Biomarkers can predict potential clinical responders to DIMS0150 a toll-like receptor 9 agonist in ulcerative colitis patients.
BACKGROUND
Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will ultimately fail to respond and progress to a more severe and difficult to manage disease state. Previous clinical studies suggest that the Toll-Like Receptor 9 (TLR9) agonist DIMS0150 not only induces production of key anti-inflammatory cytokines as IL-10 but interestingly also enhances steroid sensitivity in steroid refractory UC patients. We investigated, in the context of a clinical study, whether a pre-selection of steroid response genes could identify steroid refractory UC subjects most likely to respond to DIMS0150 treatment.


METHODS
In a non-interventional pilot study, blood from steroid refractory UC patients and healthy volunteers was taken and thirty-four previously described steroid response genes were analysed by real time PCR analysis. To establish clinical utility of the identified biomarkers, a placebo controlled, randomized, double blinded study in active steroid dependent and steroid resistant UC patients on concomitant steroid therapies was used (EudraCT number: 2006-001846-15).


RESULTS
We identified three potential biomarkers CD163, TSP-1 and IL-1RII whose response to steroids was significantly enhanced when DIMS0150 was applied. Thirty-four subjects were randomized to receive a single rectal administration of placebo or 30 mg of DIMS0150. Blood derived PBMCs were obtained prior to dosing and assayed for evidence of a steroid enhancing effect following steroid incubation in the presence of DIMS0150. Comparison to established steroid sensitivity marker IL-6 confirmed that clinical responders are steroid refractory UC patients. Upon study completion and un-blinding, the biomarker assay correctly predicted a clinical response in over 90% of the patients.


CONCLUSIONS
Using specific steroid response biomarkers, GCS refractory UC patients most likely to benefit from DIMS0150 treatment could be identified and illustrates the usefulness of a personalized treatment approach.
Nikolai V
NV
Kuznetsov
Arezou
A
Zargari
Alexander W
AW
Gielen
Oliver D
OD
von Stein
Eugen
E
Musch
Ragnar
R
Befrits
Robert
R
Lofberg
InDex Pharmaceuticals, Tomtebodavägen 23a, 171 77 Stockholm, Sweden. petra.stein@indexpharma.com.
Petra
P
von Stein
D000285:Administration, Rectal; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D015415:Biomarkers; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics; D004247:DNA / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D016896:Treatment Outcome; D055815:Young Adult; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers; D000098902:CD163 Antigen; C582905:DIMS0150; D005938:Glucocorticoids; C508592:IL1R2 protein, human; D007155:Immunologic Factors; D011956:Receptors, Cell Surface; D053574:Receptors, Interleukin-1 Type II; C481348:SPZ1 protein, human; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D004247:DNA