Exabis Library

AJM300 (INN; carotegrast methyl), an orally active small molecule antagonist of the α4 subunit of α4β1/α4β7 integrins, demonstrated the efficacy and safety in patients with moderately active ulcerative colitis (UC) in a phase 2 study. The phase 3 study (NCT 03531892) of AJM300 as induction therapy was conducted in patients with moderately active UC.

Eligible patients were moderately active Japanese UC, defined as total Mayo Clinic scores (MCS) of 6-10, endoscopic subscores (ES) ≥2, and rectal bleeding subscores (RBS) ≥1, who had inadequate response or intolerance to oral 5-ASA. Followed by a 2-week single-blind placebo (PBO) run-in phase, patients were randomized 1:1 to receive AJM300 960 mg or PBO 3 times daily for 8 weeks. Responders or remitters were allowed to receive AJM300 960 mg again at the subsequent relapse (open-label). The primary endpoint was clinical response at week 8, defined as reduction of the MCS of ≥3-pts and ≥30%, reduction in RBS of ≥1-pt or RBS of ≤1, and ES ≤1.

The randomized 203 patients had moderately active endoscopic evidence at baseline with median UC duration of 6.1 years and MCS of 7.8. For the primary endpoint, 45.1% (46/102) and 20.8% (21/101) of patients in the AJM300 and PBO groups, respectively, achieved clinical response at week 8 (OR=3.30 [95% CI, 1.73-6.29]; p=0.0003). Symptomatic remission, endoscopic improvement and endoscopic remission were also statistically significant for AJM300 vs PBO (Table). In case of episodic AJM300 treatment, AJM300 exhibited similar response to initial treatment. Overall, the incidence of AEs and serious AEs were similar between AJM300 and PBO. There were no deaths or cases of progressive multifocal leukoencephalopathy.

AJM300 induced clinical response as well as endoscopic remission with good tolerability. AJM300 may become a novel therapeutic option for patients who had inadequate response or intolerance to oral 5-ASA.

Table. Efficacy results at Week 8

Clinical response=a reduction of the MCS of ≥3-pts and ≥30%, reduction in RBS of ≥1-pt or RBS of ≤1, and ES ≤1; Clinical remission=MCS≤2 and no subscores >1; Symptomatic remission=total of RBS and stool frequency subscores ≤1; Endoscopic improvement=ES ≤1; Endoscopic remission=ES =0.
CI, confidence interval; ES, endoscopic subscores; MCS, Mayo Clinic Score; PBO, placebo; RBS, rectal bleeding subscores.

The STARDUST study demonstrated that ustekinumab (UST), using either a treat-to-target (T2T) or standard of care (SoC) strategy, may induce and maintain endoscopic and clinical response and remission in Crohn’s disease (CD). Primary endpoint, safety, and efficacy have been reported previously.¹ Because corticosteroid (CS) sparing is an important aim of CD management, we compared the efficacy of UST T2T vs SoC in achieving CS-free clinical remission and endoscopic response.

Adult patients (pts) with moderate–severely active CD who were CDAI 70 responders after 16 weeks (W) of induction, comprising a single dose of UST 6 mg/kg iv followed by UST 90 mg SC at W8, were randomized to either T2T or SoC arms. In the T2T arm, choice of UST maintenance dosage (q12w or q8w) was based on endoscopic improvement at W16, followed by clinical and biomarker-directed dose escalation up to q4w; in the SoC arm, UST q12w or q8w dosage was based on EU SmPC. Primary endpoint was endoscopic response (Simple Endoscopic Score in CD [SES-CD] decrease from baseline [BL] ≥50%) at W48. For pts on CS at W16, CS tapering was mandatory. At W48, CS-free clinical remission (CDAI <150 and no CS for ≥30 days) and CS-free endoscopic response (reduction from BL in SES-CD ≥50% and no CS for ≥30 days) were evaluated.

Of 500 pts enrolled, 441 achieved a CDAI 70 response at W16 and were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3%, respectively, completed W48. Among clinical remitters and responders at W16 (start of CS tapering), in both T2T and SoC arms more than 70% were still in remission or response at W48 (Figure 1). CS use throughout 48 weeks of treatment is summarized in Table 1. At W48, in T2T and SoC arms similar rates were noted for CS-free endoscopic response (33.6% and 28.5%, respectively) and CS-free clinical remission (56.4% and 63.3%, respectively). Notably, in T2T and SoC arms the CS-free clinical remission rate among pts on CS at BL was 44.1% and 45.1%, respectively (Figure 2). Among W48 endoscopic responders (T2T, n=83; SoC, n=66), CS-free endoscopic response rate was 89.2% and 95.5%, respectively; among W48 clinical remitters (T2T, n=135; SoC, n=154), CS-free clinical remission rate was 91.9% and 90.9%, in T2T and SoC arms, respectively.

Pts treated with UST under T2T or SoC strategies achieved similar rates of CS-free clinical remission and endoscopic response over 48 weeks. Overall for pts on CS at BL, UST reduced the need for CS while achieving response/remission. Most (>89%) pts with endoscopic response/clinical remission at W48 were also CS-free responders/remitters.  

1. Danese S, et al. United European Gastroenterol J. 2020;8:1264–1265 (Abstract LB11).