Leaflet TREMFYA 200mg solution for injection in pre-filled pen
Indicated for: autoimmune inflammatory diseases
Route of administration: injectable
Substance: guselkumab (monoclonal antibody)
ATC: L04AC16 (Antineoplastic and immunomodulating agents | Immunosuppressants | Interleukin inhibitors)
Risk of severe allergic reaction. Seek urgent medical help if serious symptoms occur.
This medicine is subject to additional monitoring.
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
Guselkumab is a monoclonal antibody used for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis. It works by blocking interleukin-23 (IL-23), a protein involved in the chronic inflammation associated with these conditions.
The medication is administered via subcutaneous injection, usually once every few weeks, as directed by a physician. Guselkumab has shown high efficacy in reducing skin lesions and joint symptoms.
Common side effects include upper respiratory tract infections, headaches, and injection site reactions. It is important for patients to be monitored for signs of infections or other complications.
Guselkumab provides a modern and effective option for patients with psoriasis and psoriatic arthritis, helping to improve their quality of life.
General data about TREMFYA 200mg
- Substance: guselkumab
- Date of latest medicines list: 01-11-2025
- Product code: W71368002
- Concentration: 200mg
- Pharmaceutical form: solution for injection in pre-filled pen
- Quantity: 2
- Product type: Original
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for guselkumab
Concentrations available for guselkumab
- 100mg
- 200mg
- 45mg/0.45ml
Leaflet TREMFYA 200mg
Contents of the package leaflet for the medicine TREMFYA 200mg solution for injection in pre-filled pen
1. NAME OF THE MEDICINAL PRODUCT
Tremfya 200 mg solution for injection in pre-filled syringe
Tremfya 200 mg solution for injection in pre-filled pen
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Tremfya 200 mg solution for injection in pre-filled syringe
Each pre-filled syringe contains 200 mg of guselkumab in 2 mL solution.
Tremfya 200 mg solution for injection in pre-filled pen
Each pre-filled pen contains 200 mg of guselkumab in 2 mL solution.
Guselkumab is a fully human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody (mAb)produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.
Excipient(s) with known effectThis medicinal product contains 1 mg of polysorbate 80 (E433) in each pre-filled syringe/pre-filledpen which is equivalent to 0.5 mg/mL.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection)
Solution for injection (injection) in pre-filled pen (PushPen)
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.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Tremfya is indicated for the treatment of adult patients with moderately to severely active ulcerativecolitis who have had an inadequate response, lost response, or were intolerant to either conventionaltherapy, or a biologic treatment.
Crohn’s diseaseTremfya is indicated for the treatment of adult patients with moderately to severely active Crohn’sdisease who have had an inadequate response, lost response, or were intolerant to either conventionaltherapy or a biologic treatment.
4.2 Posology and method of administration
This medicinal product is intended for use under the guidance and supervision of a physicianexperienced in the diagnosis and treatment of conditions for which it is indicated.
PosologyUlcerative colitis
Either of the following two induction dose regimens are recommended:
- 200 mg administered by intravenous infusion at Week 0, Week 4 and Week 8. See SmPC for
Tremfya 200 mg concentrate for solution for infusion.or
- 400 mg administered by subcutaneous injection (given as two consecutive injections of 200 mgeach) at Week 0, Week 4 and Week 8.
After completion of the induction dose regimen, the recommended maintenance dose starting at
Week 16 is 100 mg administered by subcutaneous injection every 8 weeks (q8w). Alternatively, forpatients who do not show adequate therapeutic benefit to induction treatment according to clinicaljudgement, a maintenance dose of 200 mg administered by subcutaneous injection starting at Week 12and every 4 weeks (q4w) thereafter, may be considered (see section 5.1). For the 100 mg dose, see
SmPC for Tremfya 100 mg solution for injection.
Immunomodulators and/or corticosteroids may be continued during treatment with guselkumab. Inpatients who have responded to treatment with guselkumab, corticosteroids may be reduced ordiscontinued in accordance with standard of care.
Consideration should be given to discontinuing treatment in patients who have shown no evidence oftherapeutic benefit after 24 weeks of treatment.
Crohn’s diseaseEither of the following two induction dose regimens are recommended:
- 200 mg administered by intravenous infusion at Week 0, Week 4, and Week 8. See SmPC for
Tremfya 200 mg concentrate for solution for infusion.or
- 400 mg administered by subcutaneous injection (given as two consecutive injections of 200 mgeach) at Week 0, Week 4 and Week 8.
After completion of the induction dose regimen, the recommended maintenance dose starting at
Week 16 is 100 mg administered by subcutaneous injection every 8 weeks (q8w). Alternatively, forpatients who do not show adequate therapeutic benefit to induction treatment according to clinicaljudgement, a maintenance dose regimen of 200 mg administered by subcutaneous injection starting at
Week 12 and every 4 weeks (q4w) thereafter, may be considered (see section 5.1). For the 100 mgdose, see SmPC for Tremfya 100 mg solution for injection.
Immunomodulators and/or corticosteroids may be continued during treatment with guselkumab. Inpatients who have responded to treatment with guselkumab, corticosteroids may be reduced ordiscontinued in accordance with standard of care.
Consideration should be given to discontinuing treatment in patients who have shown no evidence oftherapeutic benefit after 24 weeks of treatment.
Missed doseIf a dose is missed, the dose should be administered as soon as possible. Thereafter, dosing should beresumed at the regular scheduled time.
Special populationsElderly
No dose adjustment is required (see section 5.2).
There is limited information in patients aged ≥ 65 years and very limited information in patients aged≥ 75 years (see section 5.2).
Renal or hepatic impairmentTremfya 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.
Paediatric populationThe safety and efficacy of Tremfya in children and adolescents with ulcerative colitis and Crohn’sdisease below the age of 18 years have not been established. No data are available.
Method of administrationSubcutaneous use only. Sites for injection include the abdomen, thigh and back of the upper arm.
Tremfya should not be injected into areas where the skin is tender, bruised, red, hard, thick or scaly.
After proper training in subcutaneous injection technique, patients may inject Tremfya if a physiciandetermines that this is appropriate. However, the physician should ensure appropriate medicalfollow-up of patients. Patients should be instructed to inject the full amount of solution according tothe ‘Instructions for use’ provided in the carton.
For instructions on preparation of the medicinal product before administration, see section 6.6.
4.3 Contraindications
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).
4.4 Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
InfectionsGuselkumab 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.
HypersensitivitySerious 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).
When prescribing guselkumab q4w in psoriatic arthritis, it is recommended to evaluate liver enzymesat baseline and thereafter according to routine patient management. If increases in alanineaminotransferase [ALT] or aspartate aminotransferase [AST] are observed and drug-induced liverinjury is suspected, treatment should be temporarily interrupted until this diagnosis is excluded.
ImmunisationsPrior to initiating therapy, completion of all 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.
Excipients with known effectPolysorbate 80 content
This medicinal product contains 1 mg of polysorbate 80 (E433) in each pre-filled syringe/pre-filledpen which is equivalent to 0.5 mg/mL. Polysorbates may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
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. In psoriatic arthritis studies,concomitant methotrexate (MTX) use did not appear to influence the safety or efficacy of guselkumab.
In ulcerative colitis and Crohn’s disease studies, concomitant use of immunomodulators (e.g.,azathioprine [AZA], 6-mercaptopurine [6-MP]) or corticosteroids did not appear to influence thesafety or efficacy of guselkumab.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential should use effective methods of contraception during treatment andfor at least 12 weeks after treatment.
PregnancyThere 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.
Breast-feedingIt 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.
FertilityThe 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).
4.7 Effects on ability to drive and use machines
Tremfya has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
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.
Tabulated list of adverse reactionsTable 1 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 1: 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
Description of selected adverse reactionsTransaminases 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%). Through1 year, adverse reactions of increased transaminases (as above) were reported in 12.9% of patients inthe q4w 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 2). 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 2: 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.
Injection site reactionsIn 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 rate ofinjections associated with injection site reactions observed in psoriatic arthritis clinical studies throughthe 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.
ImmunogenicityThe 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 pooled Phase II and Phase III analyses in patients with ulcerative colitis who were treated withintravenous induction followed by subcutaneous maintenance, approximately 12% (n=58) of patientstreated with guselkumab for up to 56 weeks developed antidrug antibodies. Of the patients whodeveloped antidrug antibodies, approximately 16% (n=9) had antibodies that were classified asneutralising, which equates to 2% of all patients treated with guselkumab. In a Phase III analysis up to
Week 24 in patients with ulcerative colitis who were treated with subcutaneous induction followed bysubcutaneous maintenance, approximately 9% (n=24) of patients treated with guselkumab developedantidrug antibodies. Of the patients who developed antidrug antibodies, 13% (n=3) had antibodies thatwere classified as neutralising antibodies, which equates to 1% of guselkumab treated patients.
Antidrug antibodies were not associated with lower efficacy or the development of injection sitereactions.
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 withsubcutaneous induction followed by subcutaneous maintenance dose regimen, approximately 9%(n=24) of patients treated with guselkumab developed antidrug antibodies. Of these patients, 13%(n=3) had antibodies that were classified as neutralising antibodies, which equates to 1% ofguselkumab treated patients. Antidrug antibodies were not associated with lower efficacy ordevelopment of injection site reactions.
Reporting of suspected adverse reactionsReporting 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.
4.9 Overdose
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC16.
Mechanism of actionGuselkumab 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 patients with ulcerativecolitis or Crohn’s disease, levels of IL-23 are elevated in the colon tissue. 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, psoriatic arthritis, ulcerative colitis, and Crohn’s diseasethrough blockade of the IL-23 cytokine pathway.
Myeloid cells expressing Fc-gamma receptor 1 (CD64) have been shown to be a predominant sourceof IL-23 in inflamed tissue in psoriasis, ulcerative colitis, and Crohn’s disease. Guselkumab hasdemonstrated in vitro blocking of IL-23 and binding to CD64. These results indicate that guselkumabis able to neutralise IL-23 at the cellular source of inflammation.
Pharmacodynamic effectsIn 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.
In patients with ulcerative colitis or Crohn’s disease, guselkumab treatment led to decreases ininflammatory markers including C-reactive protein (CRP) and faecal calprotectin through induction
Week 12, which were sustained through one year of maintenance treatment. Serum protein levels of
IL-17A, IL-22 and IFNγ were reduced as early as Week 4, and continued to decrease throughinduction Week 12. Guselkumab also reduced colon mucosal biopsy RNA levels of IL-17A, IL-22 and
IFNγ at Week 12.
Clinical efficacy and safetyUlcerative colitis
The efficacy and safety of guselkumab were evaluated in three Phase III multicentre, randomised,double-blind, placebo-controlled studies (QUASAR intravenous induction study, QUASARmaintenance study, and ASTRO subcutaneous induction study) in adult patients with moderately toseverely active ulcerative colitis who had an inadequate response, loss of response, or intolerance tocorticosteroids, conventional immunomodulators (AZA, 6-MP), biologic therapy (TNF blockers,vedolizumab), a Janus kinase (JAK) inhibitor, and/or sphingosine-1-phosphate receptor modulators(S1PRM) applicable only for ASTRO. In addition, efficacy and safety of guselkumab were evaluatedin a randomised, double-blind, placebo-controlled, Phase IIb induction dose-finding study (QUASARinduction dose-ranging study) that enrolled a similar ulcerative colitis patient population as the
Phase III induction study.
Disease activity was assessed by the modified Mayo score (mMS), a 3-component Mayo score (0-9)which consists of the sum of the following subscores (0 to 3 for each subscore): stool frequency (SFS),rectal bleeding (RBS), and findings on centrally reviewed endoscopy (ES). Moderately to severelyactive ulcerative colitis was defined as a mMS between 5 and 9, a RBS ≥ 1, and an ES of 2 (defined bymarked erythema, absent vascular pattern, friability, and/or erosions) or an ES of 3 (defined byspontaneous bleeding and ulceration).
Induction study: QUASAR IS
In the induction study QUASAR IS, patients were randomised in a 3:2 ratio to receive eitherguselkumab 200 mg or placebo by intravenous infusion at Week 0, Week 4, and Week 8. A total of701 patients were evaluated. At baseline the median mMS was 7, with 35.5% of patients having abaseline mMS of 5 to 6 and 64.5% having a mMS of 7 to 9, and 67.9% of patients with a baseline ESof 3. The median age was 39 years (ranging from 18 to 79 years); 43.1% were female; and 72.5%identified as White, 21.4% as Asian and 1% as Black.
Enrolled patients were permitted to use stable doses of oral aminosalicylates, MTX, 6-MP, AZAand/or oral corticosteroids. At baseline, 72.5% of patients were receiving aminosalicylates, 20.8% ofpatients were receiving immunomodulators (MTX, 6-MP, or AZA), and 43.1% of patients werereceiving corticosteroids. Concomitant biologic therapies or JAK inhibitors were not permitted.
A total of 49.1% of patients had previously failed at least one biologic therapy, and/or JAK inhibitor.
Of these patients, 87.5%, 54.1% and 18% had previously failed a TNF blocker, vedolizumab or a JAKinhibitor, respectively, and 47.4% had failed treatment with 2 or more of these therapies. A total of48.4% of patients were biologic and JAK inhibitor naïve, and 2.6% had previously received but hadnot failed a biologic or JAK inhibitor.
The primary endpoint was clinical remission as defined by the mMS at Week 12. Secondary endpointsat Week 12 included symptomatic remission, endoscopic healing, clinical response, histologicendoscopic mucosal healing, fatigue response and IBDQ remission (Table 3).
Significantly greater proportions of patients were in clinical remission at Week 12 in the guselkumabtreated group compared to the placebo group.
Table 3: Proportion of patients meeting efficacy endpoints at Week 12 in QUASAR IS
Endpoint Placebo Guselkumab Treatment% 200 mg intravenous Differenceinductiona (95% CI)%
Clinical remissionb
Total population 8% (N=280) 23% (N=421) 15% (10%, 20%)c
Biologic and JAK inhibitor 12% (N=137) 32% (N=202) 20% (12%, 28%)naïved
Prior biologic and/or JAK 4% (N=136) 13% (N=208) 9% (3%, 14%)inhibitor failuree
Symptomatic remissionf
Total population 21% (N=280) 50% (N=421) 29% (23%, 36%)c
Biologic and JAK inhibitor 26% (N=137) 60% (N=202) 34% (24%, 44%)naïved
Prior biologic and/or JAK 14% (N=136) 38% (N=208) 24% (16%, 33%)inhibitor failuree
Endoscopic healingg
Total population 11% (N=280) 27% (N=421) 16% (10%, 21%)c
Biologic and JAK inhibitor 17% (N=137) 38% (N=202) 21% (12%, 30%)naïved
Prior biologic and/or JAK 5% (N=136) 15% (N=208) 10% (4%, 16%)inhibitor failuree
Clinical responseh
Total population 28% (N=280) 62% (N=421) 34% (27%, 41%)c
Biologic and JAK inhibitor 35% (N=137) 71% (N=202) 36% (26%, 46%)naïved
Prior biologic and/or JAK 20% (N=136) 51% (N=208) 32% (22%, 41%)inhibitor failuree
Histologic endoscopic mucosal healingi
Total Population 8% (N=280) 24% (N=421) 16% (11%, 21%)c
Biologic and JAK inhibitor 11% (N=137) 33% (N=202) 22% (13%, 30%)naïved
Prior biologic and/or JAK 4% (N=136) 13% (N=208) 9% (3%, 15%)inhibitor failuree
Fatigue responsej
Total population 21% (N=280) 41% (N=421) 20% (13%, 26%)c
Biologic and JAK inhibitor 29% (N=137) 42% (N=202) 12% (2%, 23%)naïved
Prior biologic and/or JAK 13% (N=136) 38% (N=208) 25% (17%, 34%)inhibitor failuree
IBDQ remissionk
Total population 30% (N=280) 51% (N=421) 22% (15%, 29%)c
Biologic and JAK inhibitor 34% (N=137) 62% (N=202) 28% (18%, 38%)naïved
Prior biologic and/or JAK 24% (N=136) 39% (N=208) 15% (5%, 25%)inhibitor failureea Guselkumab 200 mg as an intravenous induction at Week 0, Week 4, and Week 8.b A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0or 1 with no friability.c p < 0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method (adjusted for stratification factors:
biologic and/or JAK-inhibitor failure status and concomitant use of corticosteroids at baseline).d An additional 7 patients in the placebo group and 11 patients in the guselkumab group were previously exposed to but did not fail abiologic or JAK inhibitor.e Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) and/or a Janus kinase(JAK) inhibitor for ulcerative colitis.f A stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0.g An endoscopy subscore of 0 or 1 with no friability.h Decrease from induction baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a ≥ 1-point decrease frombaseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.i A combination of histologic healing [neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations orgranulation tissue according to the Geboes grading system] and endoscopic healing as defined above.j Fatigue was assessed using the PROMIS-Fatigue Short form 7a. Fatigue response was defined as a ≥ 7-point improvement frombaseline which is considered clinically meaningful.k Total Inflammatory Bowel Disease Questionnaire score ≥ 170.
QUASAR IS and QUASAR induction dose-ranging study also enrolled 48 patients with a baselinemMS of 4, including an ES of 2 or 3 and a RBS ≥ 1. In patients with a baseline mMS of 4,guselkumab efficacy relative to placebo, as measured by clinical remission, clinical response, andendoscopic healing at Week 12, was consistent with the total moderately to severely active ulcerativecolitis population.
Rectal bleeding and stool frequency subscores
Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 inpatients treated with guselkumab and continued to decrease through Week 12.
Maintenance study: QUASAR MS
The QUASAR MS evaluated 568 patients who achieved clinical response at 12 weeks following theintravenous administration of guselkumab in either QUASAR IS or from the QUASAR inductiondose-ranging study. In the QUASAR MS, these patients were randomised to receive a subcutaneousmaintenance regimen of either guselkumab 100 mg every 8 weeks, guselkumab 200 mg every 4 weeksor placebo for 44 weeks.
The primary endpoint was clinical remission as defined by mMS at Week 44. Secondary endpoints at
Week 44 included but were not limited to symptomatic remission, endoscopic healing, corticosteroid-free clinical remission, histologic endoscopic mucosal healing, fatigue response and IBDQ remission(Table 4).
Significantly greater proportions of patients were in clinical remission at Week 44 in both guselkumabtreated groups compared to the placebo.
Table 4: Proportion of patients meeting efficacy endpoints at Week 44 in QUASAR MS
Endpoint Placebo Guselkumab Guselkumab Treatment Difference% 100 mg q8w 200 mg q4w (95% CI)subcutaneous subcutaneous Guselkumab Guselkumabinjectiona injectionb 100 mg 200 mg% %
Clinical remissionc
Total populationd 19% (N=190) 45% (N=188) 50% (N=190) 25% 30%(16%, 34%)e (21%, 38%)e
Biologic and JAK- 26% (N=108) 50% (N=105) 58% (N=96) 24% 29%inhibitor naïvef (12%, 36%) (17%, 41%)
Prior biologic and/or 8% (N=75) 40% (N=77) 40% (N=88)30% 32%
JAK-inhibitorg (19%, 42%) (21%, 44%)failure
Symptomatic remissionh
Total populationd 37% (N=190) 70% (N=188) 69% (N=190) 32% 31%(23%, 41%)e (21%, 40%)e
Biologic and JAK- 46% (N=108) 74% (N=105) 76% (N=96) 28% 28%inhibitor naïvef (15%, 40%) (15%, 41%)
Prior biologic and/or 24% (N=75) 65% (N=77) 60% (N=88)39% 37%
JAK-inhibitorg (26%, 52%) (23%, 50%)failure
Corticosteroid-free clinical remissioni
Total populationd 18% (N=190) 45% (N=188) 49% (N=190) 26% 29%(17%, 34%)e (20%, 38%)e
Biologic and JAK- 26% (N=108) 50% (N=105) 56% (N=96) 24% 27%inhibitor naïvef (12%, 36%) (14%, 39%)
Prior biologic and/or 7% (N=75) 40% (N=77) 40% (N=88)32% 34%
JAK-inhibitorg (21%, 43%) (23%, 45%)failure
Endoscopic healingj
Total populationd 19% (N=190) 49% (N=188) 52% (N=190) 30% 31%(21%, 38%)e (22%, 40%)e
Biologic and JAK- 26% (N=108) 53% (N=105) 59% (N=96) 27% 30%inhibitor naïvef (15%, 40%) (18%, 42%)
Prior biologic and/or 8% (N=75) 45% (N=77) 42% (N=88)36% 35%
JAK-inhibitor failureg (24%, 48%) (23%, 46%)
Histologic endoscopic mucosal healingk
Total populationd 17% (N=190) 44% (N=188) 48% (N=190) 26% 30%(17%, 34%)e (21%, 38%)e
Biologic and JAK- 23% (N=108) 50% (N=105) 56% (N=96) 26% 30%inhibitor naïvef (14%, 38%) (17%, 42%)
Prior biologic and/or 8% (N=75) 38% (N=77) 39% (N=88)28% 31%
JAK-inhibitorg (16%, 39%) (20%, 43%)failure
Clinical responsel
Total populationd 43% (N=190) 78% (N=188) 75% (N=190) 34% 31%(25%, 43%)e (21%, 40%)e
Biologic and JAK- 54% (N=108) 83% (N=105) 81% (N=96) 29% 26%inhibitor naïvef (17%, 41%) (14%, 39%)
Prior biologic and/or 28% (N=75) 70% (N=77) 67% (N=88)41% 39%
JAK-inhibitorg (27%, 54%) (26%, 53%)failure
Maintenance of Clinical Remission at Week 44 in patients who achieved clinical remission 12 weeksafter induction
Total populationq 34% (N=59) 61% (N=66) 72% (N=69) 26% 38%(9%, 43%)m (23%, 54%)e
Biologic and JAK- 34% (N=41) 65% (N=43) 79% (N=48) 31% 45%inhibitor naïver (9%, 51%) (25%, 62%)
Prior biologic and/or 27% (N=15) 60% (N=20) 56% (N=18)33% 29%
JAK-inhibitorg (-1%, 62%) (-6%, 59%)failure
Endoscopic normalisationn
Total populationd 15% (N=190) 35% (N=188) 34% (N=190) 18% 17%(10%, 27%)e (9%, 25%)e
Biologic and JAK- 20% (N=108) 38% (N=105) 42% (N=96) 17% 17%inhibitor naïve f (6%, 29%) (6%, 29%)
Prior biologic and/or 8% (N=75) 31% (N=77) 24% (N=88)21% 16%
JAK-inhibitorg (10%, 33%) (6%, 26%)failure
Fatigue responseo
Total population d 29% (N=190) 51% (N=188) 43% (N=190) 20% 13%(11%, 29%)e (3%, 22%)m
Biologic and JAK- 36% (N=108) 51% (N=105) 53% (N=96) 15% 16%inhibitor naïvef (2%, 28%) (3%, 29%)
Prior biologic and/or 19% (N=75) 47% (N=77) 32% (N=88)27% 13%
JAK-inhibitorg (13%, 40%) (1%, 26%)failure
IBDQ remissionp
Total populationd 37% (N=190) 64% (N=188) 64% (N=190) 26% 26%(17%, 36%)e (16%, 35%)e
Biologic and JAK- 49% (N=108) 68% (N=105) 74% (N=96) 19% 24%inhibitor naïve f (6%, 32%) (11%, 37%)
Prior biologic and/or 19% (N=75) 58% (N=77) 53% (N=88)38% 35%
JAK-inhibitorg (26%, 50%) (23%, 48%)failurea Guselkumab 100 mg as a subcutaneous injection every 8 weeks after the induction regimen.b Guselkumab 200 mg as a subcutaneous injection every 4 weeks after the induction regimen.c A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0or 1 with no friability.d Patients who achieved clinical response 12 weeks following the intravenous administration of guselkumab in either QUASARinduction study or QUASAR induction dose-ranging study.e p <0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomisationstratification factors.f An additional 7 patients in the placebo group, 6 patients in the guselkumab 100 mg group, and 6 patients in the guselkumab 200 mggroup were previously exposed to but did not fail a biologic or JAK inhibitor.g Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) and/or a Janus kinase[JAK] inhibitor for ulcerative colitis.h A stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0.i Not requiring any treatment with corticosteroids for at least 8 weeks prior to Week 44 and also meeting the criteria for clinicalremission at Week 44.j An endoscopy subscore of 0 or 1 with no friability.k A combination of histologic healing [neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations orgranulation tissue according to the Geboes grading system] and endoscopic healing as defined above.l Decrease from induction baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a ≥ 1-point decrease frombaseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.m p < 0.01, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomisation stratificationfactorsn An endoscopy subscore of 0.o Fatigue was assessed using the PROMIS-Fatigue Short form 7a. Fatigue response was defined as a ≥ 7-point improvement frominduction baseline which is considered clinically meaningful.p Total Inflammatory Bowel Disease Questionnaire score ≥ 170.q Subjects who achieved clinical remission 12 weeks following intravenous administration of guselkumab in either QUASARinduction study or QUASAR induction dose-ranging study.r An additional 3 patients in the placebo group, 3 patients in the guselkumab 100 mg group, and 3 patients in the guselkumab 200 mggroup were previously exposed to but did not fail a biologic or JAK inhibitor.
In QUASAR IS and QUASAR MS, the efficacy and safety of guselkumab was consistentlydemonstrated regardless of age, sex, race, body weight, and previous treatment with a biologic therapyor JAK inhibitor.
In QUASAR MS, patients with high inflammatory burden after completion of induction dosingderived additional benefit from guselkumab 200 mg subcutaneous q4w compared to 100 mgsubcutaneous q8w dosing. Clinically meaningful numerical differences of > 15% were observedbetween the two guselkumab dose groups among patients with a CRP level of > 3 mg/L aftercompletion of induction dosing for the following endpoints at Week 44: clinical remission (48%200 mg q4w vs. 30% 100 mg q8w), maintenance of clinical remission (88% 200 mg q4w vs. 50%100 mg q8w), corticosteroid-free clinical remission (46% 200 mg q4w vs. 30% 100 mg q8w),endoscopic healing (52% 200 mg q4w vs. 35% 100 mg q8w), and histologic-endoscopic mucosalhealing (46% 200 mg q4w vs. 29% 100 mg q8w).
QUASAR MS enrolled 31 patients with an induction baseline mMS of 4, including an ES of 2 or 3and a RBS ≥ 1 who achieved clinical response 12 weeks following the intravenous administration ofguselkumab in QUASAR IS or QUASAR induction dose-ranging study. In these patients, guselkumabefficacy relative to placebo as measured by clinical remission, clinical response, and endoscopichealing at Week 44 was consistent with the total population.
Symptomatic remission over time
In QUASAR MS symptomatic remission defined as stool frequency subscore of 0 or 1 and notincreased from induction baseline, and a rectal bleeding subscore of 0 was sustained through Week 44in both guselkumab treatment groups, while a decline was observed in the placebo group (Figure 1):
Figure 1: Proportion of patients in symptomatic remission through Week 44 in QUASAR MS
Week 24 responders to guselkumab extended treatment
Guselkumab treated patients who were not in clinical response at induction Week 12, receivedguselkumab 200 mg subcutaneous at Weeks 12, 16 and 20. In QUASAR IS, 66/120 (55%)guselkumab treated patients who were not in clinical response at induction Week 12 achieved clinicalresponse at Week 24. Week 24 responders to guselkumab entered QUASAR MS and receivedguselkumab 200 mg subcutaneous every 4 weeks. At Week 44 of QUASAR MS, 83/123 (67%) ofthese patients maintained clinical response and 37/123 (30%) achieved clinical remission.
Recapture of efficacy after loss of response to guselkumab
Nineteen patients receiving guselkumab 100 mg subcutaneous q8w who experienced a first loss ofresponse (10%) between Week 8 and 32 of QUASAR MS received blinded guselkumab dosing with200 mg guselkumab subcutaneous q4w and 11 of these patients (58%) achieved symptomatic responseand 5 patients (26%) achieved symptomatic remission after 12 weeks.
Histologic and endoscopic assessment
Histologic remission was defined as a Geboes histologic score ≤ 2 B.0 (absence of neutrophils fromthe mucosa [both lamina propria and epithelium], no crypt destruction, and no erosions, ulcerations orgranulation tissue according to the Geboes grading system). In QUASAR IS, histologic remission at
Week 12 was achieved in 40% of patients treated with guselkumab and 19% of patients in the placebogroup. In QUASAR MS, histologic remission at Week 44 was achieved in 59% and 61% of patientstreated with guselkumab 100 mg subcutaneous q8w and guselkumab 200 mg subcutaneous q4w and27% of patients in the placebo group.
Normalisation of the endoscopic appearance of the mucosa was defined as ES of 0. In QUASAR IS,endoscopic normalisation at Week 12 was achieved in 15% of patients treated with guselkumab and5% of patients in the placebo group.
Composite histologic-endoscopic mucosal outcomes
Combined symptomatic remission, endoscopic normalisation, histologic remission, and faecalcalprotectin ≤ 250 mg/kg at Week 44 was achieved by a greater proportion of patients treated withguselkumab 100 mg subcutaneous q8w or 200 mg subcutaneous q4w compared to placebo (22% and28% vs 9%, respectively).
Health-related quality of lifeAt Week 12 of QUASAR IS, patients receiving guselkumab showed greater and clinically meaningfulimprovements from baseline when compared with placebo in inflammatory bowel disease (IBD)-specific quality of life assessed by IBDQ total score, and all IBDQ domain scores (bowel symptomsincluding abdominal pain and bowel urgency, systemic function, emotional function, and socialfunction). These improvements were maintained in guselkumab treated patients in QUASAR MSthrough Week 44.
Ulcerative colitis related hospitalisations
Through Week 12 of QUASAR IS, lower proportions of patients in the guselkumab group comparedwith the placebo group had ulcerative colitis-related hospitalisations (1.9%, 8/421 vs. 5.4%, 15/280).
ASTRO
In ASTRO, patients were randomised in a 1:1:1 ratio to receive guselkumab 400 mg subcutaneousinduction at Weeks 0, 4 and 8 followed by guselkumab 100 mg subcutaneous maintenance every8 weeks; or guselkumab 400 mg subcutaneous induction at Weeks 0, 4 and 8, followed byguselkumab 200 mg subcutaneous maintenance every 4 weeks; or placebo.
A total of 418 patients were evaluated. The median age of patients was 40 years (ranging from 18 to80 years); 38.8% were female; and 64.6% identified as White, 28.9% as Asian, and 3.1% as Black.
Enrolled patients were permitted to use stable doses of oral aminosalicylates, immunomodulators(AZA, 6-MP, MTX), and/or oral corticosteroids (up to 20 mg/day prednisone or equivalent). Atbaseline, 77.3% of patients were receiving aminosalicylates, 20.1% of patients were receivingimmunomodulators, and 32.8% of patients were receiving corticosteroids. Concomitant biologictherapies, JAK inhibitors, or S1PRMs were not permitted. A total of 40.2% of patients had previouslyfailed treatment with at least one biologic therapy, JAK inhibitor, and/or S1PRM, 58.1% werebiologic, JAK inhibitor, and S1PRM naïve, and 1.7% had previously received but had not failed abiologic, JAK inhibitor, or S1PRM.
In ASTRO, the primary endpoint was clinical remission at Week 12 as defined by the mMS.
Secondary endpoints at Week 12 included symptomatic remission, endoscopic healing, clinicalresponse and histologic-endoscopic mucosal healing (see Table 5). Secondary endpoints at Week 24included clinical remission and endoscopic healing (see Table 6).
Table 5: Proportion of patients meeting efficacy endpoints at Week 12 in ASTRO
Endpoint Placebo Guselkumab Treatment Difference% 400 mg vs Placebo
Subcutaneous (95% CI)b
Inductiona%
Clinical remissionc
Total Population 6% (N=139) 28% (N=279) 21% (15%, 28%)e
Biologic, JAK-inhibitor, and 9% (N=79) 36% (N=164) 27% (18%, 37%)
S1PRM naïvef
Prior biologic, JAK-inhibitor, 4% (N=56) 16% (N=112) 12% (3%, 20%)and/or S1PRM failureg
Symptomatic remissiond
Total Population 21% (N=139) 51% (N=279) 30% (22%, 39%)e
Biologic, JAK-inhibitor, and 25% (N=79) 59% (N=164) 34% (22%, 46%)
S1PRM naïvef
Prior biologic, JAK-inhibitor, 14% (N=56) 41% (N=112) 26% (13%, 39%)and/or S1PRM failureg
Endoscopic healingh
Total Population 13% (N=139) 37% (N=279) 24% (17%, 32%)e
Biologic, JAK-inhibitor, and 18% (N=79) 46% (N=164) 28% (17%, 40%)
S1PRM naïvef
Prior biologic, JAK-inhibitor, 7% (N=56) 24% (N=112) 16% (6%, 26%)and/or S1PRM failureg
Clinical responsei
Total Population 35% (N=139) 66% (N=279) 31% (22%, 40%)e
Biologic, JAK-inhibitor, and 42% (N=79) 71% (N=164) 30% (17%, 43%)
S1PRM naïvef
Prior biologic, JAK-inhibitor, 25% (N=56) 57% (N=112) 31% (17%, 45%)and/or S1PRM failureg
Histologic endoscopic mucosal healingj
Total Population 11% (N=139) 30% (N=279) 20% (12%, 27%)e
Biologic, JAK-inhibitor, and 14% (N=79) 38% (N=164) 25% (14%, 35%)
S1PRM naïvef
Prior biologic, JAK-inhibitor, 7% (N=56) 19% (N=112) 11% (1%, 20%)and/or S1PRM failurega Guselkumab 400 mg subcutaneous induction at Week 0, Week 4, and Week 8b The adjusted treatment difference and the CIs were based on the common risk difference by use of Mantel-Haenszel stratum weightsand Sato variance estimator. The stratification variables used were prior biologic, JAK inhibitor, and/or S1PRM failure status (Yes or
No), and Mayo endoscopy subscore at baseline (moderate [2] or severe [3]).
c A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0or 1 with no friabilityd A stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0e p < 0.001f An additional 4 patients in the placebo group and 3 patients in the guselkumab group were previously exposed to but did not fail abiologic, JAK inhibitor or S1PRMg Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab), JAK inhibitor,and/or S1PRM for ulcerative colitish An endoscopy subscore of 0, or 1 with no friabilityi Decrease from baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a ≥ 1 point decrease from baseline in therectal bleeding subscore or a rectal bleeding subscore of 0 or 1j An endoscopy subscore of 0, or 1 with no friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in < 5% of crypts, nocrypt destruction, and no erosions, ulcerations, or granulation tissue)
Table 6: Proportion of patients meeting efficacy endpoints at Week 24 in ASTRO
Endpoint Placebo Guselkumab Guselkumab Treatment Difference vs% 400 mg SC 400 mg SC Placeboinduction→ induction→ (95% CI)c100 mg q8w 200 mg q4w Guselkumab Guselkumab
Subcutaneous Subcutaneous 100 mg 200 mg
Injectiona Injectionb% %
Clinical remissiond
Total population 9% (N=139) 35% (N=139) 36% (N=140) 26% 27%(17%, 35%)e (18%, 36%)e
Biologic, JAK- 13% (N=79) 49% (N=81) 43% (N=83) 37% 31%inhibitor, and (24%, 50%) (18%, 44%)
S1PRM naïvef
Prior biologic, 5% (N=56) 16% (N=57) 27% (N=55) 10% 21%
JAK-inhibitor, (-1%, 21%) (9%, 34%)and/or S1PRMfailureg
Endoscopic healingh
Total population 12% 40% (N=139) 45% (N=140) 28% 33%(N=139) (18%, 38%)e (23%, 42%)e
Biologic, JAK- 18% (N=79) 54% (N=81) 52% (N=83) 37% 34%inhibitor, and (23%, 51%) (21%, 48%)
S1PRM naïvef
Prior biologic, 5% (N=56) 19% (N=57) 36% (N=55) 13% 30%
JAK-inhibitor, (1%, 25%) (17%, 44%)and/or S1PRMfailurega Guselkumab 400 mg SC induction at Weeks 0, 4 and 8 followed by guselkumab 100 mg SC maintenance every 8 weeksb Guselkumab 400 mg SC induction at Weeks 0, 4 and 8, followed by guselkumab 200 mg SC maintenance every 4 weeksc The adjusted treatment difference and the CIs were based on the common risk difference by use of Mantel-Haenszel stratum weightsand Sato variance estimator. The stratification variables used were prior biologic, JAK inhibitor, and/or S1PRM failure status (Yes or
No), and Mayo endoscopy subscore at baseline (moderate [2] or severe [3]).
d A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of0, or 1 with no friabilitye p < 0.001f An additional 4 patients in the placebo group, 1 patient in the guselkumab 100 mg group, and 2 patients in the guselkumab 200 mggroup were previously exposed to but did not fail a biologic, JAK inhibitor or S1PRMg Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab), JAK inhibitor,and/or S1PRM for ulcerative colitish An endoscopy subscore of 0, or 1 with no friability
Symptomatic remission over time
In ASTRO, symptomatic remission defined as stool frequency subscore of 0 or 1 and not increasedfrom baseline, and a rectal bleeding subscore of 0 observed through Week 12, a greater proportion ofpatients in the guselkumab treatment groups achieved symptomatic remission compared with theplacebo group (Figure 2):
Figure 2: Proportion of patients in symptomatic remission through Week 12 in ASTRO
Rectal bleeding and stool frequency subscores
Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 inpatients treated with guselkumab compared to placebo.
Histologic and endoscopic assessment
Histologic remission at Week 12 was achieved in 44% of patients treated with guselkumab 400 mgsubcutaneous induction compared to 20% of patients on placebo.
Endoscopic normalisation at Week 24 was achieved in 21% and 26% of patients treated withguselkumab 400 mg subcutaneous induction, followed by guselkumab 100 mg administered bysubcutaneous injection at Week 16, and every 8 weeks thereafter, or guselkumab 200 mg administeredby subcutaneous injection at Week 12, and every 4 weeks thereafter, respectively, compared to 4% ofpatients on placebo.
Abdominal pain and bowel urgency
A greater proportion of patients treated with guselkumab 400 mg subcutaneous induction compared toplacebo had no abdominal pain (56% vs 31%), and no bowel urgency (49% vs 24%) at Week 12.
Health-related quality of lifeDisease-specific health-related quality of life was assessed with the IBDQ. A greater proportion ofpatients in the combined 400 mg SC guselkumab group (61%) achieved IBDQ remission at Week 12compared with the placebo group (34%).
Crohn’s diseaseThe efficacy and safety of guselkumab were evaluated in three Phase III clinical studies in adultpatients with moderately to severely active Crohn’s disease who had an inadequate response, loss ofresponse or intolerance to either oral corticosteroids, conventional immunomodulators (AZA, 6-MP,
MTX) and/or biologic therapy (TNF blocker or vedolizumab): two identically designed 48-Weekmulticentre, randomised, double-blind, placebo- and active-controlled (ustekinumab), parallel groupstudies (GALAXI 2 and GALAXI 3) and one 24-Week multicentre, randomised, double-blind,placebo-controlled, parallel group study (GRAVITI). All three studies had a treat-through studydesign: patients randomised to guselkumab (or ustekinumab for GALAXI 2 and GALAXI 3)maintained that treatment assignment for the duration of the study.
GALAXI 2 and GALAXI 3
In the Phase III studies GALAXI 2 and GALAXI 3, moderately to severely active Crohn’s disease wasdefined as a Crohn’s Disease Activity Index [CDAI] score of ≥ 220 and ≤ 450 and a Simple
Endoscopic Score for CD (SES-CD) of ≥ 6 (or ≥ 4 for patients with isolated ileal disease). Additionalcriteria for GALAXI 2/3 included a mean daily stool frequency (SF) > 3 or mean daily abdominal painscore (AP) > 1.
In GALAXI 2 and GALAXI 3 studies, patients were randomised in a 2:2:2:1 ratio to receiveguselkumab 200 mg intravenous induction at Weeks 0, 4 and 8 followed by guselkumab 200 mgsubcutaneous q4w maintenance; or guselkumab 200 mg intravenous induction at Weeks 0, 4 and 8,followed by guselkumab 100 mg subcutaneous q8w maintenance; or ustekinumab approximately6 mg/kg intravenous induction at Week 0 followed by ustekinumab 90 mg subcutaneous q8wmaintenance; or placebo. Placebo non-responders received ustekinumab starting at Week 12.
A total of 1021 patients were evaluated in GALAXI 2 (n=508) and GALAXI 3 (n=513). The medianage was 34 years (ranging from 18 to 83 years), 57.6% were male; and 74.3% identified as White,21.3% as Asian and 1.5% as Black.
In GALAXI 2, 52.8% of patients had previously failed treatment with at least one biologic therapy(50.6% were intolerant or failed at least 1 prior anti-TNFα therapy, 7.5% were intolerant or failed priorvedolizumab therapy), 41.9% were biologic naïve, and 5.3% had previously received but had notfailed a biologic. At baseline, 37.4% of the patients were receiving oral corticosteroids and 29.9% ofthe patients were receiving conventional immunomodulators.
In GALAXI 3, 51.9% of patients had previously failed treatment with at least one biologic therapy(50.3% were intolerant or failed at least 1 prior anti-TNFα therapy, 9.6% were intolerant or failed priorvedolizumab therapy), 41.5% were biologic naïve, and 6.6% had previously received but had notfailed a biologic. At baseline, 36.1% of the patients were receiving oral corticosteroids and 30.2% ofthe patients were receiving conventional immunomodulators.
The results of the co-primary and major secondary endpoints compared to placebo in GALAXI 2 and
GALAXI 3 are presented in Tables 7 (Week 12) and 8 (Week 48). The results of the major secondaryendpoints at Week 48 compared to ustekinumab are presented in Tables 9 and 10.
Table 7: Proportion of patients meeting co-primary and major secondary efficacyendpoints with guselkumab versus placebo at Week 12 in GALAXI 2 and
GALAXI 3
GALAXI 2 GALAXI 3
Placebo Guselkumab Placebo Guselkumab% intravenous % intravenousinductiona inductiona% %
Co-primary efficacy endpoints
Clinical remissionb at Week 12
Total population 22% (N=76) 47%i (N=289) 15% (N=72) 47%i (N=293)
Biologic naïvec 18% (N=34) 50% (N=121) 15% (N=27) 50% (N=123)
Prior biologic failured 23% (N=39) 45% (N=150) 15% (N=39) 47% (N=150)
Endoscopic responsee at Week 12
Total population 11% (N=76) 38%i (N=289) 14% (N=72) 36%i (N=293)
Biologic naïvec 15% (N=34) 51% (N=121) 22% (N=27) 41% (N=123)
Prior biologic failured 5% (N=39) 27% (N=150) 8% (N=39) 31% (N=150)
Major secondary efficacy endpoints
PRO-2 remissionf at Week 12
Total population 21% (N=76) 43%i (N=289) 14% (N=72) 42%i(N=293)
Biologic naïvec 24% (N=34) 43% (N=121) 15% (N=27) 47% (N=123)
Prior biologic failured 13% (N=39) 41% (N=150) 13% (N=39) 39% (N=150)
Fatigue responseg at Week 12
Total population 29% (N=76) 45%j (N=289) 18% (N=72) 43%i(N=293)
Biologic naïvec 32% (N=34) 48% (N=121) 19% (N=27) 46% (N=123)
Prior biologic failured 26% (N=39) 41% (N=150) 18% (N=39) 43% (N=150)
Endoscopic remissionh at Week 12
Total population 1% (N=76) 15% (N=289) 8% (N=72) 16% (N=293)
Biologic naïvec 3% (N=34) 22% (N=121) 19% (N=27) 25% (N=123)
Prior biologic failured 0% (N=39) 9% (N=150) 0% (N=39) 9% (N=150)a Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 - Two guselkumab treatment groups werecombined for this column as patients received the same intravenous induction dose regimen prior to Week 12.
b Clinical remission is defined as CDAI score < 150.c An additional 9 patients in the placebo group and 38 patients in the guselkumab 200 mg intravenous group werepreviously exposed to but did not fail a biological therapy.d Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers or vedolizumab) for
Crohn’s disease.e Endoscopic response is defined as ≥ 50% improvement from baseline in SES-CD score or SES-CD Score ≤ 2.f PRO-2 remission is defined as AP mean daily score at or below 1 and SF mean daily score at or below 3, and noworsening of AP or SF from baseline.g Fatigue response is defined as improvement of ≥ 7 points in PROMIS Fatigue Short Form 7a.h Endoscopic remission is defined as SES-CD Score ≤ 2.i p < 0.001j p < 0.05
Table 8: Proportion of patients meeting major secondary efficacy endpoints withguselkumab versus placebo at Week 48 in GALAXI 2 and GALAXI 3
GALAXI 2 GALAXI 3
Placebo Guselkumab Guselkumab Placebo Guselkumab Guselkumabintravenous intravenous (N=72) intravenous intravenousinduction→ induction→ induction→ induction→100 mg q8w 200 mg q4w 100 mg q8w 200 mg q4wsubcutaneous subcutaneous subcutaneous subcutaneousinjectiona injectionb injectiona injectionb
Corticosteroid-free clinical remissionc at Week 48f
Total 12% 45%e 51%e 14% 44%e 48%epopulation (N=76) (N=143) (N=146) (N=72) (N=143) (N=150)
Endoscopic responsed at Week 48f
Total 7% 38%e 38%e 6% 33%e 36%epopulation (N=76) (N=143) (N=146) (N=72) (N=143) (N=150)a Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 100 mgsubcutaneous q8w thereafter for up to 48 weeks.b Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 200 mgsubcutaneous q4w thereafter for up to 48 weeks.c Corticosteroid-free clinical remission is defined as CDAI score < 150 at Week 48 and not receiving corticosteroids at
Week 48.d Endoscopic response is defined as ≥ 50% improvement from baseline in SES-CD score or SES-CD Score ≤ 2.e p < 0.001f Participants who met inadequate response criteria at Week 12 were considered non-responders at Week 48, regardlessof treatment arm.
Table 9: Proportion of patients meeting major secondary efficacy endpoints withguselkumab versus ustekinumab at Week 48 in GALAXI 2 and GALAXI 3
GALAXI 2 GALAXI 3
Ustekinumab Guselkumab Guselkumab Ustekinumab Guselkumab Guselkumab6 mg/kg intravenous intravenous 6 mg/kg intravenous intravenousintravenous induction→ induction → intravenous induction→ induction →induction → 100 mg 200 mg q4w induction → 100 mg 200 mg q4w90 mg q8w q8w subcutaneous 90 mg q8w q8w subcutaneoussubcutaneous subcutaneous injectionc subcutaneous subcutaneous injectioncinjectiona injectionb injectiona injectionb
Clinical remission at Week 48 and endoscopic responsed at Week 48
Total 39% 42% 49% 28% 41%k (N=143) 45%k (N=150)population (N=143) (N=143) (N=146) (N=148)
Endoscopic responsee at Week 48l
Total 42% 49% 56% 32% 47% 49%population (N=143) (N=143) (N=146) (N=148) (N=143) (N=150)
Endoscopic remissionf at Week 48
Total 20% 27% 24% 13% 24%k (N=143) 19%population (N=143) (N=143) (N=146) (N=148) N=150)
Clinical remissiong at Week 48
Total 65% 64% 75% 61% 66% 66%population (N=143) (N=143) (N=146) (N=148) (N=143) (N=150)
Corticosteroid-free clinical remissionh at Week 48l
Total 61% 63% 71% 59% 64% 64%population (N=143) (N=143) (N=146) (N=148) (N=143) (N=150)
Durable clinical remissioni at Week 48
Total 45% 46% 52% 39% 50% 49%population (N=143) (N=143) (N=146) (N=148) (N=143) (N=150)
PRO-2 remissionj at Week 48
Total 59% 60% 69% 53% 58% 56%population (N=143) (N=143) (N=146) (N=148) (N=143) (N=150)a Ustekinumab 6 mg/kg intravenous induction at Week 0 followed by ustekinumab 90 mg subcutaneous q8w thereafterfor up to 48 weeks.
b Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 100 mgsubcutaneous q8w thereafter for up to 48 weeks.
c Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 200 mgsubcutaneous q4w thereafter for up to 48 weeks.
d A combination of clinical remission and endoscopic response as defined below.e Endoscopic response is defined as ≥ 50% improvement from baseline in SES-CD score or SES-CD Score ≤ 2.f Endoscopic remission is defined as SES-CD Score ≤ 2.g Clinical remission is defined as CDAI score < 150.h Corticosteroid-free clinical remission is defined as CDAI score < 150 at Week 48 and not receiving corticosteroids at
Week 48.i Durable clinical remission is defined as CDAI < 150 for ≥ 80% of all visits between Week 12 and Week 48 (at least 8of 10 visits), which must include Week 48.j PRO-2 remission is defined as AP mean daily score at or below 1 and SF mean daily score at or below 3, and noworsening of AP or SF from baseline.k p < 0.05l Responses at Week 48 were evaluated irrespective of clinical response at Week 12
Table 10: Proportion of patients meeting efficacy endpoints with guselkumab versusustekinumab at Week 48 in pooled GALAXI 2 and GALAXI 3
Guselkumab Guselkumab
Ustekinumab 6 mg/kg intravenous induction intravenous inductionintravenous induction → 100 mg →→ 90 mg q8w q8w 200 mg q4wsubcutaneous subcutaneous subcutaneousinjectiona injectionb injectionc
Clinical remission at Week 48 and endoscopic responsed at Week 48
Total 34% (N=291) 42% (N=286) 47% (N=296)population
Biologic naïvee 43% (N=121) 51% (N=116) 55% (N=128)
Prior biologic 26% (N=156) 37% (N=153) 41% (N=147)failuref
Endoscopic responseg at Week 48
Total 37% (N=291) 48% (N=286) 53% (N=296)population
Biologic naïvee 43% (N=121) 59% (N=116) 59% (N=128)
Prior biologic 31% (N=156) 43% (N=153) 47% (N=147)failuref
Endoscopic remissionh at Week 48
Total 16% (N=291) 25% (N=286) 21% (N=296)population
Biologic naïvee 19% (N=121) 34% (N=116) 27% (N=128)
Prior biologic 13% (N=156) 21% (N=153) 14% (N=147)failuref
Clinical remissioni at Week 48
Total 63% (N=291) 65% (N=286) 70% (N=296)population
Biologic naïvee 75% (N=121) 73% (N=116) 77% (N=128)
Prior biologic 53% (N=156) 61% (N=153) 64% (N=147)failurefa Ustekinumab 6 mg/kg intravenous induction at Week 0 followed by ustekinumab 90 mg subcutaneous q8w thereafterfor up to 48 weeks.
b Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 100 mgsubcutaneous q8w thereafter for up to 48 weeks.
c Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 200 mgsubcutaneous q4w thereafter for up to 48 weeks.
d A combination of clinical remission and endoscopic response as defined below.e An additional 14 patients in the ustekinumab group, 21 patients in the guselkumab 200 mg subcutaneous q4w group,and 17 patients in the guselkumab 100 mg subcutaneous q8w group were previously exposed to but did not fail abiological therapy.
f Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) for
Crohn’s disease.g Endoscopic response is defined as ≥ 50% improvement from baseline in SES-CD score or SES-CD Score ≤ 2.h Endoscopic remission is defined as SES-CD Score ≤ 2.i Clinical remission is defined as CDAI score < 150.
In GALAXI 2 and GALAXI 3, the efficacy and safety of guselkumab was consistently demonstratedregardless of age, sex, race and body weight.
In the pooled GALAXI Phase III studies subpopulation analysis, patients with high inflammatoryburden after completion of induction dosing derived additional benefit from guselkumab 200 mgsubcutaneous q4w compared to the 100 mg subcutaneous q8w maintenance dose regimens. Aclinically meaningful difference was observed between the two guselkumab dose groups amongpatients with a CRP level of > 5 mg/L after completion of induction, for the endpoints of clinicalremission at Week 48 (100 mg subcutaneous q8w: 54.1% vs 200 mg subcutaneous q4w: 71.0%);endoscopic response at Week 48 (100 mg subcutaneous q8w: 36.5% vs 200 mg subcutaneousq4w: 50.5%); and PRO-2 remission at Week 48 (100 mg subcutaneous q8w: 51.8% vs 200 mgsubcutaneous q4w: 61.7%).
Clinical remission over time
CDAI scores were recorded at each patient visit. The proportion of patients in clinical remissionthrough Week 48 is presented in Figure 3.
Figure 3: Proportion of patients in clinical remission through Week 48 in pooled GALAXI 2and GALAXI 3
Health-related quality of lifeGreater improvements from baseline were seen at Week 12 in guselkumab treatment groups whencompared with placebo for inflammatory bowel disease (IBD)-specific quality of life assessed by
IBDQ total score. The improvements were maintained through Week 48 in both studies.
GRAVITI
In the Phase III GRAVITI study, moderately to severely active Crohn’s disease was defined as a
CDAI score of ≥ 220 and ≤ 450 and a CD (SES-CD) of ≥ 6 (or ≥ 4 for patients with isolated ilealdisease) and a mean daily SF ≥ 4 or mean daily AP score ≥ 2.
In GRAVITI, patients were randomised in a 1:1:1 ratio to receive guselkumab 400 mg subcutaneousinduction at Weeks 0, 4 and 8 followed by guselkumab 100 mg q8w subcutaneous maintenance; orguselkumab 400 mg subcutaneous induction at Weeks 0, 4 and 8, followed by guselkumab 200 mgq4w subcutaneous maintenance; or placebo. All patients in the placebo group who met rescue criteriareceived the induction dosing with guselkumab 400 mg subcutaneous at Weeks 16, 20, and 24followed by guselkumab 100 mg subcutaneous q8w.
A total of 347 patients were evaluated. The median age of patients was 36 years (ranging from 18 to83 years), 58.5% were male, and 66% identified as White, 21.9% as Asian and 2.6% as Black.
In GRAVITI, 46.4% of patients had previously failed treatment with at least one biologic therapy,46.4% were biologic naïve, and 7.2% had previously received but had not failed a biologic. Atbaseline, 29.7% of the patients were receiving oral corticosteroids and 28.5% of the patients werereceiving conventional immunomodulators.
The results of the co-primary and major secondary efficacy endpoints compared to placebo at
Week 12 are presented in Table 11.
Table 11: Proportion of patients meeting co-primary and major secondary efficacyendpoints with guselkumab versus placebo at Week 12 in GRAVITI
Placebo Guselkumab 400 mgsubcutaneous injectiona
Co-primary efficacy endpoints
Clinical remissionb at Week 12
Total population 21% (N=117) 56%c (N=230)
Biologic naïved 25% (N=56) 50% (N=105)
Prior biologic failuree 17% (N=53) 60% (N=108)
Endoscopic responsef at Week 12
Total population 21% (N=117) 41%c (N=230)
Biologic naïved 27% (N=56) 49% (N=105)
Prior biologic failuree 17% (N=53) 33% (N=108)
Major secondary efficacy endpoints
Clinical responseg at Week 12
Total population 33% (N=117) 73%c (N=230)
Biologic naïved 38% (N=56) 68% (N=105)
Prior biologic failuree 28% (N=53) 78% (N=108)
PRO-2 remissionh at Week 12
Total population 17% (N=117) 49%c (N=230)
Biologic naïved 18% (N=56) 44% (N=105)
Prior biologic failuree 17% (N=53) 52% (N=108)a Guselkumab 400 mg subcutaneous at Week 0, Week 4 and Week 8b Clinical remission: CDAI score < 150c p< 0.001d An additional 8 patients in the placebo group and 17 patients in the guselkumab 400 mg subcutaneous group, werepreviously exposed to but did not fail a biological therapy.e Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) for
Crohn’s disease.f Endoscopic response: ≥ 50% improvement from baseline in SES-CD score.g Clinical response: ≥ 100-point reduction from baseline in CDAI score or CDAI score < 150.h PRO-2 remission: AP mean daily score at or below 1 and SF mean daily score at or below 3, and no worsening of APor SF from baseline.
Clinical remission at Week 24 was achieved by a significantly greater proportion of patients treatedwith guselkumab 400 mg subcutaneous induction followed by guselkumab 100 mg subcutaneous q8wor 200 mg subcutaneous q4w compared to placebo (60.9% and 58.3% vs 21.4% respectively, both p-values < 0.001). Clinical remission at Week 48 was achieved by 60% and 66.1% of patients treatedwith guselkumab 400 mg subcutaneous induction followed by guselkumab 100 mg subcutaneous q8wor 200 mg subcutaneous q4w, respectively (both p-values < 0.001 compared to placebo).
Endoscopic response at Week 48 was achieved by 44.3% and 51.3% of patients treated withguselkumab 400 mg subcutaneous induction followed by guselkumab 100 mg subcutaneous q8w or200 mg subcutaneous q4w, respectively (both p-values < 0.001 compared to placebo).
Health-related quality of lifeIn GRAVITI, clinically meaningful improvements were observed in IBD-specific quality of life asassessed with IBDQ total score at Week 12 and Week 24 compared to placebo.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies withguselkumab in one or more subsets of the paediatric population in ulcerative colitis and Crohn’sdisease (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
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.
The pharmacokinetics of guselkumab in patients with psoriatic arthritis was similar to that in patientswith psoriasis. Following subcutaneous administration of guselkumab 100 mg at Weeks 0, 4, andevery 8 weeks thereafter, mean steady-state trough serum guselkumab concentration was alsoapproximately 1.2 mcg/mL. Following subcutaneous administration of guselkumab 100 mg every4 weeks, mean steady-state trough serum guselkumab concentration was approximately 3.8 mcg/mL.
The pharmacokinetics of guselkumab were similar in patients with ulcerative colitis and Crohn’sdisease. Following the recommended intravenous induction dose regimen of guselkumab 200 mg at
Weeks 0, 4, and 8, mean peak serum guselkumab concentration at Week 8 was 68.27 mcg/mL inpatients with ulcerative colitis, and 70.5 mcg/mL in patients with Crohn’s disease.
Following the recommended subcutaneous induction dose regimen of guselkumab 400 mg at
Weeks 0, 4, and 8, mean peak serum guselkumab concentration at Week 8 was estimated tobe 28.8 mcg/mL in patients with ulcerative colitis and 27.7 mcg/mL in patients with Crohn’s disease.
The total systemic exposure (AUC) after the recommended induction dose regimen was similarfollowing subcutaneous and intravenous induction.
Following subcutaneous maintenance dosing of guselkumab 100 mg every 8 weeks or guselkumab200 mg every 4 weeks in patients with ulcerative colitis, mean steady-state trough serum guselkumabconcentrations were approximately 1.4 mcg/mL and 10.7 mcg/mL, respectively.
Following subcutaneous maintenance dosing of guselkumab 100 mg every 8 weeks or guselkumab200 mg every 4 weeks in patients with Crohn’s disease, mean steady-state trough serum guselkumabconcentrations were approximately 1.2 mcg/mL and 10.1 mcg/mL, respectively.
DistributionMean volume of distribution during the terminal phase (Vz) following a single intravenousadministration to healthy subjects ranged from approximately 7 to 10 L across studies.
BiotransformationThe 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.
EliminationMean 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, and approximately 17 days in patients with ulcerative colitis or Crohn’sdisease.
Population pharmacokinetic analyses indicated that concomitant use of NSAIDs, AZA, 6-MP, oralcorticosteroids and csDMARDs such as MTX, did not affect the clearance of guselkumab.
Linearity/non-linearityThe 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. Serum guselkumab concentrations wereapproximately dose proportional following intravenous administration in patients with ulcerativecolitis or Crohn’s disease.
Paediatric populationThe pharmacokinetics of guselkumab in paediatric patients with ulcerative colitis and Crohn’s diseasehave not been established.
Elderly patientsNo specific studies have been conducted in elderly patients. Of the 1 384 plaque psoriasis patientsexposed to guselkumab in Phase III clinical studies and included in the population pharmacokineticanalysis, 70 patients were 65 years of age or older, including 4 patients who were 75 years of age orolder. Of the 746 psoriatic arthritis patients exposed to guselkumab in Phase III clinical studies, a totalof 38 patients were 65 years of age or older, and no patients were 75 years of age or older. Of the859 ulcerative colitis patients exposed to guselkumab in Phase II/III clinical studies and included inthe population pharmacokinetic analysis, a total of 52 patients were 65 years of age or older, and9 patients were 75 years of age or older. Of the 1 009 Crohn’s disease patients exposed to guselkumabin Phase III clinical studies and included in the population pharmacokinetic analysis, a total of39 patients were 65 years of age or older, and 5 patients were 75 years of age or older.
Population pharmacokinetic analyses in plaque psoriasis, psoriatic arthritis, ulcerative colitis, and
Crohn’s disease patients indicated no apparent changes in CL/F estimate in patients ≥ 65 years of agecompared to patients < 65 years of age, suggesting no dose adjustment is needed for elderly patients.
Patients with renal or hepatic impairmentNo 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, creatinine clearance or hepatic function did not have a meaningful impacton guselkumab clearance.
Body weightClearance and volume of distribution of guselkumab increases as body weight increases, however,observed clinical trial data indicate that dose adjustment for body weight is not warranted.
5.3 Preclinical safety data
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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Histidine
Histidine monohydrochloride monohydrate
Polysorbate 80 (E433)
Sucrose
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the pre-filled syringe or pre-filled pen in the outer carton in order to protect from light.
6.5 Nature and contents of container
Tremfya 200 mg solution for injection in pre-filled syringe2 mL solution in a pre-filled glass syringe with a bromobutyl rubber stopper with a fixed needle and aneedle shield, assembled in an automatic needle guard.
Tremfya is available in packs containing one pre-filled syringe and in multipacks containing2 (2 packs of 1) pre-filled syringes.
Not all pack sizes may be marketed.
Tremfya 200 mg solution for injection in pre-filled pen2 mL solution in a pre-filled glass syringe with a bromobutyl rubber stopper, assembled in a pre-filledpen with an automatic needle guard.
Tremfya is available in a pack containing one pre-filled pen and in a multipack containing 2 (2 packsof 1) pre-filled pens.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
After removing the pre-filled syringe or pre-filled pen from the refrigerator, keep the pre-filled syringeor pre-filled pen inside the carton and allow to reach room temperature by waiting for 30 minutesbefore injecting Tremfya. The pre-filled syringe or pre-filled pen should not be shaken.
Prior to use, a visual inspection of the pre-filled syringe or pre-filled pen is recommended. Thesolution should be clear, colourless to light yellow, and may contain a few small white or clearparticles. Tremfya should not be used if the solution is cloudy or discoloured, or contains largeparticles.
Each pack is provided with an ‘Instructions for use’ leaflet that fully describes the preparation andadministration of the pre-filled syringe or pre-filled pen.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu