Omvoh 100 mg solution for injection in pre-filled pen and Omvoh 200 mg solution for injection in pre-filled pen

Omvoh is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic treatment.

This medicinal product is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of Crohn's disease.

Omvoh 100 mg solution for injection and Omvoh 200 mg solution for injection should only be used for the subcutaneous maintenance doses.

Posology

The recommended mirikizumab dose regimen has 2 parts.

Induction dose

The induction dose is 900 mg (3 vials of 300 mg each) by i.v. infusion for at least 90 minutes at weeks 0, 4 and 8.

(See Summary of Product Characteristics for Omvoh 300 mg concentrate for solution for infusion, section 4.2.)

Maintenance dose

The maintenance dose is 300 mg (i.e. one pre‑filled syringe or pre‑filled pen of 100 mg and one pre‑filled syringe or pre‑filled pen of 200 mg) by subcutaneous injection every 4 weeks after completion of induction dosing.

The injections may be administered in any order.

The 200 mg pre-filled syringe and the 200 mg pre-filled pen are only for the treatment of Crohn's disease.

Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by week 24.

Missed dose

In case of a missed dose, instruct patients to inject as soon as possible. Thereafter, resume dosing every 4 weeks.

Special populations

Elderly

No dose adjustment is required (see section 5.2). There is limited information in subjects aged ≥ 75 years.

Renal or hepatic impairment

Omvoh has not been studied in these patient populations. These conditions are generally not expected to have any significant impact on the pharmacokinetics of monoclonal antibodies and no dose adjustments are considered necessary (see section 5.2).

Paediatric population

The safety and efficacy of Omvoh in children and adolescents aged 2 to less than 18 years have not yet been established. No data are available.

There is no relevant use of Omvoh in children below 2 years for the indication of Crohn's disease.

Method of administration

For subcutaneous injection only.

Sites for injection include the abdomen, thigh, and back of the upper arm. After training in subcutaneous injection technique, a patient may self‑inject with mirikizumab.

Patients should be instructed to inject in a different location every time. For example, if the first injection was in the abdomen, the second injection—to complete a full dose—could be in another area of the abdomen.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important active infections (active tuberculosis).

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity reactions

In clinical studies, hypersensitivity reactions have been reported. Most were mild or moderate, severe reactions were uncommon (see section 4.8). If a serious hypersensitivity reaction, including anaphylaxis, occurs, mirikizumab must be discontinued immediately and appropriate therapy must be initiated.

Infections

Mirikizumab may increase the risk of severe infection (see section 4.8). Treatment with mirikizumab should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated (see section 4.3). The risks and benefits of treatment should be considered prior to initiating use of mirikizumab in patients with a chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms of clinically important acute or chronic infection occur. If a serious infection develops, discontinuation of mirikizumab should be considered until the infection resolves.

Pre-treatment evaluation for tuberculosis

Prior to initiating treatment, patients should be evaluated for tuberculosis (TB) infection. Patients receiving mirikizumab should be monitored for signs and symptoms of active TB during and after treatment. Anti‑TB therapy should be considered prior to initiating treatment in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed.

Hepatic enzyme elevations

Cases of drug-induced liver injury (including one case meeting Hy's Law criteria) occurred in patients receiving mirikizumab in clinical trials. Liver enzymes and bilirubin should be evaluated at baseline and monthly during induction (including extended induction period, if applicable). Thereafter, liver enzymes and bilirubin should be monitored (every 1 ‑ 4 months) according to standard practice for patient management and as clinically indicated. If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are observed and drug-induced liver injury is suspected, mirikizumab must be discontinued until this diagnosis is excluded.

Immunisations

Prior to initiating therapy with mirikizumab, completion of all appropriate immunisations should be considered according to current immunisation guidelines. Avoid use of live vaccines in patients treated with mirikizumab. No data are available on the response to live or non-live vaccines.

Excipients with known effect

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 300 mg dose, that is to say essentially “sodium-free”.

Polysorbate

This medicinal product contains 0.3 mg/mL of polysorbate 80 in each pen or syringe which is equivalent to 0.9 mg for the maintenance dose to treat Crohn's disease. Polysorbates may cause allergic reactions.

No interaction studies have been performed.

In clinical studies, concomitant use of corticosteroids or oral immunomodulators did not influence the safety of mirikizumab.

Population pharmacokinetic data analyses indicated that the clearance of mirikizumab was not impacted by concomitant administration of 5‑ASAs (5‑aminosalicylic acid), corticosteroids or oral immunomodulators (azathioprine, 6-mercaptopurine, thioguanine, and methotrexate).

Women of childbearing potential

Women of childbearing potential should use an effective method of contraception during treatment and for at least 10 weeks after treatment.

Pregnancy

There is a limited amount of data from the use of mirikizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Omvoh during pregnancy.

Breast-feeding

It is unknown whether mirikizumab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Omvoh therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of mirikizumab on human fertility has not been evaluated (see section 5.3).

Omvoh has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse reactions are upper respiratory tract infections (9.8 %, most frequently nasopharyngitis), headache (3.2 %), rash (1.3 %) and injection site reactions (10.8 %, maintenance period).

Tabulated list of adverse reactions

Adverse reactions from clinical studies (Table 1) are listed by MedDRA system organ class. The frequency category for each reaction is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 1: Adverse reactions

^a Includes: acute sinusitis, COVID-19, nasopharyngitis, oropharyngeal discomfort, oropharyngeal pain, pharyngitis, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection.

^b Includes: rash, rash macular, rash maculo-papular, and rash papular and rash pruritic.

^c Reported during mirikizumab maintenance therapy where mirikizumab treatment is administered as subcutaneous injection.

^d Reported during mirikizumab induction therapy where mirikizumab treatment is administered as intravenous infusion.

Description of selected adverse reactions

Infusion-related hypersensitivity reactions (induction therapy)

Infusion‑related hypersensitivity reactions were reported in 0.4 % of mirikizumab‑treated patients. All infusion‑related hypersensitivity reactions were reported as non-serious.

Injection site reactions (maintenance therapy)

Injection site reactions were reported in 10.8 % of mirikizumab ‑treated patients. The most frequent reactions were injection site pain, injection site reaction and injection site erythema. These symptoms were reported as non‑serious, mild and transient in nature.

The results described above were obtained with the original formulation of Omvoh. In a double blind, 2-arm, randomised, single-dose, parallel design study in 60 healthy subjects comparing 200 mg mirikizumab (2 injections of 100 mg in a pre-filled syringe) of the original formulation with the revised formulation statistically significantly lower VAS pain scores were obtained with the revised (12.6) vs. the original formulation (26.1) 1 minute after injection.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased

In the first 12 weeks, ALT increased was reported in 0.6 % mirikizumab‑treated patients. AST increased was reported by 0.4 % mirikizumab‑treated patients. All adverse reactions were reported as mild to moderate in severity and non‑serious.

Over all mirikizumab treatment periods in the ulcerative colitis and Crohn's disease clinical development program (including the placebo‑controlled and open label induction and maintenance periods), there have been elevations of ALT to ≥ 3 x upper limit of normal (ULN) (2.3 %), ≥ 5 x ULN (0.7 %) and ≥ 10 x ULN (0.2 %) and AST to ≥ 3 x ULN (2.2 %), ≥ 5 x ULN (0.8 %) and ≥ 10 x ULN (0.1 %) in patients receiving mirikizumab (see section 4.4). These elevations have been noted with and without concomitant elevations in total bilirubin.

Immunogenicity

In the ulcerative colitis studies, up to 23 % of mirikizumab‑treated patients with 12 months of treatment developed anti‑drug antibodies, most of which were of low titer and tested positive for neutralising activity. Higher antibody titers in approximately 2 % of subjects treated with mirikizumab were associated with lower serum mirikizumab concentrations and reduced clinical response.

In the Crohn's disease study, 12.7% of mirikizumab-treated patients with 12 months of treatment developed anti-drug antibodies, most of which were of low titer and tested positive for neutralising activity. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics or effectiveness of mirikizumab.

No association was found between anti‑mirikizumab antibodies and hypersensitivity or injection-related events in either the ulcerative colitis or the Crohn's disease studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Mirikizumab doses up to 2 400 mg intravenously and up to 500 mg subcutaneously have been administered in clinical trials without dose‑limiting toxicity. In the event of overdose, the patient must be monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment must be started immediately.

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 and Crohn's disease 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 up to 52 weeks.

Clinical efficacy and safety

Ulcerative colitis

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)

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)

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.

Crohn's disease

The efficacy and safety of mirikizumab was evaluated in a randomized, double-blind, placebo- and active controlled treat-through designed clinical study VIVID-1 in adult patients with moderately to severely active Crohn's disease who had an inadequate response with, loss of response, or intolerance to corticosteroids, immunomodulators (e.g. azathioprine, 6-mercaptopurine), or a biologic treatment (e.g. TNFα antagonist or integrin receptor antagonist). This study included a mirikizumab 12-week intravenous infusion induction period followed by a 40-week subcutaneous injection maintenance period. This study also included an ustekinumab comparator arm in the induction and maintenance periods.

VIVID-1

In VIVID-1, efficacy was evaluated in 1065 patients who were randomized 6:3:2 to receive mirikizumab 900 mg by intravenous infusion (IV) at week 0, week 4, and week 8 followed by a maintenance dose of 300 mg by subcutaneous injection (SC) at week 12 and then every 4 weeks (Q4W) for 40 weeks, ustekinumab approximately 6 mg/kg by IV administration at week 0 followed by 90 mg SC administration every 8 weeks (Q8W) starting at week 8, or placebo. Patients randomised to placebo at baseline who achieved clinical response by Patient-Reported Outcome (PRO) at week 12 (defined as at least a 30% decrease in stool frequency (SF) and/or abdominal pain (AP) with neither score worse than baseline) remained on placebo. Patients randomized to placebo at baseline who did not achieve clinical response by PRO at week 12 received mirikizumab 900 mg by IV infusion at week 12, week 16, and week 20 followed by a maintenance dose of 300 mg Q4W SC at week 24 through week 48.

Disease activity at baseline was assessed by (1) the unweighted daily average of SF (2), the unweighted daily average AP (ranging from 0 to 3) and (3) Simple Endoscopic Score for Crohn's disease (SES-CD) (ranging from 0 to 56).

Moderately to severely active CD was defined by SF ≥4 and/or AP ≥2 and SES-CD ≥7 (centrally read) for patients with ileal-colonic and isolated colonic disease or ≥4 for patients with isolated ileal disease. At baseline patients had a median SF of 6, AP of 2 and SES-CD of 12.

Patients had a mean age of 36 years (range 18 to 76 years); 45 % were female; and 72 % identified as White, 25 % as Asian, 2 % as Black, and 1 % as another racial group. Patients were permitted to use stable doses of corticosteroids, immunomodulators (e.g., 6-mercatopurine, azathioprine or methotrexate) and/or aminosalicylates. At baseline, 31 % of patients were receiving oral corticosteroids, 27 % were receiving immunomodulators, and 44 % were receiving aminosalicylates.

At baseline, 49 % had a loss of response, inadequate response, or intolerance to one or more biologic therapy (prior biologic failure); 46 % of patients had failed TNFα inhibitors and 11 % had failed vedolizumab therapy.

The co-primary endpoints of VIVID-1 were (1) clinical response by PRO at week 12 and endoscopic response at week 52 versus placebo and (2) clinical response by PRO at week 12 and clinical remission by Crohn's Disease Activity Index (CDAI) at week 52; the results for the co-primary endpoints and the major secondary endpoints at week 52 versus placebo are provided in table 4.

The major secondary endpoints at week 12 versus placebo are provided in table 5.

Table 4. Proportion of patients with Crohn's disease meeting efficacy endpoints in VIVID-1 at week 52

Abbreviations: AP = abdominal pain; CDAI = Crohn's Disease Activity Index; CI = confidence interval; PRO = 2 of the patient‑reported items of the CDAI (SF and AP); SES‑CD = Simple Endoscopic Score for Crohn's Disease; SF = stool frequency.

a Following mirikizumab 900 mg as an IV infusion at week 0, week 4, and week 8 patients received mirikizumab 300 mg as a SC injection at week 12 and every 4 weeks thereafter for up to an additional 40 weeks.

b For binary endpoints adjusted treatment difference was based on Cochran-Mantel-Haenszel method adjusted for baseline covariates.

c Clinical response by PRO is defined as at least a 30% decrease in SF and/or AP and neither score worse than baseline.

d Endoscopic response is defined as ≥50% reduction from baseline in SES‑CD total score, based on central reading.

e p <0.000001

f Prior biologic failure includes loss of response, inadequate response, or intolerance to one or more biologic therapy (e.g. TNFα antagonist or integrin receptor antagonist).

g Clinical remission by CDAI is defined as CDAI total score < 150.

h Placebo sample size includes all patients randomized to placebo at baseline. Placebo patients that did not achieve clinical response by PRO at week 12 were considered non-responders at week 52.

i Clinical remission by PRO is defined as SF ≤3 and not worse than baseline (according to the Bristol Stool Scale Category 6 or 7) and AP ≤1 and not worse than baseline.

j Endoscopic remission is defined as SES‑CD Total Score ≤4 and at least a 2‑point reduction versus baseline and no subscore >1 in any individual variable, based on central reading.

k Corticosteroid‑free is defined as patients who were corticosteroid‑free from week 40 to week 52.

Bowel urgency remission

Bowel urgency remission was assessed during VIVID-1 with an urgency numeric rating scale (NRS) of 0 to 10. A greater proportion of patients with a baseline urgency NRS weekly average score ≥3 treated with mirikizumab compared to placebo achieved clinical response by PRO at week 12 and an urgency NRS weekly average score of ≤ 2 at week 52 (33 % versus 11 %).

Table 5. Proportion of patients with Crohn's disease meeting efficacy endpoints in VIVID -1 at week 12

Abbreviations: FACIT-fatigue = Functional Assessment of Chronic Illness Therapy – fatigue; LS Mean = Least Square Mean; SE = Standard Error; others see above table 4.

a Weeks 0, 4, 8

b see table 4. Also see footnote k.

c, d, e, g, j see table 4

f p-value <0.005

h For change from baseline in FACIT-fatigue, the LS means and treatment difference were based on ANCOVA model adjusted for baseline FACIT-fatigue and other covariates. At baseline, mean FACIT-fatigue values were similar across treatment groups and ranged from 32.3-31.5.

Improvements in clinical remission by CDAI were observed as early as week 4 in a greater proportion of patients treated with mirikizumab compared to placebo.

Reductions in abdominal pain were observed as early as week 4 and in stool frequency as early as week 6 in patients treated with mirikizumab compared to placebo.

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.

Active comparator arm

At week 52, mirikizumab demonstrated non-inferiority (pre-specified margin of -10%) to ustekinumab on clinical remission by CDAI (mirikizumab 54 %; ustekinumab 48 %). Superiority over ustekinumab in week 52 endoscopic response was not achieved (mirikizumab 48 %, ustekinumab 46 %).

Histologic outcome

Across all five intestinal segments 44 % of patients on mirikizumab achieved the composite endpoint of clinical response by PRO at week 12 and histologic response at week 52 compared to 16 % of patients on placebo. Histologic response at week 52 was achieved by 58 % of patients compared to 49% on ustekinumab.

Health-related quality of life

At week 12, change in the Inflammatory Bowel Disease Questionnaire (IBDQ) score was 36.9 for mirikizumab and 17.4 for placebo; IBDQ response and remission were achieved in 69 % and 52 % of mirikizumab-treated patients versus 45 % and 28 % in placebo patients respectively. These improvements were maintained at week 52.

Paediatric population

The licensing authority 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 and Crohn's disease (see section 4.2 for information on paediatric use).

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

Exposure

Ulcerative colitis

Mean (coefficient of variation in %) C_max 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 µg/mL (22.7 %) and 538 µg*day/mL (34.4 %), respectively. The mean (CV %) C_max and AUC after maintenance dosing (200 mg every 4 weeks by subcutaneous injection) were 10.1 µg/mL (52.1 %) and 160 µg*day/mL (57.6 %), respectively.

Crohn's disease

Mean (coefficient of variation in %) C_max and area under the curve (AUC) after induction dosing (900 mg every 4 weeks administered by intravenous infusion) in patients with Crohn's disease were 332 µg/mL (20.6 %) and 1820 µg*day/mL (38.1 %), respectively. The mean (CV %) C_max and AUC after maintenance dosing (300 mg every 4 weeks by subcutaneous injection) were 13.6 µg/mL (48.1 %) and 220 µg*day/mL (55.9 %), respectively.

Absorption

Following subcutaneous dosing of mirikizumab for ulcerative colitis, median (range) Tmax was 5 (3.08-6.75) days post dose and geometric mean (CV%) absolute bioavailability of 44 % (34 %).

Following subcutaneous dosing of mirikizumab for Crohn's disease, median (range) Tmax was 5 (3 to 6.83) days post dose and geometric mean (CV%) absolute bioavailability was 36.3% (31%).

Injection site location did not significantly influence absorption of mirikizumab.

Distribution

The geometric mean total volume of distribution was 4.83 L (21%) in patients with ulcerative colitis and 4.40 L (14%) in patients with Crohn's disease.

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, geometric mean (CV %) clearance was 0.0229 L/hr (34 %) and the geometric mean half‑life is approximately 9.3 days (40 %) in patients with ulcerative colitis. The geometric mean (CV%) clearance was 0.0202 L/hr (38 %) and the geometric mean (CV %) half-life is also approximately 9.3 days (26 %) in patients with Crohn's disease. 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 Crohn's disease 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.

In patients with ulcerative colitis, 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.

In patients with Crohn's disease, population pharmacokinetic analysis showed that creatinine clearance (range of 26.5 to 269 mL/min) or total bilirubin (range of 1.5 to 36 µmol/L) did not affect mirikizumab pharmacokinetics.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development.

Carcinogenesis / mutagenesis

Non‑clinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of mirikizumab.

Impairment of fertility

No reproductive organ weight or histopathology effects were observed in sexually mature cynomolgus monkeys that received mirikizumab once weekly for 26 weeks, at a dose of 100 mg/kg (at least 20 times the human maintenance dose).

Histidine

Histidine monohydrochloride

Sodium chloride

Mannitol (E 421)

Polysorbate 80 (E 433)

Water for injections

Not applicable.

2 years.

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

Omvoh may be stored unrefrigerated for up to 2 weeks at a temperature not above 30 °C.

If these conditions are exceeded, Omvoh must be discarded.

Omvoh 100 mg solution for injection in pre-filled pen and 200 mg solution for injection in pre-filled pen

Pre-filled pens with 1 mL and 2 mL solution in a type I clear glass syringe.

Each syringe is encased in a disposable, single‑dose pen with bromobutyl rubber plunger.

Pack sizes:

• Packs of 2 pre-filled pens (1 pre-filled pen of 100 mg and 1 pre-filled pen of 200 mg)

• Multipacks containing 6 pre-filled pens (3 packs of 1 pre-filled pen of 100 mg and 1 pre-filled pen of 200 mg each).

Not all pack sizes may be marketed.

For single use only. Omvoh should not be used if particles appear or if the solution is cloudy and/or distinctly brown.

Do not use Omvoh that has been frozen.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.