Lokivetmab – a new treatment for canine atopic dermatitis

Why do this module? Lokivetmab is a new treatment for reducing the clinical signs of atopic dermatitis in dogs. It is also a new type of medicine (a monoclonal antibody) for the treatment of animals in the UK. This module explains about monoclonal antibodies, and summarises what is known about the efficacy and safety of lokivetmab in the treatment of canine atopic dermatitis, including how it compares with other options for the management of atopic dermatitis. 

Why do this module?

Lokivetmab is a new treatment for reducing the clinical signs of atopic dermatitis in dogs. It is also a new type of medicine (a monoclonal antibody) for the treatment of animals in the UK. This module explains about monoclonal antibodies, and summarises what is known about the efficacy and safety of lokivetmab in the treatment of canine atopic dermatitis, including how it compares with other options for the management of atopic dermatitis. 

Lokivetmab (loe-key-vet-mab; brand name Cytopoint, marketed by Zoetis) is a monoclonal antibody that was licensed in April 2017 for the treatment of clinical manifestations of atopic dermatitis in dogs (Zoetis press release 2017; Cytopoint SPC 2017). The antibody is designed to bind to the antigen interleukin-31 (IL-31), a T-cell-derived pro-inflammatory cytokine protein which belongs to the IL-6 family of cytokines (CVMP 2017), and a mediator of pruritus (Gonzales et al 2013). Binding prevents IL-31 from interacting with its receptor thereby preventing activation of a signalling cascade (Cytopoint SPC 2017). IL-31 is involved in innate and adaptive immunity in tissues that are in close contact with the environment, such as the skin and the airways; it is associated with other diseases as well as atopic dermatitis (CVMP 2017).

Lokivetmab is available as a solution for injection, in single-dose vials. It is given as a 1mL dose subcutaneously (equivalent to 1 to 3.3mg/kg). Once-monthly dosing is recommended in the summary of product characteristics (SPC) with no specified limit to the duration of treatment. The product needs to be stored in a fridge (Cytopoint SPC 2017).

Antibodies are immunoglobulins produced by B-lymphocytes in response to stimulation by antigens. They are made up of four amino acid chains and comprise two distinct regions: the constant region (called the Fc domain); and the variable region (called the fragment antigen binding [Fab] domain) (DTB 2007).

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In the constant region (Fc), the amino acid sequence is identical for all antibodies in a given class (i.e. IgA, IgD, IgE, IgG, IgM). This determines the antibody’s effector function (such as activation of the complement cascade or interaction with specific effector cells) (DTB 2007). Lokivetmab is of the IgG class. The variable region (Fab) serves as the antigen-binding site. 

Monoclonal antibodies are produced by a single clone of B-lymphocytes, so each antibody molecule is identical in every respect and all interact with the same epitope. Specific monoclonal antibodies can be manufactured to interact with predefined antigenic targets with the aim of activating a particular immune reaction. The specific target of lokivetmab is an epitope on canine IL-31 which, when bound to lokivetmab, is prevented from interacting with its receptor (CVMP 2017). 

Originally, monoclonal antibodies were made by fusing immunised mouse B-lymphocytes (which conferred the ability to synthesise specific IgG antibodies) with immortal myeloma cells (which provided the capacity for indefinite growth) (Kohler & Milstein 1975). This enabled large quantities of identical antibodies to be produced over a long period. The resulting monoclonal antibodies were entirely murine in composition (Dubel 2007). Molecular engineering techniques are now used to partially or totally replace components of the mouse monoclonal antibody with species-specific amino acid sequences (DTB 2007). 

Lokivetmab contains 31 amino acids derived from a mouse anti-IL-31 monoclonal antibody (following immunisation of mice with a canine IL-31 immunogen). These amino acids are incorporated into the variable region of a canine IgG antibody (CVMP 2017). 

Studies in healthy laboratory dogs with induced itchiness after being given IL-31 have shown that lokivetmab starts to work to reduce itching 8 hours after injection and that the effect lasts 28 days (CVMP 2017).

There are two published randomised placebo-controlled trials of lokivetmab in client-owned dogs with chronic atopic dermatitis: one (involving 211 dogs) was a dose-determining trial (Michels et al 2016a); the other (in 245 dogs) was designed to test the safety of two doses of lokivetmab one month apart (Michels et al 2016b). 

The main clinical trial evidence is a blinded comparison of lokivetmab with ciclosporin (Atopica) in 274 client-owned dogs with atopic dermatitis (CVMP 2017). Dogs were randomised to 3 months’ treatment with either a monthly subcutaneous injection of lokivetmab 1mg/kg, or oral ciclosporin at the licensed dose; placebo capsules and saline injections were also used to maintain blinding. The trial was designed to test whether the effect of lokivetmab was non-inferior to ciclosporin. This trial and its result are summarised in the European assessors’ report, but have not yet been published in full (CVMP 2017). 

There were two primary outcome measures: owner-evaluated itchiness score on a visual analogue scale, and clinician-evaluated skin lesion score: 

  • On day 28 of the trial, the mean percentage reduction in owner-evaluated itchiness score was 52% with lokivetmab vs. 44% with ciclosporin; the statistical test for non-inferiority was stated to have been met (CVMP 2017). 
  • The mean percentage reduction in clinician-evaluated skin lesion score was 54% with lokivetmab vs. 57% with ciclosporin; the statistical test for non-inferiority was stated to have not been met. The severity of skin lesions in both groups of dogs improved from ‘severe’ at the start of the trial to ‘moderate‘ at day 28 to ‘mild’ by day 84 (CVMP 2017). 

It normally takes 4 to 6 weeks for ciclosporin to become effective (Olivry et al 2010), so comparing efficacy at 4 weeks may have underestimated the efficacy of ciclosporin; a comparison at 8 weeks would be more meaningful. 

Eight dogs (5%) on lokivetmab were withdrawn versus 2 dogs on ciclosporin (1.5%) due to lack of efficacy. The lack of efficacy of lokivetmab may be due to the development of anti-drug antibodies, which occurs in a few dogs, or because IL-31 is not a main factor in a specific dog’s disease (CVMP 2017). Anti-drug antibodies were reported in three dogs on lokivetmab which correlated to reduced efficacy of lokivetmab in at least one dog (CVMP 2017).  

How does lokivetmab compare with other treatments?

Lokivetmab has not been compared with glucocorticoids or oclacitinib

No adverse effects considered related to lokivetmab were noted in the trials and so no adverse effects are listed in the SPC, apart from hypersensitivity reactions, which may occur rarely. Bacterial skin infections were common (in 7% of dogs) with lokivetmab in the first few weeks of therapy but this may have been due to the skin disease rather than the treatment. Nevertheless the SPC recommends monitoring dogs for bacterial infections associated with atopic dermatitis, especially during the first weeks of treatment. Around 60% of the dogs on lokivetmab in the comparative trial continued on lokivetmab (unblinded) for a further 6 months for evaluation of safety, which means that continuous use for 9 months has been studied, during which there were no signs of immunosuppression or increased use of antibiotics (CVMP 2017).

Lokivetmab should not be used in dogs that weigh under 3kg or that are pregnant or lactating (Cytopoint SPC 2017).

Lokivetmab is not known to interact with any substances. The SPC recommends that vaccinations given at the same time should be injected at a different site to lokivetmab (Cytopoint SPC 2017).

If there is repeated accidental injection, there is potential danger to people administering lokivetmab from development of an immune response.  Lokivetmab cannot bind to IL-31 in humans (CVMP 2017; Cytopoint SPC 2017).

Management of atopic dermatitis requires a combination of preventive measures and treatment for acute flare-ups, and control of chronic pruritus and dermatitis. Prevention includes identification and avoidance of triggers (such as foods, dust mites, pollen), flea control, regular bathing to improve skin and coat condition and prevent microbial infections, and possibly the use of topical moisturisers, essential fatty acid supplements and allergen-specific immunotherapy, and topical or oral antimicrobial therapy when necessary. (Olivry et al 2015).

Lokivetmab may be suitable if treatment is needed to reduce the clinical signs (including pruritus) of atopic dermatitis, but other options are contraindicated or not tolerated, or are ineffective. It may be particularly suitable for owners who cannot or will not give oral medication.  Some specialists suggest that lokivetmab's narrow spectrum of activity makes it best suited to managing pruritus and mild inflammation in early cases of canine atopic dermatitis (Godfrey & Nutall 2017). In the USA, a higher dose (at least 2mg/kg) and a frequency according to response (every 4 to 8 weeks) is recommended (Plumb’s Veterinary Drugs 2017); use at frequencies of between 2 weeks and more than 8 weeks between injections have been reported (these are unlicensed frequencies in the UK) (Godfrey & Nuttall 2017). The SPC advises that if no, or limited, response is seen within 1 month after initial dosing, an improvement in response may be seen after a second dose 1 month later; however, if the animal does not show a better response after the second dose, the vet should consider alternative treatments.

  • The product should help relieve itching but will not cure any underlying condition.
  • Agree a way that the owner can monitor the effects of the treatment (e.g. using a diary to record the severity of itching; Zoetis has produced one for use by owners).
  • Ask the owner to report back any suspected adverse effects.

Lokivetmab is a monoclonal antibody licensed for the treatment of clinical signs associated with atopic dermatitis in dogs. It specifically blocks the action of interleukin-31, a cytokine implicated in pruritus associated with atopic dermatitis. It is given by monthly subcutaneous injections and starts to work 8 hours after injection.

The results of one randomised controlled trial (not yet published in full) indicate that it is no less effective than ciclosporin in reducing itching. How it compares with glucocorticoids or oclacitinib is not known. Lokivetmab may not work in all dogs, perhaps because IL-31 is not a contributor to atopic disease in an individual dog, or because occasionally anti-drug antibodies develop which neutralise the drug. 

No specific adverse effects have been noted in clinical trials. As with all new drugs, the limited experience with lokivetmab means that the full adverse effect profile may not yet be known. It is therefore important to report adverse effects that become apparent with use.

Update

Since we published this module, the clinical trial comparing lokivetmab with ciclosporin has been published (Moyaert et al 2017).

PODCAST

If you prefer, you can listen to the whole audio presentation of this module using the following podcast. Don't forget that you can also download the podcast to your iPod, music player, tablet or smartphone using the Download link on the right of the audio player.

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Click the play button below to answer the multiple choice questions on this module. Start by entering your first and second names and your email address so we can send you a CPD certificate for your records. 

 

References

Understanding monoclonal antibodies. DTB 2007; 45: 56-7.

Committee for Medicinal Products for Veterinary Use. CVMP Assessment report for CYTOPOINT (EMEA/V/C/003939/0000), February 2017.

Cytopoint solution for injection for dogs. Summary of product characteristics, UK. Zoetis, April 2017. [Accessed 25 August 2017].

Godfrey D, Nuttall T. Lokivetmab. Vetlexicon Canis. {Accessed 12.9.17].

Gonzales A et al. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol 2013; 24: 48–e12.

Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495–7.

Michels GM et al. 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. Vet Dermatol 2016a; 27: 478-87.

Michels GM et al. 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. Vet Dermatol 2016b; 27: 505-7.

Moyaert H et al. A blinded, randomized clinical trial evaluating the efficacy and safety of lokivetmab compared to ciclosporin in client-owned dogs with atopic dermatitis. Vet Dermatol 2017; DOI: 10.1111/vde.12378.

Olivry T et al. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol 2010; 21: 233–48.

Olivry T et al. Treatment of canine atopic dermatitis: 2015 updated guidelines from the International Committee on Allergic Diseases of Animals (ICADA). BMC Vet Res 2015; 11: 210.

Plumb's Veterinary Drugs. Lokivetmab. [Accessed 12.9.17].

Zoetis. Zoetis receives European Commission marketing authorization for Cytopoint (lokivetmab) [Press release]. April 2017.