When
I've checked for novel drug candidates, I've stumpled on CR6086.
Somehow the number reminded me of Intel's 8086-series and others
might associate Nokia's 6086-series. But CR6086 is an EP4
[a prostanoid receptor] receptor antagonist, which “may improve the
response of tumours to immuno-oncology therapies, e.g. immune
checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 drugs” [1].
CR6086 wouldn't be the first drug that proves useful not only in
oncology but also in rheumatology.
There
had been a study at the
2016
ACR/ARHP Annual Meeting [2], in which the authors concluded: "CR6086
was safe up to the maximum tested dose of 300 mg."
Adis
Insight [3] has data up to March 28th
2020 (“No recent reports of development identified for phase-I
development in Rheumatoid-arthritis(In volunteers) in Italy (PO)”),
and mentions two dates for study NCT03163966 in the Czech Republic
(3rd
November 2017) and the preliminary data presented at the 2018
ACR/ARHP Annual Meeting as CREATIVE trial data [4]. Now there is data
on study NCT03163966.
K.
Pavelka and colleagues presented the following study [5] at the 2020
EULAR Online Meetin: „AB0360 EFFICACY
AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED
TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2
RANDOMIZED CONTROLLED TRIAL“.
The authors concluded: „There was no benefit demonstrated for
CR6086 added to MTX in the study cohort as a whole. However,
in a post-hoc analysis, enhanced responses were observed with CR6086
90mg bid added to MTX in patients >6 months disease duration. This
generated the hypothesis that addition of CR6086 90mg bid may benefit
in RA patients initiating MTX after the window of opportunity, to
be tested in further studies.“ There aren't any irregularities in
methods and results. Even without post-hoc analysis there's a
difference for MTX with or without CR6086. But 'll show you, why I
habor doubts.
I've
looked at a study by G. Caselli and colleagues [6]: „Pharmacological
Characterisation of CR6086, a Potent Prostaglandin E2 Receptor 4
Antagonist, as a New Potential Disease-Modifying Anti-Rheumatic
Drug“. In results the authors tell us: „ In models of human
immune cells in culture, CR6086 reduced key cytokine players of RA
(IL-6 and VEGF expression in macrophages, IL-23 release from
dendritic cells, IL-17 release from Th17 cells). In the CIA model of
RA in rats and mice, CR6086 significantly improved all features of
arthritis: severity, histology, inflammation and pain. In rats,
CR6086 was better than the selective cyclooxygenase-2 inhibitor
rofecoxib and at least as effective as the Janus kinase inhibitor
tofacitinib.“ But there's no hint to what happens to MTX if
combined with CR6086.
J.M.
Kremer and R.A. Hamilton published in 1995 [7]: „The effects of
nonsteroidal antiinflammatory drugs on methotrexate (MTX)
pharmacokinetics: impairment of renal clearance of MTX at weekly
maintenance doses but not at 7.5 mg“. So NSAIDs alter renal
clearance of MTX at normal weekly maintenance doses. In a more recent
study (2011) Yuichi Uwai and colleagues [8] showed in their
meta-analysis „that NSAIDs increase blood levels of methotrexate by
influencing renal excretion of the antifolate“.
Now,
CR6086 isn't an NSAID, but it may (ot may not) effect the renal
clearance of MTX.
K.
Pavelka and colleagues stated the „hypothesis that addition of
CR6086 90mg bid may benefit in RA patients initiating MTX after the
window of opportunity“. I have my doubts, but I agree that this has
to be tested in further studies.
Hopefully, K. Pavelka and colleagues are right.
Links
and References:
[2]
Persiani S, Manzotti C, Vitalini C, Giacovelli G, Girolami F, D'Amato
M, Caselli G, Rovati LC. a First-in-Human Study of CR6086, a New
Potent EP4 Prostanoid Receptor Antagonist, Demonstrates Good Safety
and Tolerability at Therapeutically Relevant Exposures [abstract].
Arthritis
Rheumatol.
2016; 68 (suppl 10).
https://acrabstracts.org/abstract/a-first-in-human-study-of-cr6086-a-new-potent-ep4-prostanoid-receptor-antagonist-demonstrates-good-safety-and-tolerability-at-therapeutically-relevant-exposures/.
Accessed July 2, 2020.
[4]
Vitalini C, Barbetta B, Giacovelli G, Brambilla N, D'Amato M,
Girolami F, Rovati LC. Acr Hybrid Analysis: Blinded Data from the
Ongoing Phase IIb Trial with the EP4 Receptor Antagonist CR6086 in
DMARD-Naïve Patients with Early Rheumatoid Arthritis [abstract].
Arthritis
Rheumatol.
2018; 70 (suppl 10).
https://acrabstracts.org/abstract/acr-hybrid-analysis-blinded-data-from-the-ongoing-phase-iib-trial-with-the-ep4-receptor-antagonist-cr6086-in-dmard-naive-patients-with-early-rheumatoid-arthritis/.
Accessed July 3, 2020.
[5]
K. Pavelka1, I. D. Delina2, M. Mazur3, M. D’amato4, G. Giacovelli4,
F. Girolami4, M. Krogulec5, R. Ostgard6, A. R. Bihlet7, O.
Kubassova8, L. Rovati4,9, P. C. Taylor10. AB0360 EFFICACY
AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED
TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2
RANDOMIZED CONTROLLED TRIAL.
DOI:
10.1136/annrheumdis-2020-eular.5636
[6]
Caselli G, Bonazzi A, Lanza M, et al. Pharmacological
characterisation of CR6086, a potent prostaglandin E2
receptor 4 antagonist, as a new potential disease-modifying
anti-rheumatic drug. Arthritis Res Ther. 2018;20(1):39.
Published 2018 Mar 1. doi:10.1186/s13075-018-1537-8
[7]
Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory
drugs on methotrexate (MTX) pharmacokinetics: impairment of renal
clearance of MTX at weekly maintenance doses but not at 7.5 mg. J
Rheumatol.
1995;22(11):2072-2077. https://pubmed.ncbi.nlm.nih.gov/8596147/
[8] Uwai
Y, Suzuki R, Iwamoto K. Yakugaku
Zasshi.
2011;131(5):853-861. doi:10.1248/yakushi.131.853
https://pubmed.ncbi.nlm.nih.gov/21532282/
.
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