Introduction
Cobitolimod (MW 5925.18 Da) is a DNA-based oligonucleotide functioning as an immunomodulatory Toll-like receptor 9 agonist. Cobitolimod is in phase III clinical development as a new therapy for moderate to severe left-sided ulcerative colitis (UC). This phase Ib study aimed to evaluate the pharmacokinetics (PK), safety and tolerability of rectally administered cobitolimod in patients with moderate to severe UC.
Aims & Methods
The phase Ib open-label study was conducted at a single center in Sweden (NCT05404074). The patients had moderate to severe UC defined by a 3-component Mayo score of 5 to 9, with an Investigator read endoscopic subscore ≥2, and with stool frequency and rectal bleeding subscores each ≥1. Patients received one cobitolimod enema (500 mg/50 ml) at week 0, and blood samples for PK analysis were collected pre-dose, 15 min, 30 min, 1h, 2h, 4h, 8h, 12h and 24h after dosing. Patients received a second cobitolimod enema (500 mg/50 ml) at week 3, and at week 6 the degree of clinical remission was evaluated. Clinical remission was defined by the 3-component Mayo score with a rectal bleeding subscore = 0, a stool frequency subscore ≤1 (≥1 point decrease from baseline), and an Investigator read endoscopic subscore ≤1. Patients in clinical remission at week 6 received a third cobitolimod enema (500 mg/50 ml), and blood samples were collected for a second PK analysis as described above. The primary endpoint was PK parameters: maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the curve from 0 to timepoint t (AUCt) and half-life (T1/2). Secondary endpoints included safety and tolerability.
Results
Eight patients with active disease were enrolled in the study and included in the safety analysis set. One patient was excluded from the pharmacokinetic analysis set (PKAS) due to an immediate bowel movement following administration. Of the 7 patients included in the PKAS, 4 patients achieved clinical remission at week 6. Rectal administration of 500 mg cobitolimod at week 0 resulted in median Cmax of 21.7 ng/ml, median Tmax of 1h, median Tlast of 4h, and median AUC0-last of 71.7 h*ng/ml (n=7). For the 4 patients in remission at week 6, corresponding numbers were: median Cmax of 15.5 ng/ml, median Tmax of 0.5h, median Tlast of 4h and median AUC0-last of 27.6 h*ng/ml. T1/2 was <2.5h both at week 0 and week 6.
In total, 24 adverse events occurred in the study, out of which the majority was mild and judged as unlikely related to study drug. No serious adverse events were reported.
Table 1. PK parameters per patient
| Patient No | Tmax (h) | Cmax (ng/mL) | AUClast (h*ng/mL) | Tlast (h) |
| Week 0 | Week 6 | Week 0 | Week 6 | Week 0 | Week 6 | Week 0 | Week 6 |
| 101* | 1 | 0.5 | 165.0 | 6.4 | 371.6 | 11.7 | 4 | 4 |
| 102 | 1 | - | 17.0 | - | 28.1 | - | 4 | - |
| 103* | 2 | 0.5 | 19.9 | 24.5 | 71.7 | 36.4 | 8 | 4 |
| 105* | 2 | 1 | 51.9 | 9.4 | 192.5 | 18.9 | 8 | 4 |
| 106 | 2 | - | 43.8 | - | 149.7 | - | 8 | - |
| 107* | 1 | 0.5 | 20.0 | 21.6 | 29.2 | 66.7 | 4 | 4 |
| 108 | 0.5 | - | 21.7 | - | 25.6 | - | 4 | - |
*Patients in clinical remission at week 6 received a 3
rd dose of cobitolimod for a 2
nd PK analysis.
Conclusion
The study demonstrates that rectally administered cobitolimod results in a low systemic exposure of short duration both in patients with active disease and in clinical remission. Cobitolimod was safe and well tolerated at a dose of 500 mg.
Disclosure
Thomas Knittel is a consultant for and a shareholder in InDex Pharmaceuticals, Sweden. Pernilla Sandwall is a former employee and a shareholder in InDex Pharmaceuticals, Sweden. Christine Dieterich Johansson is employed by InDex Pharmaceuticals, Sweden. Arezou Zargari is employed by and a shareholder in InDex Pharmaceuticals, Sweden. Johan Bring is a consultant for InDex Pharmaceuticals, Sweden. Per Hellström receives consultancy fees from: Clinical trial consultants, Sweden; ROSE pharma, USA; Pharmanovia, Denmark; Swedish Agricultural University, Uppsala; Pharmacosmos, Denmark; Stockholm Diabetes Association, Sweden; Celltrion, Finland; Mag-tarmförbundet, Sweden; Karolinska Institutet, Sweden; Bristol-Myers Squibb, Sweden; ClinSmart, Sweden; InDex Pharmaceuticals, Sweden; Takeda pharmaceutical company; Mediahuset, Sweden; Bonnier Healthcare Sweden; Folkuniversitetet, Stockholm, Sweden; Biogaia, Stockholm, Sweden; Norgine, Denmark; Nanologica AB, Södertälje, Sweden.