Introduction
Mufemilast is a novel investigational small-molecule oral phosphodiesterase 4 inhibitor that selectively downregulates PDE4b expression under development for the treatment of ulcerative colitis (UC). It was approved for plaque psoriasis in October 2025. C14 Pharmacokinetics studies confirmed gut-selective distribution in rodents (Gut/Plasma ratio >100). We present efficacy and safety data from the 12-week double-blind, placebo-controlled induction trial in patients with moderate to severe ulcerative colitis (UC), and safety and efficacy data from the 24-week open- label extension (OLE). (NCT05486104).
Aims & Methods
Patients (n=92) with moderate to severe UC randomized (1:1:1) placebo (n=31), mufemilast 45mg b.d (n=31) or 60mg b.d (n=30) for 12 weeks. After a 12-week induction, all patients were switched to 60mg b.d. Seventy continued into the OLE period. Patients were included with mMS of 4-9, including an endoscopy score of ≥ 2, and inadequate /loss of response to conventional/advanced therapy. Co-treatment with oral 5-ASAs and corticosteroids was permitted if stable for at least 2 weeks before the pre-screening colonoscopy period and required remaining stable. Patients with positive Quantiferon tests were also included. The primary endpoint was clinical remission rate after 12 weeks of treatment; Safety was also analyzed.
Results
Clinical Response: 1) a reduction from baseline in mMS of ≥ 2 points and ≥ 30% from baseline, 2) a decrease from baseline in RB subscore of ≥ 1 point or an absolute RB subscore of ≤ 1 point Clinical Remission per FDA: Modified Mayo score(mMS), stool frequency (SF) subscore of 0 or 1, no greater than baseline; 2) mMS rectal bleeding (RB) subscore of 0; 3) mMS endoscopy (ES) subscore of 0 or 1(without friability) Endoscopic Improvement: Modified Mayo score endoscopic subscore ≤ 1
|
Table 1 Treatment
| Placebo | 45mg bd | 60mg bd |
| Time | 12 week | 24 week | 12 week
| 24 week
| 12 week
| 24 week
|
Clinical response % (n)
| 42 (13/31)
| 81 (13/16)
| 87 (27/31)
| 90 (26/29)
| 80 (24/30)
| 72 (18/25)
|
Clinical remission % (n)
| 13 (4/31)
| 75 (12/16)
| 39 (12/31)
| 62 (18/29)
| 57 (17/30)
| 52 (13/25)
|
Endoscopic Improvement % (n)
| 16 (5/31)
| 75 (12/16)
| 42 (13/31)
| 66 (19/29)
| 67 (20/30)
| 64 (16/25)
|
The efficacy endpoints are summarized in Table 1 for the full analysis set for clinical remission, clinical response, and endoscopic improvement. Responses were similar in biologic naïve and bio-experienced patients. At 24 weeks, clinical remission rate (CRR) increased from 13% to 75% in placebo patients who switched to 60mg (12/16). In the 45 mg group, 29 patients switched to 60mg, and the CRR increased from 39% at 12 weeks to 62% (18/29). In the 60 mg group, 25 patients remained on treatment at 24 weeks, and the 24-week CRR (13/25) was 52%. At 24 weeks, the endoscopic improvement rate increased from 16% to 75% (placebo switched group;12/16), and from 42% to 66% (19/29; 45 mg group switched to 60mg), and remained stable at 64 % in the 60mg group at 24 weeks (16/25). Locally and centrally read endoscopic data showed consistent efficacy results across endpoints. During the entire 24-week observation period, there was 1 SAE (thrombophlebitis, a preexisting condition) and 2AEs that led to discontinuation in the 60 mg group (1 pain in the extremities, 1 headache). In the OLE (weeks 12-24), 3 subjects discontinued the drug (1 for SAE and lack of efficacy, 2 withdrew for lack of efficacy). Most AEs were mild or moderate; the number of subjects reporting AEs was evenly distributed between the placebo and mufemilast groups. During the OLE, there was a reduction in headache frequency (60mg from 9% to 3%). There were no clinically relevant changes in vital signs, laboratory values, or ECG parameters.
Conclusion
The data support mufemilast as a viable treatment option for patients with moderate-to-severe UC, regardless of prior biologic use. Efficacy was maintained to week 24, with remission rates increasing in placebo and 45mg switched subjects. Mufemilast was well tolerated. These findings support initiating a phase 3 trial in patients with moderate-to-severe UC.
References
1Jones, C.; Zhang, J.; Wang, L.; Dai, X.; Wang, H.; Bi, X.; Duan, X.; Meng, Z.; Tian, Z.; Xu, A.; et al. A Double-Blind, Placebo-Parallel Controlled Phase III Clinical Study of the Efficacy and Safety of Hemay005 Tablets in Patients with Moderate to Severe Chronic Plaque Psoriasis in China. Arthritis Rheumatol ACR Converg. 2023, 75.
Disclosure
CRJ is an employee of Hemay Pharmaceuticals. YYZ is an employee of Hemay Pharmaceuticals. AHH is an employee of Hemay Pharmaceuticals. HH is an employee of Hemay Pharmaceuticals. ZHW is an employee of Hemay Pharmaceuticals. HSZ is an employee of Hemay Pharmaceuticals.
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