TALTZ 80mg injection solution in pre-filled syringe medication leaflet

Taltz 40 mg solution for injection in pre-filled syringe

Taltz 80 mg solution for injection in pre-filled syringe

Ixekizumab is produced in CHO cells by recombinant DNA technology.

Taltz 40 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 40 mg ixekizumab in 0.5 mL.

One mL of solution contains 0.30 mg polysorbate 80.

Taltz 80 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 80 mg ixekizumab in 1 mL.

One mL of solution contains 0.30 mg polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

The solution is clear and colourless to slightly yellow, with a pH not less than 5.2 and not morethan 6.2, and an osmolarity not less than 235 mOsm/kg and not more than 360 mOsm/kg.

Plaque psoriasis

Taltz is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidatesfor systemic therapy.

Taltz is indicated for the treatment of moderate to severe plaque psoriasis in children from the ageof 6 years and with a body weight of at least 25 kg and adolescents who are candidates forsystemic therapy.

Taltz, alone or in combination with methotrexate, is indicated for the treatment of active psoriaticarthritis in adult patients who have responded inadequately to, or who are intolerant to one or moredisease-modifying anti-rheumatic drug (DMARD) therapies (see section 5.1).

Ankylosing spondylitis (radiographic axial spondyloarthritis)

Taltz is indicated for the treatment of adult patients with active ankylosing spondylitis who haveresponded inadequately to conventional therapy.

Non-radiographic axial spondyloarthritis

Taltz is indicated for the treatment of adult patients with active non-radiographic axialspondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein(CRP) and/or magnetic resonance imaging (MRI) who have responded inadequately to nonsteroidalanti-inflammatory drugs (NSAIDs).

This medicinal product is intended for use under the guidance and supervision of a physicianexperienced in the diagnosis and treatment of conditions for which it is indicated.

Plaque psoriasis in adults

The recommended dose is 160 mg by subcutaneous injection at week 0, followed by 80 mg atweeks 2, 4, 6, 8, 10, and 12, then maintenance dosing of 80 mg every 4 weeks (Q4W).

Paediatric plaque psoriasis (age 6 years and above)

Efficacy and safety data is not available in children below the age of 6 years (see section 5.1).

Available data do not support a posology below a body weight of 25 kg.

The recommended dose given by subcutaneous injection in children is based on the following weightcategories:

Children’s body Recommended starting Recommended dose everyweight dose (week 0) 4 weeks (Q4W) thereafter

Greater than 50 kg 160 mg 80 mg25 to 50 kg 80 mg 40 mg

For children prescribed 80 mg, Taltz can be used directly from the pre-filled syringe.

If the 40 mg pre-filled syringe is not available, doses less than 80 mg must be prepared by a healthcareprofessional. For instructions on preparation of ixekizumab doses of 40 mg, see section 6.6.

Taltz is not recommended for use in children with a body weight below 25 kg. Paediatric body weightsmust be recorded and regularly re-checked prior to dosing.

The recommended dose is 160 mg by subcutaneous injection at week 0, followed by 80 mg every4 weeks thereafter. For psoriatic arthritis patients with concomitant moderate to severe plaquepsoriasis, the recommended dosing regimen is the same as for plaque psoriasis.

Axial spondyloarthritis (radiographic and non-radiographic)

The recommended dose is 160 mg by subcutaneous injection at week 0, followed by 80 mg every4 weeks (see section 5.1 for further information).

For all indications (plaque psoriasis in adults and children, psoriatic arthritis, axial spondyloarthritis)consideration should be given to discontinuing treatment in patients who have shown no response after16 to 20 weeks of treatment. Some patients with initially partial response may subsequently improvewith continued treatment beyond 20 weeks.

No dose adjustment is required in subjects aged ≥ 65 years (see section 5.2).

There is limited information in subjects aged ≥ 75 years.

Taltz has not been studied in these patient populations. No dose recommendations can be made.

Paediatric plaque psoriasis (below a body weight of 25 kg and below the age of 6 years)

There is no relevant use of Taltz in children below a body weight of 25 kg and below the age of6 years in the treatment of moderate to severe plaque psoriasis.

Paediatric psoriatic arthritis

The safety and efficacy of Taltz in children and adolescents aged 2 to less than 18 years in thetreatment of psoriatic arthritis (a category of juvenile idiopathic arthritis) have not yet beenestablished. No data are available.

There is no relevant use of Taltz in children below 2 years for the indication of psoriatic arthritis.

Subcutaneous use.

Taltz is for subcutaneous injection. Injection sites may be alternated. If possible, areas of the skin thatshow psoriasis should be avoided as injection sites. The solution/the syringe must not be shaken.

After proper training in subcutaneous injection technique, patients may self-inject Taltz if a healthcareprofessional determines that it is appropriate. However, the physician should ensure appropriatefollow-up of patients. Comprehensive instructions for administration are given in the package leafletand the user manual.

If the 40 mg pre-filled syringe is not available, doses less than 80 mg which require dose preparationshould only be administered by a healthcare professional.

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

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

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

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

Treatment with Taltz is associated with an increased rate of infections such as upper respiratory tractinfection, oral candidiasis, conjunctivitis, and tinea infections (see section 4.8).

Taltz should be used with caution in patients with clinically important chronic infection or a history ofrecurrent infection. Patients should be instructed to seek medical advice if signs or symptomssuggestive of an infection occur. If an infection develops, patients should be carefully monitored and

Taltz discontinued if the patient is not responding to standard therapy or if the infection becomesserious. Taltz should not be resumed until the infection resolves.

Taltz must not be given to patients with active tuberculosis (TB). Anti-TB therapy prior to initiation of

Taltz in patients with latent TB should be considered.

Serious hypersensitivity reactions, including some cases of anaphylaxis, angioedema, urticaria and,rarely, late (10-14 days following injection) serious hypersensitivity reactions including widespreadurticaria, dyspnea and high antibody titres have been reported. If a serious hypersensitivity reactionoccurs, administration of Taltz should be discontinued immediately and appropriate therapy initiated.

Inflammatory bowel disease (including Crohn's disease and ulcerative colitis)

Cases of new or exacerbations of inflammatory bowel disease have been reported with ixekizumab(see section 4.8). Ixekizumab is not recommended in patients with inflammatory bowel disease. If apatient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation ofpre-existing inflammatory bowel disease, ixekizumab should be discontinued and appropriate medicalmanagement should be initiated.

Taltz should not be used with live vaccines. No data are available on the response to live vaccines;there are insufficient data on response to inactive vaccines (see section 5.1).

This medicinal product contains less than 1 mmol sodium (23 mg) per 40 mg dose and per 80 mgdose, that is to say essentially “sodium-free”.

Polysorbate

This medicinal product contains 0.15 mg of polysorbate 80 in each 40 mg pre-filled syringe which isequivalent to 0.30 mg/mL. This medicinal product contains 0.3 mg of polysorbate 80 in each 80 mgpre-filled syringe which is equivalent to 0.30 mg/mL. . Polysorbates may cause allergic reactions.

In plaque psoriasis studies, the safety of Taltz in combination with other immunomodulatory agents orphototherapy has not been evaluated.

In population pharmacokinetic analyses, clearance of ixekizumab was not affected by concomitantadministration of oral corticosteroids, NSAIDs, sulfasalazine, or methotrexate.

Cytochrome P450 substrates

Results from an interaction study in patients with moderate-to-severe psoriasis determined that12 weeks of administration of ixekizumab with substances metabolised by CYP3A4 (i.e., midazolam),

CYP2C9 (i.e., warfarin), CYP2C19 (i.e., omeprazole), CYP1A2 (i.e., caffeine) or CYP2D6 (i.e.,dextromethorphan) does not have a clinically significant impact on the pharmacokinetics of thesesubstances.

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

There is a limited amount of data from the use of ixekizumab in pregnant women. Animal studies donot indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetaldevelopment, parturition or post-natal development (see section 5.3). As a precautionary measure, it ispreferable to avoid the use of Taltz during pregnancy.

It is not known whether ixekizumab is excreted in human milk or absorbed systemically afteringestion. However, ixekizumab is excreted at low levels in the milk of cynomolgus monkeys. Adecision should be made whether to discontinue breast-feeding or to discontinue Taltz taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

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

The most frequently reported adverse reactions were injection site reactions (15.5 %) and upperrespiratory tract infections (16.4 %) (most frequently nasopharyngitis).

Adverse reactions from clinical studies and post-marketing reports (Table 1) are listed by MedDRAsystem organ class. Within each system organ class, the adverse reactions are ranked by frequency,with the most frequent reactions first. Within each frequency grouping, adverse reactions are presentedin order of decreasing seriousness. In addition, the corresponding frequency category for each adversereaction is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10);uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

A total of 8 956 patients have been treated with Taltz in blinded and open-label clinical studies inplaque psoriasis, psoriatic arthritis, axial spondyloarthritis, and other autoimmune conditions. Of these,6 385 patients were exposed to Taltz for at least one year, cumulatively representing19 833 adult patient years of exposure and 196 children cumulatively representing 207 patient years ofexposure.

Table 1. List of adverse reactions in clinical studies and post-marketing reports

System organ class Frequency Adverse reaction

Infections and infestations Very common Upper respiratory tractinfection

Common Tinea infection,

Herpes simplex(mucocutaneous)

Uncommon Influenza,

Rhinitis,

Oral candidiasis,

Conjunctivitis,

Cellulitis

Rare Oesophageal candidiasis

Blood and lymphatic system Uncommon Neutropenia,disorders Thrombocytopenia

Immune system disorders Uncommon Angioedema

Rare Anaphylaxis

Respiratory, thoracic and Common Oropharyngeal painmediastinal disorders

Gastrointestinal disorders Common Nausea

Uncommon Inflammatory bowel disease

Skin and subcutaneous Uncommon Urticaria,disorders Rash,

Eczema

General disorders and Very common Injection site reactionsaadministration site conditionsa See section description of selected adverse reactions

The most frequent injection site reactions observed were erythema and pain. These reactions werepredominantly mild to moderate in severity and did not lead to discontinuation of Taltz.

In the adult plaque psoriasis studies, injection site reactions were more common in subjects with abody weight < 60 kg compared with the group with a body weight ≥ 60 kg (25 % vs. 14 % for thecombined Q2W and Q4W groups). In the psoriatic arthritis studies, injection site reactions were morecommon in subjects with a body weight < 100 kg compared with the group with a body weight≥ 100 kg (24 % vs. 13 % for the combined Q2W and Q4W groups). In the axial spondyloarthritisstudies, injection site reactions were similar in subjects with a body weight < 100 kg compared withthe group with a body weight ≥ 100 kg (14 % vs. 9 % for the combined Q2W and Q4W groups). Theincreased frequency of injection site reactions in the combined Q2W and Q4W groups did not result inan increase in discontinuations in either the plaque psoriasis, the psoriatic arthritis or the axialspondyloarthritis studies.

The results described above are obtained with the original formulation of Taltz. In a single-blinded,randomised cross-over study in 45 healthy subjects comparing the original formulation with therevised, citrate-free formulation, statistically significantly lower Visual Analogue Scale (VAS) painscores were obtained with the citrate-free vs. the original formulation during injection (difference in

LS Mean VAS score -21.69) and 10 min after injection (difference in LS Mean VAS score -4.47).

In the placebo-controlled period of the phase III clinical studies in plaque psoriasis in adults, infectionswere reported in 27.2 % of patients treated with Taltz for up to 12 weeks compared with 22.9 % ofpatients treated with placebo.

The majority of infections were non-serious and mild to moderate in severity, most of which did notnecessitate treatment discontinuation. Serious infections occurred in 13 (0.6 %) of patients treated with

Taltz and in 3 (0.4 %) of patients treated with placebo (see section 4.4). Over the entire treatmentperiod infections were reported in 52.8 % of patients treated with Taltz (46.9 per 100 patient years).

Serious infections were reported in 1.6 % of patients treated with Taltz (1.5 per 100 patient years).

Infection rates observed in psoriatic arthritis and axial spondyloarthritis clinical studies were similar tothose observed in the plaque psoriasis studies with the exception of the frequencies of the adversereactions of influenza and conjunctivitis which were common in patients with psoriatic arthritis.

Laboratory assessment of neutropenia and thrombocytopenia

In plaque psoriasis studies, 9% of patients receiving Taltz developed neutropenia. In most cases, theblood neutrophil count was ≥1 000 cells/mm3. Such levels of neutropenia may persist, fluctuate or betransient. 0.1% of patients receiving Taltz developed a neutrophil count <1 000 cells/mm3. In general,neutropenia did not require discontinuation of Taltz. 3% of patients exposed to Taltz had a shift from anormal baseline platelet value to <150 000 platelet cells/mm3 to ≥75 000 cells/mm3.

Thrombocytopenia may persist, fluctuate or be transient.

The frequency of neutropenia and thrombocytopenia in psoriatic arthritis and axial spondyloarthritisclinical studies is similar to that observed in the plaque psoriasis studies.

Approximately 9-17% of adult plaque psoriasis patients treated with Taltz at the recommended dosingregimen developed anti-drug antibodies, the majority of which were low titres and not associated withreduced clinical response up to 60 weeks of treatment. However, approximately 1% of patients treatedwith Taltz had confirmed neutralising antibodies associated with low drug concentrations and reducedclinical response.

In psoriatic arthritis patients treated with Taltz at the recommended dosing regimen up to 52 weeks,approximately 11% developed anti-drug antibodies, the majority of which were low titre, andapproximately 8% had confirmed neutralising antibodies. No apparent association between thepresence of neutralising antibodies and impact on drug concentration or efficacy was observed.

In paediatric psoriasis patients treated with Taltz at the recommended dosing regimen up to 12 weeks,21 patients (18%) developed anti-drug antibodies, approximately half were low titer and 5 patients(4%) had confirmed neutralizing antibodies associated with low drug concentrations. There was noassociation with clinical response or adverse events.

In radiographic axial spondyloarthritis patients treated with Taltz at the recommended dosing regimenup to 16 weeks, pct. 5.2% developed anti-drug antibodies, the majority of which were low titer, and 1.5%(3 patients) had neutralising antibodies (NAb). In these 3 patients, NAb-positive samples had lowixekizumab concentrations and none of these patients achieved an ASAS40 response. Innon-radiographic axial spondyloarthritis patients treated with Taltz at the recommended dosingregimen for up to 52 weeks, 8.9% developed anti-drug antibodies, all of which were low titer; nopatient had neutralising antibodies; and no apparent association between the presence of anti-drugantibodies and drug concentration, efficacy, or safety was observed.

Across all indications, an association between immunogenicity and treatment emergent adverse eventshas not been clearly established.

The safety profile observed in children with plaque psoriasis treated with Taltz every 4 weeks isconsistent with the safety profile in adult patients with plaque psoriasis with the exception of thefrequencies of conjunctivitis, influenza, and urticaria which were common. Inflammatory boweldisease was also more frequent in paediatric patients, although it was still uncommon. In the paediatricclinical study, Crohn’s disease occurred in 0.9% of patients in the Taltz group and 0% of patients inthe placebo group during the 12-week, placebo-controlled period. Crohn’s disease occurred in a totalof 4 Taltz treated subjects (2.0%) during the combined placebo-controlled and maintenance periods ofthe paediatric clinical study.

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

Doses up to 180 mg have been administered subcutaneously in clinical trials without dose-limitingtoxicity. Overdoses up to 240 mg, subcutaneously, as a single administration in clinical trials, havebeen reported without any serious adverse events.

In the event of overdose, it is recommended that the patient be monitored for any signs or symptomsof adverse reactions and appropriate symptomatic treatment be instituted immediately.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC13

Ixekizumab is an IgG4 monoclonal antibody that binds with high affinity (< 3 pM) and specificity tointerleukin 17A (both IL-17A and IL-17A/F). Elevated concentrations of IL-17A have been implicatedin the pathogenesis of psoriasis by promoting keratinocyte proliferation and activation, as well as inthe pathogenesis of psoriatic arthritis and axial spondyloarthritis by driving inflammation leading toerosive bone damage and pathological new bone formation. Neutralisation of IL-17A by ixekizumabinhibits these actions. Ixekizumab does not bind to ligands IL-17B, IL-17C, IL-17D, IL-17E or

IL-17F.

In vitro binding assays confirmed that ixekizumab does not bind to human Fcγ receptors I, IIa, and IIIaor to complement component C1q.

Ixekizumab modulates biological responses that are induced or regulated by IL-17A. Based onpsoriatic skin biopsy data from a phase I study, there was a dose-related trend towards decreasedepidermal thickness, number of proliferating keratinocytes, T cells, and dendritic cells, as well asreductions in local inflammatory markers from baseline to day 43. As a direct consequence treatmentwith ixekizumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.

Ixekizumab has been shown to lower (within 1 week of treatment) levels of C-reactive protein, whichis a marker of inflammation.

Adult plaque psoriasis

The efficacy and safety of ixekizumab were assessed in three randomised, double-blind,placebo-controlled phase III studies in adult patients (N=3 866) with moderate to severe plaquepsoriasis who were candidates for phototherapy or systemic therapy (UNCOVER-1, UNCOVER-2,and UNCOVER-3). The efficacy and safety of ixekizumab were also evaluated versus etanercept(UNCOVER-2 and UNCOVER-3). Patients randomised to ixekizumab who were sPGA (0,1)responders (static Physicians Global Assessment) at week 12 were re-randomised to receive placeboor ixekizumab for an additional 48 weeks (UNCOVER-1 and UNCOVER-2); patients randomised toplacebo, etanercept or ixekizumab who were sPGA (0,1) non-responders received ixekizumab for upto 48 weeks. In addition, long-term efficacy and safety were evaluated in all three studies for up to atotal of 5 years in patients who participated through the entire study.

64 % of patients had received prior systemic therapy (biologic, conventional systemic or psoralen andultraviolet A (PUVA)), 43.5 % prior phototherapy, 49.3 % prior conventional systemic therapy, and26.4 % prior biologic therapy. 14.9 % had received at least one anti-TNF alpha agent, and 8.7 % ananti-IL-12/IL-23. 23.4 % of patients had a history of psoriatic arthritis at baseline.

In all three studies, the co-primary endpoints were the proportion of patients who achieved a PASI 75response (Psoriasis Area and Severity Index) and an sPGA of “0” (“clear”) or 1 (“minimal”) responseat week 12 versus placebo. The median baseline PASI score ranged from 17.4 to 18.3; 48.3 % to51.2 % of patients had a baseline sPGA score of severe or very severe, and mean baseline itch

Numeric Rating Scale (itch NRS) ranged from 6.3 to 7.1.

Clinical response at 12 weeks

UNCOVER-1 randomised 1 296 patients (1:1:1) to receive either placebo or ixekizumab (80 mg everytwo or four weeks [Q2W or Q4W] following a 160 mg starting dose) for 12 weeks.

Table 2. Efficacy results at week 12 in UNCOVER-1

Number of patients (%) Difference from placebo inresponse rate (95% CI)

Endpoints

Placebo Ixekizumab Ixekizumab Ixekizumab Ixekizumab(N = 431) 80 mg Q4W 80 mg Q2W 80 mg Q4W 80 mg Q2W(N = 432) (N = 433)sPGA of “0”(clear) or “1” 14 (3.2) 330 (76.4)a 354 (81.8)a 73.1 (68.8, 77.5) 78.5 (74.5, 82.5)(minimal)sPGA of “0” 0 149 (34.5)a 160 (37.0)a 34.5 (30.0, 39.0) 37.0 (32.4, 41.5)(clear)

PASI 75 17 (3.9) 357 (82.6)a 386 (89.1)a 78.7 (74.7, 82.7) 85.2 (81.7, 88.7)

PASI 90 2 (0.5) 279 (64.6)a 307 (70.9)a 64.1 (59.6, 68.7) 70.4 (66.1, 74.8)

PASI 100 0 145 (33.6)a 153 (35.3)a 33.6 (29.1, 38.0) 35.3 (30.8, 39.8)

Itch NRS 58 (15.5) 305 (80.5)a 336 (85.9)a 65.0 (59.5, 70.4) 70.4 (65.4, 75.5)reduction ≥ 4b

Abbreviations: N = number of patients in the intent-to-treat population

Note: patients with missing data were counted as non-respondersa p < 0.001 compared with placebob Patients with Itch NRS ≥ 4 at baseline: placebo N = 374, ixekizumab 80 mg Q4W N = 379,ixekizumab 80 mg Q2W N = 391

UNCOVER-2 randomised 1 224 patients (1:2:2:2) to receive either placebo, or ixekizumab (80 mgevery two or four weeks [Q2W or Q4W] following a 160 mg starting dose) or etanercept 50 mg twiceweekly for 12 weeks.

Table 3. Efficacy results at week 12 in UNCOVER-2

Difference from placebo in

Number of patients (%) response rate (95% CI)

Endpoints Ixekizumab Ixekizumab Etanercept Ixekizumab Ixekizumab

Placebo(N = 168) 80 mg Q4W 80 mg Q2W 50 mg twice 80 mg Q4W 80 mg Q2W(N = 347) (N = 351) weekly(N = 358)sPGA of “0”(clear) or “1” 4 (2.4) 253 (72.9)a,b 292 (83.2)a,b 129 (36.0)a 70.5 (65.3, 80.8 (76.3,(minimal) 75.7) 85.4)sPGA of “0”(clear) 1 (0.6) 112 (32.3)a,b 147 (41.9)a,b 21 (5.9)c 31.7 (26.6, 41.3 (36.0,36.7) 46.6)

PASI 75 4 (2.4) 269 (77.5)a,b 315 (89.7)a,b 149 (41.6)a 75.1 (70.2, 87.4 (83.4,80.1) 91.3)

PASI 90 1 (0.6) 207 (59.7)a,b 248 (70.7)a,b 67 (18.7)a 59.1 (53.8, 70.1 (65.2,64.4) 75.0)

PASI 100 1 (0.6) 107 (30.8)a,b 142 (40.5)a,b c 30.2 (25.2, 39.9 (34.6,19 (5.3) 35.2) 45.1)

Itch NRSreduction ≥ 4d 19 (14.1) 225 (76.8)a,b 258 (85.1)a,b 177 (57.8)a 62.7 (55.1, 71.1 (64.0,70.3) 78.2)

Abbreviations: N = number of patients in the intent-to-treat population

Note: patients with missing data were counted as non-responders.a p < 0.001 compared with placebo; b p < 0.001 compared with etanercept;c p < 0.01 compared with placebod Patients with Itch NRS ≥ 4 at baseline: placebo N = 135, ixekizumab 80 mg Q4W N = 293, ixekizumab80 mg Q2W N = 303, etanercept N = 306

UNCOVER-3 randomised 1 346 patients (1:2:2:2) to receive either placebo, or ixekizumab (80 mgevery two or four weeks [Q2W or Q4W] following a 160 mg starting dose) or etanercept 50 mg twiceweekly for 12 weeks.

Table 4. Efficacy results at week 12 in UNCOVER-3

Difference from placebo in

Number of patients (%) response rate (95% CI)

Endpoints

Ixekizumab Ixekizumab Etanercept

Placebo 80 mg Q4W 80 mg Q2W 50 mg twice Ixekizumab Ixekizumab(N = 193) (N = 386) (N = 385) weekly 80 mg Q4W 80 mg Q2W(N = 382)sPGA of “0”(clear) or “1” 13 (6.7) 291 (75.4)a,b 310 (80.5)a,b 159 (41.6)a 68.7 (63.1, 73.8 (68.5,(minimal) 74.2) 79.1)sPGA of “0”(clear) 0 139 (36.0)a,b 155 (40.3)a,b 33 (8.6)a 36.0 (31.2, 40.3 (35.4,40.8) 45.2)

PASI 75 14 (7.3) 325 (84.2)a,b 336 (87.3)a,b 204 (53.4)a 76.9 (71.8, 80.0 (75.1,82.1) 85.0)

PASI 90 6 (3.1) 252 (65.3)a,b 262 (68.1)a,b 98 (25.7)a 62.2 (56.8, 64.9 (59.7,67.5) 70.2)37.7 (32.8,

PASI 100 0 135 (35.0)a,b 145 (37.7)a,b 28 (7.3)a 35 (30.2, 39.7) 42.5)

Itch NRSreduction 33 (20.9) 250 (79.9)a,b 264 (82.5)a,b 200 (64.1)a 59.0 (51.2, 61.6 (54.0,≥ 4c 66.7) 69.2)

Abbreviations: N = number of patients in the intent-to-treat population

Note: patients with missing data were counted as non-respondersa p < 0.001 compared with placebob p < 0.001 compared with etanerceptc Patients with Itch NRS ≥ 4 at baseline: placebo N = 158, ixekizumab 80 mg Q4W N = 313, ixekizumab80 mg Q2W N = 320, etanercept N = 312

Ixekizumab was associated with a fast onset of efficacy with > 50 % reduction in mean PASI byweek 2 (Figure 1). The percentage of patients achieving PASI 75 was significantly greater forixekizumab compared with placebo and etanercept as early as week 1. Approximately 25 % of patientstreated with ixekizumab achieved a PASI score < 5 by week 2, more than 55 % achieved the PASIscore < 5 by week 4, and increased to 85 % by week 12 (compared to 3 %, 14 % and 50 % foretanercept). Significant improvements in itch severity were seen at week 1 in patients treated withixekizumab.

Figure 1. PASI score, percent improvement at each post baseline visit (mBOCF)) in theintent-to-treat population during the induction dosing period - UNCOVER-2 and UNCOVER-3

The efficacy and safety of ixekizumab was demonstrated regardless of age, gender, race, body weight,

PASI baseline severity, plaques location, concurrent psoriatic arthritis, and previous treatment with abiologic. ixekizumab was efficacious in systemic treatment-naive, biologic-naive,biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients.

For patients identified as an sPGA (0,1) non-responder to etanercept at week 12 in UNCOVER-2(N = 200) and who were switched to ixekizumab 80 mg Q4W after a 4 week washout period, 73 %and 83.5 % of patients achieved sPGA (0,1) and PASI 75, respectively, after 12 weeks of treatmentwith ixekizumab.

In the 2 clinical studies that included an active comparator (UNCOVER-2 and UNCOVER-3), the rateof serious adverse events was 1.9 % for both etanercept and for ixekizumab, and the rate ofdiscontinuation due to adverse events was 1.2 % for etanercept and 2.0 % for ixekizumab. The rate ofinfections was 21.5 % for etanercept and 26.0 % for ixekizumab, with 0.4 % being serious foretanercept and 0.5 % for ixekizumab.

Maintenance of response at week 60 and up to 5 years

Patients originally randomised to ixekizumab and who were responders at week 12 (i.e., sPGA scoreof 0,1) in UNCOVER-1 and UNCOVER-2 were re-randomised to an additional 48 weeks of treatmentwith placebo or ixekizumab (80 mg every four or twelve weeks [Q4W or Q12W]).

For sPGA (0,1) responders at week 12 re-randomised to treatment withdrawal (i.e., placebo), themedian time to relapse (sPGA ≥ 3) was 164 days in integrated UNCOVER-1 and UNCOVER-2studies. Among these patients, 71.5 % regained at least an sPGA (0,1) response within 12 weeks ofrestarting treatment with ixekizumab 80 mg Q4W.

Table 5. Maintenance of response and efficacy at week 60(Studies UNCOVER-1 and UNCOVER-2)

Difference from placebo in

Number of patients (%) response rate (95% CI)

Endpoints 80 mg Q4W 80 mg Q2W 80 mg Q4W 80 mg Q2W 80 mg Q4W 80 mg Q2W(induction)/(induction)/(induction)/(induction)/(induction)/(induction) /

Placebo Placebo 80 mg Q4W 80 mg Q4W 80 mg Q4W 80 mg Q4W(maintenance) (maintenance) (maintenance) (maintenance) (maintenance) (maintenance)(N = 191) (N = 211) (N = 195) (N = 221)

Maintained 62.4 (55.1, 70.7 (64.2,sPGA of “0” a a 69.8) 77.2)(clear) or “1” 12 (6.3) 16 (7.6) 134 (68.7) 173 (78.3)(minimal)

Maintained or 47.7 (40.4, 56.0 (49.1,achievedsPGA 0 3 (1.6) 6 (2.8) 96 (49.2)a 130 (58.8)a 54.9) 62.8)(clear)

Maintained or 66.5 (59.3, 74.3 (68.0,achieved 15 (7.9) 19 (9.0) 145 (74.4)a 184 (83.3)a 73.7) 80.5)

PASI 75

Maintained or 62.0 (54.7, 71.7 (65.4,achieved 9 (4.7) 10 (4.7) 130 (66.7)a 169 (76.5)a 69.2) 78.0)

PASI 90

Maintained or 48.2 (40.9, 54.6 (47.7,achieved 3 (1.6) 6 (2.8) 97 (49.7)a 127 (57.5)a 55.4) 61.5)

PASI 100

Abbreviations: N = number of patients in the analysis population

Note: patients with missing data were counted as non-respondersa p < 0.001 compared with placebo

Ixekizumab was efficacious in the maintenance of response in systemic treatment-naive,biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients.

Significantly greater improvements at week 12 from baseline compared to placebo and etanerceptwere demonstrated in nail psoriasis (as measured by the Nail Psoriasis Severity Index [NAPSI]), inscalp psoriasis (as measured by Psoriasis Scalp Severity Index [PSSI]) and in palmoplantar psoriasis(as measured by Psoriasis Palmoplantar Severity Index [PPASI]) and were maintained at week 60 inpatients treated with ixekizumab who were sPGA (0,1) responders at week 12.

Of 591 subjects who received ixekizumab Q2W during the Induction Period then Q4W afterward instudy UNCOVER-1, UNCOVER-2, and UNCOVER-3, 427 subjects completed 5 years of ixekizumabtreatment, among those 101 patients required a dose escalation. Among the patients who completedthe week 264 assessment (N=427), 295 patients (69%), 289 patients (68%) and 205 patients (48%)were observed to have sPGA (0,1), PASI 90 and PASI 100 response, respectively, at week 264. DLQIwere collected after Induction Period in UNCOVER-1 and UNCOVER-2, 113 patients (66%) wereobserved to have DLQI (0,1) response.

Quality of life/patient-reported outcomes

At week 12 and across studies, ixekizumab was associated with statistically significant improvementin Health-related Quality of Life as assessed by mean decrease ranges from baseline in the

Dermatology Life Quality Index (DLQI) (ixekizumab 80 mg Q2W from -10.2 to -11.1, ixekizumab80 mg Q4W from -9.4 to -10.7, etanercept from -7.7 to -8.0 and placebo -1.0 to -2.0). A significantlygreater proportion of patients treated with ixekizumab achieved a DLQI 0 or 1. Across studies asignificantly greater proportion of patients treated with ixekizumab achieved a reduction of Itch NRS≥ 4 points at week 12 (84.6% for ixekizumab Q2W, 79.2% for ixekizumab Q4W and 16.5% forplacebo) and the benefit was sustained over time up to week 60 in patients treated with ixekizumabwho were sPGA (0 or 1) responders at week 12. There was not any evidence of worsening ofdepression up to 60 weeks treatment with ixekizumab as assessed by the Quick Inventory of

Depressive Symptomatology Self Report.

Post-marketing direct comparative studies

IXORA-S: In a double-blind study ixekizumab was superior against ustekinumab on the primary studyobjective PASI 90 response at week 12 (Table 6). Onset of response was superior on PASI 75 as earlyas week 2 (p < 0.001) and on PASI 90 and PASI 100 by week 4 (p < 0.001). Superiority ofixekizumab versus ustekinumab was also demonstrated in the subgroups stratified by weight.

Table 6. PASI-response rates from comparative study ixekizumab versus ustekinumabweek 12 week 24 week 52

Ixekizumab * Ustekinumab** Ixekizumab * Ustekinumab** Ixekizumab

* Ustekinumab**

Patients (n) 136 166 136 166 136 166

PASI 75, n (%) 120 (88.2 %) 114 (68.7 %) 124 (91.2 %) 136 (81.9%) 120 (88.2%) 126 (75.9 %)

PASI 90, n (%) 99 (72.8%)§ 70 (42.2 %) 113 (83.1 %) 98 (59.0 %) 104 (76.5%) 98 (59.0 %)

PASI 100, n (%) 49 (36.0 %) 24 (14.5 %) 67 (49.3%) 39 (23.5 %) 71 (52.2%) 59 (35.5 %)

* Ixekizumab 160 mg given as a loading dose followed by 80 mg at week 2,4,6,8,10 and 12, and80 mg Q4W thereafter

** Weight based dosing: Patients treated with ustekinumab received 45 mg or 90 mg at weeks 0 and 4,then every 12 weeks until week 52 (dosed by weight as per approved posology)§p < 0.001 versus ustekinumab (p value only provided for primary endpoint)

IXORA-R: Efficacy and safety of ixekizumab was also investigated in a 24-week randomised,double-blind, parallel-group study comparing ixekizumab to guselkumab, with ixekizumab beingsuperior as early as week 4 in achieving complete skin clearance and on the primary study objective(PASI 100 at week 12) and non-inferior on PASI 100 at week 24 (Table 7).

Table 7. Efficacy Responses from comparative study ixekizumab versus guselkumab,

Intent-to-Treat Populationa

Guselkulmab Ixekizumab Difference

Endpoint Time point (N=507) (N=520) (IXE - GUS), p-valueresponse, n (%) response, n (%) % (CI)

Primary Objective

PASI 100 Week 12 126 (24.9) 215 (41.3) 16.5 (10.8, 22.2) <0.001

Major Secondary Objectives

PASI 75 Week 2 26 (5.1) 119 (22.9) 17.8 (13.7, 21.8) <0.001

PASI 90 Week 4 40 (7.9) 109 (21.0) 13.1 (8.9, 17.3) <0.001

PASI 100 Week 4 7 (1.4) 35 (6.7) 5.4 (3.0, 7.7) <0.001

PASI 90 Week 8 182 (35.9) 304 (58.5) 22.6 (16.6, 28.5) <0.001sPGA (0) Week 12 128 (25.2) 218 (41.9) 16.7 (11.0, 22.4) <0.001

PASI 50 Week 1 47 (9.3) 143 (27.5) 18.2 (13.6, 22.8) <0.001

PASI 100 Week 8 69 (13.6) 154 (29.6) 16.0 (11.1, 20.9) <0.001

PASI 100 Week 24 265 (52.3) 260 (50.0) -2.3 (-8.4, 3.8) 0.414

Abbreviations: CI = confidence interval; GUS = guselkumab; IXE = ixekizumab; N = number ofpatients in the analysis population; n = number of patients in the specified category; PASI =psoriasis area and severity index; sPGA = static physician global assessment.

a Endpoints were gated in this order

Figure 2: PASI 100 at weeks 4, 8, 12 and 24, NRI

*p<0.001 vs guselkumab at weeks 4, 8, and 12

NRI = Non-Responder Imputation

Efficacy in genital psoriasis

A randomised, double-blind, placebo-controlled study (IXORA-Q) was conducted in 149 adultsubjects (24% females) with moderate to severe genital psoriasis (sPGA of Genitalia score of ≥3), aminimum body surface area (BSA) involvement of 1% (60.4% had a BSA ≥ 10%) and previous failureof or intolerance to at least one topical therapy for genital psoriasis. Patients had at least moderateplaque psoriasis (defined as sPGA score of ≥ 3 and being candidates for phototherapy and/or systemictherapy) for at least 6 months.

Subjects randomised to ixekizumab received an initial dose of 160 mg followed by 80 mg every2 weeks for 12 weeks. The primary endpoint was the proportion of patients who achieved at least a '0'(clear) or '1' (minimal) response on the sPGA of Genitalia (sPGA of Genitalia 0/1). At week 12,significantly more subjects in the ixekizumab group than placebo group achieved a sPGA of Genitalia0/1 and a sPGA 0/1 independent of baseline BSA (baseline BSA 1% - <10% resp. ≥10%: sPGA of

Genitalia ‘’0” or “1”: Ixekizumab 71%, resp. 75%; placebo: 0%, resp. 13%). A significantly greaterproportion of patients treated with ixekizumab achieved a reduction in the PROs of severity of genitalpain, genital itch, impact of genital psoriasis on sexual activity, and Dermatology Quality of Life

Index (DLQI).

Table 8. Efficacy results at week 12 in Adults with genital psoriasis in trial IXORA-Q; NRI a

Endpoints Ixekizumab Placebo Difference fromplacebo (95% CI)

Number of patients (N) randomised N=75 N=74sPGA of Genitalia “0” or “1” 73% 8% 65% (53%, 77%)sPGA “0” or “1” 73% 3% 71% (60%, 81%)

DLQI 0,1b 45% 3% 43% (31%, 55%)

N with baseline GPSS Itch NRS Score ≥3 N=62 N=60

GPSS Genital Itch (≥3 point improvement) 60% 8% 51% (37%, 65%)

N with baseline SFQ Item 2 Score ≥2 N=37 N=42

SFQ-item 2 score, “0” (never limited) or 78% 21% 57% (39%, 75%)“1” (rarely limited)a Abbreviations: NRI = Non-Responder Imputation; sPGA = static Physician Global Assessment;

GPSS = Genital Psoriasis Symptom Scale; SFQ = Sexual Frequency Questionnaire; DLQI =

Dermatology Quality of Life Index; b Total DLQI score of 0,1 indicates skin condition has no effect atall on patient’s life. sPGA of “0” or “1” is equivalent to “clear” or “minimal”; NRS = Numeric

Rating Scale

A randomised, double-blind, multicenter, placebo-controlled trial (IXORA-Peds) enrolled201 children 6 to less than 18 years of age, with moderate to severe plaque psoriasis (as defined by asPGA score ≥3, involving ≥10% of the body surface area, and a PASI score ≥12) who were candidatesfor phototherapy or systemic therapy, or were inadequately controlled on topical therapy.

Patients were randomised to placebo (n=56), etanercept (n=30) or ixekizumab (n=115) with dosingstratified by weight:

<25 kg: 40 mg at week 0 followed by 20 mg Q4W (n=4)25 kg to 50 kg: 80 mg at week 0 followed by 40 mg Q4W (n=50)>50 kg: 160 mg at week 0 followed by 80 mg Q4W (n=147)

Patients randomised to etanercept (patients with severe psoriasis) received 0.8 mg/kg, not exceeding50 mg per dose, every week from week 0 through week 11.

Response to treatment was assessed after 12 weeks and defined by the proportion of patients whoachieved the co-primary endpoint of an sPGA score of “0” (clear) or “1” (almost clear) with at least a2 point improvement from baseline and the proportion of patients that achieved a reduction in PASIscore of at least 75% (PASI 75) from baseline.

Other evaluated outcomes at week 12 included the proportion of patients who achieved PASI 90,

PASI 100, sPGA of “0” and an improvement of itch severity as measured by a reduction of at least4 points on an 11-point itch Numeric Rating Scale.

Patients had a median baseline PASI of 17 score ranging from 12-49. Baseline sPGA score wassevere or very severe in 49%. Of all patients, 22% had received prior phototherapy and 32% hadreceived prior conventional systemic therapy for the treatment of psoriasis.25% of patients (n=43) were below 12 years (14% of patients [n=24] were 6-9 years and 11% ofpatients [n=19] were 10-11 years); 75% (n=128) were 12 years or above.

The clinical response data are presented in Table 9.

Table 9. Efficacy results in pediatric patients with plaque psoriasis, NRI

Endpoints Ixekizumaba Placebo Difference vs Etanerceptb Difference vs(N=115) (N=56) placebo (95% (N=30) etanercept (95%n (%) n (%) CI) n (%) CI)bsPGA “0” (clear) or“1” (almost clear)cweek 4 55 (48) 4 (7) 40.7 (29.3, 52.0)f 0(0) 36.8 (21.5, 52.2)week 12c 93 (81) 6 (11) 70.2 (59.3, 81.0)f 16 (53) 23.0 (0.6, 45.4)sPGA “0” (clear) d 60 (52) 1 (2) 50.4 (40.6, 60.2)f 5 (17) 46.5 (26.2, 66.8)

PASI 75week 4 62 (54) 5 (9) 45.0 (33.2, 56.8)f 3 (10) 34.7 (15.6, 53.8)week 12c 102 (89) 14 (25) 63.7 (51.0, 76.4)f 19 (63) 20.9 (0.1, 41.7)

PASI 90d 90 (78) 3 (5) 72.9 (63.3, 82.5)f 12 (40) 36.3 (14.2, 58.5)

PASI 100d 57 (50) 1 (2) 47.8 (38.0, 57.6)f 5 (17) 43.9 (23.4, 64.3)

Itch NRS (≥4 point 59 (71) 8 (20) 51.1 (35.3, 66.9)f Not evaluated ---improvement) d, e

Abbreviations: N = Number of patients in the intent-to-treat population; NRI = Non-Responder

Imputation.

a At week 0, subjects received 160 mg, 80 mg, or 40 mg of ixekizumab, followed by 80 mg, 40 mg,or 20 mg every 4 weeks, depending on weight category, for 12 weeks.

b Comparisons to etanercept were performed within the sub-population of patients outside of US and

Canada with severe Ps (N for ixekizumab = 38).

c Co-primary endpoints.d Results at week 12.e Itch NRS (≥4 improvement) in patients with baseline Itch NRS ≥4. The number of ITT patientswith baseline Itch NRS Score ≥4 are as follows: ixekizumab, n = 83; PBO, n = 40.f p<0.001

Figure 3. Percent of patients achieving PASI 75 in pediatric psoriasis through week 12

Patients in the ixekizumab treatment group had clinically meaningful higher CDLQI/DLQI (0,1)responses at week 12 (NRI) compared with placebo. The difference between treatment groups wasapparent from as early as week 4.

There were greater improvements at week 12 from baseline compared to placebo in nail psoriasis (asmeasured by the Nail Psoriasis Severity Index [NAPSI=0: ixekizumab 18% (6/34), placebo 0%(0/12)]), in scalp psoriasis (as measured by Psoriasis Scalp Severity Index [PSSI=0: ixekizumab 69%(70/102), placebo 16% (8/50)]) and in palmoplantar psoriasis (as measured by Psoriasis Palmoplantar

Severity Index [PPASI 75: ixekizumab 53% (9/17), placebo 11% (1/9)]).

Ixekizumab was assessed in two randomised, double-blind, placebo-controlled phase III studies in780 patients with active psoriatic arthritis (≥3 swollen and ≥3 tender joints). Patients had a diagnosisof psoriatic arthritis (Classification Criteria for Psoriatic Arthritis [CASPAR] criteria) for a median of5.33 years and had current plaque psoriasis skin lesions (94.0%) or a documented history of plaquepsoriasis, with 12.1% of patients with moderate to severe plaque psoriasis at baseline. Over 58.9%and 22.3% of the psoriatic arthritis patients had enthesitis and dactylitis at baseline, respectively.

Primary endpoint of both studies was American College of Rheumatology (ACR) 20 response atweek 24, followed by a long-term extension period from week 24 to week 156 (3 years).

In Psoriatic Arthritis Study 1 (SPIRIT-P1), patients naive to biologic therapy with active psoriaticarthritis were randomised to placebo, adalimumab 40 mg once every 2 weeks (active control referencearm), ixekizumab 80 mg once every 2 weeks (Q2W), or 80 mg once every 4 weeks (Q4W). Bothixekizumab regimens included a 160 mg starting dose. 85.3% of patients in this study had receivedprior treatment with ≥1 cDMARD. 53% of patients had concomitant use of MTX at a mean weeklydose of 15.8 mg. 67% of patients who had concomitant use of MTX had a dose of 15 mg or greater.

Patients with an inadequate response at week 16 received rescue therapy (modification to backgroundtherapy). Patients on ixekizumab Q2W or Q4W remained on their originally assigned dose ofixekizumab. Patients receiving adalimumab or placebo were re-randomised 1:1 to ixekizumab Q2W or

Q4W at week 16 or 24 based on responder status. 243 patients completed the extension period of3 years on ixekizumab.

Psoriatic Arthritis Study 2 (SPIRIT-P2) enrolled patients who were previously treated with ananti-TNF agent and discontinued the anti-TNF agent for either lack of efficacy or intolerance(anti-TNF-IR patients). Patients were randomised to placebo, ixekizumab 80 mg once every 2 weeks(Q2W), or 80 mg once every 4 weeks (Q4W). Both ixekizumab regimens included a 160 mg startingdose. 56% and 35% of patients were inadequate responders to 1 anti-TNF or 2 anti-TNF, respectively.

SPIRIT-P2 evaluated 363 patients, of whom 41% had concomitant use of MTX at a mean weekly doseof 16.1 mg. 73.2% of patients who had concomitant use of MTX had a dose of 15 mg or greater.

Patients with an inadequate response at week 16 received rescue therapy (modification to backgroundtherapy). Patients in ixekizumab Q2W or Q4W remained on their originally assigned dose ofixekizumab. Patients receiving placebo were re-randomised 1:1 to ixekizumab Q2W or Q4W at week16 or 24 based on responder status. 168 patients completed the extension period of 3 years onixekizumab.

Signs and symptoms

Treatment with ixekizumab resulted in significant improvement in measures of disease activitycompared to placebo at week 24 (see Table 10).

Table 10. Efficacy results in SPIRIT-P1 and SPIRIT-P2 at week 24

SPIRIT-P1 SPIRIT-P2

Endpoints Difference from Difference fromplacebo in response placebo in responserate (95% CI) rate (95% CI)

PBO Ixekizumab Ixekizumab ADA Ixekizum Ixekizum PBO Ixekizumab Ixekizumab Ixekizum Ixekizum(N = 106) Q4W Q2W (N = 101) ab Q4W ab Q2W (N = 118) Q4W Q2W ab Q4W ab Q2W(N = 107) (N = 103) (N = 122) (N = 123)

ACR 20 response, n (%)week 24 27.8 31.9 33.8 28.532 (30.2) 62 (57.9) 64 (62.1) 58 (57.4) (15.0, (19.1, 23 (19.5) 65 (53.3) 59 (48.0) (22.4, (17.1,40.6)c 44.8)c 45.2)c 39.8)c

ACR 50 response, n (%)week 24 25.1 31.5 30.2 28.316 (15.1) 43 (40.2) 48 (46.6) 39 (38.6) (13.6, (19.7, 6 (5.1) 43 (35.2) 41 (33.3) (20.8, (19.0,36.6)c 43.3)c 39.5)c 37.5)c

ACR 70 response, n (%)week 24 28.3 22.117.7 (8.6, 12.2 (6.4,6 (5.7) 25 (23.4) 35 (34.0) 26 (25.7) c (18.2, 0 27 (22.1) 15 (12.2) (14.8,26.8) 18.0)c38.5)c 29.5)c

Minimal disease activity (MDA) n (%)week 24 25.7 24.5 20.214.8 (3.8,16 (15.1) 32 (29.9) 42 (40.8) 32 (31.7) (14.0, 4 (3.4) 34 (27.9) 29 (23.6) (15.9, (12.0,25.8)a37.4)c 33.1)c 28.4)c

ACR 50 and PASI 100 in patients with ≥3% BSA psoriasis skin involvement at baseline, n (%)week 24 27.3 30.717.6 (8.6, 14.7 (6.3,1 (1.5) 21 (28.8) 19 (32.2) 9 (13.2) (16.5, (18.4, 0 (0.0) 12 (17.6) 10 (14.7)26.7)cc 23.1)c38.1) 43.0)b

Abbreviations: ACR 20/50/70 = American College of Rheumatology 20%/50%/70% response rate;

ADA = adalimumab; BSA = body surface area; CI = confidence interval; Q4W = ixekizumab 80 mgevery 4 weeks; Q2W = ixekizumab 80 mg every 2 weeks; N = number of patients in the analysispopulation; n = number of patients in the specified category; NRI = non-responder imputation; PASI100 = psoriasis area and severity index 100% improvement; PBO = placebo.

Note: patients who were rescued at week 16 or discontinued or with missing data were imputed asnon-responders for week 24 analyses.

Concomitant cDMARDs included MTX, leflunomide and sulfasalazine.a p<0.05; b p<0.01; c p<0.001 compared with placebo.

In patients with pre-existing dactylitis or enthesitis, treatment with ixekizumab Q4W resulted inimprovement in dactylitis and enthesitis at week 24 compared to placebo (resolution: 78% vs. 24%;p<0.001, and 39% vs. 21%; p<0.01, respectively).

In patients with ≥3% BSA, the improvement in skin clearance at week 12 as measured by 75%improvement in Psoriasis Area Severity Index (PASI 75), was 67% (94/141) for those treated with the

Q4W dosing regimen, and 9% (12/134) for those treated with placebo (p<0.001). The proportion ofpatients achieving a PASI 75, PASI 90, and PASI 100 response at week 24 was greater withixekizumab Q4W compared to placebo (p<0.001). In patients with concomitant moderate to severepsoriasis and psoriatic arthritis, ixekizumab Q2W dose regimen showed significantly higher responserate for PASI75, PASI 90 and PASI 100 compared to placebo (p<0.001) and demonstrated clinicallymeaningful benefit over the Q4W dose regimen.

Treatment responses on ixekizumab were significantly greater than those on placebo as early asweek 1 for ACR 20, week 4 for ACR 50 and week 8 for ACR 70 and persisted through week 24;effects were maintained through 3 years for patients who remained in the study.

Figure 4. ACR 20 response in SPIRIT-P1 over time up to week 24100 PBO (N=106) ADA (N=101) IXE Q4 (N=107) IXE Q2 (N=103)c70 c c c c60 c50 cb0 2 4 6 8 10 12 14 16 18 20 22 24

Treatment Week

For both ixekizumab Q2W and Q4W: b p<0.01 and c p<0.001 compared with placebo.

In SPIRIT-P1 and SPIRIT-P2, similar responses for ACR 20/50/70 were seen in patients with psoriaticarthritis regardless of whether they were on concomitant cDMARDs, including MTX treatment, ornot.

In SPIRIT-P1and SPIRIT-P2, improvements were shown in all components of the ACR scoresincluding patient assessment of pain. At week 24 the proportion of patients achieving a modified

Psoriatic Arthritis Response Criteria (PsARC) response was greater in the ixekizumab -treated patientscompared to placebo.

ACR20 Responders, %

In SPIRIT-P1, efficacy was maintained up to week 52 as assessed by ACR 20/50/70, MDA, enthesitisresolution, dactylitis resolution, and PASI 75/90/100 response rates.

The efficacy and safety of ixekizumab was demonstrated regardless of age, gender, race, diseaseduration, baseline body weight, baseline psoriasis involvement, baseline CRP, baseline DAS28-CRP,concomitant corticosteroid use, and previous treatment with a biologic. Ixekizumab was efficacious inbiologic-naive, biologic-exposed and biologic-failure patients.

In SPIRIT-P1, 63 patients completed 3 years of Q4W ixekizumab treatment. Among the 107 patientswho were randomised to ixekizumab Q4W (NRI analysis in ITT population), 54 patients (50%),41 patients (38%), 29 patients (27%), and 36 patients (34%) were observed to have ACR20, ACR50,

ACR70, and MDA response, respectively, at week 156.

In SPIRIT-P2, 70 patients completed 3 years of Q4W ixekizumab treatment. Among the 122 patientswho were randomised to ixekizumab Q4W (NRI analysis in ITT population), 56 patients (46%),39 patients (32%), 24 patients (20%) and 33 (27%) were observed to have ACR20, ACR50, ACR70,and MDA response, respectively, at week 156.

In SPIRIT-P1, inhibition of progression of structural damage was assessed radiographically andexpressed as the change in modified total Sharp Score (mTSS) and its components, the Erosion

Score (ES) and the Joint Space Narrowing score (JSN) at weeks 24 and 52, compared to baseline.week 24 data are presented in Table 11.

Table 11. Change in modified Total Sharp Score in SPIRIT-P1

Difference from placebo(95% CI)

PBO Ixekizumab Ixekizumab ADA Ixekizumab Ixekizumab(N = 106) Q4W Q2W (N = 101) Q4W Q2W(N = 107) (N = 103)

Baseline score, mean (SD) 17.6 (28.62) 19.2 (32.68) 15.2 (28.86) 15.9 (27.37) NA NA

Change from baseline at -0.33 -0.42week 24, LSM (SE) 0.51 (0.092) 0.18 (0.090) 0.09 (0.091) 0.13 (0.093) (-0.57,-0.09)b (-0.66,-0.19)c

Abbreviations: ADA = adalimumab; CI = confidence interval; Q4W = ixekizumab 80 mg every4 weeks; Q2W = ixekizumab 80 mg every 2 weeks; LSM = least squares mean; N = number of patientsin the analysis population; PBO = placebo; SE = standard error; SD = standard deviation.b p<0.01; c p<0.001 compared with placebo.

Radiographic joint damage progression was inhibited by ixekizumab (Table 11) at week 24, and thepercentage of patients with no radiographic joint damage progression (defined as a change frombaseline in mTSS of ≤0.5) from randomisation to week 24 was 94.8% for ixekizumab Q2W (p<0.001),89.0% for ixekizumab Q4W (p=0.026), 95.8% for adalimumab (p<0.001), all compared to 77.4% forplacebo. At week 52, the mean change from baseline in mTSS was 0.27 for placebo/ ixekizumab Q4W,0.54 for ixekizumab Q4W/ ixekizumab Q4W, and 0.32 for adalimumab/ ixekizumab Q4W. Thepercentage of patients with no radiographic joint damage progression from randomisation to week 52was 90.9% for placebo/ ixekizumab Q4W, 85.6% for ixekizumab Q4W/ ixekizumab Q4W, and 89.4%for adalimumab/ ixekizumab Q4W. Patients had no structural progression from baseline (defined asmTSS≤0.5) in the treatment arms as follows: Placebo/ ixekizumab Q4W 81.5% (N=22/27),ixekizumab Q4W/ ixekizumab Q4W 73.6% (N=53/72), and adalimumab/ ixekizumab Q4W 88.2%(N=30/34).

In both SPIRIT-P1 and SPIRIT-P2, patients treated with ixekizumab Q2W (p<0.001) and Q4W(p<0.001) showed significant improvement in physical function compared to patients treated withplacebo as assessed by Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 24,and maintained at week 52 in SPIRIT-P1.

Ixekizumab -treated patients reported improvements in health-related quality of life as measured bythe Physical Component Summary of the Short Form-36 Health Survey (SF-36 PCS) score(p<0.001). There were also improvements demonstrated in fatigue as assessed by Fatigue severity

NRS scores (p<0.001).

Post-marketing phase 4, direct comparative study

Efficacy and safety of ixekizumab was investigated in a multicenter, randomised, open-label,rater-blinded, parallel-group study (SPIRIT-H2H) compared to adalimumab (ADA) in 566 patientswith PsA who were naïve to biologic disease-modifying anti-rheumatic drugs (bDMARD). Patientswere stratified at baseline based on concomitant cDMARD use and presence of moderate-to-severepsoriasis (PASI≥12, BSA≥10 and sPGA≥3).

Ixekizumab was superior to ADA on the primary study objective: simultaneous achievement of

ACR 50 and PASI 100 response at week 24 (ixekizumab 36.0% vs ADA 27.9%; p=0.036; 95%confidence interval [0.5%, 15.8%]). Ixekizumab also showed non-inferiority (pre-specified margin of -12%) to ADA on ACR 50 (ITT analysis: ixekizumab 50.5% vs ADA 46.6%; 3.9% difference vs.

ADA; 95% confidence interval [-4.3%; 12.1%]; PPS analysis ixekizumab: 52.3%, ADA: 53.1%,difference: -0.8% [CI: -10.3%; 8.7%]) and superiority on PASI 100 at week 24 (60.1 % withixekizumab vs 46.6% with ADA, p=0.001), which were the major secondary endpoints in the study.

At week 52 a higher proportion of patients treated with ixekizumab versus ADA simultaneouslyachieved ACR50 and PASI 100 [39% (111/283) versus 26% (74/283)] and PASI 100 [64% (182/283)versus 41% (117/283)]. Ixekizumab and ADA treatment resulted in similar responses for ACR50[49.8% (141/283) versus 49.8% (141/283)]. Responses to ixekizumab were consistent when used asmonotherapy or with concomitant use of methotrexate.

Figure 5. Primary endpoint (simultaneous ACR 50 & PASI 100) and major secondaryendpoints (ACR 50; PASI 100) response rates week 0 - 24 [ITT population, NRI]**

** Ixekizumab 160 mg week 0, then 80 mg every 2 weeks to week 12 and every 4 weeks thereafter forpatients with moderate to severe plaque psoriasis or 160 mg week 0, then 80 mg every 4 week forother patients, ADA 80 mg week 0, then 40 mg every 2 weeks from week 1 for patients with moderateto severe plaque psoriasis or 40 mg week 0, then 40 mg every 2 weeks for other patients.

Significance level only provided for endpoint that was pre-defined and multiplicity tested.

Ixekizumab was assessed in a total of 960 adult patients with axial spondyloarthritis in threerandomised placebo-controlled studies (two in radiographic and one in non-radiographic axialspondyloarthritis).

Radiographic axial spondyloarthritis

Ixekizumab was assessed in a total of 657 patients in two randomised, double-blind,placebo-controlled studies (COAST-V and COAST-W) in adult patients who had active disease asdefined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 and total back pain≥4 on a numeric rating scale despite non-steroidal anti-inflammatory drug (NSAID) therapy. Acrossboth studies at baseline, patients had symptoms for a mean of 17 years (median of 16 years). Atbaseline, approximately 32% of the patients were on a concomitant cDMARD.

COAST-V evaluated 341 biologic-naive patients treated with either ixekizumab 80 mg or 160 mg atweek 0 followed by 80 mg every 2 weeks (Q2W) or 4 weeks (Q4W), adalimumab 40 mg every2 weeks, or with placebo. Patients receiving placebo were re-randomised at week 16 to receiveixekizumab (160 mg starting dose, followed by 80 mg Q2W or Q4W). Patients receiving adalimumabwere re-randomised at week 16 to receive ixekizumab (80 mg Q2W or Q4W).

COAST-W evaluated 316 patients who had prior experience with 1 or 2 TNF-inhibitors (90% wereinadequate responders and 10% were intolerant to TNF inhibitors). All patients were treated withixekizumab 80 or 160 mg at week 0 followed by 80 mg Q2W or Q4W, or with placebo. Patientsreceiving placebo were re-randomised at week 16 to receive ixekizumab (160 mg initial dose,followed by 80 mg Q2W or Q4W).

The primary endpoint in both studies was the percentage of patients achieving an Assessment of

Spondyloarthritis International Society 40 (ASAS40) response at week 16.

In both studies, patients treated with ixekizumab 80 mg Q2W or 80 mg Q4W demonstrated greaterimprovements in ASAS40 and ASAS20 responses compared to placebo at week 16 (Table 12).

Responses were similar in patients regardless of concomitant therapies. In COAST-W, responses wereseen regardless of the number of prior TNF inhibitors.

Table 12. Efficacy results in COAST-V and COAST-W at week 16

COAST-V, biologic-naive COAST-W, TNF-inhibitor experienced

Ixekizumab Difference Adalimumab Ixekizum80 mg from placebo g ab

Q4Wa Placebo 40 mg Placebo(N=81) (N=87) Q2W 80 mg

Q4Wc (N=104) Difference(N=90) from placebo g(N=114)

ASAS20 responseb, n (%), 52 (64.2%) 35 24.0 (9.3, 53 (58.9%) 55 31 18.4 (5.7, 31.1)

NRI (40.2%) 38.6) ** (48.2%) (29.8%) **

ASAS40 responseb,c, n (%), 39 (48.1%) 16 29.8 (16.2, 32 (35.6%) 29 13 12.9 (2.7, 23.2)

NRI (18.4%) 43.3) *** (25.4%) (12.5%) *

ASDAS

Change from baseline -1.4 -0.5 -1.0 (-1.3, -0.7) -1.3*** -1.2 -0.1 -1.1 (-1.3, -0.8)

Baseline 3.7 3.9 *** 3.7 4.2 4.1 ***

BASDAI Score

Change from baseline -2.9 -1.4 -1.5 (-2.1, -0.9) -2.5*** -2.2 -0.9 -1.2 (-1.8, -0.7)

Baseline 6.8 i 6.8 i *** 6.7 i 7.5 7.3 ***

MRI Spine SPARCCd

Change from baseline -11.0 -1.5 -9.5 (-12.6, -11.6*** -3.0 3.3 -6.3 (-10.0,

Baseline 14.5 15.8 -6.4) *** 20.0 8.3 6.4 -2.5) **

BASDAI50e n (%), NRI 34 (42.0%) 15 24.7 (11.4, 29 (32.2%)* 25 10 12.3 (2.8,(17.2%) 38.1) *** (21.9%)i (9.6%)i 21.8)*

ASDAS <2.1, n (%) (low 35 (43.2%)h 11 30.6 (17.7, 34 20 5 (4.8%) 12.7 ( 4.6,disease activity), NRI (12.6%) 43.4) *** (37.8%)*** h (17.5%) 20.8) **h

ASDAS <1.3, n (%) 13 (16.0%) 2 13.8 (5.2, 22.3) 14 (15.6%)** 4 (3.5%)i 1 (1.0%)i 2.5 (-1.3, 6.4)(inactive disease), NRI (2.3%) **

ASAS HIf

Change from baseline -2.4 -1.3 -1.1 (-2.0, -0.3) -2.3* -1.9 -0.9 -1.0 (-1.9, -0.1)

Baseline 7.5 8.1 * 8.2 10.0 9.0 *

SF-36 PCS

Change from baseline 7.7 3.6 4.1 (1.9, 6.2) 6.9** 6.6 1.4 5.2 (3.0, 7.4)

Baseline 34.0 32.0 *** 33.5 27.5 30.6 ***

Abbreviations: N = number of patients in the intent-to-treat population; NRI = Non-responder

Imputation; patients with missing data were counted as non-responders.

ASAS HI = Assessment of SpondyloArthritis International Society Health Index; ASDAS = Ankylosing

Spondylitis Disease Activity Score; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index;

CFB = least square mean change from baseline at week 16; MRI Spine SPARCC = Spondyloarthritis

Research Consortium of Canada Magnetic Resonance Imaging Scoring of the Spine(23 discovertebral unit scale)a At week 0, patients received 80 mg or 160 mg of ixekizumab.b An ASAS20 response is defined as a ≥20% improvement and an absolute improvement frombaseline of ≥1 unit (range 0 to 10) in ≥3 of 4 domains (Patient Global, Spinal Pain, Function,and Inflammation), and no worsening of ≥20% and ≥1 unit (range 0 to 10) in the remainingdomain. An ASAS40 response is defined as a ≥40% improvement and an absolute improvementfrom baseline of ≥2 units in ≥3 of 4 domains without any worsening in the remaining domain.

c Primary endpoint.d The numbers of ITT patients with MRI data at baseline are as follows: COAST-V: ixekizumab,n = 81; PBO, n = 82; ADA, n=85. COAST-W: ixekizumab, n = 58; PBO, n = 51.e BASDAI50 response defined as an improvement of ≥50% of the BASDAI score from baseline.f ASAS HI: Assessment of SpondyloArthritis International Society Health Index (ASAS HI) acrossall domains.g The reported values are difference in %( 95% CI) for categorical variables, and difference in

LSM (95% CI) for continuous variables.h post hoc analysis, not multiplicity corrected.i prespecified, but not multiplicity gated.

* p<0.05; ** p<0.01; *** p<0.001 compared with placebo.

There were improvements in the main components of the ASAS40 response criteria (spinal pain,

BASFI, patient global assessment, stiffness) and other measures of disease activity, including CRP, atweek 16.

Figure 6. Percent of patients achieving ASAS40 responses in COAST-V and COAST-Wthrough week 16, NRIaa Patients with missing data were counted as non-responders.

* p<0.05; ** p<0.01; *** p<0.001 compared with placebo.

Similar response in ASAS40 was seen in patients regardless of baseline CRP levels, baseline ASDASscores and MRI spine SPARCC scores. The ASAS40 response was demonstrated regardless of age,gender, race, disease duration, baseline body weight, baseline BASDAI score and prior biologictreatment.

In COAST-V and COAST-W efficacy was maintained up to week 52 as assessed by the endpointspresented in Table 12, including ASAS20, ASAS40, ASDAS, BASDAI, and ASAS HI response rates.

Health-related outcomes

Spinal pain showed improvements versus placebo as early as week 1, maintained through week 16[ixekizumab vs placebo: COAST-V -3.2 vs -1.7; COAST-W -2.4 vs -1.0]; fatigue and spinal mobilityshowed improvements versus placebo at week 16. Improvements in spinal pain, fatigue and spinalmobility were maintained through week 52.

Non-radiographic axial spondyloarthritis

Ixekizumab was assessed in a randomised, double-blind study with a 52-week placebo-controlledperiod (COAST-X) in 303 adult patients with active axial spondyloarthritis for at least 3 months.

Patients must have had objective signs of inflammation indicated by elevated C-reactive protein (CRP)and/or sacroiliitis on magnetic resonance imaging (MRI), and no definitive radiographic evidence ofstructural damage on sacroiliac joints. Patients had active disease as defined by the Bath Ankylosing

Spondylitis Disease Activity Index (BASDAI) ≥4, and spinal pain ≥4 on a 0 to 10 Numerical Rating

Scale (NRS), despite non-steroidal anti-inflammatory drug (NSAID) therapy. Patients were treatedwith either ixekizumab 80 mg or 160 mg at week 0, followed by 80 mg every 2 weeks (Q2W) or80 mg every 4 weeks (Q4W) or with placebo. Dose adjustment and/or initiation of concomitantmedications (NSAIDs, cDMARDs, corticosteroids, analgesics) were permitted starting at week 16.

At baseline, patients had symptoms of non-radiographic axSpA for an average of 11 years.

Approximately 39% of the patients were on a concomitant cDMARD.

The primary endpoint was the percentage of patients achieving an Assessment of Spondyloarthritis

International Society 40 (ASAS40) response at week 16.

Higher proportions of patients treated with ixekizumab 80 mg Q4W achieved ASAS40 responsecompared to placebo at week 16 (Table 13). Responses were similar regardless of concomitanttherapies.

Table 13. Efficacy results at week 16 in COAST-X, NRI a,b

Ixekizumab 80 mg Q4Wc Placebo(N=96) (N=105) Difference fromplacebo h

ASAS20 responsed, n (%), NRI 52 (54.2%) 41 (39.0%) 15.1 (1.5, 28.8)*

ASAS40 responsed,e, n (%), NRI 34 (35.4%) 20 (19.0%) 16.4 (4.2, 28.5)**

ASDAS

Change from baseline -1.1 -0.6 -0.5 (-0.8, -0.3) ***

Baseline 3.8 3.8

BASDAI Score

Change from baseline -2.2 -1.5 -0.7 (-1.3, -0.1) *

Baseline 7.0 7.2

MRI SIJ SPARCCf

Change from baseline -3.4 -0.3 -3.1 (-4.6, -1.6) ***

Baseline 5.1 6.3

ASDAS <2.1, n (%) 26 (27.7%) 13 (12.4%) 15.3 (4.3, 26.3) **(low disease activity), NRIg

SF-36 PCS

Change from baseline 8.1 5.2 2.9 (0.6, 5.1) *

Baseline 33.5 32.6a Abbreviations: N = number of patients in the intent-to-treat population; NRI = Non-responder

Imputation. ASDAS = Ankylosing Spondylitis Disease Activity Score; BASDAI = Bath Ankylosing

Spondylitis Disease Activity Index; Change from baseline = least square mean change from baselineat week 16; MRI SIJ SPARCC = Spondyloarthritis Research Consortium of Canada Magnetic

Resonance Imaging Scoring of the sacroiliac joint.

b Patients with missing data were counted as non-responders.c At week 0, patients received 80 mg or 160 mg of ixekizumab.d An ASAS20 response is defined as a ≥20% improvement and an absolute improvement from baselineof ≥1 units (range 0 to 10) in ≥3 of 4 domains (Patient Global, Spinal Pain, Function, and

Inflammation), and no worsening of ≥20% and ≥1 unit (range 0 to 10) in the remaining domain. An

ASAS40 response is defined as a ≥40% improvement and an absolute improvement from baseline of≥2 units in ≥3 of 4 domains without any worsening in the remaining domain.

e Primary endpoint at week 16.f The numbers of ITT patients with MRI data at baseline and week 16 are as follows: ixekizumab,n = 85; PBO, n = 90.g Patients with missing data were counted as non-responders. Percentages are based on the number ofpatients in the ITT population with baseline ASDAS ≥2.1.h The reported values are difference in %( 95% CI) for categorical variables, and difference in

LSM (95% CI) for continuous variables.

* p<0.05; ** p<0.01; *** p<0.001 compared with placebo.

The improvement in the main components of the ASAS40 response criteria (spinal pain, BASFI,patient global assessment, stiffness) and other measures of disease activity demonstrated significantclinical improvement at week 16.

Figure 7. Percent of patients achieving ASAS40 response through week 16 in COAST-X, NRIaa Patients with missing data were counted as non-responders.

** p<0.01 compared with placebo.

Efficacy was maintained up to week 52 as assessed by the endpoints presented in Table 13.

Health-related outcomes

Spinal pain showed improvements versus placebo as early as week 1 and was maintained throughweek 16 [ixekizumab vs placebo: COAST-X: -2.4 vs -1.5]. In addition, more patients on ixekizumabcompared with placebo achieved good health status (ASAS HI ≤5) at week 16 and week 52.

Long-term outcomes Axial Spondyloarthritis

Patients who completed one of the three pivotal studies COAST-V/W/X (52 weeks) were offeredparticipation in a long-term extension and randomised withdrawal study (COAST-Y, with 350 and423 patients enrolled on ixekizumab Q4W and Q2W, respectively). Among those who achievedremission 157/773 (20.3%) (Ankylosing Spondylitis Disease Activity Score [ASDAS] <1.3 at leastonce, and no ASDAS score ≥2.1, at weeks 16 and 20), 155 patients exposed to ixekizumab up to76 weeks were randomised at week 24 of the COAST-Y study (Placebo, N=53; ixekizumab Q4W,

N=48; and ixekizumab Q2W, N=54); of these, 148 (95.5%) completed the week 64 visit (Placebo,

N=50; ixekizumab Q4W, N=47; ixekizumab Q2W, N=51). The primary endpoint was the proportionof patients in the randomised withdrawal population who did not experience a flare duringweeks 24-64 (combined ixekizumab Q2W and ixekizumab Q4W groups versus placebo). Asignificantly larger proportion of patients (NRI) in the combined ixekizumab groups (83.3% (85/102),p<0.001) and ixekizumab Q4W (83.3 % (40/48), p=0.003) had no flare during weeks 24-64 comparedwith those who withdrew from ixekizumab to placebo (54.7 % (29/53)). ixekizumab (in bothcombined ixekizumab groups and ixekizumab Q4W group) significantly delayed the time to flare(Log-Rank Test p<0.001 and p<0.01, respectively) compared to Placebo.

In patients who received ixekizumab Q4W continuously (N=157), the ASAS40, ASDAS <2.1 and

BASDAI50 responses were maintained to week 116.

In a study in healthy subjects, no safety concerns were identified of two inactivated vaccines (tetanusand pneumococcal), received after two doses of ixekizumab (160 mg followed by a second dose of80 mg two weeks later). However, the data concerning immunisation were insufficient to conclude onan adequate immune response to these vaccines following administration of ixekizumab.

The European Medicines Agency has deferred the obligation to submit the results of studies withixekizumab in one or more subsets of the paediatric population in the treatment of plaque psoriasis andpsoriatic arthritis/axial spondyloarthritis (see section 4.2 for information on paediatric use).

Following a single subcutaneous dose of ixekizumab in patients with psoriasis, mean peakconcentrations were achieved within 4 to 7 days, across a dose range of 5 to 160 mg. The mean (SD)maximum plasma concentration (Cmax) of ixekizumab, after the 160 mg starting dose, was19.9 (8.15) µg/mL.

After the 160 mg starting dose, steady state was achieved by week 8 with the 80 mg Q2W dosingregimen. Mean (SD) Cmax,ss, and C trough,ss estimates are 21.5 (9.16) µg/mL, and 5.23 (3.19) µg/mL.

After switching from the 80 mg Q2W dosing regimen to the 80 mg Q4W dosing regimen at week 12,steady state would be achieved after approximately 10 weeks. Mean (SD) Cmax,ss, and Ctrough,ss estimatesare 14.6 (6.04) µg/mL, and 1.87 (1.30) µg/mL.

The average bioavailability of ixekizumab after subcutaneous administration was 54 % to 90 % acrossanalyses.

From population pharmacokinetic analyses, the mean total volume of distribution at steady state was7.11 L.

Ixekizumab is a monoclonal antibody and is expected to be degraded into small peptides and aminoacids via catabolic pathways in the same manner as endogenous immunoglobulins.

In the population PK analysis, mean serum clearance was 0.0161 L/hr. Clearance is independent ofdose. The mean elimination half-life, as estimated from population pharmacokinetic analysis, is13 days in patients with plaque psoriasis.

Exposure (Area Under the Curve or AUC) increased proportionally over a dose range of 5 to 160 mggiven as a subcutaneous injection.

Pharmacokinetic properties across indications

The pharmacokinetic properties of ixekizumab were similar across the plaque psoriasis, psoriaticarthritis, radiographic axial spondyloarthritis and non-radiographic axial spondyloarthritis indications.

Of the 4 204 plaque psoriasis patients exposed to ixekizumab in clinical studies, a total of 301 were65 years of age or older and 36 patients were 75 years of age or older. Of the 1 118 psoriatic arthritispatients exposed to ixekizumab in clinical studies, a total of 122 patients were 65 years of age or olderand 6 patients were 75 years of age or older.

Based on population pharmacokinetic analysis with a limited number of elderly patients (n = 94 forage ≥ 65 years and n = 12 for age ≥ 75 years), clearance in elderly patients and patients less than65 years of age was similar.

Specific clinical pharmacology studies to evaluate the effects of renal impairment and hepaticimpairment on the PK of ixekizumab have not been conducted. Renal elimination of intactixekizumab, an IgG MAb, is expected to be low and of minor importance; similarly, IgG MAbs aremainly eliminated via intracellular catabolism and hepatic impairment is not expected to influenceclearance of ixekizumab.

Paediatric psoriasis patients (age 6 to less than 18 years) were administered ixekizumab at therecommended paediatric dosing regimen for 12 weeks. Patients weighing >50 kg and 25 to 50 kg hada mean ±SD steady-state trough concentration of 3.8 ±2.2 µg/mL and 3.9 ±2.4 µg/mL, respectively, atweek 12.

Non-clinical data reveal no special hazard for humans based on repeat-dose toxicity studies, safetypharmacology evaluations, and reproductive and developmental toxicity studies.

Ixekizumab administration to cynomolgus monkeys for 39 weeks at subcutaneous doses up to50 mg/kg weekly produced no organ toxicity or undesirable effects on immune function (e.g. T-celldependent antibody response and NK cell activity). A weekly subcutaneous dose of 50 mg/kg tomonkeys is approximately 19 times the 160 mg starting dose of ixekizumab and in monkeys results inexposure (AUC) that is at least 61-fold higher than the predicted mean steady-state exposure inhumans administered the recommended dose regimen.

Non-clinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential ofixekizumab.

No effects on reproductive organs, menstrual cycles or sperm were observed in sexually maturecynomolgus monkeys that received ixekizumab for 13 weeks at a weekly subcutaneous dose of50 mg/kg.

In developmental toxicity studies, ixekizumab was shown to cross the placenta and was present in theblood of offspring for up to 6 months of age. A higher incidence of postnatal mortality occurred in theoffspring of monkeys given ixekizumab compared to concurrent controls. This was related primarilyto early delivery or maternal neglect of offspring, common findings in nonhuman primate studies, andconsidered clinically irrelevant.

Sucrose

Polysorbate 80 (E 433)

Water for injections

Sodium hydroxide (for pH adjustment)

Not applicable.

2 years.

Store in a refrigerator (2 ºC to 8 ºC).

Do not freeze.

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

Taltz may be stored unrefrigerated for up to 5 days at a temperature not above 30 ºC.

Taltz 40 mg solution for injection in pre-filled syringe0.5 mL solution in a type I clear glass syringe.

Pack size of 1 pre-filled syringe.

Taltz 80 mg solution for injection in pre-filled syringe1 mL solution in a type I clear glass syringe.

Pack sizes of 1, 2, or 3 pre-filled syringes.

Not all pack sizes may be marketed.

The instructions for using the syringe, included with the package leaflet, must be followed carefully.

The pre-filled syringe is for single use only.

Taltz should not be used if particles appear or if the solution is cloudy and/or distinctly brown.

Taltz that has been frozen must not be used.

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

40 mg preparation of ixekizumab for children 25 - 50 kg body weight

If the 40 mg pre-filled syringe is not available, ixekizumab doses of 40 mg must be prepared andadministered by a qualified healthcare professional. Use only Taltz 80 mg solution for injection inpre-filled syringe when preparing the prescribed 40 mg paediatric doses.

1. Expel the entire contents of the pre-filled syringe into a sterile, clear glass vial. DO NOT shakeor swirl the vial.2. Use a 0.5 mL or 1 mL disposable syringe and sterile needle to withdraw the prescribed dose(0.5 mL for 40 mg) from the vial.3. Change the needle and use a 27-gauge, sterile needle to inject the patient. Discard any unusedixekizumab in the vial.

The prepared ixekizumab must be administered within 4 hours of puncturing the sterile vial atroom temperature.

Eli Lilly and Company (Ireland) Limited, Dunderrow, Kinsale, Co. Cork, Ireland.

EU/1/15/1085/004

EU/1/15/1085/005

EU/1/15/1085/006

EU/1/15/1085/007

Date of first authorisation: 25 April 2016

Date of latest renewal: 17 December 2020

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

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