Introduction
Mirikizumab (miri), a p19-directed IL-23 antibody, was efficacious in inducing clinical remission at Week (W)12 (LUCENT-1) and maintaining clinical remission at W52 (LUCENT-2) in patients with moderately to severely active UC in whom conventional or advanced therapy failed. We present results from the ongoing open-label LUCENT-3 extension study evaluating long-term efficacy and safety of miri.
Aims & Methods
In LUCENT-3, patients received 200 mg miri Q4W subcutaneously. Following 104W of continuous miri treatment, we report clinical response and remission, corticosteroid-free (CSF) remission, endoscopic remission, histologic-endoscopic mucosal improvement (HEMI) and histologic-endoscopic mucosal remission (HEMR), symptomatic remission, bowel urgency clinical meaningful improvement (CMI) and remission scores for patients who were W52 responders and remitters, including induction baseline biologic failure status. Symptom scores for abdominal pain, bowel urgency, stool frequency (SF), and rectal bleeding (RB) from induction baseline were recorded for all patients completing W52. Discontinuations or missing data were handled using non-responder imputation. All data were summarized as descriptive. Biologic Failed was defined as prior inadequate response, loss of response, or intolerance to biologic therapy or Janus kinase inhibitors; otherwise, patients were categorized as Not Biologic Failed. Safety data were assessed.
Results
Among W52 miri responders (N=239), 74.5% demonstrated clinical response at W104. Remission rates at W104 for W52 clinical responders were: 54.0% clinical, 52.7% CSF, 65.3% endoscopic, 47.7% HEMR, 67.8% symptomatic and 50.2% bowel urgency. Patients achieving HEMI and bowel urgency CMI at W104 were 53.1% and 67.0%, respectively. For W52 miri remitters, 76.6% demonstrated clinical response at W104. Remission rates at W104 for W52 clinical remitters (N=154) were: 65.6% clinical, 64.3% CSF, 77.3% endoscopic, 59.1% HEMR, 74.0% symptomatic and 51.3% bowel urgency. Patients achieving HEMI and bowel urgency CMI at W104 were 66.2% and 67.3%, respectively.
Biologic Failed/Non-failed subgroup data were generally similar (Table). Symptom score reductions from induction baseline at W52 were sustained through W104; W52 and W104 scores were respectively: SF: -1.68, -1.79; RB: -1.45, -1.45; bowel urgency: -4.03, -4.44; and abdominal pain: -3.74, -3.91. Severe TEAEs were reported in 4.5% of patients, while 5.2% experienced serious AEs,and 2.8% discontinued treatment due to an AE. Most common TEAEs (≥5%) reported were: COVID-19 (12.1), colitis ulcerative (7.6), arthralgia (6.2), headache (6.2), nasopharyngitis (5.9).There were 0 deaths. AEs of interest were: opportunistic infection (1.7%); cerebrocardiovascular event (0.7%); malignancy (0%); hepatic (2.1%); injection site reaction (5.5%).
Table. LUCENT-3 Response and Remission at 104 Weeks of Continuous Treatment in LUCENT-2 Responders1 and Remitters2 - mITT Population, NRI
|
| In Week 52 Responders
|
| In Week 52 Remitters
|
Endpoints W104
| n=239
% All
(95% CI3)
| n=166
% NBF
(95% CI3) | n=73
% BF
(95% CI3) |
| n=154
% All
(95% CI3)
| n=107
% NBF
(95% CI3)
| n=47
% BF
(95% CI3)
|
Clinical Response4
----------
Clinical Remission5
| 74.5
(68.6, 79.6)
--------
54.0
(47.6, 60.2)
| 77.1
(70.1, 82.8)
--------
56.0
(48.4, 63.4)
| 68.5
(57.1, 78.0)
--------
49.3
(38.2, 60.5)
|
| 76.6
(69.3, 82.6)
--------
65.6
(57.8, 72.6)
| 75.7
(66.8, 82.8)
--------
67.3
(57.9, 75.4)
| 78.7
(65.1, 88.0)
--------
61.7
(47.4, 74.2)
|
Symptomatic Remission6
| 67.8
(61.6, 73.4)
| 69.9
(62.5, 76.3) | 63.0
(51.5, 73.2)
|
| 74.0
(66.6, 80.3)
| 73.8
(64.8, 81.2)
| 74.5
(60.5, 84.7)
|
Corticosteroid-free Remission7
| 52.7
(46.4, 59.0)
| 54.8
(47.2, 62.2)
| 47.9
(36.9, 59.2) |
| 64.3
(56.5, 71.4)
| 66.4
(57.0, 74.6)
| 59.6
(45.3, 72.4)
|
HEMI8
----------
HEMR9
| 53.1
(46.8, 59.4)
--------
47.7
(41.5, 54.0)
| 54.2
(46.6, 61.6)
--------
48.2
(40.7, 55.7)
| 50.7
(39.5, 61.8)
--------
46.6
(35.6, 57.9)
|
| 66.2
(58.5, 73.2)
--------
59.1
(51.2, 66.5)
| 67.3
(57.9, 75.4)
--------
59.8
(50.3, 68.6)
| 63.8
(49.5, 76.0)
--------
57.4
(43.3, 70.5)
|
Endoscopic Remission10
| 65.3
(59.0, 71.0)
| 68.7
(61.3, 75.2)
| 57.5
(46.1, 68.2)
|
| 77.3
(70.0, 83.2)
| 80.4
(71.9, 86.8)
| 70.2
(56.0, 81.3)
|
Bowel Urgency Remission11
----------
Bowel Urgency CMI12
| 50.2
(43.9, 56.5)
--------
n=22413
67.0
(60.6, 72.8)
| 54.2
(46.6, 61.6)
--------
n=15513
71.0
(63.4, 77.5)
| 41.1
(30.5, 52.6)
--------
n=6913
58.0
(46.2, 68.9) |
| 51.3
(43.5, 59.1)
--------
n=14713
67.3
(59.4, 74.4)
| 55.1
(45.7, 64.2)
--------
n=10213
68.6
(59.1, 76.8)
| 42.6
(29.5, 56.7)
--------
n=4513
64.4
(49.8, 76.8)
|
BF=Biofailed; CI=Confidence Interval; ES=Endoscopic Subscore; HEMI=Histologic-endoscopic Mucosal Improvement; HEMR=Histologic-endoscopic Mucosal Remission; mITT=Modified Intent-to-Treat; NBF=Not Biofailed; NRI=Nonresponder Imputation; Not Biologic Failed: failed conventional treatments (i.e., immunomodulators/corticosteroids); may include some participants who were exposed to but did not fail biologic treatment; Biologic Failed: Inadequate response, loss of response, or intolerant to a biologic therapy or the Janus kinase inhibitors for UC. CMI = Clinical Meaningful Improvement, NRS = Numeric Rating Scale
1Responders = (≥30% and 2-point decrease from baseline in the composite clinical endpoint of the sum of endoscopic (ES), stool frequency (SF) and rectal bleeding (RB) subscores, and RB = 0 or 1, or ≥1 pt decrease from baseline)
2Remitters = (Mayo Modified Score [MMS] SF = 0 or SF = 1 with ≥ 1-point decrease from baseline; RB = 0; ES = 0 or 1) cohort of LUCENT-2 at W52
3 Response confidence intervals are constructed using Wilson method, without continuity correction
4 Clinical response: ≥2-point and ≥30% decrease in MMS from baseline; RB=0 or 1 or, RB ≥1-point decrease from baseline
5 Clinical remission: SF=0 or SF=1 with ≥1-point decrease in MMS from baseline; RB=0; and ES=0 or 1 (excluding friability)
6 Symptomatic remission: SF=0 or SF=1 with ≥1-point decrease in MMS from baseline; RB=0
7 Corticosteroid-free remission: Defined as clinical remission, and no corticosteroid use for at least 12 weeks prior to Week 52; SF = 0, or SF = 1 with a ≥1‑point decrease from induction baseline; RB = 0; ES = 0 or 1 (excluding friability)
8 HEMI: Endoscopic subscore=0 or 1 (excluding friability) + Geboes≤3.1
9 HEMR: Endoscopic subscore=0 or 1 (excluding friability) + Geboes≤2B.0
10 Endoscopic remission: ES=0 or 1 (excluding friability); score ranges 0 to 4; a lower score indicates less mucosal damage
11 Bowel urgency remission: UNRS=0 or 1
12 Bowel urgency CMI: Change from baseline in UNRS≥3 in patients with UNRS≥3 at induction baseline
13 In patients who had BU NRS≥3 at induction baseline
|
Conclusion
These data support the long-term benefit of continuous miri treatment through W104 on clinical, endoscopic, histologic, and symptomatic endpoints, including biologic-failed patients, with no new safety signals identified or deaths reported.
Disclosure
BES consulting fees: Abbvie,Alimentiv,Amgen,Arena,Artugen Therapeutics,Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals,Calibr,Celgene, Celltrion,ClostraBio, Equillium,Enthera,Evommune,Fresenius Kabi,Galapagos, Genentech (Roche), Gilead, GlaxoSmithKline,Gossamer Bio, Index, Innovation, Inotrem, Kaleido,Kallyope,Merck,Morphic Therapeutics,MRM Health,Progenity,Prometheus Biosciences/ Laboratories, Protagonist Therapeutics, Q32 Bio,Sun Pharma,Surrozen,Target RWE,Teva,TLL Pharmaceutical, Ventyx Biosciences;research grants, consulting/speaking fees: Abivax,Lilly, Bristol Myers Squibb, Janssen, Pfizer, Takeda, Theravance Biopharma; stock options:Ventyx.
GDH advisor fees: AbbVie, Aliimentiv, AstraZeneca,Boehringer Ingelheim, Bristol-Myers Squibb,Celltrion, Lilly, Galapagos, GlaxoSmithKline, Gossamerbio, Pfizer, Immunic,Johnson and Johnson,Takeda,Prometheus Laboratories,Protagonist, Samsung, Seres,Tillotts,Ventyx.
DBC is an Eli Lilly employee and stockholder.
PMI research grants: Celltrion,Pfizer,Takeda,Galapagos; consulting fees: AbbVie, Arena,Boehringer-Ingelheim, BMS, Celltrion, Elasmogen,Gilead,Janssen,Lilly,Pfizer,Prometheus, Sandoz; Payment for lectures/presentations: AbbVie,BMS, Celgene, Celltrion, Falk Pharma, Galapagos, Gilead, Janssen, Lilly, Pfizer, Takeda,Tillotts;meetings and travel support: Abbvie, Tillotts.
JTJ and THG are Eli Lilly employees and stockholders.
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