Grapiprant – a new drug for treating osteoarthritis in dogs

 
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Grapiprant (brand name Galliprant, marketed by Elanco) is a new class of drug licensed in Europe (via the European Medicines Agency [EMA]) for treating ‘pain associated with mild to moderate osteoarthritis in dogs’ (SPC 2018). There are concerns among dog owners and vets about the safety of NSAIDs, which is In contrast to the evidence on NSAIDs, but which has led to reluctance to use them (Belshaw et al. 2016a; Veterinary Prescriber 2018). So, there is a lot of interest in grapiprant from dog owners and vets because they hope it is an effective and safer alternative to traditional NSAIDs. By doing this module you will:

  • understand the pharmacology of grapiprant;

  • know the clinical evidence on the efficacy and safety of grapiprant;

  • be aware of what is known about how grapiprant compares with NSAIDs;

  • understand what is meant by intention-to-treat and per-protocol analysis in clinical trials result analysis;

  • understand what is meant by the number needed to treat and its relevance to clinical practice.

Grapiprant is a non-steroidal, analgesic and anti-inflammatory drug in the piprant class. Unlike NSAIDs, grapiprant does not inhibit cyclooxygenase (Kirkby Shaw et al. 2016; Nagahisa et al. 2017). In 2013, the World Health Organization (WHO) defined piprants as a newly recognised class of drugs that act as prostanoid receptor antagonists (PRAs) (WHO 2013); it has classed grapiprant among ‘other antirheumatic and anti-inflammatory agents (non-steroid)’, not as an NSAID (WHO 2018).

Grapiprant is a highly selective antagonist of the EP4 prostaglandin E2 receptor (Kirby-Shaw et al 2016). The EP4 receptor is important in pain and inflammation because it is a key mediator of prostaglandin E2-elicited sensitisation of sensory neurons and inflammation (Kirby-Shaw 2016). The EP4 receptor is also expressed in other tissues and cells, such as osteoarticular, immune, cardiovascular, gastrointestinal and respiratory (EPAR 2017). While grapiprant has been shown to have anti-inflammatory activity in rat models of acute and chronic inflammation (Nagahisa et al. 2017), in dogs a clinically proven anti-inflammatory effect has not been shown (EPAR 2017). 

Grapiprant acts on a later part of the prostaglandin pathway compared with traditional NSAIDs (see the image below). In theory, there is a potential for grapiprant to have a different safety profile from traditional NSAIDs.

Pathway for prostaglandin synthesis (prepared with help from Waller et al. 2014). 

Grapiprant is readily and rapidly absorbed from the gastrointestinal tract in dogs (Rausch-Derra et al. 2016a; SPC 2018). When given to fasted dogs, maximum grapiprant concentrations are seen in serum within 1 hour of dosing (SPC 2108). Giving a grapiprant tablet with food reduces its absorption, so that the maximum serum concentration is delayed by 1.5 hours and the total amount of drug absorbed is reduced (EPAR 2017; SPC 2018).

Grapiprant is mainly excreted as unchanged drug; about 65% is excreted in faeces and about 20% in urine (EPAR 2018). Some of the drug is metabolised into three different metabolites. The elimination half-life of grapiprant is about 5 hours (Rausch-Derra et al. 2016a; SPC 2018).

One randomised controlled trial evaluating grapiprant in dogs with osteoarthritis has been published in full (Rausch-Derra et al. 2016b). The trial, which compared grapiprant with placebo, was designed to assess whether grapiprant relieves pain and to evaluate its safety. A total of 285 client-owned dogs with osteoarthritis confirmed by X-ray and veterinary assessment were randomised to once daily oral grapiprant (2mg/kg) or placebo. 

Dogs of any breed, sex and age, and weighing 3.6kg or more, were enrolled. Dogs that were pregnant, lactating, or intended for breeding, or had clinically relevant abnormal clinical pathology findings, spinal orthopaedic abnormalities or neurological abnormalities that affected gait, were excluded.

Dogs had to have a pain severity score (PSS) and pain interference score (PIS) of at least 2 (out of a possible 10). The owners completed a weekly evaluation using the Canine Brief Pain Inventory (CBPI) (Brown et al 2008). A treatment success was defined as a dog that had a PSS that was decreased by at least 1 point, a PIS that was decreased by at least 2, and with the overall impression question rated as the same or better at day 28 compared to day 0. Veterinary assessments (in terms of total orthopaedic score) were made on screening and at days 14 and 28; the mean total orthopaedic score at baseline was approximately 10 in the treatment and placebo groups, indicating that the dogs had a mild to moderate level of osteoarthritis (EPAR 2017). Blood and urine were collected for clinical pathology testing at day 28, or on the day the dog was withdrawn from the study. The primary outcome measure was the CBPI score on day 28 compared with the CBPI score at day 0. The trial focused mainly on pain relief and improved clinical signs. Safety was evaluated by physical examination, evaluation of clinical pathology results and owner observations. 

Based on the intention-to-treat (ITT) population (285 dogs), the treatment success rate at day 28 in the grapiprant group was not statistically significantly different from that in the placebo group (45.4% versus 32.6%, p=0.08) (this information is included in the EMA’s scientific report, but not in the published trial report or the SPC) (EPAR 2017). For the per-protocol population (262 dogs), the difference was statistically significant (48.1% versus 31.3%, p=0.0315) (EPAR 2017; Rausch-Derra et al. 2016b). Secondary outcome measures of pain interference score and pain severity score also improved significantly in the grapiprant group compared with placebo at all time points (p<0.05), as did veterinary assessments at both day 14 and day 28 (p=0.0029 and p=0.0086 respectively) (Rausch-Derra et al. 2016b). 

The EMA’s report also states that more than half of the dogs (55%) in the trial did not respond to grapiprant treatment according to the primary endpoint (EPAR 2017). The report notes that there were no restrictions on feeding relative to drug administration and that this may have affected the efficacy of grapiprant. The company also provided the regulator with a combined analysis of these trial results together with those from an unpublished dose-ranging trial: this combined analysis indicates that grapiprant had a statistically significant effect compared with placebo (based on ITT analysis): success according to the primary endpoint was 51.3% (vs. 35.5% with placebo, p=0.0008) (EPAR 2017; SPC 2018). Based on these results, the number needed to treat (NNT) is 6; that is, for every 6 dogs treated for 28 days, one will benefit clinically from grapiprant treatment. 

The drug was also generally well tolerated, but a higher percentage of grapiprant-treated dogs had occasional vomiting compared with dogs in the placebo group (17.0% vs. 6.3%; significance not stated). There were no treatment-related changes in clinical pathology results (Rausch Derra et al. 2016b).

In a clinical trial, it is possible that some subjects might not receive the treatment to which they were randomised, or they might be removed from the trial before the end because of adverse effects or some other reason. If only data from subjects that properly completed the trial (called the per-protocol population) are analysed, the results may be biased. This is because removing the results from subjects that did not receive the treatment as intended tends to exaggerate any difference between the treatments. This type of bias can be avoided by using an intention-to-treat (ITT) analysis, which uses data from all the randomised subjects according to the group to which they were allocated. The ITT analysis is considered a more conservative and therefore more believable representation of the results than per-protocol analysis.

The number needed to treat (NNT) is a helpful way of summarising the results of a clinical trial in a single figure. It is the reciprocal of the absolute risk reduction (the difference between the proportion of events in the active treatment intervention group and the proportion of events in the control group). It represents the average number of animals that need to receive the treatment or other intervention for one of them to get the positive outcome in the time specified. The closer the NNT is to 1, the more effective the treatment.

For more on clinical trial design, see the Drug Trials module.

In clinical trials of grapiprant there was mild and generally transient vomiting, soft-formed faeces, diarrhoea and lack of appetite (Rausch-Derra et al. 2015; Rausch-Derra et al. 2016a; Rausch-Derra et al. 2016b). Vomiting was very common (that is, in more than 1 in 10 treated animals), whereas soft-formed faeces, diarrhoea and lack of appetite were common (that is, in more than 1 but less than 10 in 100 treated animals). Haematemesis or haemorrhagic diarrhoea have been reported in very rare cases (that is, in less than 1 animal in 10,000 treated animals, including isolated reports) (SPC 2018). 

Grapiprant was given to healthy dogs at doses of 1, 6 and 50mg/kg daily for 9 months (Rausch-Derra et al. 2015; EPAR 2017). At all dose levels there were mild gastrointestinal signs such as soft-formed faeces, faeces with mucous, and occasional blood seen in the faeces . The frequency of events was dose-dependent. No treatment-related effects were found on liver or kidney function, or gross or histopathological findings of the liver, kidney, or stomach or in any coagulation parameters.

The safety of grapiprant has not been established in dogs aged under 9 months of age or weighing less than 3.6kg, or in dogs that are pregnant, lactating or used for breeding (SPC 2018). The SPC advises that grapiprant should be used with caution in dogs with pre-existing liver, cardiovascular or renal dysfunctions or gastrointestinal disease (SPC 2018).

Grapiprant is a methylbenzenesulfonamide and so is related to sulphonamides, but it is not known whether dogs with a history of hypersensitivity to sulphonamides will show hypersensitivity to grapiprant (SPC 2018). If signs of sulphonamide hypersensitivity do occur, treatment should be stopped (SPC 2018). 

The SPC recommends avoiding concurrent use of grapiprant with anti-inflammatory drugs (including NSAIDs) because this has not been studied (SPC 2018). Before starting grapiprant, the SPC recommends a suitable washout period (based on the pharmacokinetic information about the previous drug) because previous treatment with anti-inflammatory drugs may result in additional or increased severity of adverse effects (SPC 2018). The concomitant use of protein-bound drugs with grapiprant has not been studied (SPC 2018). The potential for drug interactions should be considered in dogs that are also receiving other medication.

Grapiprant is given orally. It is available as 20mg, 60mg and 100mg tablets, which can be divided into equal halves (SPC 2018). The SPC recommends a target dose of 2mg/kg body weight daily (SPC 2018). The drug should be given once daily on an empty stomach and at least 1 hour before a meal.

The SPC states that a clinical response to treatment is usually seen within 7 days and that if no clinical improvement is apparent after 14 days, treatment should be stopped (SPC 2018). Grapiprant has not been used for longer than 28 days in clinical studies and it should only be used for longer durations after careful consideration, and with regular veterinary monitoring; the SPC suggests that intermittent treatment may be beneficial in some dogs because of the waxing and waning nature of osteoarthritis signs (SPC 2018).

Clients should be told that grapiprant is a new treatment and so there is limited evidence on its safety and efficacy. If the decision is made to try grapiprant, it is important to have clear goals for monitoring its effects. It may be useful to ask owners to record how their dogs seem on treatment (e.g. the dog’s demeanour, or how easily it walks up steps). There are validated tools available to do this, such as the CBPI (Belshaw 2016b; Brown 2008). The owner should be told to give the drug when the dog has an empty stomach (at least an hour before a meal) and to look out for any adverse effects. The treatment should be reviewed after 2 weeks and, if there is no improvement or adverse effects outweigh any benefit, the drug should be stopped.

Grapiprant is a new class of drug for relieving pain in dogs with mild to moderate osteoarthritis. It may not be effective in all dogs. According to the available clinical trial evidence, on average 6 dogs need to be treated with grapiprant for 28 days for 1 to benefit. A clinical effect should be seen within 7 days, but if no effect is seen within 14 days the drug should be stopped. Grapiprant must be given on an empty stomach or the amount absorbed, and therefore the efficacy, will be reduced. Vomiting has been reported very commonly (in more than 10% of dogs) and soft-formed faeces, diarrhoea and lack of appetite commonly (in 1–10% of dogs).

Grapiprant has not been shown to have an anti-inflammatory effect in dogs. In studies in healthy dogs, grapiprant did not have adverse effects on the kidney or liver. However, it has not been tested in dogs with kidney, liver or cardiovascular dysfunction or gastrointestinal disease. We do not know how grapiprant compares with, or whether it interacts with, NSAIDs or other drugs used in the treatment of osteoarthritis. As with any new drug, there is a limited amount of information about adverse effects. All adverse effects should be reported to the VMD or the company. 

PODCAST

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How we produced this module

Our modules start with a detailed outline and electronic literature search. The collaborating author on this module was Helen Barnett, a specialist in medicines evaluation. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration. 

References

Belshaw Z et al. The attitudes of owners and veterinary professionals in the UnitedKingdom to the risk of adverse events associated with usingnon-steroidal anti-inflammatory drugs (NSAIDs) to treat dogs with osteoarthritis. Prev Vet Med 2016a; 131: 121–6.

Belshaw Z et al. Systematic review of outcome measures reported in clinical canine osteoarthritis research. Vet Surg 2016b; 45: 480–7.

Brown DC et al. Ability of the Canine Brief Pain Inventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Ass 2008; 233: 1278–83.

European Medicines Agency. Committee for Medicinal Products for Veterinary Use. CVMP assessment report for GALLIPRANT. 2017, online.[Accessed August 2018] [EPAR}

Galliprant. Summary of product characteristics (SPC). Elanco GmbH, January 2018. [Accessed August 2018].

Kirkby Shaw K et al. Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation. Vet Med Science 2016; 2: 3–9.

Nagahisa A, Okumura T. Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Therap 2017; 40: 285–92.

Rausch-Derra LC et al. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res 2015; 76: 853–9.

Rausch-Derra LC et al. Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs. J Vet Pharmacol Therap 2016a; 39: 566–71.

Rausch-Derra LC et al. Prospective, randomized, masked, placebo-controlled multisite clinical study of grapiprant, an EP4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med 2016b; 30:756–3.

Waller DG et al. Medical Pharmacology and Therapeutics, 4th edition 2014. Saunders Elsevier.

Which NSAID? Veterinary Prescriber, August 2018.

World Health Organization. Programme on International Nonproprietary Names (INN) (2016). Pre-stems: suffixes used in the selection of INN, October 2013 .

WHO Collaborating Centre for Drug Statistics Methodology. ATCVet Index 2018. [Accessed 1 November 2018].