Leaflet TREMFYA 100mg solution for injection

Tremfya 45 mg/0.45 mL solution for injection in pre-filled pen

Each pre-filled pen contains 45 mg guselkumab in 0.45 mL. 1 mL solution contains 100 mg ofguselkumab.

Each pre-filled pen can deliver 0.1 mL to 0.45 mL (corresponding to 10 mg to 45 mg guselkumab) inincrements of 0.05 mL.

Guselkumab is a fully human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody (mAb)produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

This medicinal product contains 0.3 mg of polysorbate 80 (E433) in each pre-filled pen which isequivalent to 0.5 mg/mL.

For the full list of excipients, see section 6.1.

Solution for injection (injection) in pre-filled pen (VarioJect)

The solution is clear and colourless to light yellow and may contain a few small white or clearparticles, with target pH of 5.8 and approximate osmolarity of 367.5 mOsm/L.

Tremfya is indicated for the treatment of moderate to severe plaque psoriasis in children andadolescents from the age of 6 years who are candidates for systemic therapy.

This medicinal product is intended for use under the guidance and supervision of a physicianexperienced in the diagnosis and treatment of plaque psoriasis.

The 45 mg/0.45 mL pre-filled pen is for paediatric patients 6 years and older with a body weight lessthan 40 kg.

Each pre-filled pen is for single use in a single patient, and should be discarded immediately after use.

Paediatric plaque psoriasis (6 to 17 years)

Children from the age of 6 years with a body weight less than 40 kg

The recommended dose is shown below in Table 1, up to a maximum of 45 mg, administered bysubcutaneous injection at Weeks 0 and 4, followed by a maintenance dose every 8 weeks (q8w).

Table 1: Recommended dose of guselkumab for subcutaneous injection in paediatricpatients with body weight less than 40 kg

Body Weight (kg) Dose (mg)(at time of dosing)12-15 kg 2016-19 kg 2520-23 kg 3024-26 kg 3527-30 kg 4031-39 kg 45

Children from the age of 6 years with a body weight of 40 kg or more

For children with a body weight of 40 kg, or more a 100 mg pre-filled syringe is available. For theposology and method of administration, see section 4.2 of the Tremfya 100 mg pre-filled syringe

Summary of Product Characteristics.

Consideration should be given to discontinuing treatment in paediatric patients who have shown noresponse after 24 weeks of treatment.

If a dose is missed, the dose should be administered as soon as possible. Thereafter, dosing should beresumed at the regular scheduled time.

Tremfya has not been studied in these patient populations. These conditions are generally not expectedto have any significant impact on the pharmacokinetics of monoclonal antibodies, and no doseadjustments are considered necessary. For further information on elimination of guselkumab, seesection 5.2.

The safety and efficacy of Tremfya in patients less than 6 years have not been established.

No data are available.

Subcutaneous use only. If possible, areas of the skin that show psoriasis should be avoided as injectionsites.

Tremfya is not intended for self-administration by paediatric patients. After proper training insubcutaneous injection technique, a caregiver may inject Tremfya if a physician determines that this isappropriate. However, the physician should ensure appropriate medical follow-up of patients.

Caregivers should be instructed to inject the prescribed amount of solution according to the‘Instructions for use’ provided in the carton.

For instructions on preparation of the medicinal product before administration, see section 6.6.

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

Clinically important active infections (e.g. active tuberculosis, see section 4.4).

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

Guselkumab may increase the risk of infection. Treatment should not be initiated in patients with anyclinically important active infection until the infection resolves or is adequately treated.

Patients treated with guselkumab should be instructed to seek medical advice if signs or symptoms ofclinically important chronic or acute infection occur. If a patient develops a clinically important orserious infection or is not responding to standard therapy, the patient should be monitored closely andtreatment should be discontinued until the infection resolves.

Pre-treatment evaluation for tuberculosis

Prior to initiating treatment, patients should be evaluated for tuberculosis (TB) infection. Patientsreceiving guselkumab should be monitored for signs and symptoms of active TB during and aftertreatment. Anti-TB therapy should be considered prior to initiating treatment in patients with a pasthistory of latent or active TB in whom an adequate course of treatment cannot be confirmed.

Serious hypersensitivity reactions, including anaphylaxis, have been reported in the post-marketingsetting (see section 4.8). Some serious hypersensitivity reactions occurred several days after treatmentwith guselkumab, including cases with urticaria and dyspnoea. If a serious hypersensitivity reactionoccurs, administration of guselkumab should be discontinued immediately and appropriate therapyinitiated.

Hepatic transaminase elevations

In psoriatic arthritis clinical studies, an increased incidence of liver enzyme elevations was observed inpatients treated with guselkumab q4w compared to patients treated with guselkumab q8w or placebo(see section 4.8).

Prior to initiating therapy, completion of all age-appropriate immunisations should be consideredaccording to current immunisation guidelines. Live vaccines should not be used concurrently inpatients treated with guselkumab. No data are available on the response to live or inactive vaccines.

Before live viral or live bacterial vaccination, treatment should be withheld for at least 12 weeks afterthe last dose and can be resumed at least 2 weeks after vaccination. Prescribers should consult the

Summary of Product Characteristics of the specific vaccine for additional information and guidance onconcomitant use of immunosuppressive agents post-vaccination.

Polysorbate 80 content

This medicinal product contains 0.3 mg of polysorbate 80 (E433) in each pre-filled pen which isequivalent to 0.5 mg/mL. Polysorbates may cause allergic reactions.

Interactions with CYP450 substrates

In a Phase I study in patients with moderate to severe plaque psoriasis, changes in systemic exposures(Cmax and AUCinf) of midazolam, S-warfarin, omeprazole, dextromethorphan, and caffeine after asingle dose of guselkumab were not clinically relevant, indicating that interactions betweenguselkumab and substrates of various CYP enzymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and

CYP1A2) are unlikely. There is no need for dose adjustment when co-administering guselkumab and

CYP450 substrates.

Concomitant immunosuppressive therapy or phototherapy

In psoriasis studies, the safety and efficacy of guselkumab in combination with immunosuppressants,including biologics, or phototherapy have not been evaluated.

Women of childbearing potential should use effective methods of contraception during treatment andfor at least 12 weeks after treatment.

There are limited data from the use of guselkumab in pregnant women. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturitionor postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid theuse of Tremfya during pregnancy.

It is unknown whether guselkumab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, and decrease to low concentrations soon afterwards;consequently, a risk to the breast-fed infant during this period cannot be excluded. A decision shouldbe made whether to discontinue breast-feeding or to abstain from Tremfya therapy, taking into accountthe benefit of breast-feeding for the child and the benefit of therapy for the woman. See section 5.3 forinformation on the excretion of guselkumab in animal (cynomolgus monkey) milk.

The effect of guselkumab on human fertility has not been evaluated. Animal studies do not indicatedirect or indirect harmful effects with respect to fertility (see section 5.3).

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

The most common adverse reaction was respiratory tract infections (approximately 8% of patients inulcerative colitis studies, 11% of patients in the Crohn’s disease studies, and 15% of patients in thepsoriasis and psoriatic arthritis clinical studies).

The overall safety profile in patients treated with Tremfya is similar for patients with psoriasis,psoriatic arthritis, ulcerative colitis, and Crohn’s disease.

Table 2 provides a list of adverse reactions from psoriasis, psoriatic arthritis, ulcerative colitis, and

Crohn’s disease clinical studies as well as adverse reactions reported from post-marketing experience.

The adverse reactions are classified by MedDRA System Organ Class and frequency, using thefollowing 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), not known (cannot be estimated fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 2: List of adverse reactions

System Organ Class Frequency Adverse reactions

Infections and infestations Very common Respiratory tract infections

Uncommon Herpes simplex infections

Uncommon Tinea infections

Uncommon Gastroenteritis

Immune system disorders Rare Hypersensitivity

Rare Anaphylaxis

Nervous system disorders Common Headache

Gastrointestinal disorders Common Diarrhoea

Skin and subcutaneous tissue Common Rashdisorders Uncommon Urticaria

Musculoskeletal and connective Common Arthralgiatissue disorders

General disorders and administration Common Injection site reactionssite conditions

Investigations Common Transaminases increased

Uncommon Neutrophil count decreased

Transaminases increased

In two Phase III psoriatic arthritis clinical studies, through the placebo-controlled period, adversereactions of increased transaminases (includes ALT increased, AST increased, hepatic enzymeincreased, transaminases increased, liver function test abnormal, hypertransaminasaemia) werereported more frequently in the guselkumab treated groups (8.6% in the 100 mg subcutaneous q4wgroup and 8.3% in the 100 mg subcutaneous q8w group) than in the placebo group (4.6%). Through 1-year, adverse reactions of increased transaminases (as above) were reported in 12.9% of patients in theq4w group and 11.7% of patients in the q8w group.

Based on laboratory assessments, most transaminase increases (ALT and AST) were ≤ 3 x upper limitof normal (ULN). Transaminase increases from > 3 to ≤ 5 x ULN and > 5 x ULN were low infrequency, occurring more often in the guselkumab q4w group compared with the guselkumab q8wgroup (Table 3). A similar pattern of frequency by severity and by treatment group was observedthrough the end of the 2-year Phase III psoriatic arthritis clinical study.

Table 3: Frequency of patients with transaminase increases post-baseline in two Phase IIIpsoriatic arthritis clinical studies

Through Week 24a Through 1 yearb

Placebo guselkumab guselkumab guselkumab guselkumab

N=370c 100 mg q8w 100 mg q4w 100 mg q8w 100 mg q4w

N=373c N=371c N=373c N=371c

ALT>1 to ≤3 x ULN 30.0% 28.2% 35.0% 33.5% 41.2%>3 to ≤ 5 x ULN 1.4% 1.1% 2.7% 1.6% 4.6%>5 x ULN 0.8% 0.8% 1.1% 1.1% 1.1%

AST>1 to ≤3 x ULN 20.0% 18.8% 21.6% 22.8% 27.8%>3 to ≤ 5 x ULN 0.5% 1.6% 1.6% 2.9% 3.8%>5 x ULN 1.1% 0.5% 1.6% 0.5% 1.6%a placebo-controlled period.b patients randomised to placebo at baseline and crossed over to guselkumab are not included.c number of patients with at least one post-baseline assessment for the specific laboratory test within the time period.

In the psoriasis clinical studies, through 1 year, the frequency of transaminase increases (ALT and

AST) for the guselkumab q8w dose was similar to that observed for the guselkumab q8w dose in thepsoriatic arthritis clinical studies. Through 5 years, the incidence of transaminase elevation did notincrease by year of guselkumab treatment. Most transaminase increases were ≤ 3 x ULN.

In most cases, the increase in transaminases was transient and did not lead to discontinuation oftreatment.

In pooled Phase II and Phase III Crohn’s disease clinical studies, through the placebo-controlledinduction period (Week 0-12), adverse reactions of increased transaminases (includes ALT increased,

AST increased, hepatic enzyme increased, transaminases increased, and liver function test increased)were reported more frequently in the guselkumab treated groups (1.7% of patients) than in the placebogroup (0.6% of patients). In pooled Phase II and Phase III Crohn’s disease clinical studies, through thereporting period of approximately one year, adverse reactions of increased transaminases (includes

ALT increased, AST increased, hepatic enzyme increased, transaminases increased, hepatic functionabnormal, and liver function test increased) were reported in 3.4% of patients in the guselkumab200 mg subcutaneous q4w treatment group and 4.1% of patients in the guselkumab 100 mgsubcutaneous q8w treatment group compared to 2.4% in the placebo group.

Based on laboratory assessments in pooled Phase II and Phase III Crohn’s disease clinical studies, thefrequency of ALT or AST elevations were lower than those observed in psoriatic arthritis Phase IIIclinical studies. In pooled Phase II and Phase III Crohn’s disease clinical studies, through the placebo-controlled period (Week 12), ALT (< 1% of patients) and AST (< 1% of patients) elevations ≥ 3x

ULN were reported in guselkumab treated patients. In pooled Phase II and Phase III Crohn’s diseaseclinical studies, through the reporting period of approximately one year, ALT and/or AST elevations≥ 3x ULN were reported in 2.7% of patients in the guselkumab 200 mg subcutaneous q4w treatmentgroup and 2.6% of patients in the guselkumab 100 mg subcutaneous q8w treatment group compared to1.9% in the placebo group. In most cases, the increase in transaminases was transient and did not leadto discontinuation of treatment.

Neutrophil count decreased

In two Phase III psoriatic arthritis clinical studies, through the placebo-controlled period, the adversereaction of decreased neutrophil count was reported more frequently in the guselkumab treated group(0.9%) than in the placebo group (0%). Through 1 year, the adverse reaction of decreased neutrophilcount was reported in 0.9% of patients treated with guselkumab. In most cases, the decrease in bloodneutrophil count was mild, transient, not associated with infection and did not lead to discontinuationof treatment.

Gastroenteritis

In two Phase III psoriasis clinical studies through the placebo-controlled period, gastroenteritisoccurred more frequently in the guselkumab treated group (1.1%) than in the placebo group (0.7%).

Through Week 264, 5.8% of all guselkumab treated patients reported gastroenteritis. Adversereactions of gastroenteritis were non-serious and did not lead to discontinuation of guselkumabthrough Week 264. Gastroenteritis rates observed in psoriatic arthritis clinical studies through theplacebo-controlled period were similar to those observed in the psoriasis clinical studies.

In two Phase III psoriasis clinical studies through Week 48, 0.7% of guselkumab injections and 0.3%of placebo injections were associated with injection site reactions. Through Week 264, 0.4% ofguselkumab injections were associated with injection site reactions. Injection site reactions weregenerally mild to moderate in severity; none were serious, and one led to discontinuation ofguselkumab.

In two Phase III psoriatic arthritis clinical studies through Week 24, the number of patients thatreported 1 or more injection site reactions was low and slightly higher in the guselkumab groups thanin the placebo group; 5 (1.3%) patients in the guselkumab q8w group, 4 (1.1%) patients in theguselkumab q4w group, and 1 (0.3%) patient in the placebo group. One patient discontinuedguselkumab due to an injection site reaction during the placebo-controlled period of the psoriaticarthritis clinical studies. Through 1 year, the proportion of patients reporting 1 or more injection sitereactions was 1.6% and 2.4% in the guselkumab q8w and q4w groups, respectively. Overall, the rateof injections associated with injection site reactions observed in psoriatic arthritis clinical studiesthrough the placebo-controlled period was similar to rates observed in the psoriasis clinical studies.

In the Phase III ulcerative colitis maintenance clinical study through Week 44, the proportion ofpatients that reported 1 or more injection site reactions to guselkumab was 7.9% (2.5% of injections)in the guselkumab 200 mg subcutaneous q4w group (guselkumab 200 mg was administered as two100 mg injections in the Phase III ulcerative colitis maintenance clinical study) and no injection sitereactions in the guselkumab 100 mg subcutaneous q8w group. Most injection site reactions were mildand none were serious.

In Phase II and Phase III Crohn’s disease clinical studies through Week 48, the proportion of patientsthat reported 1 or more injection site reactions to guselkumab was 4.1% (0.8% of injections) in thetreatment group which received guselkumab 200 mg intravenous induction followed by 200 mgsubcutaneous q4w, and 1.4% (0.6% of injections) of patients in the guselkumab 200 mg intravenousinduction followed by 100 mg subcutaneous q8w group. Overall injection site reactions were mild;none were serious.

In a Phase III Crohn’s disease clinical study through Week 48, the proportion of patients that reported1 or more injection site reactions to guselkumab was 7% (1.3% of injections) in the treatment groupwhich received 400 mg subcutaneous induction followed by 200 mg subcutaneous q4w and 4.3%(0.7% of injections) of patients in the 400 mg guselkumab subcutaneous induction followed by100 mg subcutaneous q8w group. Most injection site reactions were mild; none were serious.

The immunogenicity of guselkumab was evaluated using a sensitive and drug-tolerant immunoassay.

In pooled Phase II and Phase III analyses in patients with psoriasis and psoriatic arthritis, 5% (n=145)of patients treated with guselkumab developed antidrug antibodies in up to 52 weeks of treatment. Ofthe patients who developed antidrug antibodies, approximately 8% (n=12) had antibodies that wereclassified as neutralising, which equates to 0.4% of all patients treated with guselkumab. In pooled

Phase III analyses in patients with psoriasis, approximately 15% of patients treated with guselkumabdeveloped antidrug antibodies in up to 264 weeks of treatment. Of the patients who developedantidrug antibodies, approximately 5% had antibodies that were classified as neutralising, whichequates to 0.76% of all patients treated with guselkumab. Antidrug antibodies were not associated withlower efficacy or development of injection site reactions.

In the Phase III paediatric study, 18% (n=21) of paediatric psoriasis patients treated with guselkumabdeveloped antidrug antibodies in up to week 44. Of the patients who developed antidrug antibodies,none had antibodies that were classified as neutralising. Antibodies to guselkumab were not associatedwith changes in pharmacokinetics, clinical efficacy or development of injection site reactions.

However, the number of patients who were positive for antibodies to guselkumab is too small fordefinitive conclusions about the impact on efficacy and safety of guselkumab.

In pooled Phase II and Phase III analyses in patients with ulcerative colitis, approximately 12% (n=58)of patients treated with guselkumab for up to 56 weeks developed antidrug antibodies. Of the patientswho developed antidrug antibodies, approximately 16% (n=9) had antibodies that were classified asneutralising, which equates to 2% of all patients treated with guselkumab. Antidrug antibodies werenot associated with lower efficacy or the development of injection site reactions.

In pooled Phase II and Phase III analyses up to Week 48 in patients with Crohn’s disease who weretreated with intravenous induction followed by subcutaneous maintenance dose regimen,approximately 5% (n=30) of patients treated with guselkumab developed antidrug antibodies. Of thepatients who developed antidrug antibodies, approximately 7% (n=2) had antibodies that wereclassified as neutralising antibodies, which equates to 0.3% of guselkumab treated patients. In a

Phase III analysis up to Week 48 in patients with Crohn’s disease who were treated with subcutaneousinduction followed by subcutaneous maintenance dose regimen, approximately 9% (n=24) of patientstreated with guselkumab developed antidrug antibodies. Of these patients, 13% (n=3) had antibodiesthat were classified as neutralising antibodies, which equates to 1% of guselkumab treated patients.

Antidrug antibodies were not associated with lower efficacy or development of injection site reactions.

Plaque psoriasis

The safety of guselkumab was assessed in a Phase III placebo- and active-controlled study inpaediatric patients with moderate to severe plaque psoriasis. This clinical study evaluated safety for upto 52 weeks in 120 patients 6 to 17 years of age. The safety profile for guselkumab subcutaneousinjection using the 45 mg/0.45 mL pre-filled pen or the 100 mg pre-filled syringe in paediatric patients6 to 17 years was consistent with the safety profile reported in the adult plaque psoriasis studies (seesection 4.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Guselkumab intravenous doses up to 1 200 mg as well as subcutaneous doses up to 400 mg at a singledosing visit have been administered in clinical studies without dose-limiting toxicity. In the event ofoverdose, the patient must be monitored for any signs or symptoms of adverse reactions andappropriate symptomatic treatment must be administered immediately.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC16.

Guselkumab is a human IgG1λ monoclonal antibody (mAb) that binds selectively to the interleukin 23(IL-23) protein with high specificity and affinity through the antigen binding site. IL-23 is a cytokinethat is involved in inflammatory and immune responses. By blocking IL-23 from binding to itsreceptor, guselkumab inhibits IL-23-dependent cell signalling and release of proinflammatorycytokines.

Levels of IL-23 are elevated in the skin of patients with plaque psoriasis. In in vitro models,guselkumab was shown to inhibit the bioactivity of IL-23 by blocking its interaction with cell surface

IL-23 receptor, disrupting IL-23-mediated signalling, activation and cytokine cascades. Guselkumabexerts clinical effects in plaque psoriasis and psoriatic arthritis through blockade of the IL-23 cytokinepathway.

Myeloid cells expressing Fc-gamma receptor 1 (CD64) have been shown to be a predominant sourceof IL-23 in inflamed tissue in psoriasis. Guselkumab has demonstrated in vitro blocking of IL-23 andbinding to CD64. These results indicate that guselkumab is able to neutralise IL-23 at the cellularsource of inflammation.

In a Phase I study, treatment with guselkumab resulted in reduced expression of IL-23/Th17 pathwaygenes and psoriasis-associated gene expression profiles, as shown by analyses of mRNA obtainedfrom lesional skin biopsies of patients with plaque psoriasis at Week 12 compared to baseline. In thesame Phase I study, treatment with guselkumab resulted in improvement of histological measures ofpsoriasis at Week 12, including reductions in epidermal thickness and T-cell density. In addition,reduced serum IL-17A, IL-17F and IL-22 levels compared to placebo were observed in guselkumabtreated patients in Phase II and Phase III plaque psoriasis studies. These results are consistent with theclinical benefit observed with guselkumab treatment in plaque psoriasis.

In psoriatic arthritis patients in Phase III studies, serum levels of acute phase proteins C-reactiveprotein, serum amyloid A, and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 wereelevated at baseline. Guselkumab decreased the levels of these proteins within 4 weeks of initiation oftreatment. Guselkumab further reduced the levels of these proteins by Week 24 compared to baselineand also to placebo.

Adult plaque psoriasis

The efficacy and safety of guselkumab was assessed in three randomised, double-blind, activecontrolled Phase III studies in adult patients with moderate to severe plaque psoriasis, who werecandidates for phototherapy or systemic therapy.

VOYAGE 1 and VOYAGE 2

Two studies (VOYAGE 1 and VOYAGE 2) evaluated the efficacy and safety of guselkumab versusplacebo and adalimumab in 1 829 adult patients. Patients randomised to guselkumab (N=825) received100 mg at Weeks 0 and 4, and every 8 weeks (q8w) thereafter through Week 48 (VOYAGE 1) and

Week 20 (VOYAGE 2). Patients randomised to adalimumab (N=582) received 80 mg at Week 0 and40 mg at Week 1, followed by 40 mg every other week (q2w) through Week 48 (VOYAGE 1) and

Week 23 (VOYAGE 2). In both studies, patients randomised to placebo (N=422) received guselkumab100 mg at Weeks 16, 20 and q8w thereafter. In VOYAGE 1, all patients, including those randomisedto adalimumab at Week 0, started to receive open-label guselkumab q8w at Week 52. In VOYAGE 2,patients randomised to guselkumab at Week 0 who were Psoriasis Area and Severity Index (PASI) 90responders at Week 28 were re-randomised to either continue treatment with guselkumab q8w(maintenance treatment) or receive placebo (withdrawal treatment). Withdrawal patients re-initiatedguselkumab (dosed at time of retreatment, 4 weeks later and q8w thereafter) when they experienced atleast a 50% loss of their Week 28 PASI improvement. Patients randomised to adalimumab at Week 0who were PASI 90 non-responders received guselkumab at Weeks 28, 32 and q8w thereafter. In

VOYAGE 2, all patients started to receive open-label guselkumab q8w at Week 76.

Baseline disease characteristics were consistent for the study populations in VOYAGE 1 and 2 with amedian body surface area (BSA) of 22% and 24%, a median baseline PASI score of 19 for bothstudies, a median baseline dermatology quality of life index (DLQI) score of 14 and 14.5, a baselineinvestigator global assessment (IGA) score of severe for 25% and 23% of patients, and a history ofpsoriatic arthritis for 19% and 18% of patients, respectively.

Of all patients included in VOYAGE 1 and 2, 32% and 29% were naïve to both conventional systemicand biologic therapy, 54% and 57% had received prior phototherapy, and 62% and 64% had receivedprior conventional systemic therapy, respectively. In both studies, 21% had received prior biologictherapy, including 11% who had received at least one anti-tumour necrosis factor alpha (TNFα) agent,and approximately 10% who had received an anti-IL-12/IL-23 agent.

The efficacy of guselkumab was evaluated with respect to overall skin disease, regional disease (scalp,hand and foot and nails) and quality of life and patient reported outcomes. The co-primary endpointsin VOYAGE 1 and 2 were the proportion of patients who achieved an IGA score of cleared orminimal (IGA 0/1) and a PASI 90 response at Week 16 versus placebo (see Table 4).

Overall skin disease

Treatment with guselkumab resulted in significant improvements in the measures of disease activitycompared to placebo and adalimumab at Week 16 and compared to adalimumab at Weeks 24 and 48.

The key efficacy results for the primary and major secondary study endpoints are shown in Table 4below.

Table 4: Summary of clinical responses in VOYAGE 1 and VOYAGE 2

Number of patients (%)

VOYAGE 1 VOYAGE 2

Placebo guselkumab adalimumab Placebo guselkumab adalimumab(N=174) (N=329) (N=334) (N=248) (N=496) (N=248)

Week 16

PASI 75 10 (5.7) 300 (91.2)a 244 (73.1)b 20 (8.1) 428 (86.3)a 170 (68.5)b

PASI 90 5 (2.9) 241 (73.3)c 166 (49.7)b 6 (2.4) 347 (70.0)c 116 (46.8)b

PASI 100 1 (0.6) 123 (37.4)a 57 (17.1)d 2 (0.8) 169 (34.1)a 51 (20.6)d

IGA 0/1 12 (6.9) 280 (85.1)c 220 (65.9)b 21 (8.5) 417 (84.1)c 168 (67.7)b

IGA 0 2 (1.1) 157 (47.7)a 88 (26.3)d 2 (0.8) 215 (43.3)a 71 (28.6)d

Week 24

PASI 75 - 300 (91.2) 241 (72.2)e - 442 (89.1) 176 (71.0)e

PASI 90 - 264 (80.2) 177 (53.0)b - 373 (75.2) 136 (54.8)b

PASI 100 - 146 (44.4) 83 (24.9)e - 219 (44.2) 66 (26.6)e

IGA 0/1 - 277 (84.2) 206 (61.7)b - 414 (83.5) 161 (64.9)b

IGA 0 - 173 (52.6) 98 (29.3)b - 257 (51.8) 78 (31.5)b

Week 48

PASI 75 - 289 (87.8) 209 (62.6)e - - -

PASI 90 - 251 (76.3) 160 (47.9)b - - -

PASI 100 - 156 (47.4) 78 (23.4)e - - -

IGA 0/1 - 265 (80.5) 185 (55.4)b - - -

IGA 0 - 166 (50.5) 86 (25.7)b - - -a p < 0.001 for comparison between guselkumab and placebo.b p < 0.001 for comparison between guselkumab and adalimumab for major secondary endpoints.c p < 0.001 for the comparisons between guselkumab and placebo for the co-primary endpoints.d comparisons between guselkumab and adalimumab were not performed.e p < 0.001 for comparison between guselkumab and adalimumab.

Response over time

Guselkumab demonstrated rapid onset of efficacy, with a significantly higher percent improvement in

PASI as compared with placebo as early as Week 2 (p < 0.001). The percentage of patients achieving a

PASI 90 response was numerically higher for guselkumab than adalimumab starting at Week 8 withthe difference reaching a maximum around Week 20 (VOYAGE 1 and 2) and maintained through

Week 48 (VOYAGE 1) (see Figure 1).

Figure 1: Percent of patients who achieved a PASI 90 response through week 48 by visit(patients randomised at week 0) in VOYAGE 1

In VOYAGE 1, for patients receiving continuous guselkumab treatment, the PASI 90 response ratewas maintained from Week 52 through Week 252. For patients randomised to adalimumab at Week 0who crossed over to guselkumab at Week 52, the PASI 90 response rate increased from Week 52through Week 76 and was then maintained through Week 252 (see Figure 2).

Figure 2: Percent of patients who achieved a PASI 90 response by visit in the open-label phasein VOYAGE 1

The efficacy and safety of guselkumab was demonstrated regardless of age, gender, race, body weight,plaques location, PASI baseline severity, concurrent psoriatic arthritis, and previous treatment with abiologic therapy. Guselkumab was efficacious in conventional systemic- naïve, biologic naïve, andbiologic-exposed patients.

In VOYAGE 2, 88.6% of patients receiving guselkumab maintenance treatment at Week 48 were

PASI 90 responders compared to 36.8% of patients who were withdrawn from treatment at Week 28(p < 0.001). Loss of PASI 90 response was noted as early as 4 weeks after withdrawal of guselkumabtreatment with a median time to loss of PASI 90 response of approximately 15 weeks. Among patientswho were withdrawn from treatment and subsequently re-initiated guselkumab, 80% regained a

PASI 90 response when assessed 20 weeks after initiation of retreatment.

In VOYAGE 2, among 112 patients randomised to adalimumab who failed to achieve a PASI 90response at Week 28, 66% and 76% achieved a PASI 90 response after 20 and 44 weeks of treatmentwith guselkumab, respectively. In addition, among 95 patients randomised to guselkumab who failedto achieve a PASI 90 response at Week 28, 36% and 41% achieved a PASI 90 response with anadditional 20 and 44 weeks of continued treatment with guselkumab, respectively. No new safetyfindings were observed in patients who switched from adalimumab to guselkumab.

Regional disease

In VOYAGE 1 and 2, significant improvements were seen in scalp, hand and foot, and nail psoriasis(as measured by the Scalp-specific Investigator Global Assessment [ss-IGA], Physician’s Global

Assessment of Hands and/or Feet [hf-PGA], Fingernail Physician’s Global Assessment [f-PGA] and

Nail Psoriasis Severity Index [NAPSI], respectively) in guselkumab treated patients compared toplacebo-treated patients at Week 16 (p < 0.001, Table 5). Guselkumab demonstrated superioritycompared to adalimumab for scalp and hand and foot psoriasis at Week 24 (VOYAGE 1 and 2) and

Week 48 (VOYAGE 1) (p ≤ 0.001, except for hand and foot psoriasis at Week 24 [VOYAGE 2] and

Week 48 [VOYAGE 1], p < 0.05).

Table 5: Summary of regional disease responses in VOYAGE 1 and VOYAGE 2

VOYAGE 1 VOYAGE 2guselkuma

Placebo guselkumab adalimumab Placebo adalimumabbss-IGA (N)a 145 277 286 202 408 194ss-IGA 0/1b, n (%)

Week 16 21 (14.5) 231 (83.4)c 201 (70.3)d 22 (10.9) 329 (80.6)c 130 (67.0)dhf-PGA (N)a 43 90 95 63 114 56hf-PGA 0/1b, n (%)

Week 16 6 (14.0) 66 (73.3)e 53 (55.8)d 9 (14.3) 88 (77.2)e 40 (71.4)df-PGA (N)a 88 174 173 123 246 124f-PGA 0/1, n (%)

Week 16 14 (15.9) 68 (39.1)e 88 (50.9)d 18 (14.6) 128 (52.0)e 74 (59.7)d

NAPSI (N)a 99 194 191 140 280 140

Percent Improvement, mean (SD)39.6

Week 16 -0.9 (57.9) 34.4 (42.4)e 38.0 (53.9)d 1.8 (53.8) 46.9 (48.1)d(45.6)ea Includes only patients with ss-IGA, f-PGA, hf-PGA score ≥ 2 at baseline or baseline NAPSI score > 0.b Includes only patients achieving ≥ 2-grade improvement from baseline in ss-IGA and/or hf-PGA.c p < 0.001 for comparison between guselkumab and placebo for the major secondary endpoint.d comparisons between guselkumab and adalimumab were not performed.e p < 0.001 for comparison between guselkumab and placebo.

Health-related quality of life/Patient reported outcomes

Across VOYAGE 1 and 2 significantly greater improvements in health-related quality of life asmeasured by Dermatology Life Quality Index (DLQI) and in patient-reported psoriasis symptoms(itching, pain, burning, stinging and skin tightness) and signs (skin dryness, cracking, scaling,shedding or flaking, redness and bleeding) as measured by the Psoriasis Symptoms and Signs Diary(PSSD) were observed in guselkumab patients compared to placebo patients at Week 16 (Table 6).

Signs of improvement on patient-reported outcomes were maintained through Week 24 (VOYAGE 1and 2) and Week 48 (VOYAGE 1). In VOYAGE 1, for patients receiving continuous guselkumabtreatment, these improvements were maintained in the open-label phase through Week 252 (Table 7).

Table 6: Summary of patient reported outcomes at week 16 in VOYAGE 1 and

VOYAGE 2

VOYAGE 1 VOYAGE 2

Placebo guselkumab adalimum Placebo guselkumab adalimumabab

DLQI, patients170 322 328 248 495 247with baseline score

Change from baseline, mean (standard deviation)

Week 16 -0.6 (6.4) -11.2 (7.2)c -9.3 (7.8)b -2.6 (6.9) -11.3 (6.8)c -9.7 (6.8)b

PSSD Symptomscore, patients with 129 248 273 198 410 200baseline score > 0

Symptom score = 0, n (%)

Week 16 1 (0.8) 67 (27.0)a 45 (16.5)b 0 112 (27.3)a 30 (15.0)b

PSSD Sign score,patients with 129 248 274 198 411 201baseline score > 0

Sign score = 0, n (%)

Week 16 0 50 (20.2)a 32 (11.7)b 0 86 (20.9)a 21 (10.4)ba p < 0.001 for comparison between guselkumab and placebo.b comparisons between guselkumab and adalimumab were not performed.c p < 0.001 for comparison between guselkumab and placebo for major secondary endpoints.

Table 7: Summary of patient reported outcomes in the open-label phase in VOYAGE 1guselkumab adalimumab-guselkumab

Week 76 Week 156 Week 252 Week 76 Week 156 Week 252

DLQI score > 1 at445 420 374 264 255 235baseline, n

Patients with DLQI 337 308 272 198 190 1740/1 (75.7%) (73.3%) (72.7%) (75.0%) (74.5%) (74.0%)

PSSD Symptom

Score, patients347 327 297 227 218 200with baseline score> 0

Symptom 136 130 126 99 96 96score = 0, n (%) (39.2%) (39.8%) (42.4%) (43.6%) (44.0%) (48.0%)

PSSD Sign score,patients with 347 327 297 228 219 201baseline score > 0

Sign score = 0, n 102 94 98 71 69 76(%) (29.4%) (28.7%) (33.0%) (31.1%) (31.5%) (37.8%)

In VOYAGE 2, guselkumab patients had significantly greater improvement from baseline comparedto placebo in health-related quality of life, anxiety and depression, and work limitation measures at

Week 16, as measured by the 36-item Short Form (SF-36) health survey questionnaire, Hospital

Anxiety and Depression Scale (HADS), and Work Limitations Questionnaire (WLQ), respectively.

The improvements in SF-36, HADS and WLQ were all maintained through Week 48 and in theopen-label phase through Week 252 among patients randomised to maintenance therapy at Week 28.

NAVIGATE

The NAVIGATE study examined the efficacy of guselkumab in patients who had an inadequateresponse (i.e., who had not achieved a ‘cleared’ or ‘minimal’ response defined as IGA ≥ 2) toustekinumab at Week 16. All patients (N=871) received open-label ustekinumab (45 mg ≤100 kg and90 mg >100 kg) at Weeks 0 and 4. At Week 16, 268 patients with an IGA ≥ 2 score were randomisedto either continue ustekinumab treatment (N=133) q12w, or to initiate guselkumab treatment (N=135)at Weeks 16, 20, and q8w thereafter. Baseline characteristics for randomised patients were similar tothose observed in VOYAGE 1 and 2.

After randomisation, the primary endpoint was the number of post-randomisation visits between

Weeks 12 and 24 at which patients achieved an IGA score 0/1 and had ≥ 2 grade improvement.

Patients were examined at four-week intervals for a total of four visits. Among patients whoinadequately responded to ustekinumab at the time of randomisation, significantly greaterimprovement of efficacy was observed in patients who switched to guselkumab treatment compared topatients who continued ustekinumab treatment. Between 12 and 24 weeks after randomisation,guselkumab patients achieved an IGA score 0/1 with ≥ 2 grade improvement twice as often asustekinumab patients (mean 1.5 vs 0.7 visits, respectively, p < 0.001). Additionally, at 12 weeks afterrandomisation a higher proportion of guselkumab patients compared to ustekinumab patients achievedan IGA score 0/1 and ≥ 2 grade improvement (31.1% vs. 14.3%, respectively; p = 0.001) and a

PASI 90 response (48% vs 23%, respectively, p < 0.001). Differences in response rates betweenguselkumab and ustekinumab-treated patients were noted as early as 4 weeks after randomisation(11.1% and 9.0%, respectively) and reached a maximum 24 weeks after randomisation (see Figure 3).

No new safety findings were observed in patients who switched from ustekinumab to guselkumab.

Figure 3: Percent of patients who achieved an IGA Score of cleared (0) or minimal (1) and atleast a 2-grade improvement in IGA from week 0 through week 24 by visit afterrandomisation in NAVIGATE

ECLIPSE

Efficacy and safety of guselkumab were also investigated in a double-blind study compared tosecukinumab. Patients were randomised to receive guselkumab (N=534; 100 mg at Week 0, 4 and q8wthereafter), or secukinumab (N=514; 300 mg at Week 0, 1, 2, 3, 4, and q4w thereafter). The last dosewas at week 44 for both treatment groups.

Baseline disease characteristics were consistent with a population of moderate to severe plaquepsoriasis with a median BSA of 20%, a median PASI score of 18, and an IGA score of severe for 24%of patients.

Guselkumab was superior to secukinumab as measured by the primary endpoint of PASI 90 responseat Week 48 (84.5% versus 70.0%, p < 0.001). Comparative PASI response rates are presented in

Table 8.

Table 8: PASI response rates in ECLIPSE

Number of patients (%)guselkumab (N=534) secukinumab (N=514)

Primary Endpoint

PASI 90 response at Week 48 451 (84.5%)a 360 (70.0%)

Major Secondary Endpoints

PASI 75 response at both Week 12452 (84.6%)b 412 (80.2%)and Week 48

PASI 75 response at Week 12 477 (89.3%)c 471 (91.6%)

PASI 90 response at Week 12 369 (69.1%)c 391 (76.1%)

PASI 100 response at Week 48 311 (58.2%)c 249 (48.4%)a p < 0.001 for superiorityb p < 0.001 for non-inferiority, p=0.062 for superiorityc formal statistical testing was not performed

Guselkumab and secukinumab PASI 90 response rates through Week 48 are presented in Figure 4.

Figure 4: Percent of patients who achieved a PASI 90 response through week 48 by visit(Patients randomised at Week 0) in ECLIPSE

The safety and efficacy of guselkumab were assessed in one multicentre, randomised, placebo- andactive biological comparator-controlled study (PROTOSTAR) in 120 paediatric patients 6 to 17 yearsof age with moderate to severe plaque psoriasis who were candidates for phototherapy or systemictherapy and were inadequately controlled by phototherapy and/or topical therapies. PROTOSTAR wasconducted in two parts. Part 1 consisted of a 16-week randomised, placebo and active comparator-controlled period followed by an uncontrolled period of withdrawal and retreatment or initiation oftreatment with guselkumab through Week 52. Part 2 consisted of an open-label guselkumab armthrough Week 52.

Enrolled patients had an IGA score of ≥3 on a 5-point scale of overall disease severity, a PASI ≥12,and a minimum affected BSA of ≥10%, and at least one of the following: 1) very thick lesions, 2)clinically relevant facial, genital, or hand/foot involvement, 3) PASI ≥20, 4) BSA >20%, or 5) IGA=4.

Subjects with guttate, erythrodermic, or pustular psoriasis were excluded.

In Part 1, 92 patients 6 to 17 years of age were randomised to receive subcutaneous injection of eitherguselkumab (n=41) or placebo (n=25) at Week 0, 4, and 12, or an active biological comparator (n=26)weekly. In Part 2, 28 additional adolescent patients 12 to 17 years of age were enrolled to receivesubcutaneous injection of guselkumab at Week 0, 4, and every 8 weeks thereafter. In the guselkumabgroup, patients with a body weight less than 70 kg received 1.3 mg/kg administered with the45 mg/0.45 mL pre-filled pen, and patients with a body weight of 70 kg or more received 100 mgadministered with the pre-filled syringe.

The co-primary endpoints were the proportion of patients who achieved a PASI 75 response and theproportion of patients who achieved an IGA score of 0 (“cleared”) or 1 (“minimal”) at Week 16.

Secondary endpoints included but were not limited to the proportion of patients who achieved a

PASI 90 response, an IGA score of 0 (“cleared”) or a PASI 100 response at Week 16.

Of the 92 patients in the controlled part of the study, baseline demographic characteristics weregenerally comparable across treatment groups. Overall, over 55% were male, 85% were white, themean body weight was approximately 57.3 kg, and the mean age was 12.9 years with 33% of thepatients less than 12 years.

The baseline disease characteristics were generally comparable across treatment groups with medianbaseline BSA of 20%, median baseline PASI score of approximately 17, and baseline IGA score ofsevere for 20% (placebo) and 24% (guselkumab) of patients, and a history of psoriatic arthritis for3.3% of patients.

Overall skin disease

Treatment with guselkumab resulted in significant improvements in the outcome measures of diseaseactivity compared to placebo at Week 16. The key efficacy results for the study endpoints are shownin Table 9 below.

Table 9: Summary of endpoints at week 16 in PROTOSTAR

Placebo Guselkumab(N=25) (N=41) P-value

IGA scores of cleared (0) or4 (16.0%) 27 (65.9%) <0.001minimal (1), n (%)

IGA scores of cleared (0), n (%) 1 (4.0%) 16 (39.0%) 0.004

PASI 75 responders, n (%) 5 (20.0%) 31 (75.6%) <0.001

PASI 90 responders, n (%) 4 (16.0%) 23 (56.1%) 0.003

PASI 100 responders, n (%) 0 14 (34.1%) 0.002

Change from baseline in CDLQI,a -1.88 (-3.81, 0.05) -7.28 (-8.87, -5.68) <0.001

LSMean (95% CI)

CDLQI = Children’s Dermatology Life Quality Indexa LSMean = least squares mean

Beyond the 16-week placebo-controlled period in Part 1 of PROTOSTAR, the guselkumab treatedpatients who achieved PASI 90 at Week 16 were withdrawn from treatment. Loss of PASI 90 responsewas noted as early as 12 weeks after withdrawal of guselkumab treatment with a median time to lossof PASI 90 response of approximately 24 weeks. Of the guselkumab treated patients who failed toachieve a PASI 90 response at Week 16, 72.2% of patients that received an additional 32 weeks ofcontinued guselkumab treatment were PASI 75 responders at Week 52, and 61.1% achieved a

PASI 90 response at Week 52.

In patients randomised to placebo at Week 0 who failed to achieve a PASI 90 response at Week 16and crossed over to receive guselkumab 95.0% and 65.0% achieved PASI 75 and PASI 90 response,respectively, at Week 52.

Steady-state serum trough concentrations of guselkumab were achieved by Week 20 in paediatricpatients 6 to 17 years of age with moderate to severe plaque psoriasis treated with guselkumabsubcutaneous injection using the 45 mg/0.45 mL pre-filled pen or the 100 mg pre-filled syringe (seesection 4.2), and were within the range of those observed in adults.

The recommended dosing regimen results in similar predicted serum guselkumab exposure inpaediatric patients with plaque psoriasis as compared to adults across the body weight range.

Adult population

Following a single 100 mg subcutaneous injection in healthy subjects, guselkumab reached a mean(± SD) maximum serum concentration (Cmax) of 8.09 ± 3.68 mcg/mL by approximately 5.5 days postdose. The absolute bioavailability of guselkumab following a single 100 mg subcutaneous injectionwas estimated to be approximately 49% in healthy subjects.

In patients with plaque psoriasis, following subcutaneous administrations of guselkumab 100 mg at

Weeks 0 and 4, and every 8 weeks thereafter, steady-state serum guselkumab concentrations wereachieved by Week 20. The mean (± SD) steady-state trough serum guselkumab concentrations in two

Phase III studies in patients with plaque psoriasis were 1.15 ± 0.73 mcg/mL and 1.23 ± 0.84 mcg/mL.

Mean volume of distribution during the terminal phase (Vz) following a single intravenousadministration to healthy subjects ranged from approximately 7 to 10 L across studies.

The exact pathway through which guselkumab is metabolised has not been characterised. As a human

IgG mAb, guselkumab is expected to be degraded into small peptides and amino acids via catabolicpathways in the same manner as endogenous IgG.

Mean systemic clearance (CL) following a single intravenous administration to healthy subjectsranged from 0.288 to 0.479 L/day across studies. Mean half-life (T1/2) of guselkumab wasapproximately 17 days in healthy subjects and approximately 15 to 18 days in patients with plaquepsoriasis across studies.

Population pharmacokinetic analyses indicated that concomitant use of NSAIDs, oral corticosteroidsand csDMARDs such as MTX, did not affect the clearance of guselkumab.

The systemic exposure of guselkumab (Cmax and AUC) increased in an approximatelydose-proportional manner following a single subcutaneous injection at doses ranging from 10 mg to300 mg in healthy subjects or patients with plaque psoriasis.

No specific study has been conducted to determine the effect of renal or hepatic impairment on thepharmacokinetics of guselkumab. Renal elimination of intact guselkumab, an IgG mAb, is expected tobe low and of minor importance; similarly, hepatic impairment is not expected to influence clearanceof guselkumab as IgG mAbs are mainly eliminated via intracellular catabolism. Based on populationpharmacokinetic analyses in adults, creatinine clearance or hepatic function did not have a meaningfulimpact on guselkumab clearance.

Clearance and volume of distribution of guselkumab increases as body weight increases and doses areadjusted for body weight up 40 kg.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeat-dose toxicity, toxicity to reproduction and pre- and post-natal development.

In repeat-dose toxicity studies in cynomolgus monkeys, guselkumab was well tolerated viaintravenous and subcutaneous routes of administration. A weekly subcutaneous dose of 50 mg/kg tomonkeys resulted in exposure (AUC) values that were at least 23 times the maximum clinicalexposures following a dose of 200 mg given intravenously. Additionally, there were no adverseimmunotoxicity or cardiovascular safety pharmacology effects noted during the conduct of therepeat-dose toxicity studies or in a targeted cardiovascular safety pharmacology study in cynomolgusmonkeys.

There were no preneoplastic changes observed in histopathology evaluations of animals treated up to24-weeks, or following the 12-week recovery period during which active substance was detectable inthe serum.

No mutagenicity or carcinogenicity studies were conducted with guselkumab.

Guselkumab could not be detected in breast milk from cynomolgus monkeys as measured at post-natalday 28.

Histidine

Histidine monohydrochloride monohydrate

Polysorbate 80 (E433)

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the pre-filled pen in the outer carton in order to protect from light.

0.45 mL solution in a pre-filled glass syringe assembled in a single use, pre-filled pen with anautomatic needle guard and an adjustable dose selection plunger.

Tremfya is available in packs containing one pre-filled pen.

After removing the pre-filled pen from the refrigerator, keep the pre-filled pen inside the carton andallow to reach room temperature by waiting for 30 minutes before injecting Tremfya. The pre-filledpen should not be shaken.

Prior to use, a visual inspection of the pre-filled pen is recommended. The solution should be clear,colourless to light yellow, and may contain a few small white or clear particles. Tremfya should not beused if the solution is cloudy or discoloured, or contains large particles.

Each pack is provided with an ‘Instructions for use’ leaflet that fully describes the preparation andadministration of the pre-filled pen.

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

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/17/1234/012 1 pre-filled pen

Date of first authorisation: 10 November 2017

Date of latest renewal: 15 July 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu