.5 kg body weight.

CAUTIONS:

SOLENSIA contains a felinized monoclonal antibody. Discontinue use if signs of intolerance or anaphylaxis are observed.

The safe use of anti-NGF monoclonal antibodies (mAbs) with concurrent NSAIDs has not been studied in cats. The safe use of this product with other concurrent mAbs is not known.

The safety and efficacy of this product has not been investigated in cats with kidney disease IRIS stages 3 and 4. Use of the product in such cases should be based on a benefit-risk assessment performed by the treating veterinarian.

Since it may take at least two (2) monthly injections to reach steady-state drug concentrations, discontinuation prior to the second treatment may not result in maximum pain reduction (See EFFICACY section). If the response to treatment is not as desired after the second dose, the veterinarian should consider alternative treatments.

This drug may induce transient or persistent anti-drug antibodies. The induction of such antibodies is uncommon and may have no effect or may result in a decrease in efficacy in animals that responded to treatment previously. (See IMMUNOGENICITY section.)

If a vaccine is to be administered at the same time as treatment with SOLENSIA, they should be administered in different sites.

Warnings

Keep out of reach of children.

Wash hands after use.

Hypersensitivity reactions, including anaphylaxis, could potentially occur in the case of accidental self-injection.

The importance of Nerve Growth Factor in ensuring normal fetal nervous system development is well-established and laboratory studies conducted on nonhuman primates with human anti-NGF antibodies have shown evidence of reproductive and developmental toxicity. Pregnant women, women trying to conceive, and breastfeeding women should take extreme care to avoid accidental self-injection or needle stick injuries.

In case of accidental self-injection, seek medical advice immediately and show the package insert or the label to the physician.

Adverse Reactions

Mild, focal skin reactions (dermatitis, alopecia and pruritus) were observed commonly in field trials. The clinical safety of SOLENSIA dosed at 28-day intervals was assessed in a masked, controlled 112-day US field study evaluating the effectiveness of SOLENSIA for the alleviation of pain associated with osteoarthritis. Enrollment included 275 cats, 182 cats treated with SOLENSIA and 93 cats treated with placebo (vehicle control). Adverse reactions reported (and percent of cats affected) are provided below.

Table 2. Adverse Reactions Reported in the Field Study

¹ If a cat experienced the same event more than once, only the first occurrence is reported

² Behavior abnormal for the individual cat

³ Individual cats may have more than one abnormal clinical sign: anxiety disorder (1), hiding (1), hypersomnia (1), inappropriate urination (5), sleeping with owner (1), vocalization (3), aggressive behavior (1)

⁴ Individual cats may have more than one abnormal clinical sign: anxiety (2), disorientation (1), inappropriate urination (2), vocalization (1)

⁵ If in an animal the renal condition worsened more than once during the study, only the first occurrence is reported

⁶ New lameness or worsening of previous lameness

The safety of SOLENSIA was also evaluated in a masked, controlled 56-day exploratory field study to evaluate the effectiveness of SOLENSIA for the alleviation of pain associated with osteoarthritis in cats. Enrollment included 126 cats; 85 cats were treated with a frunevetmab injection manufactured similarly to SOLENSIA and 41 cats were administered a vehicle control. Cats were dosed at 28-day intervals and received up to two injections. The most frequently reported adverse reactions were digestive tract disorders, including vomiting and diarrhea, and skin disorders, including dermatitis/eczema and alopecia that were mostly attributed to irritation by an activity monitor collar required for the study.

The majority of adverse events reported during the study included signs associated with co-morbidities often found in a population of cats.

Clinical Pharmacology

Mode of Action

Frunevetmab, a felinized therapeutic monoclonal antibody, is part of a new class of analgesics. Its therapeutic effect is due to the neutralization of nerve growth factor (NGF), which is released during inflammation and contributes to pain associated with several chronic conditions [1, 2, 3]. The neutralizing antibody frunevetmab has been shown to alleviate osteoarthritis pain in cats for approximately four weeks.

Pharmacokinetics

In a laboratory safety study, healthy cats were administered frunevetmab injection subcutaneously 1X, 3X or 5X the maximum recommended dosage of 2.8 mg/kg once every twenty-eight days for six consecutive doses. The area under the plasma-concentration time curve, from time zero to the end of the dose interval (AUC_0-t) and maximum plasma concentration (C_max) increased in a less than dose proportional manner. Dosing every 28 days resulted in minimal accumulation over the course of five consecutive frunevetmab injection doses of 14 mg/kg (5X).

In cats with naturally-occurring osteoarthritis frunevetmab half-life was 10-12 days, the SC bioavailability was approximately 60% with maximum drug levels observed at 3-7 days after dose (T_max).

In a field effectiveness study at the label dose in cats with osteoarthritis, steady-state was achieved after approximately 2 doses.

The metabolic pathway of SOLENSIA has not been characterized. As a monoclonal antibody, it is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.

EFFICACY:

Pilot Efficacy Study

A 56-day, masked, controlled exploratory field study was conducted at fourteen U.S. veterinary clinics. The study enrolled 126 client-owned cats with clinical signs of osteoarthritis (OA) confirmed by radiography and orthopedic examination; enrolled cats needed to be ≥ 2.5 kg and over 6 months old. The enrolled cats were randomized to treatment with frunevetmab injection (n=85) or vehicle control (n=41). Frunevetmab was either administered subcutaneously on Days 0 and 28 or intravenously on Day 0 and subcutaneously on Day 28. Cats were dosed with frunevetmab injection or vehicle control based on body weight (2.5-7 kg cats received 1 mL, 7.1-14 kg cats received 2 mL).

Outcome measures for the control of pain associated with OA included comparison of the owner’s evaluation of Client Specific Outcomes Measures (CSOM) at Days 14, 28, 42, and 56 compared to baseline (Day 0 before treatment); Owner Global Assessments on Days 28 and 56; and total orthopedic pain score completed by the veterinarian on Days 0, 28, and 56. The overall activity of the cats was recorded using accelerometers. For the CSOM, treatment success was defined as a reduction of at least 2 in the total CSOM score compared with the score at baseline. Cats that had an increase in score for any individual CSOM activity (regardless of the total CSOM score) were considered treatment failures. For the Owner Global Assessment, success was defined as an owner’s impression of the response to treatment as Good or Excellent (versus Fair or Poor). Success was not defined for the veterinarian-assessed total orthopedic pain score. The proportion of cats considered treatment successes based on the owner CSOM assessment and the Owner Global Assessment was greater in the frunevetmab group compared to the control group for all assessments. There were no significant differences between treatment groups for the total pain score or the total joint debility score obtained in the veterinarian’s orthopedic examination. Mean weekly activity counts in the frunevetmab group showed little change (mean decrease 0.9%), while the placebo group showed an average of 9.3% decrease in weekly activity (P=0.0637).

Table 3. Percent CSOM Success by Assessment Day

Table 4. Percent Owner Global Assessment Success by Assessment Day

Field Efficacy Study

A 112-day, masked, randomized, controlled field study was conducted at twenty-one U.S. veterinary clinics. The study enrolled 275 client-owned cats with clinical signs of osteoarthritis (OA) confirmed by radiography and orthopedic examination; enrolled cats weighed 2.5-11.4 kg and were 1.6-22.4 years old. The enrolled cats were randomized to treatment with SOLENSIA (n=182) or vehicle control (n=93), administered subcutaneously on Days 0, 28, and 56. Cats were dosed with SOLENSIA or the vehicle control based on body weight (2.5-7 kg cats received 1 mL, 7.1-14 kg cats received 2 mL).

The primary outcome measure for success for the control of pain associated with OA was comparison of the owner’s evaluation of CSOM at Day 56 compared to baseline (Day 0 before treatment). Treatment success was defined as a reduction of at least 2 in the total CSOM score at Day 56 compared with the score at baseline. Cats that had an increase in score for any individual CSOM activity (regardless of the total CSOM score) or that received rescue analgesia prior to Day 56 were considered treatment failures. Secondary outcome measures included the total CSOM score on Days 28 and 84; Owner Global Assessments on Days 28, 56, and 84; and total orthopedic pain score completed by the veterinarian on Days 28, 56, and 84. Success was not defined for the veterinarian-assessed total pain score.

Statistically, cats in the SOLENSIA group had a significantly higher success rate at Day 56 (primary outcome) than cats in the control group (P = 0.0306). Cats in the SOLENSIA group had a statistically higher success rate than cats in the control group (P = 0.0176) on Day 28. On Day 84, cats in the SOLENSIA group had a numerically higher success rate than cats in the control group, but the difference was not statistically significant (P = 0.0820).

Table 5. Percent CSOM Success by Assessment Day

On Days 28 and 56, treatment related differences in the Owner Global Assessment scores were statistically significant (P = 0.0271 and P = 0.0354, respectively). There was no significant difference between treatment groups for the Owner Global Assessment scores on Day 84 (P=0.0969); however, the SOLENSIA group received a numerically higher percentage of excellent assessments (25.0%) compared to the control group (16.9%).

Table 6. Percent Owner Global Assessment Success by Assessment Day

Statistically significant differences in the orthopedic examination variables between frunevetmab and placebo were observed on Day 56 and 84 (P=0.0238 and P=0.0350, respectively).

Table 7. Mean Veterinarian-Assessed Total Pain Score by Assessment Day

ANIMAL SAFETY:

SOLENSIA was administered to healthy seven to eight-month-old cats (8 cats per group) at doses of 2.8 mg/kg (1X), 8.4 mg/kg (3X), and 14 mg/kg (5X) every 28 days for six consecutive doses. The control group (8 cats) received vehicle injections.

The most common findings included vomiting and diarrhea observed sporadically in all groups. The highest frequency of vomiting occurred in the 1X group. Clinically relevant skin findings included abrasions, alopecia, or scabs mostly around the face and ears. These findings were noted in three 1X cats, three 3X cats, and one 5X cat. Another 1X cat developed a 2 cm ventral neck lesion following clipping and blood collection on Day 87. Although irritation appeared related to the clipping, the pruritus and prolonged recovery were deemed drug-related. The lesion healed when self-trauma was prevented including the placement of an e-collar for the remainder of the study. Body tremors and shivering were noted in one 3X cat on Day 28.

Flinching was occasionally associated with injections, most frequently noted during the first dosing in all dosing groups. Occasionally, scabs, small abrasions, or spot of alopecia were observed at the injection sites in all dosing groups. A few cats had transient swelling at injection sites.

Serum creatinine values in females were significantly higher in the 5X group compared to controls (P < 0.10). Creatinine values on Day 28 were significantly higher (P= 0.0239) in the 1X group compared to the control group. On Day 112, values were significantly higher (P = 0.0443) in the 5X group compared to the control group. Creatinine values did not exceed the reference ranges in cats of either sex at any time point.

There was one 1X cat with mild focal discoloration of the left tibiofemoral joint cruciate ligament on gross pathology. There was no correlative pathology on microscopic examination. No lameness was reported in this cat or any cat over the course of this study.

One 1X cat had a small amount of bilirubinuria on Day 43. This cat had dark urine and hematuria on Days 43-45 with no evidence of UTI on urinalysis. The cat responded to a canned prescription urinary diet and recovered. This cat also vomited food, bile or hair on three days and had diarrhea or dark, tarry stools on two days. Another 3X cat had a small amount of bilirubinuria on Day 83 and orange colored urine. This cat also had elevated serum lactate dehydrogenase activity at three time points.

There was one 5X cat that had a small amount of bilirubinuria at the end of the study with lipid sediment. This cat also had focal hepatic lipidosis on histopathology.

No clinically significant changes related to frunevetmab were observed among the cats for food consumption, physical and neurological examinations, body weight, clinical pathology (hematology, coagulation and serum chemistry), gross pathology, histopathology or organ weights.

IMMUNOGENICITY:

All therapeutic proteins have the potential for immunogenicity, including the production of antibodies that bind to the therapeutic protein and may decrease efficacy. Such host-derived antibodies are also termed anti-drug antibodies (ADA). Monoclonal antibodies such as frunevetmab are a specific subclass of therapeutic proteins, and therefore have the potential to cause the cat to produce ADAs against frunevetmab.

The presence of binding antibodies to frunevetmab in cats was assessed using a screening and confirmatory assay approach. In controlled studies in cats with osteoarthritis, four out of 259 cats that received SOLENSIA once monthly developed anti-drug antibodies (ADAs). One cat tested positive for ADAs on Days 0, 28, 56, and 84. This cat had non-detectable plasma drug concentration levels of SOLENSIA on Days 28 and 56, and was a treatment failure in the CSOM effectiveness analysis. However, this cat showed some improvement on the veterinary pain assessment throughout the study. No assessment for neutralizing antibodies was performed.

The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SOLENSIA with the incidence of antibodies to other products may not be appropriate.

Storage

Store between 2-8°C. Do not freeze. Store in the original package. Protect from light.

PRESENTATION:

SOLENSIA is supplied in 1 mL single vials. The vials are packaged in cardboard boxes with either 1 vial, 2 vials, or 6 vials of 1 mL. Not all pack sizes may be marketed.

References

1. Isola M, Ferrari V, Miolo A, Stabile F, Bernardini D, Carnier P, Busetto R. Nerve growth factor concentrations in the synovial fluid from healthy dogs and dogs with secondary osteoarthritis. Veterinary and Comparative Orthopaedics and Traumatology. 2011; 115: 189-204.

2. Enomoto M, Mantyh PW, Murrell J, Innes JF, Lascelles BDX. Anti-nerve growth factor monoclonal antibodies for the control of pain in dogs and cats. Vet Rec. 2019; 184(1): 23. doi:10.1136/vr.104590.

3. Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of drugs based on antagonism of NGF. Trends in Pharmacological Sciences 2006; 27:85-91.

Zoetis^® and Solensia are registered trademarks of Zoetis or its licensors.

Zoetis Canada Inc., Kirkland QC H9H 4M7

10023071-11-2

October 2023

CPN: 1198580.2