Fig. 1 Targeting the prostaglandin E pathway in osteoarthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation via the depletion of prostaglandin H and the subsequent elimination of prostaglandin E2 (PGE2). LYA directly reduces the production of PGE2 by inhibiting microsomal prostaglandin E synthase-1 (mPGES1). PGE2 exerts its biological effects by binding to four specific membrane-bound G protein–coupled receptors (EP1 to EP4). LYB is a specific antagonist of the EP4 receptor (indicated by || in the figure). EP, E-type prostanoid; LYA, mPGES1 inhibitor; LYB, EP4 antagonist.
Fig. 4 Change from baseline CBPI domains. (A) CBPI pain interference, (B) CBPI pain severity, (C) CBPI overall impression, and (D) LOAD mobility. At week 2, placebo, n = 43; LYA, n = 39; LYB, n = 40; carprofen, n = 38. At week 4, placebo, n = 43; LYA, n = 39; LYB, n = 39; carprofen, n =38. Changes from baseline in the active treatment groups were not statistically different from placebo in any of the CBPI domains by MMRM analyses of the full analysis set. *P = 0.011 for carprofen versus placebo by MMRM analyses of the full analysis set. LSM, least squares mean; MMRM, mixed-effect model for repeated measures.
- Table 1 Baseline demographics and disease characteristics.
Data are means (SD) unless stated otherwise. Pairwise comparisons between treatments and placebo were not significant (P > 0.05), unless otherwise indicated. F, female; LOAD, Liverpool Osteoarthritis in Dogs; M, male.
Placebo
(n = 43)LYA
(n = 39)LYB
(n = 42)Carprofen
(n = 39)Total
(N = 163)Age, year 9.8 (2.8) 9.2 (2.8) 9.0 (3.1) 8.9 (3.3) 9.3 (3.0) Weight, n (%) 15–32 kg 24 (55.8) 21 (53.8) 23 (54.8) 21 (53.8) 89 (54.6) >32–50 kg 19 (44.2) 18 (46.2) 19 (45.2) 18 (46.2) 74 (45.4) Gender, n (%) F, spayed 25 (58.1) 21 (53.8) 26 (61.9) 16 (41.0)* 88 (54.0) F, intact 0 0 0 1 (2.6) 1 (0.6) M, neutered 15 (34.9) 15 (38.5) 16 (38.1) 22 (56.4) 68 (41.7) M, intact 3 (7.0) 3 (7.7) 0 0 6 (3.7) Breed, n (%) Large mixed breed 12 (27.9) 11 (28.2) 13 (31.0) 17 (43.6) 53 (32.5) Labrador Retriever 8 (18.6) 6 (15.4) 9 (21.4) 7 (17.9) 30 (18.4) Golden Retriever 4 (9.3) 3 (7.7) 4 (9.5) 3 (7.7) 14 (8.6) German Shepherd 4 (4.9) 4 (10.3) 1 (2.4) 1 (2.6) 10 (6.1) CBPI pain interference 5.2 (2.0) 4.8 (2.0) 5.1 (2.3) 5.2 (2.1) 5.1 (2.1) CBPI pain severity 4.2 (1.8) 4.1 (1.9) 4.2 (1.9) 4.4 (1.9) 4.2 (1.9) CBPI overall impression, n (%) Excellent 1 (2.3) 2 (5.1) 4 (9.5) 3 (7.7) 10 (6.1) Very good 11 (25.6) 10 (25.6) 16 (38.1) 7 (17.9) 44 (27.0) Good 22 (51.2) 19 (48.7) 14 (33.3) 23 (59.0) 78 (47.9) Fair 9 (20.9) 7 (17.9) 7 (16.7) 6 (15.4) 29 (17.8) Poor 0 1 (2.6) 1 (2.4) 0 2 (1.2) LOAD mobility 24.0 (5.7) 23.7 (4.9) 23.1 (6.0) 25.6 (5.6) 24.1 (5.6) *P = 0.040 versus placebo.
- Table 2 Probability of superiority to placebo in the change from baseline after 2 weeks of treatment and 2 weeks of follow-up for the efficacy endpoints.
Bayesian MMRM model: change from baseline = baseline + treatment + visit + baseline * visit + treatment * visit + site + body weight, with unstructured variance-covariance structure for a dog’s measurements at end of treatment and after 2 weeks of follow-up. ITT population. n, number of evaluable canines at week 2; PIS, Pain Interference Score; PSS, Pain Severity Score.
Endpoint Placebo
(n = 43)LYA
(n = 39)LYB
(n = 42)Carprofen
(n = 39)CBPI PIS Week 2, n 43 39 40 38 Posterior mean (95%
credible region)−1.5
(−1.99, −1.01)−1.8
(−2.35, −1.34)−1.5
(−2.05, −1.04)−2.1
(−2.64, −1.61)Probability of
superiority to placebo– 80% 54% 93% Week 4, n 43 39 39 38 Posterior mean
(95% credible region)−1.2
(−1.63, −0.80)−0.7
(−1.10, −0.25)−1.0
(−1.38, −0.53)−0.8
(−1.19, −0.34)Probability of
superiority to placebo– 6% 23% 10% CBPI PSS Week 2, n 43 39 40 38 Posterior mean (95%
credible region)−1.14
(−1.53, −0.75)−1.66
(−2.06, −1.25)−1.39
(−1.79, −0.98)−1.56
(−1.97, −1.16)Probability of
superiority to placebo– 94% 78% 90% Week 4, n 43 39 39 38 Posterior mean (95%
credible region)−0.65
(−1.00, −0.31)−0.70
(−1.05, −0.34)−0.68
(−1.04, −0.32)−0.25
(−0.61, 0.11)Probability of
superiority to placebo– 57% 54% 8% CBPI overall impression Week 2, n 43 39 40 38 Posterior mean (95%
credible region)0.35
(0.14, 0.56)0.56
(0.34, 0.78)0.37
(0.15, 0.59)0.61
(0.39, 0.83)Probability of
superiority to placebo– 89% 56% 93% Week 4, n 43 39 39 38 Posterior mean (95%
credible region)0.18
(−0.01, 0.37)−0.04
(−0.24, 0.15)0.23
(0.03, 0.43)−0.04
(−0.16, 0.23)Probability of
superiority to placebo– 8% 6% 19% LOAD mobility Week 2, n 43 39 40 38 Posterior mean (95%
credible region)−3.55
(−5.36, −1.74)−6.17
(−8.05, −4.31)−5.43
(−7.29, −3.58)−7.52
(−9.42, −5.63)Probability of
superiority to placebo– 96% 89% 99% Week 4, n 43 39 39 38 Posterior mean (95%
credible region)−1.53
(−2.90, −0.16)−1.65
(−3.06, −0.24)−2.77
(−4.18, −1.36)−1.52
(2.93, −0.10)Probability of
superiority to placebo– 54% 87% 50% - Table 3 Summary of key pharmacokinetic parameters for LYA and LYB.
The pharmacokinetics of LYA and LYB were analyzed with conventional noncompartmental analysis methods to obtain Cmax (maximum drug concentration), Ctrough, and tmax (time of maximum observed drug concentration) at steady state. They were also analyzed with population PK analysis methods based on a one-compartment model with first-order absorption to obtain PK parameters such as CL/F (apparent clearance) and V/F (apparent volume of distribution) and to derive parameters such as t1/2 and AUCss,24hr (area under the concentration versus time profile at steady state over 24 hours). As reference, the IC90 (drug concentration to achieve 90% of the maximum inhibition effect) of the in vitro target engagement assay was 113 ng/ml for LYA, and the IC80 of the in vitro target engagement assay was 864 ng/ml for LYB. Ctrough,ss, predose concentration at steady state.
Parameter based on
noncompartmental
analysisLYA (n = 39) LYB (n = 42) Estimate Estimate Steady-state Cmax
(ng/ml)*722 (67.0%) 7930 (75.5%) Steady-state Ctrough,ss
(ng/ml)*436 (77.8%) 3080 (68.2%) Steady-state tmax
(hours)†3.13 (0.85–5.33) 3.07 (0.75–4.68) Parameter based on
population PK
analysesPopulation estimate Population estimate CL/F (liters/hour)‡ 3.12 (2.66–3.71) 7.18 (5.45–8.42) V/F (liters)‡ 39.5 (35.5–50.2) 89.3 (34.7–141) t1/2 (hours)§ 8.78 8.62 AUCss,24hr (mg·hour/
liter)║15.3 (38.7) 115 (35.0) *Reported as geometric mean [geometric %CV (percent coefficient of variation)].
†Reported as median (range).
‡Reported as mean (95% confidence interval).
§Derived using the population estimate of CL/F and V/F based on the following equation: log(2)/(CL/V).
║Reported as geometric mean (%CV), calculated using the post hoc estimate of CL/F of each patient, following the equation dose/(CL/F).
- Table 4 Adverse event summary.
Pairwise comparisons between treatments and placebo were not significant (P > 0.05) unless otherwise indicated. Data are n (%). AE, adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event.
Incidence, n (%) Placebo (n = 43) LYA (n = 39) LYB (n = 42) Carprofen (n = 39) Patients with ≥1 TEAE* 14 (32.6) 14 (35.9) 25 (59.5)† 10 (25.6) ≥TEAE in system organ class
of digestive tract
disorders7 (16.3) 10 (25.6) 11 (26.2) 6 (15.4) Patients with ≥1 SAE‡ 0 0 2 (4.8%)§ 0 Discontinued due to ≥1 AE║ 0 0 3 (7.1%)¶ 0 Died/euthanized 0 0 1 (2.4) 0 *P = 0.017 versus placebo.
†Assessed during the treatment period.
‡Assessed over the duration of the study, including follow-up.
§SAEs were allergic edema, conjunctivitis, and lethargy in one patient and multiorgan failure, neoplasm, and death in another patient.
║At any point over the duration of the study, including follow-up.
¶Discontinuations were due to the SAEs listed above and due to diarrhea in an additional patient.
- Table 5 Treatment-emergent adverse events with frequency of >5% in any treatment group.
Pairwise comparisons between treatments and placebo were not significant (P > 0.05). NOS, not otherwise specified.
Preferred
term, n (%)Placebo
(n = 43)LYA
(n = 39)LYB
(n = 42)Carprofen
(n = 39)Emesis 3 (7.0) 6 (15.4) 6 (14.3) 3 (7.7) Diarrhea 5 (11.6) 5 (12.8) 5 (11.9) 2 (5.1) Polydipsia 2 (4.7) 3 (7.7) 6 (14.3) 2 (5.1) Anorexia 1 (2.3) 3 (7.7) 5 (11.9) 1 (2.6) Lethargy 1 (2.3) 3 (7.7) 1 (2.4) 1 (2.6) Polyuria 1 (2.3) 0 (0) 3 (7.1) 1 (2.6) Bacterial skin
infections1 (2.3) 0 (0) 0 (0) 2 (5.1) Eye disorder
NOS0 (0) 0 (0) 3 (7.1) 0 (0) Pruritus 0 (0) 2 (5.1) 0 (0) 0 (0)
Supplementary Materials
stm.sciencemag.org/cgi/content/full/11/516/eaaw9993/DC1
Table S1. Proportion of CBPI PIS responders after 2 weeks of treatment.
Table S2. Rates of treatment-emergent abnormal laboratory values occurring in ≥5% of dogs in any treatment group during the treatment period.
Additional Files
This PDF file includes:
- Table S1. Proportion of CBPI PIS responders after 2 weeks of treatment.
- Table S2. Rates of treatment-emergent abnormal laboratory values occurring in ≥5% of dogs in any treatment group during the treatment period.
