Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC24 
Mechanism of action

Mirikizumab is a humanised IgG4 monoclonal, anti-interleukin-23 (anti-IL-23) antibody that selectively binds to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor.

IL-23, a regulatory cytokine, affects the differentiation, expansion, and survival of T cell subsets, (e.g., Th17 cells and Tc17 cells) and innate immune cell subsets, which represent sources of effector cytokines, including IL-17A, IL-17F and IL-22 that drive inflammatory disease. In humans, selective blockade of IL-23 was shown to normalise production of these cytokines.

Pharmacodynamic effects

Inflammatory biomarkers were measured in the phase 3 ulcerative colitis studies. Mirikizumab administered intravenously every 4 weeks during induction dosing significantly reduced levels of fecal calprotectin and C-reactive protein from baseline to week 12. Also, mirikizumab administered subcutaneously every 4 weeks during maintenance dosing sustained significantly reduced levels of fecal calprotectin and C-reactive protein through 40 weeks.


Clinical efficacy and safety

The efficacy and safety of mirikizumab was evaluated in adult patients with moderately to severely active ulcerative colitis in two randomised, double-blind, placebo-controlled, multicentre studies.
Enrolled patients had a confirmed diagnosis of ulcerative colitis for at least 3 months and moderately to severely active disease, defined as a modified Mayo score of 4 to 9, including a Mayo endoscopy subscore ≥ 2. Patients had to have failed (defined as loss of response, inadequate response or intolerance) corticosteroids or immunomodulators (6-mercaptopurine, azathioprine) or at least one biologic (a TNFα antagonist and/or vedolizumab) or tofacitinib.

LUCENT-1 was an intravenous induction study with treatment of up to 12 weeks, followed by a 40 week subcutaneous randomised withdrawal maintenance study (LUCENT-2), representing at least
52 weeks of therapy. Mean age was 42.5 years. 7.8 % of patients were ≥ 65 of age and 1.0 % of patients ≥ 75 of age. 59.8 % were men; 40.2 % were women. 53.2 % had severely active disease with a modified Mayo score 7 to 9.

Efficacy results presented for LUCENT-1 and LUCENT-2 were based on central reading of endoscopies and histology.

LUCENT-1
LUCENT-1 included 1 162 patients in the primary efficacy population. Patients were randomised to receive a dose of 300 mg mirikizumab via intravenous infusion or placebo, at week 0, week 4 and week 8 with a 3:1 treatment allocation ratio. The primary endpoint for the induction study was the proportion of subjects in clinical remission [modified Mayo score (MMS) defined as: Stool frequency (SF) subscore = 0 or 1 with a ≥ 1-point decrease from baseline, and rectal bleeding (RB) subscore = 0, and Endoscopic subscore (ES) = 0 or 1 (excluding friability)] at week 12.

Patients in these studies may have received other concomitant therapies including aminosalicylates (74.3 %), immunomodulatory agents (24.1 % such as azathioprine, 6-mercaptopurine or methotrexate), and oral corticosteroids (39.9 %; prednisone daily dose up to 20 mg or equivalent) at a stable dose prior to and during the induction period. Per protocol oral corticosteroids were tapered after induction.

Of the primary efficacy population, 57.1 % were biologic-naive and tofacitinib-naive. 41.2 % of patients had failed a biologic or tofacitinib. 36.3 % of the patients had failed at least 1 prior anti-TNF therapy, 18.8 % had failed vedolizumab and 3.4 % of patients had failed tofacitinib. 20.1 % had failed more than one biologic or tofacitinib. An additional 1.7 % had previously received but had not failed a biologic or tofacitinib.

In LUCENT-1 a significantly greater proportion of patients were in clinical remission in the mirikizumab treated group compared to placebo at week 12 (Table 2). As early as week 2, mirikizumab-treated patients achieved a greater reduction in RB subscores and decreases in SF subscores.

Table 2: Summary of key efficacy outcomes in LUCENT-1 (week 12 unless indicated otherwise)

Placebo          Mirikizumab IV
N = 294             N = 868                Treatment difference
N          %            N           %        and 99.875 % CI

11.1 %
Clinical remission*1                     39       13.3 %        210       24.2 % (3.2 %, 19.1 %)c
Patients who were biologic and
27/171      15.8 %      152/492     30.9 %              ---
JAK-inhibitor naïve a

     Patients who failed b at least
10/118       8.5 %       55/361      15.2 %          --- one biologic or JAK-inhibitor d
11.1 %
Alternate clinical remission*2            43        14.6 %        222        25.6 % (3.0 %, 19.3 %)c
Patients who were biologic and
31/171      18.1 %      160/492      32.5 %          ---
JAK-inhibitor naïve a
Patients who failed b at least
10/118       8.5 %       59/361      16.3 %          --- one biologic or JAK-inhibitor d
21.4 %
Clinical response*3                       124       42.2 %        551        63.5 % (10.8 %, 32.0 %)c
Patients who were biologic and
86/171      50.3 %      345/492      70.1 %          ---
JAK-inhibitor naïve a
Patients who failed b at least
35/118      29.7 %      197/361      54.6 %          --- one biologic or JAK-inhibitor d
15.4 %
Endoscopic improvement*4                  62        21.1 %        315        36.3 % (6.3 %, 24.5 %)c
Patients who were biologic and
48/171      28.1 %      226/492      45.9 %          ---
JAK-inhibitor naïve a
Patients who failed b at least
12/118      10.2 %       85/361      23.5 %          --- one biologic or JAK-inhibitor d
Symptomatic remission                                                                       9.2 % 38        12.9 %        189        21.8 %
(week 4)*5                                                                             (1.4 %, 16.9 %)c Patients who were biologic and
26/171      15.2 %      120/492      24.4 %          ---
JAK-inhibitor naïve a
Patients who failed b at least
10/118       8.5 %       67/361      18.6 %          --- one biologic or JAK-inhibitor d
17.5 %
Symptomatic remission*5                   82        27.9 %        395        45.5 % (7.5 %, 27.6 %)c
Patients who were biologic and
57/171      33.3 %      248/492      50.4 %          ---
JAK-inhibitor naïve a
Patients who failed b at least
22/118      18.6 %      139/361      38.5 %          --- one biologic or JAK-inhibitor d
Histo-endoscopic mucosal                                                                    13.4 % 41        13.9 %        235        27.1 % improvement*6                                                                          (5.5 %, 21.4 %)c Patients who were biologic and
32/171      18.7 %      176/492      35.8 %          ---
JAK-inhibitor naïve a
Patients who failed b at least
8/118       6.8 %       56/361      15.5 %          --- one biologic or JAK-inhibitor d

Placebo             Mirikizumab IV
N = 294                 N = 868             Treatment difference
LS    Standard          LS     Standard     and 99.875 % CI mean     error          mean      error
-0.95
Bowel urgency severity*7                 -1.63       0.141       -2.59       0.083 (-1.47, -0.44)c
Patients who were biologic and
-2.08       0.174       -2.72       0.101           ---
JAK-inhibitor naïve a
Patients who failed b at least
-0.95       0.227       -2.46       0.126           --- one biologic or JAK-inhibitor d
Abbreviations: CI = confidence interval; IV = intravenous; LS = least square 
*1 Clinical remission is based on the modified Mayo score (MMS) and is defined as: Stool frequency (SF) subscore = 0 or 1 with a ≥ 1-point decrease from baseline, and Rectal bleeding (RB) subscore = 0, and Endoscopic subscore (ES) = 0 or 1 (excluding friability) 
*2 Alternate clinical remission is based on the modified Mayo score (MMS) and is defined as: Stool frequency (SF) subscore = 0 or 1, and Rectal bleeding (RB) subscore = 0, and Endoscopic subscore (ES) = 0 or 1 (excluding friability)
*3 Clinical response based on the MMS and is defined as: A decrease in the MMS of ≥ 2 points and ≥ 30 % decrease from baseline, and a decrease of ≥ 1 point in the RB subscore from baseline or a RB score of 0 or 1
4
* Endoscopic improvement defined as: ES = 0 or 1 (excluding friability) *5 Symptomatic remission defined as: SF = 0, or SF = 1 with a ≥ 1-point decrease from baseline, and RB = 0
6
* Histo-endoscopic mucosal improvement defined as achieving both: 1. Histologic improvement, defined using Geboes scoring system with neutrophil infiltration in < 5 % of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue. 2. Endoscopic improvement, defined as ES = 0 or 1 (excluding friability).
*7 Change from baseline in the Urgency Numeric Rating Scale score
 a) An additional 5 patients on placebo and 15 patients on mirikizumab where previously exposed to but did not fail a biologic or JAK-inhibitor.
b) Loss of response, inadequate response or intolerance.
c) p < 0.001 d) Mirikizumab results in the subgroup of patients who failed more than one biologic or JAK-inhibitor were consistent with results in the overall population.

LUCENT-2
LUCENT-2 evaluated 544 patients out of the 551 patients who achieved clinical response with mirikizumab in LUCENT-1 at week 12 (see Table 2). Patients were re-randomised in a 2:1 treatment allocation ratio to receive a subcutaneous maintenance regimen of 200 mg mirikizumab or placebo every 4 weeks for 40 weeks (which is 52 weeks from initiation of the induction dose). The primary endpoint for the maintenance study was the proportion of subjects in clinical remission (same definition as in LUCENT-1) at week 40. Corticosteroid tapering was required upon entrance into LUCENT-2 for patients who were receiving corticosteroids during LUCENT-1. Significantly greater proportions of patients were in clinical remission in the mirikizumab-treated group compared to the placebo group at week 40 (see Table 3).

Table 3: Summary of key efficacy measures in LUCENT-2 (week 40; 52 weeks from initiation of the induction dose)

Treatment
Placebo           Mirikizumab SC difference and
N = 179               N = 365
95 % CI
N           %           N       %
23.2 %
Clinical remission*1                  45        25.1 %        182     49.9 % (15.2 %, 31.2 %)c
Patients who were biologic                                118/22
35/114     30.7 %                51.5 %           --- and JAK-inhibitor naïve a                                   9
Patients who failed b at least
10/64      15.6 %       59/128   46.1 %           --- one biologic or JAK-inhibitor d
24.1 %
Alternate clinical remission*2        47        26.3 %        189     51.8 % (16.0 %, 32.2 %)c
Patients who were biologic                                 124/22
37/114     32.5 %                54.1 %           --- and JAK-inhibitor naïve a                                    9
Patients who failed b at least
10/64      15.6 %       60/128   46.9 %           --- one biologic or JAK-inhibitor d
Maintenance of clinical                                                              24.8 % 24/65      36.9 %       91/143   63.6 % remission through week 40*3                                                     (10.4 %, 39.2 %)c 
     Patients who were biologic
22/47      46.8 %       65/104        62.5 %         --- and JAK-inhibitor naïve a
Patients who failed b at least
2/18       11.1 %       24/36         66.7 %         --- one biologic or JAK-inhibitor d
21.3 %
Corticosteroid-free remission*4          39        21.8 %        164          44.9 % (13.5 %, 29.1 %)c
Patients who were biologic                                   107/22
30/114      26.3 %                     46.7 %         --- and JAK-inhibitor naïve a                                      9
Patients who failed b at least
9/64       14.1 %       52/128        40.6 %         --- one biologic or JAK-inhibitor d
28.5 %
Endoscopic improvement*5                 52        29.1 %        214          58.6 % (20.2 %, 36.8 %)c
Patients who were biologic                                   143/22
39/114      34.2 %                     62.4 %         --- and JAK-inhibitor naïve a                                      9
Patients who failed b at least
13/64      20.3 %       65/128        50.8 %         --- one biologic or JAK-inhibitor d
Histo-endoscopic mucosal                                                                    19.9 % 39        21.8 %        158          43.3 % remission*6                                                                            (12.1 %, 27.6 %)c Patients who were biologic                                   108/22
30/114      26.3 %                     47.2 %         --- and JAK-inhibitor naïve a                                      9
Patients who failed b at least
9/64       14.1 %       46/128        35.9 %         --- one biologic or JAK-inhibitor d
144/33                      18.1 %
Bowel urgency remission*7              43/172      25.0 %                     42.9 % (9.8 %, 26.4 %)c
6
Patients who were biologic
31/108      28.7 %       96/206        46.6 %         --- and JAK-inhibitor naïve a
Patients who failed b at least
12/63      19.0 %       43/122        35.2 %         --- one biologic or JAK-inhibitor d

Placebo              Mirikizumab SC
N = 179                  N = 365              Treatment difference and
LS    Standard           LS    Standard           95 % CI mean     error           mean     error

Bowel urgency severity*8                                                                     -1.06 -2.74       0.202       -3.80         0.139
(-1.51, -0.61)c
Patients who were biologic
-2.69       0.233       -3.82         0.153          --- and JAK-inhibitor naïve a
Patients who failed b at least
-2.66       0.346       -3.60         0.228          --- one biologic or JAK-inhibitor d
Abbreviations: CI = confidence interval; SC = subcutaneous; LS = least square 
*1, 2 See footnotes on Table 2
*3 The proportion of patients who were in clinical remission at week 40 among patients in clinical remission at week 12, with clinical remission defined as: Stool frequency (SF) subscore = 0 or SF = 1 with a ≥ 1-point decrease from induction baseline, and Rectal bleeding (RB) subscore = 0, and Endoscopic subscore (ES) = 0 or 1 (excluding friability) *4 Corticosteroid-free remission without surgery, defined as: Clinical remission at week 40, and Symptomatic remission at week 28, and no corticosteroid use for ≥ 12 weeks prior to week 40 *5 Endoscopic improvement defined as: ES = 0 or 1 (excluding friability) *6 Histo-endoscopic mucosal remission, defined as achieving both: 1. Histologic remission, defined as Geboes subscores of 0 for grades: 2b (lamina propria neutrophils), and 3 (neutrophils in epithelium), and 4 (crypt destruction), and 5 (erosion or ulceration) and 2. Mayo endoscopic score 0 or 1 (excluding friability)
*7 Numeric Rating Scale (NRS) 0 or 1 in patients with urgency NRS ≥ 3 at baseline in LUCENT-1 *8 Change from baseline in the Urgency NRS score
 a) An additional 1 patient on placebo and 8 patients on mirikizumab where previously exposed to but did not fail a biologic or JAK-inhibitor.
b) Loss of response, inadequate response or intolerance.
c) p < 0.001 d) Mirikizumab results in the subgroup of patients who failed more than one biologic or JAK-inhibitor were consistent with results in the overall population.

The efficacy and safety profile of mirikizumab was consistent across subgroups, i.e. age, gender, body weight, disease activity severity at baseline and region. The effect size may vary.

At week 40, a greater proportion of patients were in clinical response (defined as decrease in the MMS of ≥ 2 points and ≥ 30 % decrease from baseline, and a decrease of ≥ 1 point in the RB subscore from baseline or a RB score of 0 or 1) in the mirikizumab responder group re-randomised to mirikizumab (80 %) compared to the mirikizumab responder group re-randomised to placebo (49 %).

Week 24 responders to mirikizumab extended induction (LUCENT-2)
For the mirikizumab patients who were not in response at week 12 of LUCENT-1 and received open-label additional 3 doses of 300 mg mirikizumab IV every 4 weeks (Q4W) 53.7 % achieved clinical response at week 12 of LUCENT-2 and 52.9 % mirikizumab patients continued to maintenance receiving 200 mg mirikizumab Q4W SC, and among these patients 72.2 % achieved clinical response and 36.1 % achieved clinical remission at week 40.

Recapture of efficacy after loss of response to mirikizumab maintenance (LUCENT-2) 19 patients who experienced a first loss of response (5.2 %) between week 12 and 28 of LUCENT-2 received open-label mirikizumab rescue dosing with 300 mg mirikizumab Q4W IV for 3 doses and 12 of these patients (63.2 %) achieved symptomatic response and 7 patients (36.8 %) achieved symptomatic remission after 12 weeks.

Endoscopic normalisation at week 40
Normalisation of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. At week 40 of LUCENT-2, endoscopic normalisation was achieved in 81/365 (22.2 %) of patients treated with mirikizumab and in 24/179 (13.4 %) of patients in placebo group.

Histologic outcomes
At week 12 greater proportions of patients in the mirikizumab group achieved histologic improvement (39.2 %) compared with patients in the placebo group (20.7 %). At week 40 histologic remission was observed with more patients in the mirikizumab group (48.5 %) as compared to placebo (24.6 %).

Stable maintenance of symptomatic remission
Stable maintenance of symptomatic remission was defined as the proportion of patients in symptomatic remission for at least 7 out of 9 visits from week 4 to week 36 and in symptomatic remission at week 40 among patients in symptomatic remission and clinical response at week 12 of LUCENT-1. At week 40 of LUCENT-2, the proportion of patients achieving stable maintenance of symptomatic remission was greater in patients treated with mirikizumab (69.7 %) versus placebo (38.4 %).

Health-related quality of life
At week 12 of LUCENT-1, patients receiving mirikizumab showed significantly greater clinically relevant improvements on the Inflammatory Bowel Disease Questionnaire (IBDQ) total score (p ≤ 0.001) when compared to placebo. IBDQ response was defined as at least a 16-point improvement from baseline in IBDQ score and IBDQ remission was defined as a score of at least 170. At week 12 of LUCENT-1, 57.5 % of mirikizumab-treated patients achieved IBDQ remission versus 39.8 % with placebo (p < 0.001) and 72.7 % of mirikizumab-treated patients achieved IBDQ response versus 55.8 % in placebo. In LUCENT-2 at week 40, 72.3 % of mirikizumab-treated patients achieved maintenance of IBDQ remission versus 43.0 % placebo treated patients and 79.2 % mirikizumab treated patients achieved IBDQ response versus 49.2 % of placebo treated patients.

Patient reported outcomes
Decreases in bowel urgency severity were observed as early as week 2 in patients treated with mirikizumab in LUCENT-1. Patients receiving mirikizumab achieved significant bowel urgency remission compared with patients in the placebo group at week 12 in LUCENT-1 (22.1 % vs 12.3 %), and week 40 in LUCENT-2 (42.9 % vs 25 %). Patients receiving mirikizumab showed significant improvements in fatigue as early as week 2 of LUCENT-1 and the improvements were maintained at week 40 of LUCENT-2. As early as week 4 there was also a significantly greater reduction in abdominal pain.

Hospitalisations and ulcerative colitis related surgeries
Through week 12 of LUCENT-1, the proportion of patients with UC-related hospitalisations were 0.3 % (3/868) in the mirikizumab and 3.4 % (10/294) in the placebo group. UC-related surgeries were reported in 0.3 % (3/868) patients receiving mirikizumab and 0.7 % (2/294) patients in the placebo group. There were no UC-related hospitalisations and no UC-related surgeries in LUCENT-2 in the mirikizumab arm.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Omvoh in one or more subsets of the paediatric population in the treatment of ulcerative colitis (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

There was no apparent accumulation in serum mirikizumab concentration over time when given subcutaneously every 4 weeks.

Mean (coefficient variation [CV %]) Cmax and area under the curve (AUC) after induction dosing (300 mg every 4 weeks administered by intravenous infusion) in patients with ulcerative colitis were 99.7 (22.7) µg/mL and 538 (34.4) µg*day/mL, respectively. The mean (CV %) Cmax and AUC after maintenance dosing (200 mg every 4 weeks by subcutaneous injection) were 10.1 (52.1) µg/mL and 160 (57.6) µg*day/mL, respectively.

Absorption

Following subcutaneous dosing of mirikizumab, peak serum concentrations were achieved 2-3 days post dose with an estimated absolute bioavailability of 44 %.
Injection site location did not significantly influence absorption of mirikizumab.

Distribution

The mean total volume of distribution was 4.83 L.
Biotransformation

Mirikizumab is a humanised IgG4 monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgGs.


 Elimination

In the population PK analysis, mean apparent clearance was 0.0229 L/hr and the mean elimination half-life is approximately 9.3 days in patients with ulcerative colitis. Clearance is independent of dose.

Dose proportionality

Mirikizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure over a dose range of 5 to 2 400 mg given as an intravenous infusion or over a dose range of 120 to 400 mg given as a subcutaneous injection in patients with ulcerative colitis or in healthy volunteers.

Special populations

Population pharmacokinetic analysis showed that age, sex, weight, or race/ethnicity did not have a clinically meaningful effect on the pharmacokinetics of mirikizumab (see also section 4.8, “immunogenicity”). Among the 1 362 subjects with ulcerative colitis exposed to mirikizumab in Phase 2 and Phase 3 studies, 99 (7.3 %) patients were 65 years or older and 11 (0.8 %) patients were 75 years or older.

Renal or hepatic impairment
Specific clinical pharmacology studies to evaluate the effects of renal impairment and hepatic impairment on the pharmacokinetics of mirikizumab have not been conducted. Population pharmacokinetic analysis showed that creatinine clearance (range of 36.2 to 291 mL/min) or total bilirubin (range of 1.5 to 29 µmol/L) did not affect mirikizumab pharmacokinetics.