Consumer medicine information

Tremfya

Guselkumab

BRAND INFORMATION

Brand name

Tremfya

Active ingredient

Guselkumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tremfya.

What is in this leaflet

This leaflet answers some common questions about TREMFYA (pronounced trem-fye-ah). It does not contain all the available information. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using TREMFYA against the benefits it is expected to have for you.

If you have any concerns about using this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet. You may need to read it again.

What TREMFYA is used for

TREMFYA contains the active substance guselkumab which is a type of protein called a monoclonal antibody. This medicine works by neutralising the activity of a protein called IL-23, which is present in increased levels in people with psoriasis.

TREMFYA is used to treat:

  • adults with moderate to severe plaque psoriasis, an inflammatory condition affecting the skin and nails. TREMFYA can improve skin clearance and nail appearance and reduce symptoms of psoriasis, such as scaling, shedding, flaking, itching, pain, and burning.
  • adults with active psoriatic arthritis, an inflammatory disease of the joints in which psoriasis usually occurs in association with arthritis. If you have active psoriatic arthritis, you will be given TREMFYA alone or in combination with a conventional Disease Modifying Anti-Rheumatic Drug (DMARD) such as methotrexate.

Ask your doctor if you have any questions about why TREMFYA has been prescribed for you. Your doctor may have prescribed TREMFYA for another reason.

Before you use TREMFYA

When you must not use it

Do not use TREMFYA if:

  1. You have an allergy to guselkumab (the active ingredient in the medicine) or to any of the ingredients listed at the end of this leaflet.
Symptoms of an allergic reaction may include rash, itching or hives on the skin, shortness of breath, wheezing or difficulty breathing, a tight feeling in your chest, swelling of the face, lips, tongue or other parts of the body.
  1. The packaging is torn or shows signs of tampering.
  2. The expiry date on the pack has passed.

Before you start to use it

Tell your doctor if you:

  • are being treated for an infection
  • have an infection that does not go away or keeps coming back
  • have tuberculosis (TB) or have been in close contact with someone with TB
  • think you have an infection or have symptoms of an infection such as:
    - fever or flu-like symptoms
    - blood in your phlegm (mucus)
    - muscle aches
    - cough
    - shortness of breath
    - weight loss
    - diarrhoea or stomach pain
    - burning when you urinate or urinating more often than normal
    - warm, red, or painful skin or sores on your body different from your psoriasis
    After starting TREMFYA, talk to your doctor straight away if you have any of the symptoms of infection listed above.
    TREMFYA may lower your ability to fight infections and may increase your risk of infections. Do not use TREMFYA if you have any symptoms of infection unless you are instructed to by your doctor.
  • have recently had a vaccination or if you are due to have a vaccination during treatment with TREMFYA.
    You should not be given certain types of vaccines (live vaccines) while using TREMFYA.
    If you are not sure if any of the above applies to you, talk to your doctor, pharmacist or nurse before using TREMFYA.
  • allergic reactions
    Tell your doctor or get emergency medical help right away if you think you are having an allergic reaction.
  • are pregnant or plan to become pregnant.
    The effects of this medicine in pregnant women are not known. Talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a baby.
    If you are a woman of childbearing potential, use adequate contraception while using TREMFYA and for at least 12 weeks after the last TREMFYA dose. Talk to your doctor about your contraception options.
  • are breastfeeding or planning to breastfeed. You and your doctor should decide if you will breastfeed while using TREMFYA.

If you have not told your doctor about any of the above, tell them before you start using TREMFYA.

Your doctor will discuss with you the benefits of using it against the potential risks.

Taking or being given other medicines

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

How to use TREMFYA

TREMFYA is only available on prescription.

Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if you are not sure.

TREMFYA is given by injection under your skin (subcutaneous injection). At the start of your therapy, TREMFYA may be injected by your healthcare provider. Your doctor or nurse may decide that it is right for you to learn how to inject TREMFYA yourself.

It is important not to try to inject yourself until you have been trained by a healthcare professional. If you have not been trained, please contact your healthcare provider to schedule a training session. A caregiver may also give you your TREMFYA injection after proper training.

Before use, remove the carton from the refrigerator and keep the pre-filled syringe inside the carton and allow to reach room temperature by waiting for 30 minutes.

Read the “Instructions for Use” leaflet for the pre-filled syringe or pre-filled pen carefully before using TREMFYA.

Nurse support is available by calling the Janssen Immunology Patient Support Program on 1800 666 845.

How much to use

Your doctor will decide how much TREMFYA you need and for how long.

For plaque psoriasis

  • The first dose is 100 mg (the content of 1 pre-filled syringe or 1 pre-filled pen) by subcutaneous injection. This may be given by your doctor or nurse.
  • After the first dose, you will have the next dose 4 weeks later, and then every 8 weeks. Subsequent doses are the same as the first dose (the content of 1 pre-filled syringe or 1 pre-filled pen).

For psoriatic arthritis

  • The first dose is 100 mg (the content of 1 pre-filled syringe or 1 pre filled pen) by subcutaneous injection. This may be given by your doctor or nurse.
  • After the first dose, you will have the next dose 4 weeks later, and then every 8 weeks. Subsequent doses are the same as the first dose (the content of 1 pre-filled syringe or 1 pre-filled pen).
  • TREMFYA can be used with or without a type of medicine called a conventional Disease-Modifying Anti-Rheumatic Drug (DMARD), such as methotrexate.

You should not stop using TREMFYA without speaking to your doctor first. If you stop treatment, symptoms of psoriasis may come back.

If you forget to use it

If you forget to take your TREMFYA dose, inject a dose as soon as you remember.

Then, take your next dose at your regular scheduled time

Do not use a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your pharmacist, nurse or doctor.

If you use too much (overdose)

If you have received more TREMFYA than you should, or the dose has been given sooner than prescribed, immediately telephone your doctor or the Poisons Information Centre for advice, or go to Accident and Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Poisons Information Centre telephone number:

  • Australia: 13 11 26

While you are using TREMFYA

Things you must do

Tell any other doctors, dentists and pharmacists who are treating you that you are using TREMFYA.

If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking TREMFYA.

Tell your doctor, nurse or pharmacist if the medicine starts to upset you or your symptoms become worse.

Tell your doctor immediately if you develop any symptoms of an infection (see “Before You Use TREMFYA”).

Tell your doctor if you become pregnant while using TREMFYA.

Things you must not do

You should not receive a live vaccine while taking TREMFYA. Talk to your doctor, pharmacist or nurse before receiving any vaccination while taking TREMFYA.

Do not give TREMFYA to anyone else, even if they have the same condition as you.

Do not stop using TREMFYA, or change the dose, unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how TREMFYA affects you. TREMFYA should not affect your ability to drive or use machines. However, make sure you know how you react to it before you do anything that could be dangerous if you feel dizzy.

Side effects

All medicines can have some side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Tell your doctor immediately if you experience any of the following side effects:

  • cold and/or flu symptoms, chest infection (upper respiratory infection)
  • Headache
  • joint pain (arthralgia)
  • stomach flu (gastroenteritis)
  • diarrhoea
  • redness at the injection site
  • pain at the injection site
  • cold sores (herpes simplex infections)
  • tinea
  • blood tests may show decreased number of a type of white blood cell called neutrophils or increased level of liver enzymes.

Tell your doctor if you experience any side effects even if they are not on this list or do not feel well.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Stop taking TREMFYA and tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you have any signs of an allergic reaction. You need urgent medical attention. Signs of an allergic reaction may include rash, itching or hives on the skin, shortness of breath, wheezing or difficulty breathing, a tight feeling in your chest, swelling of the face, lips, tongue or other parts of the body.

Do not be alarmed by the list of possible side effects. You may not experience any of them.

Ask your doctor, nurse or pharmacist any questions you may have.

How to store TREMFYA

Storage

Store TREMFYA in a refrigerator between 2°C and 8°C.

TREMFYA should not be frozen.

Keep the product in the original carton to protect from light until the time of use.

Do not shake TREMFYA.

Before use, remove the carton from the refrigerator and keep the pre-filled syringe or pre-filled pen inside the carton and allow to reach room temperature by waiting for 30 minutes.

Always keep medicine out of the reach of children.

After using TREMFYA

Disposal

After injecting TREMFYA, place the used syringe or pen immediately into a sharps container. Do not put the used syringe or pen into your normal household or recycling waste.

The syringe or pen should never be re-used. Discard any unused portions of TREMFYA.

If your doctor tells you to stop taking TREMFYA or it has passed its expiry date, ask your pharmacist what to do with any that is left over.

Product description

What it looks like

TREMFYA is a clear, colourless to light yellow solution and may contain clear or white particles of protein. This appearance is not unusual for solutions containing proteins.

Do not use TREMFYA if the solution is discoloured, cloudy, or you can see other particulate matter floating in it.

TREMFYA is available as a single use pre-filled syringe or pre-filled pen (One-Press® patient controlled injector) in a carton. Each carton contains 1 pre-filled syringe or 1 prefilled pen.

An instruction for use leaflet explaining how to self-administer the product is included in the pack.

Do not use TREMFYA if the packaging is torn or shows signs of tampering.

Ingredients

The active ingredient is guselkumab.

The inactive ingredients are histidine, histidine hydrochloride monohydrate, polysorbate 80, sucrose, and water for injection.

No preservatives are present.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

Australian Registration Number

100 mg pre-filled syringe: AUST R 286020

100 mg pre-filled pen: AUST R 321410

Date of Preparation

May 2022

Nurse and educational support

The Janssen Immunology Patient Support Program is available to patients prescribed TREMFYA. It offers:

  • starter kit
  • one-to-one nurse support
  • reminder service
  • ongoing education
  • wellbeing support

Call 1800 666 845

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Tremfya

Active ingredient

Guselkumab

Schedule

S4

 

1 Name of Medicine

Guselkumab.

2 Qualitative and Quantitative Composition

Tremfya contains guselkumab and is available in the following presentations:

Solution for subcutaneous injection.

Pre-filled syringe.

100 mg/1 mL; 200 mg/2 mL.

Pre-filled pen.

45 mg/0.45 mL; 100 mg/1 mL; 200 mg/2 mL.

Solution for intravenous infusion.

Single-dose vial.

200 mg/20 mL (10 mg/mL).
Guselkumab is a fully human immunoglobulin G1 lambda (IgG1 lambda) monoclonal antibody (mAb) that binds selectively to the extracellular human interleukin 23 (IL-23) protein with high specificity and affinity. Guselkumab is produced in a mammalian cell line using recombinant DNA technology.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

For subcutaneous injection.

Solution for injection in a prefilled syringe or a pre-filled pen (One-Press patient-controlled injector, auto-injector or VarioJect).

For intravenous infusion.

Concentrated solution for infusion in a single-dose vial.
Tremfya is a clear, colourless to light yellow solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Plaque psoriasis.

Tremfya is indicated for the treatment of adult patients (18 years of age or older) with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Tremfya is indicated for the treatment of paediatric patients (6 years of age or older) with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Psoriatic arthritis.

Tremfya is indicated for the treatment of adult patients with active psoriatic arthritis, who have had an inadequate response to, or are intolerant to prior DMARD therapy.

Ulcerative colitis.

Tremfya is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy, a biologic treatment, or a Janus kinase (JAK) inhibitor.

Crohn's disease.

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

4.2 Dose and Method of Administration

Tremfya is administered by intravenous infusion or subcutaneous injection.

Dosage (dose and interval).

Plaque psoriasis.

Adults (18 years of age or older).

The recommended dosage of Tremfya is 100 mg administered by subcutaneous injection at week 0, week 4 and every 8 weeks thereafter.
Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment.

Paediatric patients (6 years of age or older).

Tremfya is administered by subcutaneous injection at week 0, week 4, and every 8 weeks thereafter.
For patients weighing 40 kg or more, the recommended dose is 100 mg, administered using the 1 mL pre-filled syringe.
For patients weighing less than 40 kg, the recommended dose is shown in Table 1, up to a maximum of 45 mg, administered using the 45 mg/ 0.45 mL pre-filled pen.
Psoriatic arthritis. The recommended dosage of Tremfya is 100 mg administered by subcutaneous injection at week 0, week 4, and every 8 weeks thereafter.
Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment.
Tremfya may be administered alone or in combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD) (e.g. methotrexate).
Ulcerative colitis.

Induction.

The recommended induction dosage of Tremfya is 200 mg administered by intravenous infusion over a period of at least one hour at Week 0, Week 4 and Week 8.

Maintenance.

The recommended maintenance dosage of Tremfya is 200 mg administered by subcutaneous injection at Week 12, and every 4 weeks thereafter. For some patients, a dosage of 100 mg administered by subcutaneous injection at Week 16, and every 8 weeks thereafter, may be used.
Crohn's disease.

Induction.

The recommended induction dosage of Tremfya is:
200 mg administered by intravenous infusion over a period of at least one hour at Week 0, Week 4 and Week 8; or
400 mg administered by subcutaneous injection (given as two consecutive injections of 200 mg each) at Week 0, Week 4 and Week 8.

Maintenance.

The recommended maintenance dosage of Tremfya is 200 mg administered by subcutaneous injection at Week 12, and every 4 weeks thereafter. For some patients, a dosage of 100 mg administered by subcutaneous injection at Week 16, and every 8 weeks thereafter, may be used.
Immunomodulators and/or corticosteroids may be continued during treatment with Tremfya. In patients who have responded to treatment with Tremfya, corticosteroids may be reduced or discontinued in accordance with standard of care.

Method of administration.

Subcutaneous administration. Tremfya is administered by subcutaneous injection. If possible, areas of the skin that show psoriasis should be avoided as injection sites.
Tremfya is intended for use under the guidance and supervision of a physician. Tremfya may be administered by a health care professional, or after proper training in subcutaneous injection technique, administered by an adult caregiver or self-injected by an adult patient. Tremfya is not intended for paediatric self-administration.
After removing the pre-filled syringe or pre-filled pen from the refrigerator, keep the pre-filled syringe or pen inside the carton and allow to reach room temperature by waiting for 30 minutes before injecting Tremfya. The pre-filled syringe or pre-filled pen should not be shaken.
Comprehensive instructions for the subcutaneous administration of Tremfya are given in the Instructions for Use leaflet. Patients should be instructed to inject the prescribed dose of Tremfya according to the directions provided in this leaflet.
Tremfya is for single use in one patient only. Following administration of Tremfya, discard any unused portion. The syringe or pen should be disposed of using accepted medical practices for used syringes. The syringe or pen and its needle must never be re-used.
Substitution by any other biological medicinal product requires the consent of the prescribing physician.
Intravenous infusion (ulcerative colitis and Crohn's disease). Tremfya 200 mg vial is for IV infusion only. Intravenous infusion of Tremfya should be administered by qualified healthcare professionals.

Instructions for dilution of Tremfya 200 mg for IV infusion (ulcerative colitis and Crohn's disease).

Tremfya solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using aseptic technique. Tremfya does not contain preservatives. Each vial is for single use only.
Inspect Tremfya visually for particulate matter and discolouration prior to administration. Tremfya is a clear and colourless to light yellow solution that may contain small translucent particles. Do not use if the liquid contains large particles, is discoloured or cloudy.
Add Tremfya to a 250 mL intravenous infusion bag of 0.9% sodium chloride injection as follows:
1. Withdraw and then discard 20 mL of the 0.9% sodium chloride injection from the 250 mL infusion bag which is equal to the volume of Tremfya to be added.
2. Withdraw 20 mL of Tremfya from the vial and add it to the 250 mL intravenous infusion bag of 0.9% sodium chloride injection for a final concentration of 0.8 mg/mL. Gently mix the diluted solution. Discard the vial with any remaining solution.
3. Visually inspect the diluted solution for particulate matter and discolouration before infusion. Infuse the diluted solution over a period of at least one hour.
4. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein binding filter (pore size 0.2 micrometre).
5. Do not infuse Tremfya concomitantly in the same intravenous line with other medicinal products.
6. Dispose any unused medicinal product in accordance with local requirements.

Storage of diluted infusion solution.

To reduce microbiological hazard, use as soon as practical after dilution. If storage is necessary, the diluted infusion solution may be kept at room temperature up to 25°C for up to 10 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 10 hours after the dilution in the infusion bag.
Do not freeze.
Discard any unused portion of the infusion solution.

Missed dose.

Patients who miss a dose of Tremfya should be advised to inject this missed dose as soon as they become aware of it, and then follow with their next scheduled dose.

Special populations.

Renal or hepatic impairment. Specific studies of Tremfya have not been conducted in patients with renal or hepatic insufficiency. No dose adjustments are considered necessary (see Section 5.2 Pharmacokinetic Properties, Special populations).
Elderly (> 65 years of age). No dose adjustment is required (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties, Special populations).
Paediatrics (< 18 years of age).

Plaque psoriasis.

The safety and efficacy of Tremfya have been established in paediatric patients 6 to 17 years of age with moderate to severe plaque psoriasis (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials, Plaque psoriasis, Clinical efficacy-plaque psoriasis (paediatrics)). The safety and efficacy of Tremfya have not been established in paediatric subjects less than 6 years of age with plaque psoriasis.

Psoriatic arthritis, ulcerative colitis and Crohn's disease.

The safety and efficacy of Tremfya in paediatric patients (< 18 years of age) have not been evaluated in patients with psoriatic arthritis, ulcerative colitis and Crohn's disease.

4.3 Contraindications

Serious hypersensitivity to guselkumab or any of the excipients.

4.4 Special Warnings and Precautions for Use

Traceability.

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

Infections.

Tremfya may increase the risk of infection. Treatment with Tremfya should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.
Infections have been observed in clinical trials in plaque psoriasis (23% vs 21% placebo: ≤ 0.2% serious infections in both groups) and psoriatic arthritis (21% in both Tremfya and placebo groups: ≤ 0.8% serious infections in both groups). A similar risk of infection was seen in the placebo-controlled trials in subjects with ulcerative colitis and Crohn's disease.
Instruct patients treated with Tremfya to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Tremfya until the infection resolves.

Pre-treatment evaluation for tuberculosis.

In clinical studies, subjects with latent tuberculosis (TB) who were concurrently treated with Tremfya and appropriate TB prophylaxis did not develop TB. Evaluate patients for TB infection prior to initiating treatment with Tremfya. Initiate treatment of latent TB prior to administering Tremfya. Patients receiving Tremfya should be monitored for signs and symptoms of active TB during and after treatment. Do not administer Tremfya to patients with active TB infection. Consider anti-TB therapy prior to initiating Tremfya in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed.

Immunisations.

Prior to initiating therapy with Tremfya, complete all appropriate immunisations according to current immunisation guidelines. Live vaccines should not be used concurrently in patients treated with Tremfya. No data are available on the response to live or inactive vaccines.
Before live viral or live bacterial vaccination, treatment with Tremfya should be withheld for at least 12 weeks after the last dose and can be resumed at least 2 weeks after vaccination. Prescribers should consult the Prescribing Information of the specific vaccine for additional information and guidance on concomitant use of immunosuppressive agents post-vaccination.

Hypersensitivity reactions.

Serious hypersensitivity reactions, including anaphylaxis, have been reported in the postmarketing setting. Some serious hypersensitivity reactions occurred several days after treatment with guselkumab, including cases with urticaria and dyspnea. If a serious hypersensitivity reaction occurs, appropriate therapy should be instituted, and administration of Tremfya should be discontinued.

Use in the elderly.

Of the 5926 plaque psoriasis, psoriatic arthritis, ulcerative colitis and Crohn's disease patients exposed to Tremfya in Phase 2 and Phase 3 clinical trials, a total of 339 patients were 65 years or older, and 34 patients were 75 years or older. No overall differences in safety or effectiveness were observed between older and younger patients who received Tremfya in clinical studies. However, the number of patients aged 65 years and older was not sufficient to determine whether they respond differently from younger patients (see Section 5.2 Pharmacokinetic Properties, Special populations).

Paediatric use (< 18 years of age).

Plaque psoriasis.

The safety and efficacy of Tremfya have been established in paediatric patients 6 to 17 years of age with moderate to severe plaque psoriasis (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials, Plaque psoriasis, Clinical efficacy-plaque psoriasis (paediatrics)). The safety and efficacy of Tremfya have not been established in paediatric subjects less than 6 years of age with plaque psoriasis.

Psoriatic arthritis, ulcerative colitis and Crohn's disease.

The safety and efficacy of Tremfya in paediatric patients (< 18 years of age) have not been evaluated in patients with psoriatic arthritis, ulcerative colitis and Crohn's disease.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions with CYP450 substrates.

In a Phase 1 study in subjects with moderate to severe plaque psoriasis, changes in systemic exposures (Cmax and AUCinf) of midazolam, S-warfarin, omeprazole, dextromethorphan, and caffeine after a single dose of guselkumab were not clinically relevant (see Section 5.2 Pharmacokinetic Properties), indicating that drug interactions between guselkumab 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.

Live vaccines/therapeutic infectious agents.

Live vaccines should not be given while a patient is undergoing therapy with Tremfya (see Section 4.4 Special Warnings and Precautions for Use, Immunisations).

Concomitant immunosuppressive therapy or phototherapy.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Tremfya on human fertility has not been evaluated.
No guselkumab-related effects on fertility parameters were identified in female and male fertility studies conducted in guinea pigs. Exposures (AUC) at the 100 mg/kg twice-weekly subcutaneous no observed adverse effect level (NOAEL) dose were at least 17-fold higher than those following administration of a 200 mg intravenous dose in patients.
(Category B1)
The use of Tremfya in pregnant women has not been studied and the effect of Tremfya on human pregnancy is unknown.
No guselkumab related maternal, embryo or fetal toxicity was observed in cynomolgus monkeys after administration of weekly 50 mg/kg subcutaneous doses of guselkumab. Safety margins at the 50 mg/kg weekly NOAEL dose were approximately 26 times the clinical exposure (AUC) following a dose of 200 mg given intravenously. As with other IgG antibodies, guselkumab crosses the placenta and was detectable in newborn cynomolgus monkey serum samples indicating transplacental transfer of drug.
Tremfya should only be used during pregnancy under the advice of a physician if the potential benefit outweighs the potential risk.
 There are no data on the presence of guselkumab in human milk, the effects on a breastfed infant, or the effects on milk production. Guselkumab was not detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Tremfya.

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 Adverse Effects (Undesirable Effects)

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably causally associated with the use of guselkumab based on the comprehensive assessment of the available adverse event information. A causal relationship with guselkumab cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical trials experience in adult patients.

The safety profile of Tremfya is based on data from the Phase 2 (PSO2001, PSA2001, QUASAR induction dose-ranging study, GALAXI 1) and Phase 3 (VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, DISCOVER 1, DISCOVER 2, QUASAR induction study (IS) and QUASAR maintenance study (MS), GALAXI 2 and 3, and GRAVITI) studies in 5926 subjects, including 2711 with plaque psoriasis, 1229 subjects with psoriatic arthritis, 897 subjects with ulcerative colitis, and 1089 subjects with Crohn's disease. The duration of exposure to Tremfya is presented in Table 2.
Plaque psoriasis. The adverse reaction profile of Tremfya in 823 patients with moderate to severe plaque psoriasis is based on pooled data from two 16-week placebo-controlled phase III studies. Table 3 provides a summary of adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Tremfya group than in the placebo group during the 16-week, placebo-controlled period of the pooled clinical trials, VOYAGE 1 and VOYAGE 2.
Psoriatic arthritis. Table 4 provides a summary of adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Tremfya group than in the placebo group during the 24-week, placebo-controlled period of the pooled clinical trials, DISCOVER 1 and DISCOVER 2.
Ulcerative colitis. Tremfya was studied up to 12 weeks in patients with moderately to severely active ulcerative colitis in a randomised, double-blind, placebo-controlled induction study (QUASAR IS-2) and a randomised, double-blind, placebo-controlled, induction dose-finding study (QUASAR IS-1). Long term safety up to 44-weeks was evaluated in patients who responded to induction therapy in a randomised, double-blind, placebo-controlled maintenance study (QUASAR MS) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the two induction studies (QUASAR IS-1 and QUASAR IS-2), 1014 patients were enrolled of whom 522 patients received at least one dose of Tremfya 200 mg by intravenous infusion up to Week 12. In the maintenance study (QUASAR MS), 568 patients were randomised of whom 376 patients received either Tremfya 100 mg every 8 weeks or Tremfya 200 mg every 4 weeks by subcutaneous (SC) injection.
The overall safety profile in patients treated with Tremfya is similar for patients with psoriasis, psoriatic arthritis and ulcerative colitis.
Adverse reactions that occurred in ≥ 2% of patients in the Tremfya group and at a higher rate than placebo in the induction studies (QUASAR IS-1 and QUASAR IS-2) were rash (2.1% vs. 1.6%).
Adverse reactions that occurred in ≥ 3% of patients in the Tremfya group and at a higher rate than placebo in the maintenance study (QUASAR MS) are shown in Table 5.
Crohn's disease. The safety of Tremfya was evaluated up to 48 weeks in four trials in patients with moderately to severely active Crohn's disease: two identically designed randomised, double-blind, placebo and active-controlled parallel group trials (GALAXI 2, GALAXI 3); one randomised, double-blind, dose ranging trial (GALAXI 1) [NCT03466411]; and one randomised, double-blind, and placebo-controlled subcutaneous induction trial (GRAVITI) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The overall safety profile in patients treated with Tremfya is similar for patients with psoriasis, psoriatic arthritis, and Crohn's disease.

GALAXI 1, GALAXI 2 and GALAXI 3.

In clinical trials, GALAXI 1, GALAXI 2 and GALAXI 3, 1349 patients were enrolled of whom 649 patients were randomised to receive Tremfya 200 mg by intravenous infusion at Week 0, 4 and 8 followed by a maintenance dose of either Tremfya 200 mg subcutaneous (SC) injection at Week 12 and every 4 weeks thereafter or Tremfya 100 mg SC at Week 16 and every 8 weeks thereafter.
Adverse reactions that occurred in ≥ 3% of patients in the Tremfya groups and at a higher rate than placebo from Week 0 to Week 48 (GALAXI 1, GALAXI 2 and GALAXI 3) are shown in Table 6.

GRAVITI.

In clinical trial, GRAVITI, 347 patients were evaluated of whom 230 patients were randomised to receive Tremfya 400 mg subcutaneous induction at Week 0, 4 and 8 followed by a maintenance dose of either Tremfya 200 mg SC at Week 12 and every 4 weeks thereafter or Tremfya 100 mg SC at Week 16 and every 8 weeks thereafter.
The overall safety profile observed in patients treated with Tremfya in GRAVITI is generally consistent with the safety profile in patients treated with Tremfya in the combined studies GALAXI 1, GALAXI 2 and GALAXI 3, with the addition of gastroenteritis which in the 48-week treatment period in GRAVITI occurred in 3.5% of patients in the 100 mg SC q8w group, 1.7% of patients in the 200 mg q4w group, compared to 0.9% of patients in the placebo group.
Transaminases increased. In two Phase 3 psoriatic arthritis clinical studies, through the placebo-controlled period, adverse events of increased transaminases (includes alanine aminotransferase (ALT) Increased, aspartate aminotransferase (AST) Increased, Hepatic Enzyme Increased, Transaminases Increased, Liver Function Test Abnormal, Hypertransaminasemia) were reported more frequently in the Tremfya-treated groups (8.6% in the 100 mg q4w group and 8.3% in the 100 mg q8w group) than in the placebo group (4.6%). Through 1-year, adverse events of increased transaminases (as above) were reported in 12.9% of patients in the q4w group and 11.7% of patients in the q8w group.
Based on laboratory assessments, an increased incidence of liver enzyme elevations was observed in patients treated with Tremfya q4w compared to patients treated with Tremfya q8w or placebo. Most transaminase (ALT and AST) increases were ≤ 3 x upper limit of normal (ULN). Transaminase increases from > 3 to ≤ 5 x ULN and > 5 x ULN were low in frequency (Table 7). A similar pattern of frequency by severity and by treatment group was observed through the end of the 2-year Phase 3 psoriatic arthritis clinical study. In most cases, the increase in transaminases was transient and did not lead to discontinuation of treatment.
In pooled phase 2/3 Crohn's disease clinical studies, through the reporting period of approximately one-year, adverse events of increased transaminases (includes ALT increased, AST increased, hepatic enzyme increased, transaminases increased, hepatic function abnormal, and liver function test increased) were reported in 3.4% of patients in the Tremfya 200 mg SC q4w treatment group and 4.1% of patients in the Tremfya 100 mg SC q8w treatment group compared to 2.4% in the placebo group.
Based on laboratory assessments in pooled Phase 2/3 Crohn's disease clinical studies, the frequency of ALT or AST elevations were lower than those observed in psoriatic arthritis Phase 3 clinical studies. In pooled Phase 2/3 Crohn's disease clinical studies, through the reporting period of approximately one-year, ALT or AST elevations ≥ 3x ULN were reported in 2.7% of patients in the Tremfya 200 mg SC q4w treatment group and 2.6% of patients in the Tremfya 100 mg SC q8w treatment group compared to 1.9% in the placebo group. In most cases, the increase in transaminases was transient and did not lead to discontinuation of treatment.

Less common clinical trial adverse drug reactions (< 1%).

Adverse reactions that occurred at rates < 1% in the Tremfya group during the placebo-controlled-period of the pooled plaque psoriasis and psoriatic arthritis clinical trials were:

Infections and infestations.

Candida infections, gastroenteritis, herpes simplex infections, tinea infections.

Nervous system disorders.

Migraine.

Skin and subcutaneous tissue disorders.

Urticaria.

Clinical studies experience in paediatric subjects with psoriasis.

Tremfya was studied in one placebo- and active-controlled clinical study of paediatric subjects with moderate to severe plaque psoriasis (PROTOSTAR). This clinical study evaluated safety for up to 52 weeks in 120 subjects 6 to 17 years of age. Based on observed data the safety profile of Tremfya in this study was generally consistent with the safety profile reported in adult plaque psoriasis studies.

Postmarketing data.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported during postmarketing experience (Table 8). Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. In the table, the frequencies are provided according to the following convention:
Very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10,000 and < 1/1000; very rare: < 1/10,000, including isolated reports; not known: cannot be estimated from the available data.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Tremfya intravenous doses up to 1200 mg as well as subcutaneous doses up to 400 mg at a single dosing visit have been administered in clinical studies without dose-limiting toxicity. In the event of overdose, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Guselkumab is a human IgG1 lambda monoclonal antibody (mAb) that binds selectively to the interleukin 23 (IL-23) protein with picomolar affinity through the antigen binding site. IL-23, a regulatory cytokine, affects the differentiation, expansion, and survival of T cell subsets, (e.g. Th17 cells and Tc17 cells) and innate immune cell subsets, which represent sources of effector cytokines, including IL-17A, IL-17F and IL-22 that drive inflammatory disease. In humans, selective blockade of IL-23 was shown to normalise production of these cytokines.
Levels of IL-23 are elevated in the skin of subjects with plaque psoriasis. In patients with ulcerative colitis, and 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. Guselkumab is considered to exert its clinical effects in plaque psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease through blockade of the IL-23 cytokine pathway.
Myeloid cells expressing Fc-gamma receptor 1 (CD64) have been shown to be a predominant source of IL-23 in inflamed tissue in psoriasis, Crohn's disease, and ulcerative colitis. Guselkumab has demonstrated in vitro: blocking of IL-23 and binding to CD64. These results indicate that guselkumab is able to neutralise IL-23 at the cellular source of inflammation.

Pharmacodynamic effects.

In a Phase 1 study, treatment with guselkumab resulted in reduced expression of IL-23/Th17 pathway genes and psoriasis-associated gene expression profiles, as shown by analyses of mRNA obtained from lesional skin biopsies of psoriatic subjects at Week 12 compared to baseline. In the same Phase 1 study, treatment with guselkumab resulted in improvement of histological measures of psoriasis 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 guselkumab treated subjects in Phase 2 and Phase 3 studies in plaque psoriasis. These results are consistent with the clinical benefit observed with guselkumab treatment in plaque psoriasis.
In Phase 3 studies in psoriatic arthritis, evaluated subjects had elevated serum levels of acute phase proteins C-reactive protein, serum amyloid A and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 at baseline. Guselkumab decreased levels of these proteins within 4 weeks of initiation of treatment. By Week 24, guselkumab further reduced the levels of these proteins compared to baseline and also to placebo. In guselkumab-treated subjects, serum IL-17A and IL-17F levels were similar to those observed in a demographically matched healthy cohort at Week 24.
In patients with ulcerative colitis and Crohn's disease, guselkumab treatment led to a decrease in inflammatory markers including 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 through induction Week 12. Guselkumab also reduced colon mucosal biopsy RNA levels of IL-17A, IL-22 and IFNγ at Week 12.

Immunogenicity.

As with all therapeutic proteins, there is the potential for immunogenicity. The immunogenicity of Tremfya was evaluated using a sensitive and drug-tolerant immunoassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Tremfya with the incidences of antibodies to other products may be misleading.

Plaque psoriasis.

In pooled Phase 2 (PSO2001) and Phase 3 (VOYAGE 1, VOYAGE 2 and NAVIGATE) analyses, fewer than 6% of subjects treated with Tremfya developed antidrug antibodies in up to 52 weeks of treatment. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralising which equates to 0.4% of all subjects treated with Tremfya. In pooled Phase 3 analyses, approximately 15% of patients treated with Tremfya developed antidrug antibodies in up to 264 weeks of treatment. Of the subjects who developed antidrug antibodies, approximately 5% had antibodies that were classified as neutralising which equates to 0.76% of all subjects treated with Tremfya. Antidrug antibodies were not associated with lower efficacy or development of injection-site reactions.

Paediatric subjects.

In PROTOSTAR, 18% (n=21) of paediatric psoriasis subjects treated with Tremfya developed antidrug antibodies in up to 44 weeks of treatment. Of the subjects who developed antidrug antibodies, none had antibodies that were classified as neutralising. Antibodies to guselkumab did not appear to be associated with changes in pharmacokinetics, clinical efficacy or development of injection-site reactions. However, the small number of subjects who were positive for antibodies to guselkumab limits definitive conclusions.

Psoriatic arthritis.

In pooled Phase 3 (DISCOVER 1 and DISCOVER 2) analyses up to Week 52, 4.5% (n=49) of subjects treated with Tremfya developed antidrug antibodies. Of these subjects, 5 had antibodies that were classified as neutralising antibodies, and 3 developed injection site reactions through Week 52. Overall, the small number of subjects who were positive for antibodies to guselkumab limits definitive conclusion of the effect of immunogenicity on the pharmacokinetics and efficacy of guselkumab.

Ulcerative colitis.

In a pooled Phase 2/3 (QUASAR) analyses up to Week 56 (n = 501), 12% (n = 58) of subjects treated with Tremfya developed antidrug antibodies. Of these subjects who developed antidrug antibodies, 16% (n = 9) had antibodies that were classified as neutralising which equates to 2% of all subjects treated with Tremfya. Most of the patients who were positive for antibodies to guselkumab had low titers. Antibodies to guselkumab were not associated with changes in pharmacokinetics, clinical efficacy or development of injection-site reactions.

Crohn's disease.

In pooled Phase 2/3 (GALAXI) analyses up to Week 48, 5% (30/634) of subjects treated with Tremfya developed antidrug antibodies. Of these subjects who developed antidrug antibodies, 7% (2/30) had antibodies that were classified as neutralising antibodies, which equates to 0.3% (2/634) of Tremfya-treated subjects.
In a Phase 3 (GRAVITI) analysis up to Week 48, 9% (24/273) of subjects treated with Tremfya developed antidrug antibodies. Of these subjects who developed antidrug antibodies, 13% (3/24) had antibodies that were classified as neutralising antibodies, which equates to 1% (3/273) of Tremfya-treated subjects.
Most of the patients who were positive for antibodies to guselkumab had low titers. Antibodies to guselkumab were not associated with changes in pharmacokinetics, clinical efficacy or development of injection-site reactions.

Clinical trials.

Plaque psoriasis. Four multicentre, randomised, double-blind, placebo and/or active controlled trials (VOYAGE 1, VOYAGE 2, NAVIGATE and ORION) enrolled subjects 18 years of age and older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had an Investigator's Global Assessment (IGA) score of ≥ 3 ("moderate") on a 5-point scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score ≥ 12, and a minimum affected body surface area (BSA) of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded.

VOYAGE 1 and VOYAGE 2 placebo and adalimumab-controlled studies.

In VOYAGE 1 and VOYAGE 2, 1829 subjects were randomised to either Tremfya (100 mg at Weeks 0 and 4 and every 8 weeks thereafter), placebo or adalimumab (80 mg at Week 0 and 40 mg at Week 1, followed by 40 mg every other week thereafter through Week 47. All subjects, including those randomised to adalimumab at Week 0, received Tremfya 100 mg at Week 52 and every 8 weeks thereafter).
Both trials assessed the responses at Week 16 compared to placebo for the two co-primary endpoints:
the proportion of subjects who achieved an IGA score of 0 ("cleared") or 1 ("minimal");
the proportion of subjects who achieved at least a 90% reduction from baseline in the PASI composite score (PASI 90).
Comparisons between Tremfya and adalimumab were secondary endpoints at the following time points:
at Week 16 (VOYAGE 1 and VOYAGE 2), the proportions of subjects who achieved an IGA score of 0 or 1, a PASI 90, and a PASI 75 response;
at Week 24 (VOYAGE 1 and VOYAGE 2), and at Week 48 (VOYAGE 1), the proportions of subjects achieving an IGA score of 0, an IGA score of 0 or 1, and a PASI 90 response.
Other evaluated outcomes included improvement in psoriasis symptoms assessed on the Psoriasis Symptoms and Signs Diary (PSSD) and improvements in psoriasis of the scalp at Week 16.
Baseline disease characteristics were consistent for the study populations in VOYAGE 1 and 2 with a median BSA of 22% and 24%, a median baseline PASI score of 19 for both studies, a median baseline DLQI score of 14 and 14.5, a baseline IGA score of severe for 25% and 23% of patients, and a history of psoriatic arthritis for 19% and 18% of patients, respectively.

Overall skin disease.

Tremfya demonstrated superiority to adalimumab on PASI 75, PASI 90 and IGA cleared or minimal (0 or 1) at Week 16 in both studies (p < 0.001 for all comparisons). Tremfya also demonstrated superiority to adalimumab on PASI 75, PASI 90, PASI 100, IGA cleared (0), and IGA cleared or minimal (0 or 1) at Week 24 in both studies and at Week 48 in VOYAGE 1 (p < 0.001 for all comparisons).
The key efficacy results for the primary and major secondary study endpoints are shown in Table 9.
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 subjects achieving a PASI 90 response was numerically higher for guselkumab than adalimumab starting at Week 8 with the difference reaching a maximum around Week 20 (VOYAGE 1 and 2) and maintained through Week 48 (VOYAGE 1). In VOYAGE 1, for subjects receiving continuous guselkumab treatment, PASI 90 response was maintained from Week 52 to Week 252 with 84.1% (329/391) of patients continuing to achieve a PASI 90 response at Week 252 (see Figures 1 and 2).
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 a biologic therapy. Guselkumab was efficacious in conventional systemic-naive, biologic-naive, and biologic-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 guselkumab treatment with a median time to loss of PASI 90 response of approximately 15 weeks. Among patients who 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 adalimumab subjects who failed to achieve a PASI 90 response at Week 28, 66% and 76% achieved a PASI 90 response after 20 and 44 weeks of treatment with guselkumab respectively. No new safety findings 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 to placebo treated patients at Week 16 (p < 0.001, Table 10). Guselkumab demonstrated superiority compared 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).

Health-related quality of life/ patient reported outcomes.

Greater improvements in symptoms of psoriasis (itch, pain, stinging, burning and skin tightness) at Week 16 in Tremfya compared to placebo were observed in both trials based on the Psoriasis Symptoms and Signs Diary (PSSD). Greater proportions of subjects on Tremfya compared to adalimumab achieved a PSSD symptom score of 0 (symptom-free) at Week 24 (VOYAGE 1 and VOYAGE 2) and Week 48 (VOYAGE 1).
In VOYAGE 1, for subjects receiving continuous guselkumab treatment, improvements in PSSD scores were maintained from Week 52 through Week 252.

NAVIGATE active-controlled study in ustekinumab inadequate responders.

The NAVIGATE study examined the efficacy of guselkumab in patients who had an inadequate response (i.e. who had not achieved a 'cleared' or 'minimal' response defined as IGA ≥ 2) to ustekinumab at Week 16. All patients (N=871) received open-label ustekinumab (45 mg ≤ 100 kg and 90 mg > 100 kg) at Weeks 0 and 4. At Week 16, 268 patients with an IGA ≥ 2 score were randomised to 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 subjects were similar to those 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 who inadequately responded to ustekinumab at the time of randomisation, significantly greater improvement of efficacy was observed in patients who switched to guselkumab treatment compared to patients 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 as ustekinumab patients (mean 1.5 vs 0.7 visits, respectively, p < 0.001). Additionally, at 12 weeks after randomisation a higher proportion of guselkumab patients compared to ustekinumab patients achieved an 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 between guselkumab and ustekinumab treated patients start to become apparent at 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.

ORION placebo-controlled study with pre-filled pen.

ORION evaluated the efficacy, safety, PK, immunogenicity, usability, and acceptability of guselkumab delivered with a pre-filled pen. In this study, 78 subjects were randomised to receive either Tremfya (100 mg at Weeks 0 and 4 and every 8 weeks thereafter), or placebo. Baseline characteristics for randomised subjects were comparable to those observed in VOYAGE 1 and VOYAGE 2. The co-primary endpoints were the proportion of subjects who achieved an IGA score of 0 or 1 at Week 16 and the proportion of subjects who achieved a PASI 90 response at Week 16. The secondary endpoints included the proportion of subjects who achieved an IGA score 0 at Week 16 and the proportion of subjects who achieved a PASI 100 response at Week 16.
A significantly greater proportion of subjects in the guselkumab group achieved an IGA score of 0 or 1 or a PASI 90 response at Week 16 (80.6% and 75.8%, respectively, p < 0.001 for both endpoints) than in the placebo group (0% for both endpoints). The proportion of subjects who achieved an IGA score of 0 at Week 16 was significantly higher in the guselkumab group compared to the placebo group (56.5% vs. 0%; p < 0.001). The proportion of subjects who achieved a PASI 100 response at Week 16 was significantly higher in the guselkumab group compared to the placebo group (50.0% vs. 0%; p < 0.001).

Patient experience.

Subject experience with the pre-filled pen was assessed on a scale of 0 (worst) to 10 (best) using a validated Self-Injection Assessment Questionnaire (SIAQ) based on subject responses across 6 domains (feelings about injections, self-image, self-confidence, pain and skin reactions during or after the injection, ease of use of the self-injection device, and satisfaction with self-injection) at weeks 0, 4 and 12. At week 12, the mean score for "Satisfaction with Self Injection" was 9.18 (with 10 indicating "Very Satisfied") and the mean score for "Ease of Use" was 9.24 (with 10 indicating "Very Easy"). The mean scores for the other domains at week 12 ranged from 8.43 to 9.84.

Active-controlled study with secukinumab - ECLIPSE.

The efficacy and safety of Tremfya were also investigated in a double-blind study compared to secukinumab. Patients were randomised to receive Tremfya (N=534; 100 mg at Week 0, 4 and every 8 weeks thereafter) or secukinumab (N=514; 300 mg at Week 0, 1, 2, 3, 4, and every 4 weeks thereafter). The last dose was at Week 44 for both treatment groups. Demographic and disease characteristics were similar between the two treatment groups and consistent with those of the subjects enrolled in the pivotal Phase 3 psoriasis studies for Tremfya and secukinumab. The primary endpoint was the proportion of subjects who achieved a PASI 90 response at Week 48. Major secondary endpoints were the proportion of subjects who achieved a PASI 75 response at both Week 12 and Week 48, a PASI 90 response at Week 12, PASI 75 response at Week 12, a PASI 100 response at Week 48, an IGA score of cleared (0) at Week 48, and an IGA score of cleared (0) or minimal (1) at Week 48.
Tremfya was superior to secukinumab as measured by the primary endpoint of PASI 90 response at Week 48 (84.5% versus 70.0%, p < 0.001). Comparative clinical response rates are presented in Table 11.
Tremfya and secukinumab PASI 90 response rates through Week 48 are presented in Figure 4.

Clinical efficacy-plaque psoriasis (paediatrics).

The safety and efficacy of Tremfya were assessed in one multicentre, randomised, placebo- and active biological comparator-controlled study (PROTOSTAR) in 120 paediatric subjects 6 to 17 years old with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy and inadequately controlled by phototherapy and/or topical therapies.
Enrolled subjects had an IGA score of ≥ 3 ("moderate") 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 PROTOSTAR, 92 subjects were randomised to receive subcutaneous injection of either Tremfya (n=41) or placebo (n=25) at week 0, 4, and 12, or an active biological comparator (n=26) weekly. An additional 28 subjects enrolled in a Tremfya open-label arm. In the Tremfya group, subjects with a body weight less than 70 kg received 1.3 mg/kg administered with the 45 mg/0.45 mL pre-filled pen, and patients with a body weight of 70 kg or more received 100 mg administered with the pre-filled syringe. The coprimary endpoints and major secondary endpoints were assessed at week 16.
The co-primary endpoints were the proportion of subjects who achieved a PASI 90 response and the proportion of subjects who achieved an IGA score of 0 ("cleared") or 1 ("minimal") at week 16. The secondary endpoints were the proportion of subjects who achieved a PASI 75 response, an IGA score of cleared (0) or a PASI 100 response at week 16.
Of the 92 subjects in the controlled part of the study, baseline demographic characteristics were generally comparable across treatment groups. Overall, over 55% were male, 85% were white, the mean body weight was approximately 57.3 kg, and the mean age was 12.9 years with 33% of the subjects less than 12 years.
Baseline disease characteristics in PROTOSTAR are shown in Table 12.
The baseline disease characteristics were generally comparable across treatment groups with median baseline BSA of 20%, median baseline PASI score approximately 17, and baseline IGA score of severe for 20% and 24% of subjects, and a history of psoriatic arthritis for < 5% of subjects.

Overall skin disease.

Treatment with guselkumab resulted in significant improvements in the outcome measures of disease activity shown in Table 13 compared to placebo at Week 16. The key efficacy results for the study endpoints are shown in Table 13.

Health-related quality of life outcomes.

Change from baseline in the Children's Dermatology Life Quality Index (CDLQI) score at week 16 showed a significantly greater improvement in the CDLQI score in the Tremfya group compared with the placebo group (LSmean -7.3 vs -1.9, respectively).
Changes from baseline in the Family Dermatology Life Quality Index (FDLQI) score at week 16 also showed a numerically greater improvement in the FDLQI score in the Tremfya group compared with the placebo group (LSmean -6.0 and -0.6, respectively) (see Table 14).
Psoriatic arthritis (PsA).

DISCOVER 1 and DISCOVER 2.

The safety and efficacy of Tremfya were assessed in 1120 patients in 2 randomised, double-blind, placebo-controlled studies (DISCOVER 1 and DISCOVER 2) in adult patients with active PsA (≥ 3 swollen joints, ≥ 3 tender joints, and a C-reactive protein (CRP) level of ≥ 0.3 mg/dL in DISCOVER 1 and ≥ 5 swollen joints, ≥ 5 tender joints, and a CRP level of ≥ 0.6 mg/dL in DISCOVER 2) who had inadequate response to standard therapies. Patients in these studies had a diagnosis of PsA for at least 6 months based on the Classification Criteria for Psoriatic Arthritis (CASPAR) and a median duration of PsA of 4 years at baseline.
In DISCOVER 1 approximately 30% of subjects had been previously treated with up to 2 anti-tumour necrosis factor alpha (anti-TNFα) agents whereas in DISCOVER 2 all subjects were biologic-naïve. Approximately 58% of subjects from both studies had concomitant methotrexate (MTX) use. Patients with different subtypes of PsA were enrolled in both studies, including polyarticular arthritis with the absence of rheumatoid nodules (40%), spondylitis with peripheral arthritis (30%), asymmetric peripheral arthritis (23%), distal interphalangeal involvement (7%) and arthritis mutilans (< 1%). At baseline, over 65% and 42% of the patients had enthesitis and dactylitis, respectively and over 75% had ≥ 3% body surface area (BSA) psoriasis skin involvement.
DISCOVER 1 evaluated 381 subjects who were treated with placebo SC, Tremfya 100 mg SC at Weeks 0, 4 and every 8 weeks (q8w) thereafter, or Tremfya 100 mg SC every 4 weeks (q4w). DISCOVER 2 evaluated 739 subjects who were treated with placebo SC, Tremfya 100 mg SC at Weeks 0, 4 and q8w thereafter, or Tremfya 100 mg SC q4w. At Week 24, placebo subjects in both studies crossed over to receive Tremfya 100 mg SC q4w.
The primary endpoint in both studies was the percentage of patients achieving an ACR20 response at Week 24. Secondary endpoints included change from baseline in Disability Index of the Health Assessment Questionnaire (HAQ-DI), IGA, ACR 50, ACR 70, SF-36 PCS, SF-36 MCS and change from baseline in total modified van der Heijde-Sharp score (DISCOVER 2), at Week 24. Additionally, resolution of enthesitis and dactylitis based on the pooled data from DISCOVER 1 and DISCOVER 2 was assessed as a secondary endpoint in DISCOVER 2.

Signs and symptoms.

In both studies, patients treated with Tremfya 100 mg q8w or 100 mg q4w demonstrated a greater clinical response including ACR20, ACR50, and ACR70 compared to placebo at Week 24 (Table 15). These responses were maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2. Responses were seen regardless of prior anti-TNFα exposure (DISCOVER 1) and concomitant csDMARD use (DISCOVER 1 and DISCOVER 2). Additionally, in both studies, examination of age, gender, race, body weight, and previous treatment with csDMARDs did not identify differences in response to Tremfya among these subgroups.
Clinical response was maintained up to Week 52 as assessed by ACR 20/50/70, DAS 28 (CRP), MDA, IGA and PASI 90 response rates (see Table 16).
In DISCOVER 1 and 2, patients treated with Tremfya who had spondylitis with peripheral arthritis as their primary presentation, demonstrated greater improvement from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) compared to placebo at Week 24. Improvement in BASDAI was maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2.
In DISCOVER 2, a greater ACR 20 response was observed in both Tremfya dose groups compared with the placebo group as early as Week 4 and the treatment difference continued to increase over time through Week 24 (Figure 5).
In DISCOVER 2, for subjects receiving continuous guselkumab treatment at week 24, ACR 20 response was maintained from Week 24 to Week 52 (see Figure 6). For subjects receiving continuous guselkumab treatment at week 52, ACR 20 response was maintained from Week 52 to Week 100 (see Figure 7).
In DISCOVER 1 and DISCOVER 2, median percent improvement from baseline was observed in all components of the ACR response criteria.

Psoriasis skin response.

In DISCOVER 1 and DISCOVER 2, among subjects with mild to severe psoriasis (BSA ≥ 3% and IGA ≥ 2) at baseline, a greater proportion of subjects in both Tremfya dose groups achieved a psoriasis response, defined as an IGA of 0 (cleared) or 1 (minimal) and a ≥ 2-grade reduction from baseline, compared with the placebo group at Week 24. Results from psoriasis skin response endpoints in DISCOVER 1 and DISCOVER 2 are presented in Table 17. Responses for both IGA and PASI endpoints were maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2.

Enthesitis and dactylitis.

Enthesitis and dactylitis were assessed based on pooled data from DISCOVER 1 and DISCOVER 2. Among subjects with dactylitis at baseline, a greater proportion of subjects in both the Tremfya 100 mg q8w and the Tremfya 100 mg q4w groups achieved dactylitis resolution at Week 24 compared with the placebo group (Table 18). Among subjects with enthesitis at baseline, a greater proportion of subjects in both the Tremfya 100 mg q8w group and q4w group achieved enthesitis resolution at Week 24 compared with the placebo group (Table 18). Based on the combined data from DISCOVER 1 and DISCOVER 2, resolution of dactylitis and enthesitis were maintained from Week 24 to Week 52. In DISCOVER 2, among subjects with dactylitis and enthesitis at baseline, resolution of dactylitis and enthesitis were maintained at Week 100.

Radiographic response.

In DISCOVER 2, inhibition of structural damage progression was measured radiographically and expressed as the mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score at Week 24.
Tremfya q4w inhibited the progression of structural damage compared to placebo at Week 24. Tremfya q8w showed numerically less, but not statistically significant, progression of structural damage compared to placebo. These results are shown in Table 19.
The mean change from baseline in total modified vdH-S was similar in the guselkumab q8w and q4w groups at Week 52 (0.97 and 1.07, respectively) and at Week 100 (1.50 and 1.68 respectively).

Physical function and health-related quality of life.

Tremfya-treated patients in both the 100 mg q8w and q4w dose groups in both DISCOVER 1 and DISCOVER 2 showed greater mean improvement from baseline in physical function compared to patients treated with placebo as assessed by HAQ-DI at Weeks 16 and 24. Improvements in HAQ-DI were maintained from Week 24 to Week 52. In both studies, the proportion of HAQ-DI responders (≥ 0.35 improvement in HAQ-DI score) was greater in both Tremfya dose groups compared to placebo at weeks 16 and 24. The proportion of HAQ-DI responders was maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2. See Table 20.
At Week 24, subjects in both the Tremfya 100 mg q8w and q4w dose groups in both DISCOVER 1 and DISCOVER 2 showed greater improvement from baseline in the SF-36 PCS with no worsening in the SF-36 MCS compared with placebo. At Week 24 there was consistent evidence of effect in the physical functioning, role-physical, bodily-pain, general health, social-functioning and vitality domains but not in the role-emotional and mental health domains. At Week 24, a greater mean increase from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score was observed in guselkumab treated patients compared to placebo in both DISCOVER 1 (5.609, 5.841 and 2.206 in the 100 mg q8w, 100 mg q4w and placebo groups, respectively; both nominal p < 0.001) and DISCOVER 2 (7.550, 7.111 and 3.559 in the 100 mg q8w, 100 mg q4w and placebo groups, respectively; both nominal p < 0.001). In DISCOVER 2, greater improvements in health-related quality of life as measured by mean change from baseline in the Dermatology Life Quality Index (DLQI) were observed in guselkumab treated patients compared to placebo at Week 24 (-8.954, -8.853, and -2.129 in the 100 mg q8w, 100 mg q4w and placebo groups, respectively; both nominal p < 0.001). In DISCOVER 2, greater improvements were also observed in overall work impairment and activity impairment as assessed by the Work Productivity and Activity Impairment (WPAI)-PsA questionnaire compared to placebo at Week 24. Improvements in SF-36 PCS, SF-36 MCS, FACIT-F, DLQI and WPAI-PsA scores were maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2.
Ulcerative colitis (UC). The efficacy and safety of Tremfya were evaluated in two Phase 3 multicentre, randomised, double-blind, placebo-controlled studies (QUASAR induction study and QUASAR maintenance study) in adult patients with moderately to severely active ulcerative colitis who had an inadequate response, loss of response, or intolerance to corticosteroids, conventional immunomodulators, biologic therapy (TNF blockers, vedolizumab), and/or a Janus kinase (JAK) inhibitor. In addition, efficacy and safety of Tremfya were evaluated in a randomised, double-blind, placebo-controlled, Phase 2b induction dose-finding study (QUASAR induction dose-ranging 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 severely active ulcerative colitis was defined as a mMS between 5 and 9, a RBS > 1, and an ES of 2 (defined by marked erythema, absent vascular pattern, friability, and/or erosions) or an ES of 3 (defined by spontaneous bleeding and ulceration).

QUASAR induction study: QUASAR IS.

In the induction study QUASAR IS, patients were randomised 3:2 to receive either Tremfya 200 mg or placebo by intravenous infusion at Week 0, Week 4, and Week 8. A total of 701 patients were evaluated. At baseline the median mMS was 7, with 35.5% of patients having a baseline mMS of 5 to 6 and 64.5% having a mMS of 7 to 9, and 67.9% of patients with a baseline ES of 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, 1% as Black, 0.1% as American Indian or Alaskan Native, and 0.1% as multiple racial groups.
Enrolled patients were permitted to use stable doses of oral aminosalicylates, methotrexate, 6-MP, AZA and/or oral corticosteroids. At baseline, 72.5% of patients were receiving aminosalicylates, 20.8% of patients were receiving immunomodulators (MTX, 6-MP, or AZA), and 43.1% of patients were receiving 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, 88%, 54% and 18% had previously failed a TNF blocker, vedolizumab or a JAK inhibitor, respectively, and 47% had failed treatment with 2 or more of these therapies. A total of 48.4% of patients were biologic and JAK inhibitor naïve, and 2.6% had previously received but had not failed a biologic or JAK inhibitor.
The primary endpoint was clinical remission as defined by the mMS at Week 12. Secondary endpoints at Week 12 included symptomatic remission, endoscopic healing, clinical response, histologic endoscopic mucosal healing, and fatigue response (see Table 21).
Significantly greater proportions of patients were in clinical remission in the Tremfya treated group compared to the placebo group at Week 12.
QUASAR IS and QUASAR induction dose-ranging study also enrolled patients with a baseline mMS of 4, including an ES of 2 or 3 and a RBS ≥ 1. In these patients, Tremfya efficacy relative to placebo, as measured by clinical remission, clinical response, and endoscopic healing at Week 12, was consistent with the total moderately to severely active UC population.

Rectal bleeding subscore and stool frequency subscores.

Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in patients treated with Tremfya and continued to decrease through Week 12.

Maintenance study: QUASAR MS.

The maintenance study (QUASAR MS) evaluated 568 patients who achieved clinical response at Week 12 following the intravenous administration of Tremfya in either QUASAR IS or from the QUASAR induction dose-ranging study. These patients were randomised to receive a subcutaneous maintenance regimen of either Tremfya 100 mg every 8 weeks, Tremfya 200 mg every 4 weeks or 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, and fatigue response (see Table 22).
Significantly greater proportions of patients were in clinical remission in both Tremfya treated groups compared to the placebo group at Week 44.
In QUASAR IS and QUASAR MS, the efficacy and safety of Tremfya was consistently demonstrated regardless of age, sex, race, body weight, and previous treatment with a biologic therapy or JAK inhibitor. Tremfya was efficacious in biologic and JAK inhibitor naïve patients, as well as in patients who previously failed a biologic and/or JAK inhibitor.
In QUASAR MS, patients with high inflammatory burden after completion of induction dosing derived additional benefit from Tremfya 200 mg SC q4w compared to the 100 mg SC q8w. Clinically meaningful numerical differences were observed between the two Tremfya dose groups among patients with a CRP level of > 3 mg/L after completion 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 mucosal healing (46% 200 mg q4w vs. 29% 100 mg q8w).
In QUASAR MS, patients with extensive disease at induction baseline derived additional benefit from Tremfya 200 mg SC q4w compared to the 100 mg SC q8w. Clinically meaningful numerical differences were observed between the two Tremfya dose groups among patients with extensive disease at induction baseline for the following endpoints at Week 44: clinical remission (63% 200 mg q4w vs. 49% 100 mg q8w), maintenance of clinical remission (83% 200 mg q4w vs. 68% 100 mg q8w), corticosteroid-free clinical remission (60% 200 mg q4w vs. 49% 100 mg q8w), endoscopic healing (64% 200 mg q4w vs. 52% 100 mg q8w), and histologic-endoscopic mucosal healing (58% 200 mg q4w vs. 44% 100 mg q8w).
QUASAR MS also enrolled patients with a baseline mMS of 4, including an ES of 2 or 3 and a RBS ≥ 1 who achieved clinical response 12 weeks following the intravenous administration of Tremfya in QUASAR IS or QUASAR induction dose-ranging study. In these patients, Tremfya showed efficacy relative to placebo as measured by clinical remission, clinical response, and endoscopic healing at Week 44 was consistent with the total population.

Remission over time.

In QUASAR MS, symptomatic remission as defined as a stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0 was sustained through Week 44 in both Tremfya treatment groups, while a decline was observed in the placebo group (see Figure 8).
Week 24 responders to Tremfya. Tremfya treated patients who were not in clinical response at induction Week 12, received Tremfya 200 mg SC at induction Weeks 12, 16 and 20. In QUASAR IS, 66/120 (55%) Tremfya treated patients who were not in clinical response at induction Week 12 achieved clinical response at induction Week 24. Week 24 responders to Tremfya entered QUASAR MS and received Tremfya 200 mg SC every 4 weeks. At Week 44 of QUASAR MS, 83/123 (68%) of these patients maintained clinical response and 37/123 (30%) achieved clinical remission.
Recapture of efficacy after loss of response to Tremfya. Nineteen patients receiving 100 mg Tremfya SC every 8 weeks who experienced a first loss of response (10%) between Week 8 and 32 of QUASAR MS received blinded Tremfya dosing with 200 mg Tremfya. A SC every 4 weeks and 11 of these patients (58%) achieved symptomatic response and 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 from the mucosa [both lamina propria and epithelium], no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system). At Week 12 of QUASAR IS, histologic remission was achieved in 40% of patients treated with Tremfya and 19% of patients in the placebo group. At Week 44 of QUASAR MS, histologic remission was achieved in 59% and 61% of patients treated with Tremfya 100 mg SC every 8 weeks and Tremfya 200 mg SC every 4 weeks and 27% of patients in the placebo group.
Normalisation of the endoscopic appearance of the mucosa was defined as ES of 0. At Week 12 of QUASAR IS, endoscopic normalisation was achieved in 15% of patients treated with Tremfya and 5% of patients in the placebo group. At Week 44 of QUASAR MS, endoscopic normalisation was achieved in 35% and 34% of patients treated with Tremfya 100 mg SC every 8 weeks and Tremfya 200 mg SC every 4 weeks compared to 15% of patients on placebo.

Composite histologic-endoscopic mucosal outcomes.

Combined endoscopic normalisation and histologic remission was achieved by a greater proportion of patients treated with Tremfya 100 mg SC every 8 weeks or 200 mg SC every 4 weeks compared to placebo at Week 44 (31% and 33% vs 14% respectively).
Combined symptomatic remission, endoscopic healing, histologic healing, and faecal calprotectin ≤ 250 mg/kg was achieved by a greater proportion of patients treated with Tremfya 100 mg SC every 8 weeks or 200 mg SC every 4 weeks compared to placebo at Week 44 (31% and 35% vs 11% respectively).
Combined symptomatic remission, endoscopic normalisation, histologic remission, and faecal calprotectin ≤ 250 mg/kg was achieved by a greater proportion of patients treated with Tremfya 100 mg SC every 8 weeks or 200 mg SC every 4 weeks compared to placebo at Week 44 (22% and 28% vs 9% respectively).

Health related quality of life.

At Week 12 of QUASAR IS, patients receiving Tremfya showed greater and clinically meaningful improvements from baseline when compared with placebo in IBD-specific quality of life assessed by IBDQ total score, all IBDQ domain scores (bowel symptoms including abdominal pain and bowel urgency, systemic function, emotional function, and social function) and in fatigue by PROMIS Fatigue SF 7a. Clinically meaningful improvements in general health related quality of life were seen in all 7 domains of PROMIS-29 (i.e. depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities), as well as in summary scores of overall physical health and mental health. Improvements in general health status were also seen in the 5 dimensions of EQ-5D as well as EQ-5D-VAS. These improvements in health-related quality of life measures (IBDQ, PROMIS-Fatigue SF 7a, PROMIS-29, EQ-5D and EQ-5D VAS) were maintained in Tremfya-treated patients in QUASAR MS through Week 44.
Patients receiving Tremfya experienced greater improvements in overall work productivity and daily activity as assessed by the WPAI-GH questionnaire when compared to patients receiving placebo. These improvements in work productivity were maintained in Tremfya treated patients in QUASAR MS through Week 44.

Ulcerative colitis (UC) related hospitalisations and surgeries.

Through Week 12 of QUASAR IS, lower proportions of patients in the Tremfya group compared with the placebo group had UC-related hospitalisations (1.9%, 8/421 vs. 5.4%, 15/280). The proportions of patients who underwent UC-related surgeries were 0.5% (2/421) in the Tremfya group and 0.7% (2/280) in the placebo group.
Through Week 44 of QUASAR MS, the proportion of patients with UC-related hospitalisations were 1.6% (3/188) in patients treated with Tremfya 100 mg SC every 8 weeks and 1.1% (2/190) in patients treated with 200 mg SC every 4 weeks compared to placebo 0.5% (1/190). There were no reported UC-related surgeries across the Tremfya and placebo groups.
Crohn's disease. The efficacy and safety of Tremfya were evaluated in three trials in adult patients with moderately to severely active Crohn's disease who had an inadequate response, loss of response or intolerance to either oral corticosteroids, conventional immunomodulators (AZA, 6-MP, MTX), and/or biologic therapy (TNF blocker or vedolizumab): two identically designed 48-week multicentre, randomised, double-blind, placebo- and biologic active controlled, parallel group trials (intravenous induction and subcutaneous (SC) maintenance: (GALAXI 2 and GALAXI 3 [NCT03466411]) and one 48-week multicentre, randomised, double-blind, placebo-controlled, parallel group trial (SC induction and SC maintenance: GRAVITI [NCT05197049]). All three trials had a treat-through study design: patients randomised to Tremfya maintained that treatment assignment for the duration of the trial.

GALAXI 2 and GALAXI 3.

In GALAXI 2 and GALAXI 3 trials, moderately to severely active Crohn's disease was defined 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).
In GALAXI 2 and GALAXI 3 trials, patients were randomised in a 2:2:2:1 ratio to receive Tremfya 200 mg intravenous induction at Weeks 0, 4 and 8 followed by Tremfya 200 mg subcutaneous maintenance every 4 weeks; or Tremfya 200 mg intravenous induction at Weeks 0, 4 and 8, followed by Tremfya 100 mg subcutaneous maintenance every 8 weeks; or a biologic active control; or placebo. Placebo non-responders received the biologic active control starting at Week 12.
A total of 1021 patients were evaluated in GALAXI 2 (N = 508) and GALAXI 3 (N = 513). The median age was 34 years (ranging from 18 to 83 years); 42.4% were female; and 74.3% identified as White, 21.3% as Asian, and 1.5% as Black or African American.
In GALAXI 2, 52.8% of patients had previously failed treatment with at least one biologic therapy, 41.9% were biologic-naïve, and 5.3% had previously received but had not failed a biologic. At baseline, 37.4% of the patients were receiving oral corticosteroids and 29.9% of the patients were receiving conventional immunomodulators.
In GALAXI 3, 51.9% of patients had previously failed treatment with at least one biologic therapy, 41.5% were biologic-naïve, and 6.6% had previously received but had not failed a biologic. At baseline, 36.1% of the patients were receiving oral corticosteroids and 30.2% of the patients were receiving conventional immunomodulators.
In GALAXI 2 and GALAXI 3, the composite co-primary endpoints were (1) clinical response at Week 12 and clinical remission at Week 48 and (2) clinical response at Week 12 and endoscopic response at Week 48 compared to placebo (Table 23). Secondary endpoints included clinical and endoscopic outcomes with short-term (Week 12) and long term (through Week 48) comparisons to placebo (Tables 24 and 25). For the composite endpoints in GALAXI 2 and GALAXI 3, the same patient had to achieve both components of the endpoint.
In GALAXI 2 and GALAXI 3, a greater proportion of patients achieved clinical response (assessed by CDAI) at Week 4 as well as endoscopic remission at Week 12 in patients treated with Tremfya 200 mg intravenous induction compared to placebo.
In the pooled GALAXI Phase 3 studies subpopulation analysis, patients with high inflammatory burden after completion of induction dosing derived additional benefit from Tremfya 200 mg subcutaneous q4w compared to the 100 mg subcutaneous q8w. A clinically meaningful difference of 14 to 17 percentage points was observed between the two Tremfya dose groups among patients with a CRP level of > 5 mg/L after completion of induction, for the endpoints of clinical remission at Week 48 (100 mg subcutaneous q8w: 54% vs 200 mg subcutaneous q4w: 71%); and endoscopic response at Week 48 (100 mg subcutaneous q8w: 36% vs 200 mg subcutaneous q4w: 50%).
In the pooled GALAXI Phase 3 studies subpopulation analysis, patients with high disease severity at baseline (Week 0) derived additional benefit from Tremfya 200 mg subcutaneous q4w compared to the 100 mg subcutaneous q8w. A clinically meaningful difference of 8 to 13 percentage points was observed between the two Tremfya dose groups in patients with a baseline CDAI > 300 or a baseline SES-CD > 12, for the endpoints of clinical remission at Week 48; endoscopic response at Week 48; and the composite of clinical remission at Week 48 and endoscopic response at Week 48.

Stool frequency and abdominal pain.

Reductions in stool frequency and abdominal pain subscores were observed as early as Week 4 in a greater proportion of patients treated with Tremfya 200 mg intravenous compared to placebo, and continued improvement was observed through Week 48 with both maintenance dose regimens of Tremfya.

Other health-related outcomes.

Fatigue was assessed in GALAXI 2 and GALAXI 3 with the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue Short Form 7a (PROMIS-Fatigue SF 7a). Treatment with Tremfya 200 mg intravenously resulted in greater mean change from baseline and clinically meaningful (≥ 7 points) improvement in fatigue as measured by PROMIS-Fatigue SF 7a at Week 12 in GALAXI 2 and GALAXI 3 trials when compared with patients on placebo (45% vs. 29%, p < 0.05 (GALAXI 2) and 43% vs. 18% p < 0.001 (GALAXI 3). The improvement in fatigue response was maintained through Week 48.

GRAVITI.

In the GRAVITI trial, moderately to severely active Crohn's disease was defined 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).
In GRAVITI, patients were randomised in a 1:1:1 ratio to receive Tremfya 400 mg subcutaneous induction at Weeks 0, 4 and 8 followed by Tremfya 200 mg subcutaneous maintenance every 4 weeks; or Tremfya 400 mg subcutaneous induction at Weeks 0, 4 and 8, followed by Tremfya 100 mg subcutaneous maintenance every 8 weeks; or placebo. All patients in the placebo group who met rescue criteria received treatment with Tremfya 400 mg subcutaneous induction followed by Tremfya 100 mg subcutaneous maintenance every 8 weeks.
A total of 347 patients were evaluated. The median age of patients was 36 years (ranging from 18 to 83 years); 41.5% were female; and 66% identified as White, 21.9% as Asian, and 2.6% as Black or African American.
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. At baseline, 29.7% of the patients were receiving oral corticosteroids and 28.5% of the patients were receiving conventional immunomodulators.
In GRAVITI, the co-primary endpoints were clinical remission at Week 12 and endoscopic response at Week 12 compared to placebo (Table 26). Additional multiplicity-controlled endpoints at Week 12, Week 24, or Week 48 are included in Table 26 and Table 27.
Onset of clinical response and clinical remission based on CDAI occurred as early as Week 4 in a greater proportion of patients treated with the Tremfya induction regimen compared to placebo.

Endoscopic remission at week 48.

Endoscopic remission was observed at Week 48 in 38.3% (44/115) of patients treated with the Tremfya 400 mg subcutaneous induction followed by Tremfya 200 mg subcutaneous q4w maintenance regimen and 30.4% (35/115) of patients treated with Tremfya 400 mg subcutaneous induction followed by Tremfya 100 mg subcutaneous q8w maintenance regimen, compared to 6.0% (7/117) of patients treated with placebo.

Clinical remission at week 48 and endoscopic remission at week 48.

Clinical remission at Week 48 and endoscopic remission at Week 48 was observed in 33.9% (39/115) of patients treated with the Tremfya 400 mg subcutaneous induction followed by Tremfya 200 mg subcutaneous q4w maintenance regimen and 26.1% (30/115) of patients treated with Tremfya 400 mg subcutaneous induction followed by Tremfya 100 mg subcutaneous q8w maintenance regimen, compared to 4.3% (5/117) of patients treated with placebo.

Stool frequency and abdominal pain.

Reductions in stool frequency and abdominal pain subscores were observed as early as Week 4 in a greater proportion of patients treated with Tremfya 400 mg subcutaneous compared to placebo, and these improvements during induction were maintained through Week 48.

5.2 Pharmacokinetic Properties

Absorption.

Following a single 100 mg subcutaneous injection in healthy subjects, guselkumab reached a mean (± SD) maximum serum concentration (Cmax) of 8.09 ± 3.68 microgram/mL by approximately 5.5 days post dose. The absolute bioavailability of guselkumab following a single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects.
In subjects with plaque psoriasis, following subcutaneous administrations of 100 mg guselkumab at Weeks 0 and 4, and every 8 weeks thereafter, steady state serum guselkumab concentrations were achieved by Week 20. The mean (± SD) steady state trough serum guselkumab concentrations in two Phase 3 studies in plaque psoriasis were 1.15 ± 0.73 microgram/mL and 1.23 ± 0.84 microgram/mL. Serum guselkumab concentrations did not appear to accumulate over time when given subcutaneously every 8 weeks.
The pharmacokinetics of guselkumab in subjects with psoriatic arthritis was similar to that in subjects with plaque psoriasis. Following subcutaneous administration of 100 mg of guselkumab at Weeks 0, 4, and every 8 weeks thereafter, mean steady-state trough serum guselkumab concentration was approximately 1.2 microgram/mL. Following subcutaneous administration of 100 mg of guselkumab every 4 weeks, mean steady-state trough serum guselkumab concentration was approximately 3.8 microgram/mL.
The pharmacokinetics of Tremfya were similar in subjects with ulcerative colitis and Crohn's disease.
Following the recommended intravenous induction dose regimen of Tremfya 200 mg at Weeks 0, 4, and 8, mean peak serum guselkumab concentration at Week 8 was 68.3 microgram/mL in subjects with ulcerative colitis and 70.5 microgram/mL in subjects with Crohn's disease.
Following the recommended subcutaneous induction dose regimen of Tremfya 400 mg at Weeks 0, 4, and 8, mean peak serum concentration was estimated to be 27.7 microgram/mL in subjects with Crohn's disease. The total systemic exposure (AUC) after the recommended induction dose regimens was similar following subcutaneous and intravenous induction.
Following subcutaneous maintenance dosing of 100 mg Tremfya every 8 weeks or 200 mg Tremfya every 4 weeks in patients with ulcerative colitis, mean steady-state trough serum guselkumab concentrations were approximately 1.4 microgram/mL and 10.7 microgram/mL, respectively.
Following subcutaneous maintenance dosing of 100 mg Tremfya every 8 weeks or 200 mg Tremfya every 4 weeks in subjects with Crohn's disease, mean steady-state trough serum guselkumab concentrations were approximately 1.2 microgram/mL and 10.1 microgram/mL, respectively.

Distribution.

Mean volume of distribution during the terminal phase (Vz) following a single intravenous administration to healthy subjects ranged from approximately 7 to 10 L (98 to 123 mL/kg) across studies.

Metabolism.

The exact pathway through which guselkumab is metabolised has not been characterised. As a human IgG monoclonal antibody, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Excretion.

Mean systemic clearance (CL) following a single intravenous administration to healthy subjects ranged from 0.288 to 0.479 L/day (3.6 to 6.0 mL/day/kg) across studies.
Mean half-life (t1/2) of guselkumab was approximately 17 days in healthy subjects and approximately 15 to 18 days in subjects with plaque psoriasis across studies, and approximately 17 days in patients with ulcerative colitis and Crohn's disease.

Dose linearity.

The systemic exposure of guselkumab (Cmax and AUC) increased in an approximately dose-proportional manner following a single subcutaneous injection at doses ranging from 10 mg to 300 mg in healthy subjects or subjects with plaque psoriasis. Serum guselkumab concentrations were approximately dose proportional following IV administration in patients with ulcerative colitis or Crohn's disease.

Population pharmacokinetic analysis.

In a population pharmacokinetic analysis, the apparent clearance and apparent volume of distribution were 0.516 L/d and 13.5 L, respectively, and the t1/2 was approximately 18 days in subjects with psoriasis. The apparent clearance and apparent volume of distribution at steady-state were 0.531 L/d and 10.1 L, respectively, and the t1/2 was approximately 17 days in subjects with ulcerative colitis. The apparent clearance and apparent volume of distribution at steady-state were 0.568 L/d and 11.4 L, respectively, and the t1/2 was approximately 17 days in subjects with Crohn's disease.
In population pharmacokinetic analyses, the effects of baseline demographics (weight, age, sex, and race), immunogenicity, baseline disease characteristics, comorbidities (past and current history of diabetes, hypertension, and hyperlipidaemia), past use of therapeutic biologics, past use of methotrexate or cyclosporine, concomitant medications (NSAIDs, corticosteroids and conventional synthetic DMARDS such as methotrexate, azathioprine, 6-mercaptopurine), use of alcohol, or current smoking status, on pharmacokinetics of guselkumab was evaluated. Only the effects of body weight on clearance and volume of distribution were found to be significant, with a trend towards higher clearance in heavier subjects. However, subsequent exposure-response modelling analysis suggested that no dose adjustment would be warranted for body weight.

Cytochrome P450 substrates.

The effects of guselkumab on the pharmacokinetics of representative probe substrates of CYP isozymes (midazolam [CYP3A4], warfarin [CYP2C9], omeprazole [CYP2C19], dextromethorphan [CYP2D6], and caffeine [CYP1A2]) were evaluated in subjects with moderate to severe plaque psoriasis. Results from this study indicate that changes in Cmax and AUCinf of midazolam, S-warfarin, omeprazole, dextromethorphan, and caffeine after a single dose of guselkumab were not clinically relevant (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There is no need for dose adjustment when co-administering guselkumab and CYP450 substrates.

Special populations.

Paediatrics (6 years of age and older).

In PROTOSTAR, steady state serum concentrations of guselkumab were achieved by week 20 in paediatric subjects 6 to 17 years of age with moderate to severe plaque psoriasis.
Based on a population pharmacokinetic simulation model, the recommended dosing regimen for Tremfya results in median predicted steady state guselkumab AUC and Ctrough concentrations that fall between 90% prediction intervals of steady state guselkumab AUC and Ctrough concentrations in adults with plaque psoriasis across the body weight range.

Elderly patients (> 65 years of age and older).

Of the 1384 plaque psoriasis subjects exposed to Tremfya in phase III clinical studies and included in the population pharmacokinetic analysis (pop PK), 70 subjects were 65 years of age or older, including 4 subjects who were 75 years of age or older. Of the 746 psoriatic arthritis patients exposed to Tremfya in phase III clinical studies and included in the pop PK analysis, a total of 38 patients were 65 years of age or older, and no patients were 75 years of age and older. Of the 859 ulcerative colitis patients exposed to Tremfya in clinical studies and included in the pop PK analysis, a total of 52 patients were 65 years of age or older, including 9 patients were 75 years of age or older. Of the 1009 Crohn's disease subjects exposed to Tremfya in clinical studies and included in the pop PK analysis, a total of 39 subjects were 65 years of age or older, including 5 subjects who were 75 years of age or older. Population pharmacokinetic (pop PK) analyses indicated there were no apparent changes in CL/F estimate in subjects ≥ 65 years of age compared to subjects < 65 years of age, suggesting no dose adjustment is needed for elderly patients.

Patients with renal or hepatic impairment.

No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab.
Renal elimination of intact guselkumab, an IgG mAb, is expected to be low and of minor importance; similarly, hepatic impairment is not expected to influence clearance of guselkumab as IgG mAbs are mainly eliminated via intracellular catabolism. These conditions are generally not expected to have any significant impact on the pharmacokinetics of monoclonal antibodies. No dose adjustments are considered necessary.

5.3 Preclinical Safety Data

Genotoxicity.

Guselkumab has not been evaluated for genotoxic potential.

Carcinogenicity.

Guselkumab has not been evaluated for carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

200 mg vial.

Disodium edetate, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, sucrose, water for injections.

100 mg pre-filled syringe, 200 mg pre-filled syringe, 100 mg pre-filled pen (One-Press patient-controlled injector), 200 mg pre-filled pen (auto-injector).

Histidine, histidine hydrochloride monohydrate, polysorbate 80, sucrose, water for injections.

45 mg / 0.45 mL pre-filled pen (VarioJect).

Histidine, histidine hydrochloride monohydrate, polysorbate 80, sucrose, water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C - 8°C). Do not freeze. Do not shake.
Keep the pre-filled syringe or pre-filled pen in their original carton until time of use in order to protect from light.

6.5 Nature and Contents of Container

For subcutaneous injection.

Tremfya is supplied as a single-use sterile solution in following packaging presentations: a pre-filled 1 mL glass syringe with a fixed 27G, half inch needle assembled in a passive needle guard delivery system or in a prefilled pen with a passive needle guard enclosed in a patient-controlled injector device; a 1 mL glass syringe with fixed, 27G half inch needle assembled in a variable dose injector; a 2 mL glass syringe with a 27G, half inch fixed needle assembled in a passive needle guard system or in a pre-filled pen.
Tremfya is available in cartons containing 1 pre-filled syringe or 2 (2 packs of 1) pre-filled syringes: 100 mg (100 mg/mL in 1.0 mL syringe volume); 200 mg (100 mg/mL in 2.0 mL syringe volume).
Tremfya is available in cartons containing 1 pre-filled pen or 2 (2 packs of 1) pre-filled pens: 45 mg (45 mg in 0.45 mL, assembled in a variable dose injector (VarioJect pen). The 45 mg/0.45 mL pre-filled pen delivers one dose ranging from 10 mg to 45 mg in 5 mg increments (corresponding to dose volumes ranging from 0.10 mL to 0.45 mL in 0.05 mL increments; 100 mg (100 mg/mL in 1.0 mL pre-filled pen - One-Press patient-controlled injector); 200 mg (100 mg/mL in 2.0 mL pre-filled pen - auto-injector).

For intravenous infusion.

Tremfya is supplied as a single-use sterile concentrated solution in a type I clear glass vial closed with a chlorobutyl rubber stopper, an aluminium seal and polypropylene flip top.
Tremfya is available in cartons containing 1 vial: 200 mg (200 mg/20 mL in a single-dose vial).
Not all presentations may be marketed.
Tremfya does not contain preservatives.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1350289-85-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes