Leaflet USYMRO 130mg concentrate for solution for infusion

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC05.

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the sharedp40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits thebioactivity of human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptorprotein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that isalready bound to IL-12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute tocomplement- or antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors. IL-12 and

IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophagesand dendritic cells, and both cytokines participate in immune functions; IL-12 stimulates natural killer(NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype, IL-23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL-12 and IL-23 hasbeen associated with immune mediated diseases, such as psoriasis, psoriatic arthritis and Crohn’sdisease.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects inpsoriasis, psoriatic arthritis and Crohn’s disease through interruption of the Th1 and Th17 cytokinepathways, which are central to the pathology of these diseases.

In patients with Crohn’s disease, treatment with ustekinumab resulted in a decrease in inflammatorymarkers including C-Reactive Protein (CRP) and fecal calprotectin during the induction phase, whichwere then maintained throughout the maintenance phase. CRP was assessed during the study extensionand the reductions observed during maintenance were generally sustained through week 252.

During the long-term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated withustekinumab for at least 3.5 years mounted similar antibody responses to both pneumococcalpolysaccharide and tetanus vaccines as a non-systemically treated psoriasis control group. Similarproportions of adult patients developed protective levels of anti-pneumococcal and anti-tetanusantibodies and antibody titres were similar among ustekinumab-treated and control patients.

The safety and efficacy of ustekinumab was assessed in three randomised, double-blind, placebo-controlled, multicentre studies in adult patients with moderately to severely active Crohn’s disease(Crohn’s Disease Activity Index [CDAI] score of ≥ 220 and ≤ 450). The clinical development programconsisted of two 8-week intravenous induction studies (UNITI-1 and UNITI-2) followed by a 44 weeksubcutaneous randomised withdrawal maintenance study (IM-UNITI) representing 52 weeks oftherapy.

The induction studies included 1,409 (UNITI-1, n=769; UNITI-2 n=640) patients. The primaryendpoint for both induction studies was the proportion of subjects in clinical response (defined as areduction in CDAI score of ≥ 100 points) at week 6. Efficacy data were collected and analysedthrough week 8 for both studies. Concomitant doses of oral corticosteroids, immunomodulators,aminosalicylates and antibiotics were permitted and 75% of patients continued to receive at least oneof these medications. In both studies, patients were randomised to receive a single intravenousadministration of either the recommended tiered dose of approximately 6 mg/kg (see Table 1, section4.2), a fixed dose of 130 mg ustekinumab, or placebo at week 0.

Patients in UNITI-1 had failed or were intolerant to prior anti-TNFα therapy. Approximately 48% ofthe patients had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies.

In this study, 29.1% of the patients had an inadequate initial response (primary non-responders),69.4% responded but lost response (secondary non-responders), and 36.4% were intolerant to anti-

TNFα therapies.

Patients in UNITI-2 had failed at least one conventional therapy, including corticosteroids orimmunomodulators, and were either anti-TNF-α naïve (68.6%) or had previously received but notfailed anti-TNFα therapy (31.4%).

In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical responseand remission in the ustekinumab treated group compared to placebo (Table 4). Clinical response andremission were significant as early as week 3 in ustekinumab treated patients and continued toimprove through week 8. In these induction studies, efficacy was higher and better sustained in thetiered dose group compared to the 130 mg dose group, and tiered dosing is therefore the recommendedintravenous induction dose.

Table 4 Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

UNITI-1* UNITI-2**

Placebo Recommended Placebo Recommended

N = 247 dose of N=209 doseustekinumab ofustekinumab

N = 249 N = 209

Clinical Remission, week 8 18 (7.3%) 52 (20.9%)a 41 (19.6%) 84 (40.2%)a

Clinical Response (100 point), week 6 53 (21.5%) 84 (33.7%)b 60 (28.7%) 116 (55.5%)a

Clinical Response (100 point), week 8 50 (20.2%) 94 (37.8%)a 67 (32.1%) 121 (57.9%)a70 Point Response, week 3 67 (27.1%) 101 (40.6%)b 66 (31.6%) 106 (50.7%)a70 Point Response, week 6 75 (30.4%) 109 (43.8%)b 81 (38.8%) 135 (64.6%)a

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by atleast 100 points or being in clinical remission70 point response is defined as reduction in CDAI score by at least 70 points

* Anti-TNFα failures

** Conventional therapy failuresa p < 0.001b p < 0.01

The maintenance study (IM-UNITI), evaluated 388 patients who achieved 100 point clinical responseat week 8 of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomisedto receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mgustekinumab every 12 weeks or placebo for 44 weeks (for recommended maintenance posology, seesection 4.2 of the Usymro Solution for injection (vial) and Solution for injection in pre-filled syringe

SmPC).

Significantly higher proportions of patients maintained clinical remission and response in theustekinumab treated groups compared to the placebo group at week 44 (see Table 5).

Table 5 Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks frominitiation of the induction dose)

Placebo* 90 mg 90 mgustekinumab ustekinumabevery 8 weeks every12 weeks

N = 131† N = 128† N = 129†

Clinical Remission 36% 53%a 49%b

Clinical Response 44% 59%b 58%b

Corticosteroid-Free Clinical Remission 30% 47%a 43%c

Clinical Remission in patients:

in remission at the start of maintenance therapy 46% (36/79) 67% (52/78)a 56% (44/78)‡who entered from study CRD3002 44% (31/70) 63% (45/72)c 57% (41/72)who are Anti-TNFα naïve 49% (25/51) 65% (34/52)c 57% (30/53)§who entered from study CRD3001 26% (16/61) 41% (23/56) 39% (22/57)

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of atleast 100 points or being in clinical remission

* The placebo group consisted of patients who were in response to ustekinumab and were randomised toreceive placebo at the start of maintenance therapy.† Patients who were in 100 point clinical response to ustekinumab at start of maintenance therapy‡ Patients who failed conventional therapy but not anti-TNFα therapy§ Patients who are anti-TNFα refractory/intoleranta p < 0.01b p < 0.05c nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every 12weeks and were allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of response wasdefined as a CDAI score ≥ 220 points and a ≥ 100 point increase from the CDAI score at baseline. Inthese patients, clinical remission was achieved in 41.4% of patients 16 weeks after dose adjustment.

Patients who were not in clinical response to ustekinumab induction at week 8 of the UNITI-1 and

UNITI-2 induction studies (476 patients) entered into the non-randomised portion of the maintenancestudy (IM-UNITI) and received a 90 mg subcutaneous injection of ustekinumab at that time. Eightweeks later, 50.5% of the patients achieved clinical response and continued to receive maintenancedosing every 8 weeks; among these patients with continued maintenance dosing, a majoritymaintained response (68.1%) and achieved remission (50.2%) at week 44, at proportions that weresimilar to the patients who initially responded to ustekinumab induction.

Of 131 patients who responded to ustekinumab induction, and were randomised to the placebo groupat the start of the maintenance study, 51 subsequently lost response and received 90 mg ustekinumabsubcutaneously every 8 weeks. The majority of patients who lost response and resumed ustekinumabdid so within 24 weeks of the induction infusion. Of these 51 patients, 70.6% achieved clinicalresponse and 39.2% percent achieved clinical remission 16 weeks after receiving the firstsubcutaneous dose of ustekinumab.

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatmentin a study extension. Among the 567 patients who entered on and were treated with ustekinumab in thestudy extension, clinical remission and response were generally maintained through week 252 for bothpatients who failed TNF-therapies and those who failed conventional therapies.

No new safety concerns were identified in this study extension with up to 5 years of treatment inpatients with Crohn’s disease.

Endoscopy

Endoscopic appearance of the mucosa was evaluated in 252 patients with eligible baseline endoscopicdisease activity in a substudy. The primary endpoint was change from baseline in Simplified

Endoscopic Disease Severity Score for Crohn’s Disease (SES-CD), a composite score across 5 ileo-colonic segments of presence/size of ulcers, proportion of mucosal surface covered by ulcers,proportion of mucosal surface affected by any other lesions and presence/type of narrowing/strictures.

At week 8, after a single intravenous induction dose, the change in SES-CD score was greater in theustekinumab group (n = 155, mean change = -2.8) than in the placebo group (n = 97, mean change = -0.7, p = 0.012).

Fistula Response

In a subgroup of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) ofustekinumab-treated patients achieved a fistula response over 44 weeks (defined as ≥ 50% reductionfrom baseline of the induction study in the number of draining fistulas) compared to 5/11 (45.5%)exposed to placebo.

Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ) and

SF-36 questionnaires. At week 8, patients receiving ustekinumab showed statistically significantlygreater and clinically meaningful improvements on IBDQ total score and SF-36 Mental Component

Summary Score in both UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in

UNITI-2, when compared to placebo. These improvements were generally better maintained inustekinumab-treated patients in the IM-UNITI study through week 44 when compared to placebo.

Improvement in health-related quality of life was generally maintained during the extension throughweek 252.

Antibodies to ustekinumab may develop during ustekinumab treatment and most are neutralising. Theformation of anti-ustekinumab antibodies is associated with increased clearance of ustekinumab inpatients with Crohn’s disease. No reduced efficacy was observed. There is no apparent correlationbetween the presence of anti-ustekinumab antibodies and the occurrence of injection site reactions.

The European Medicines Agency has deferred the obligation to submit the results of studies withustekinumab in one or more subsets of the paediatric population in Crohn’s Disease (see section 4.2for information on paediatric use).

The safety and efficacy of ustekinumab was evaluated in 48 paediatric patients weighing at least 40kg, in an interim analysis of a multicentre phase 3 study (UNITI-Jr) for paediatric patients withmoderately to severely active Crohn's disease (defined by a Paediatric Crohn’s Disease Activity Index[PCDAI] score > 30) through 52 weeks of treatment (8 weeks of induction and 44 weeks ofmaintenance treatment). Patients included in the study either had not adequately responded to or hadnot tolerated prior biologic therapy or conventional therapy for Crohn’s disease. The study included anopen-label induction treatment with a single ustekinumab intravenous dose, of approximately 6 mg/kg(see section 4.2), followed by a randomised double-blind subcutaneous maintenance regimen of 90 mgustekinumab administered either every 8 weeks or every 12 weeks.

The primary endpoint of the study was clinical remission at induction week 8 (defined as PCDAI score≤ 10). The proportion of patients who achieved clinical remission was 52.1% (25/48) and iscomparable to that observed in the adult ustekinumab phase 3 studies.

Clinical response was observed as early as week 3. The proportion of patients in clinical response atweek 8 (defined as a reduction from baseline in the PCDAI score of > 12.5 points with a total PCDAIscore not more than 30) was 93.8% (45/48).

Table 6 presents the analyses for the secondary endpoints through maintenance week 44.

Table 6 Summary of Secondary endpoints through Maintenance week 4490 mg ustekinumab 90 mg ustekinumab Total number ofevery 8 weeks every 12 weeks patients

N=23 N=25 N=48

Clinical Remission * 43.5% (10/23) 60.0% (15/25) 52.1% (25/48)

Corticosteroid-free 43.5% (10/23) 60.0% (15/25) 52.1% (25/48)

Clinical Remission §

Clinical remission for 64.3% (9/14) 54.5% (6/11) 60.0% (15/25)patients who were inclinical remission atinduction week 8 *

Clinical Response † 52.2% (12/23) 60.0% (15/25) 56.3% (27/48)

Endoscopic response £ 22.7% (5/22) 28.0% (7/25) 25.5% (12/47)

* Clinical remission is defined as PCDAI score ≤ 10 points.§ Corticosteroid-free remission is defined as PCDAI score of ≤ 10 points and not receiving corticosteroids for atleast 90 days prior to Week M-44.† Clinical response is defined as a reduction from baseline in the PCDAI score of ≥ 12.5 points with a total

PCDAI score not more than 30.£ Endoscopic response is defined as a reduction in the SES-CD score of ≥ 50% or SES-CD score ≤ 2, inpatients with a baseline SES-CD score of ≥ 3.

Dosing frequency adjustment

Patients who entered the maintenance regimen and experienced loss of response (LOR) based on

PCDAI score were eligible for dose adjustment. Patients were either switched from treatment every 12weeks to every 8 weeks or stayed on treatment every 8 weeks (sham adjustment). 2 patients were doseadjusted to the shorter dosing interval. In these patients, clinical remission was achieved in 100% (2/2)of patients 8 weeks after dose adjustment.

The safety profile of the induction dose regimen and both maintenance dose regimens in the paediatricpopulation weighing at least 40 kg is comparable with that established in the adult Crohn’s diseasepopulation (see Section 4.8).

Serum and faecal inflammatory biomarkers

The mean change from baseline at maintenance week 44 in C-Reactive protein (CRP) and faecalcalprotectin concentrations were -11.17 mg/L (24.159) and -538.2 mg/kg (1271.33), respectively.

The total IMPACT-III scores and all subdomains (bowel symptoms, fatigue-related systemicsymptoms, and well-being) demonstrated clinically meaningful improvements after 52 weeks.