Tildrakizumab (ILUMYA) — Drug Profile | TrialistMD

IL-23 Antagonist · Humanized mAb · Dermatology · BLA 761067

tildrakizumab

ILUMYA™ · tildrakizumab-asmn · Merck Sharp & Dohme Corp.

Humanized IgG1/κ monoclonal antibody selectively binding the p19 subunit of IL-23 to block IL-23R interaction and downstream Th17 inflammatory signaling, indicated for moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

NDA/BLA NumberBLA 761067

FDA ApprovalMarch 2018

Priority StatusStandard Review

Formulation100 mg/mL SC injection

Pharmacologic ClassIL-23 Antagonist

ApplicantMerck Sharp & Dohme Corp.

Overview

§1

Indication

Moderate-to-Severe Plaque Psoriasis

Adults eligible for systemic therapy or phototherapy

Mechanism

IL-23p19 Antagonist

Humanized IgG1/κ monoclonal antibody · 147 kDa

Dose & Schedule

100 mg SC

Wk 0, Wk 4, then every 12 weeks (Q12W)

Phase 3 Programme

2 Pivotal Trials

P010 (N=772) + P011 (N=1,090) · 1,862 total

Mechanism of Action: Tildrakizumab binds selectively to the p19 subunit of IL-23 (Kd ~297 pM), preventing IL-23 from engaging its receptor (IL-23R). This blocks JAK2-mediated phosphorylation of STAT3, inhibiting homodimerisation and nuclear transcription of IL-17 and other pro-inflammatory cytokines central to psoriatic pathogenesis. Tildrakizumab does not bind IL-12 or the shared p40 subunit, distinguishing it from dual IL-12/23 inhibitors.

Clinical Trial Programme

§1.2

Trial (ID)	NCT Number	Design	Arms & N Randomised	Duration	Primary Endpoint
Trial P003 (Phase 2)	Not reported	R, DB, 5-arm, dose-ranging, PC	Tildrakizumab 5/25/100/200 mg + placebo; N=270; ratio 1:2:2:2:1	72 weeks	PGA success at Wk 16; PASI 75 secondary
Trial P010 (Phase 3)	NCT01722331	R, DB, PC, parallel-group, 3-part + LTE	Tildrakizumab 200 mg (N=308), 100 mg (N=309), Placebo (N=155)	64 wk base + 192 wk extension	PASI 75 + PGA 0/1 at Wk 12 (co-primary)
Trial P011 (Phase 3)	NCT01729754	R, DB, PC + active comparator (etanercept), 3-part + LTE	Tildrakizumab 200 mg (N=314), 100 mg (N=307), Etanercept 50 mg BIW (N=313), Placebo (N=156)	52 wk base + 192 wk extension	PASI 75 + PGA 0/1 at Wk 12 (co-primary)
P05661 (Phase 1)	Not reported	Rising single-dose, IV, SAD in healthy volunteers	0.1, 0.5, 3, 10 mg/kg IV + placebo; N=29	Single dose	Safety, PK
P06306 (Phase 1)	Not reported	Non-randomized, open-label, race/ethnicity PK	50, 200, 400 mg SC + 10 mg/kg IV; N=59	Single dose	PK by race (Japanese, Chinese, White)
P009 (Phase 1)	Not reported	R, fixed-sequence, open-label, DDI (CYP450 cocktail)	200 mg SC × 2 doses + probe cocktail; N=20	2 doses of tildrakizumab	CYP inhibition assessment; relative bioavailability PFS vs. autoinjector

Source: FDA Medical Review BLA 761067 (Ref ID 4233639), Table 19 (Table of Clinical Studies). R=randomized; DB=double-blind; PC=placebo-controlled; SAD=single ascending dose; LTE=long-term extension; PFS=prefilled syringe; BIW=twice weekly.

Competitive Landscape — IL-23/IL-17 Biologics in Plaque Psoriasis

§1.3

Drug (INN · Brand)	Target	Formulation	US Approval	Approved Population
Tildrakizumab-asmn · ILUMYA	IL-23p19	100 mg SC Q12W	March 2018	Adults, mod-severe plaque psoriasis
Ustekinumab · STELARA	IL-12/23 p40	45/90 mg SC Q12W	September 2009	Adults & adolescents ≥12 yr
Secukinumab · COSENTYX	IL-17A	300 mg SC Q4W (after loading)	January 2015	Adults, mod-severe plaque psoriasis
Ixekizumab · TALTZ	IL-17A	80 mg SC Q4W (after loading)	March 2016	Adults, mod-severe plaque psoriasis
Guselkumab · TREMFYA	IL-23p19	100 mg SC Q8W (after loading)	July 2017	Adults, mod-severe plaque psoriasis
Risankizumab · SKYRIZI	IL-23p19	150 mg SC Q12W	April 2019	Adults, mod-severe plaque psoriasis

Highlighted row = tildrakizumab. Competitors listed reflect class context at BLA submission (March 2017); approvals after March 2018 included for landscape context. Source: FDA Drugs@FDA; Medical Review BLA 761067 (Ref ID 4233639) §2.2.

Key Drug Information

§1.4

Parameter	Detail
Proprietary Name	ILUMYA
INN / Established Name	Tildrakizumab-asmn
Code Names (development)	SCH 900222; MK-3222
Manufacturer / Applicant	Merck Sharp and Dohme Corp. (MSD)
Drug Product Manufacturer	MSD Ireland, Dublin Road, Carlow, Ireland
Pharmacologic Class	Interleukin-23 antagonist
Molecular Type	Recombinant humanized IgG1/κ monoclonal antibody; 4 polypeptide chains (2 heavy chains 446 aa each, 2 light chains 214 aa each); expressed in CHO cell line
Molecular Weight	~147 kDa
Dosage Form & Strength	100 mg/mL solution for injection in single-dose prefilled syringe (1 mL extractable volume); 29G staked needle; passive needle guard safety device
Storage	2°C–8°C (36°F–46°F); protect from light; do not freeze; room temperature (≤25°C/77°F) up to 30 days; dating period: 36 months
Inactive Ingredients	L-histidine, L-histidine hydrochloride monohydrate, sucrose 7%, polysorbate 80 0.05%, Water for Injection; pH ~5.8 (b)(4)
Boxed Warning	None
PI Revision Date	March 2018 (original approval labeling)
Application Type	BLA 351(a), Public Health Service Act — original BLA (not a biosimilar)
US License Number	0002

Baseline Characteristics

§2

Pooled pivotal trials: Trial P010 enrolled and randomised 772 subjects at 112 investigational sites; Trial P011 enrolled and randomised 1,090 subjects at 123 investigational sites. Demographics were generally balanced across arms within each trial. Trial P010 included Japanese sites (higher Asian proportion: 23–27%); Trial P011 did not include Japanese sites (Asian: 2–4%). Prior biologic exposure was higher in P010 (23%) vs. P011 (12–13%). Full Analysis Set (FAS): all randomised subjects who received ≥1 dose.

Trial P010 — Demographics

§2.1

Parameter	Tildrakizumab 200 mg (N=308)	Tildrakizumab 100 mg (N=309)	Placebo (N=155)
Age mean (SD), yr	47 (13)	46 (13)	48 (14)
Age median, yr	48	46	48
Age range, yr	18–76	18–82	19–76
Age <65 yr, n (%)	279 (91%)	281 (91%)	136 (88%)
Age ≥65 yr, n (%)	29 (9%)	28 (9%)	18 (12%)
Male, n (%)	226 (73%)	207 (67%)	100 (65%)
White, n (%)	209 (68%)	217 (70%)	101 (65%)
Asian, n (%)	83 (27%)	70 (23%)	42 (27%)
Black, n (%)	8 (3%)	12 (4%)	6 (4%)
Other, n (%)	8 (3%)	10 (3%)	6 (4%)
Weight mean (SD), kg	89 (24)	89 (24)	88 (26)
Weight median, kg	86	86	85
Weight ≤90 kg, n (%)	182 (59%)	183 (59%)	93 (60%)
Weight >90 kg, n (%)	126 (41%)	126 (41%)	62 (40%)
Prior biologic therapy, n (%)	71 (23%)	71 (23%)	35 (23%)
U.S. sites, n (%)	126 (41%)	131 (42%)	69 (45%)

Trial P011 — Demographics

§2.2

Parameter	Tildrakizumab 200 mg (N=314)	Tildrakizumab 100 mg (N=307)	Etanercept 50 mg (N=313)	Placebo (N=156)
Age mean (SD), yr	45 (14)	45 (14)	46 (14)	46 (12)
Age median, yr	45	44	48	46
Age range, yr	19–80	19–80	19–81	20–76
Age <65 yr, n (%)	289 (92%)	280 (91%)	282 (90%)	142 (91%)
Age ≥65 yr, n (%)	25 (8%)	27 (9%)	31 (10%)	14 (9%)
Male, n (%)	225 (72%)	220 (72%)	222 (71%)	112 (72%)
White, n (%)	284 (90%)	279 (91%)	289 (92%)	144 (92%)
Asian, n (%)	14 (4%)	9 (3%)	10 (3%)	3 (2%)
Black, n (%)	8 (3%)	7 (2%)	8 (3%)	1 (1%)
Other, n (%)	8 (3%)	12 (4%)	6 (2%)	8 (5%)
Weight mean (SD), kg	88 (21)	89 (22)	88 (21)	89 (23)
Weight median, kg	86	88	86	86
Weight ≤90 kg, n (%)	180 (57%)	176 (57%)	180 (58%)	90 (58%)
Weight >90 kg, n (%)	134 (43%)	131 (43%)	133 (42%)	66 (42%)
Prior biologic therapy, n (%)	38 (12%)	39 (13%)	37 (12%)	20 (13%)
U.S. sites, n (%)	86 (27%)	85 (28%)	87 (28%)	44 (28%)

Baseline Disease Severity — Both Pivotal Trials

§2.3

Parameter	P010 · Tildra 100 mg (N=309)	P010 · Placebo (N=155)	P011 · Tildra 100 mg (N=307)	P011 · Etanercept (N=313)	P011 · Placebo (N=156)
PGA Minimal (1), n (%)	0	0	2 (1%)	0	0
PGA Mild (2), n (%)	1 (<1%)	0	9 (3%)	7 (2%)	7 (5%)
PGA Moderate (3), n (%)	206 (67%)	111 (72%)	196 (64%)	193 (62%)	91 (59%)
PGA Marked (4), n (%)	95 (31%)	41 (27%)	95 (31%)	103 (33%)	52 (34%)
PGA Severe (5), n (%)	7 (2%)	2 (1%)	5 (2%)	7 (2%)	5 (3%)
PASI mean (SD)	20.0 (7.9)	19.3 (7.1)	20.5 (7.6)	20.2 (7.4)	20.0 (7.6)
PASI median	17.2	17.2	18.4	18.4	18.3
PASI range	9–59.4	12–51.8	8.4–54.8	8.4–52.5	12–55.8
BSA % mean (SD)	30 (17)	30 (17)	34 (18)	32 (17)	31 (15)
BSA % median	24	25	30	28	29

Prior Treatment History & Comorbidities (Pooled Phase 2/3 Safety Pool)

§2.4

Parameter	Tildrakizumab 100 mg Safety Pool (N=1,083)
Prior biologic therapy	17.5% (82.5% biologic-naïve)
Prior conventional systemic therapy	40.2%
Prior phototherapy	31.6%
History of psoriatic arthropathy	10.8%
Hypertension	27.1%
Obesity	6.8%
Hyperlipidemia	6.4%
Hypercholesterolemia	6.0%
Type 2 diabetes mellitus	5.1%
Back pain history	4.8%
Prior SCC/BCC skin cancer	<1%
Race: White	81.8%
Male sex	71.4%
Median age, yr (range)	46 (18–82)
Age ≥65 yr	8.9%
Mean baseline PASI (SD)	20.0 (7.7)
Baseline PGA 3 (Moderate)	65.9%
Baseline PGA 4 (Marked)	33.7%
Median BSA involved	26% (range 5–100%)

Source: FDA Medical Review BLA 761067 (Ref ID 4233639), Tables 23–24 (demographics), §7.3.1 (safety population characteristics). Population: FAS (all randomised receiving ≥1 dose). Values for P010 tildrakizumab 100 mg arm note: 1 subject had baseline PGA of 2 and 1 subject had baseline PASI of 9 (below protocol thresholds); both retained in FAS.

Efficacy

§3

Co-primary endpoints (Week 12): PASI 75 response rate AND PGA 0/1 response (with ≥2-grade improvement from baseline). Both doses statistically superior to placebo in both trials (p < 0.001 for all 4 comparisons). Missing data: Non-Responder Imputation (NRI) — primary method. Multiplicity controlled via sequential gatekeeping: PASI 75 → PGA 0/1 → PASI 90 → PASI 100. CMH test stratified by baseline weight (≤90 kg / >90 kg) and prior biologic therapy use (Yes/No).

Trial P010 — Co-Primary Endpoints at Week 12

§3.1

TRIAL P010 · WEEK 12 · NRI · FAS Tildrakizumab 100 mg (N=309) vs. Tildrakizumab 200 mg (N=308) vs. Placebo (N=154)

PASI 75 — tildrakizumab 100 mg

64%

PASI 75 — tildrakizumab 200 mg

62%

PASI 75 — placebo

PGA 0/1 — tildrakizumab 100 mg

58%

PGA 0/1 — tildrakizumab 200 mg

59%

PGA 0/1 — placebo

p < 0.001 for both tildrakizumab doses vs. placebo on both co-primary endpoints (CMH test).

Trial P011 — Co-Primary Endpoints at Week 12

§3.2

TRIAL P011 · WEEK 12 · NRI · FAS Tildrakizumab 100 mg (N=307) vs. 200 mg (N=314) vs. Etanercept 50 mg (N=313) vs. Placebo (N=156)

PASI 75 — tildrakizumab 100 mg

61%

PASI 75 — tildrakizumab 200 mg

66%

PASI 75 — etanercept 50 mg

48%

PASI 75 — placebo

PGA 0/1 — tildrakizumab 100 mg

55%

PGA 0/1 — tildrakizumab 200 mg

59%

PGA 0/1 — etanercept 50 mg

48%

PGA 0/1 — placebo

p < 0.001 for both tildrakizumab doses vs. placebo. Etanercept vs. placebo comparison not a primary regulatory endpoint in this context; no approved comparative efficacy claim. Note: Trial P012 (etanercept comparator) was dropped; no comparative efficacy claim against etanercept was pursued. Source: FDA Medical Review BLA 761067 (Ref ID 4233639), Table 25.

Secondary Endpoints at Week 12 — PASI 90 & PASI 100

§3.3

KEY SECONDARY ENDPOINTS · WEEK 12 · NRI Both pivotal trials; tildrakizumab 100 mg vs. placebo

PASI 90 — Tildra 100 mg (P010)

35%

PASI 90 — Placebo (P010)

PASI 90 — Tildra 100 mg (P011)

39%

PASI 90 — Placebo (P011)

PASI 100 — Tildra 100 mg (P010)

14%

PASI 100 — Placebo (P010)

<1%

PASI 100 — Tildra 100 mg (P011)

12%

PASI 100 — Placebo (P011)

Response Over Time — PASI 75 (Chart.js, Reported Timepoints Only)

§3.4

Source: FDA Medical Review BLA 761067 (Ref ID 4233639), Table 25 (Week 12 values). Wk 0 and Wk 4 values not explicitly tabulated in text; shown as null. Wk 8 values not explicitly tabulated; shown as null. Only Wk 12 values were explicitly stated in the text tables extracted. spanGaps: false applied.

Source: FDA Medical Review BLA 761067 (Ref ID 4233639), Table 25 (Week 12 values). P011 includes etanercept active comparator arm. Intermediate timepoints (Wk 4, Wk 8) not explicitly tabulated; shown as null.

Maintenance of Response — Trial P010 (Week 28–64)

§3.5

Re-randomisation design (Part 3): PASI 75 responders at Week 28 were re-randomised 1:1 to continue tildrakizumab 100 mg Q12W vs. withdraw to placebo. Non-responders (PASI <50% at Week 28) were discontinued. Partial responders (PASI 50–<75%) were re-randomised to 100 or 200 mg Q12W.

TRIAL P010 · MAINTENANCE (WK 64) · RESPONDER RE-RANDOMISATION Among PASI 75 responders at Week 28 re-randomised at Part 3

PASI 75 at Wk 64 — continue tildrakizumab 100 mg

84%

PASI 75 at Wk 64 — withdrawal to placebo

22%

PGA 0/1 at Wk 64 — continue tildrakizumab 100 mg

69%

PGA 0/1 at Wk 64 — withdrawal to placebo

14%

Rebound: Defined as worsening beyond baseline PASI (>125% of baseline PASI) or new pustular/erythrodermic/inflammatory psoriasis within 2 months of stopping therapy. No rebound events were observed in either withdrawal group (100 mg → placebo; 200 mg → placebo) during Weeks 32–64 of Trial P010.

Statistical Methodology Summary

§3.6

Parameter	Specification
Analysis population	Full Analysis Set (FAS): all randomised subjects receiving ≥1 dose; subjects with missing baseline PGA/PASI imputed as non-responders
Primary missing data method	Non-responder imputation (NRI)
Sensitivity analyses	(1) LOCF; (2) Multiple imputation (MI); (3) Worst-case scenario (tildrakizumab missing = non-responder; placebo missing = responder) — tildrakizumab remained superior to placebo in all scenarios
Inference test	Cochran–Mantel–Haenszel (CMH) test stratified by baseline weight (≤90 vs. >90 kg) and prior biologic use (Yes/No)
Multiplicity control	Sequential gatekeeping: PASI 75 (200 mg) → PASI 75 (100 mg) → PGA 0/1 (200 mg) → PGA 0/1 (100 mg) → PASI 90 → PASI 100; FWER controlled at α = 0.05
Per-Protocol (PP) population	Results consistent with FAS; PP PASI 75: P010 100 mg = 64%, P011 100 mg = 61%

Source: FDA Medical Review BLA 761067 (Ref ID 4233639), Tables 25–28 and §§7.2.2–7.2.3. Maintenance (Wk 64) values for PASI 75 and PGA 0/1 sourced from FDA Medical Review §7.2.6 (Efficacy Over Time). Etanercept Week 12 PASI 75 and PGA 0/1 response rates from Table 25.

Safety & ADRs

§4

No Boxed Warning. ILUMYA does not carry a Boxed Warning in the approved prescribing information.

Safety Population (Controlled)

1,083

Subjects receiving tildrakizumab 100 mg in Phase 2/3 trials

Long-Term Exposure

469

Subjects with ≥24 months exposure; 672 with ≥12 months

Mean Treatment Duration (Base Period)

53.9 weeks

Updated mean 108.1 wk (base + extension); total 4,130 subj-yr

Most Common ADR

URI (14%)

Upper respiratory infections (nasopharyngitis, URTI, pharyngitis)

Warnings & Precautions

§4.1

Serious Hypersensitivity (§5.1 PI): Cases of angioedema and urticaria reported in post-marketing and clinical trials. Contraindicated with prior serious hypersensitivity to tildrakizumab or excipients. Discontinue immediately and initiate appropriate therapy if serious reaction occurs.
Infections (§5.2 PI): May increase susceptibility to infections. Infections reported in 23% of tildrakizumab vs. ~22% of placebo subjects. Serious infection rate: 1.0 per 100 subj-yr (tildrakizumab 100 mg) vs. 0.91 (placebo). Do not initiate in patients with active clinically important infections until resolved or adequately treated. Exercise caution in patients with chronic/recurrent infection.
Tuberculosis (§5.3 PI): Screen all patients for latent and active TB before initiating. One confirmed TB case (vertebral TB, tildrakizumab 200 mg group) was drug-related. Among 55 subjects with latent TB receiving concurrent prophylaxis plus tildrakizumab, no active TB cases occurred over mean 56.5 weeks. Do not administer to patients with active TB. Consider anti-TB therapy prior to initiating in patients with prior untreated latent TB.
Immunizations (§5.4 PI): Complete all age-appropriate immunisations according to current guidelines before initiating. Avoid live vaccines during treatment. No data available on secondary transmission of infection from live vaccine or on efficacy/safety of live or inactivated vaccines in patients receiving tildrakizumab.

Adverse Reactions ≥1% in Controlled Trials

§4.2

Adverse Reaction	Tildrakizumab 100 mg (N=705) n (%)	Placebo (N=355) n (%)
Upper respiratory infections*	98 (13.9%)	41 (11.5%)
Injection site reactions†	24 (3.4%)	8 (2.2%)
Diarrhea	13 (1.8%)	5 (1.4%)
Fatigue‡	17 (2.4%)	6 (1.7%)
Back pain‡	9 (1.3%)	4 (1.1%)
Abdominal pain‡	9 (1.3%)	2 (0.6%)

*URI pooled: nasopharyngitis, upper respiratory tract infection, viral URTI, pharyngitis. †ISR pooled: urticaria, pruritus, pain, erythema, inflammation, edema, swelling, bruising, hematoma, hemorrhage at injection site. ‡Fatigue, back pain, abdominal pain included as adverse reactions based on medical reviewer assessment of causal relationship and dose-response signal; included in PI labelling by FDA clinical reviewer recommendation. Source: FDA Medical Review BLA 761067 (Ref ID 4233639), §7.3.4, Tables 39–42. N=705 for placebo-controlled pool (Wk 0–12 of P003 and P010/P011).

Serious Adverse Events — Exposure-Adjusted (Base Period)

§4.3

System Organ Class	Tildrakizumab 100 mg (N=1,083) n (per 100 subj-yr)	Tildrakizumab 200 mg (N=1,041) n (per 100 subj-yr)	Placebo (N=588) n (per 100 subj-yr)	Etanercept 50 mg (N=313) n (per 100 subj-yr)
Any SAE	58 (5.81)	67 (7.21)	14 (6.4)	20 (13.4)
Infections & infestations	10 (1.00)	15 (1.61)	2 (0.91)	2 (1.30)
Neoplasms*	15 (1.50)	10 (1.08)	3 (1.37)	5 (3.26)
Cardiac disorders	6 (0.60)	8 (0.86)	1 (0.46)	2 (1.30)
Gastrointestinal disorders	8 (0.80)	4 (0.43)	1 (0.46)	0 (0.0)
Musculoskeletal disorders	3 (0.30)	8 (0.86)	1 (0.46)	1 (0.65)
Hepatobiliary disorders	3 (0.30)	1 (0.11)	0 (0.0)	1 (0.65)
Nervous system disorders	2 (0.20)	5 (0.54)	2 (0.91)	2 (1.30)

*Only selected skin cancers counted as SAEs per protocol definition. Neoplasms leading to discontinuation (tildrakizumab 100 mg): 2 SCC, 1 acute myeloid leukemia, 1 transitional cell bladder cancer, 1 malignant melanoma in situ, 1 rectal cancer. Source: FDA Medical Review BLA 761067 (Ref ID 4233639), Table 37 (SAEs by SOC, exposure-adjusted, all subjects as treated).

Deaths

§4.4

Seven total deaths occurred across all treatment groups during the base periods of pooled Phase 2/3 trials (P003, P010, P011). Five deaths in the tildrakizumab 100 mg group (causes: unknown, alcoholic cardiomyopathy and steatohepatitis — 2 events for these combined); 1 death in the tildrakizumab 200 mg group (aneurysm); 1 death in the etanercept/tildrakizumab 200 mg group (sepsis). None of the deaths was assessed as causally related to study product by the investigators. No deaths in the Phase 1 programme (6 trials).

Discontinuations Due to Adverse Events

§4.5

Period / Group	Discontinuation Rate	Notes
Tildrakizumab 100 mg (placebo-controlled period, Wk 0–12)	0.6%	Lowest across all groups in this period
Tildrakizumab 200 mg (placebo-controlled period)	1.3%	Cardiac disorders SOC most common (2/708: AF, CAD)
Placebo (placebo-controlled period)	1.1%	—
Etanercept (placebo-controlled period)	1.0%	—
Tildrakizumab 100 mg (base period exposure-adjusted)	2.20 per 100 subj-yr	Neoplasms SOC: highest discontinuations (6 subjects)
Tildrakizumab 200 mg (base period exposure-adjusted)	2.15 per 100 subj-yr	—
Placebo (base period exposure-adjusted)	2.28 per 100 subj-yr	—
Etanercept (base period exposure-adjusted)	5.87 per 100 subj-yr	Notably higher than tildrakizumab groups

Immunogenicity

§4.6

Anti-Drug Antibody (ADA) Incidence 6.5% of subjects developed anti-tildrakizumab antibodies by up to Week 64 of the base and extension periods. ADA incidence was measured using a validated immunoassay.

Neutralising Antibodies (nAb) ~40% of ADA-positive subjects (~2.5% of total population) had neutralising antibodies. Development of neutralising antibodies was associated with lower serum tildrakizumab concentrations and reduced clinical efficacy (exposure–response impact confirmed in PK analysis).

Nonclinical Safety Summary

§4.7

Carcinogenicity No carcinogenicity or mutagenicity studies conducted. Applicant provided a risk assessment using published literature. Nonclinical information does not suggest increased carcinogenic risk. Relevance of animal models to humans is unknown.

Genotoxicity No genetic toxicology studies conducted. As a monoclonal antibody targeting a soluble cytokine, direct genotoxic potential is not anticipated by mechanism.

Reproductive & Developmental Toxicology (NHP) Embryofetal study (cynomolgus monkeys, GD 20–118): NOAEL 300 mg/kg (79× MRHD by AUC). Pre/postnatal study: 4/14 high-dose infants died within 15 days; 2 deaths possibly tildrakizumab-related (viral infection pattern on histopathology). NOAEL maternal: 100 mg/kg (30× MRHD); NOAEL developmental: 10 mg/kg (3× MRHD). Tildrakizumab crosses placenta in monkeys.

Repeat-Dose Toxicology (NHP) 3-month study (SC 0/40/140 mg/kg; IV 140 mg/kg Q2W): No significant adverse effects; NOAEL = 140 mg/kg. 9-month study (SC 0/10/100 mg/kg Q2W): No significant adverse effects; NOAEL = 100 mg/kg (45× MRHD by AUC). Cynomolgus monkey was the only pharmacologically relevant species.

Source: FDA Medical Review BLA 761067 (Ref ID 4233639), §5 (Nonclinical Pharmacology/Toxicology); §7.3.5–7.3.7 (submission-specific safety issues, immunogenicity). MRHD = maximum recommended human dose. NHP = non-human primate. ADA data from labelling/Medical Review §7.3.6.

Pharmacology & PK

§5

PK Parameters — 100 mg SC (Approved Dose)

§5.1

Bioavailability (%F)

73–80%

Absolute SC bioavailability

Tmax (median)

~6 days

After single SC 100 mg dose

Steady-State Cmax

8.1 mcg/mL

Geometric mean (CV% 34%) at Week 16

Steady-State Ctrough (Wk 16)

1.22–1.47 mcg/mL

Mean ±SD range across arms

Volume of Distribution (Vd)

10.8 L

Geometric mean (CV% 24%)

Systemic Clearance (CL)

0.32 L/day

Geometric mean (CV% 38%)

Half-life (t½)

~23 days

Geometric mean (CV% 23%)

Steady State Achieved

Week 16

Wk 0 → Wk 4 → Q12W schedule

Dose Proportionality

Linear

50–200 mg SC (0.5× to 2× approved dose)

Absorption

§5.2

SC absorption: Absolute bioavailability 73–80% following SC injection. Median Tmax ~6 days. Dose proportionality demonstrated across 50–200 mg. No formal food-effect study conducted (SC route, not applicable). Relative bioavailability: PFS and PFS-housed autoinjector were shown to be bioequivalent in Phase 1 trial P009.

Distribution

§5.3

Volume of distribution 10.8 L (geometric mean, CV% 24%), consistent with predominantly intravascular/tissue distribution typical of a large IgG1 monoclonal antibody. Specific tissue distribution not studied in humans. Tildrakizumab crosses the placenta in cynomolgus monkeys (infant/maternal serum ratios documented); breast milk excretion was minimal (0.09–0.2% of serum concentration in monkeys).

Metabolism & Elimination

§5.4

Parameter	Detail
Metabolic pathway	Proteolytic catabolism to small peptides and amino acids via endogenous IgG catabolic pathways; no hepatic CYP450-mediated metabolism expected
Primary elimination route	Catabolism (monoclonal antibody); renal filtration not applicable at this MW (~147 kDa)
CYP involvement	None anticipated (biologic, not substrate for CYP enzymes)
Dedicated mass balance study	Not conducted

Special Population PK

§5.5

Population/Factor	Effect on PK	Clinical Action
Body weight (higher)	Higher weight associated with lower tildrakizumab concentrations (population PK analysis)	No dose adjustment required; effect not clinically significant at approved dose
Age (≥18 yr)	No clinically meaningful differences across age range studied	No dose adjustment
Race/Ethnicity	Phase 1 study P06306: Japanese, Chinese, White subjects — no clinically significant differences in PK	No dose adjustment
Renal impairment	Dedicated study not conducted; mAbs not renally cleared	No dose adjustment anticipated
Hepatic impairment	Dedicated study not conducted; hepatic CYP metabolism not applicable	No dose adjustment anticipated
Sex	Not reported as a significant covariate in population PK	No dose adjustment

Drug–Drug Interactions — CYP Probe Study (Trial P009)

§5.6

DDI rationale: IL-23 inhibition may normalise IL-6-driven CYP450 suppression in psoriasis, potentially restoring CYP450 activity. Evaluated at tildrakizumab 200 mg SC (twice the approved dose) after 2 doses at Weeks 0 and 4.

Probe Substrate	CYP Isoform	Effect (Tildrakizumab 200 mg)	Magnitude	Clinical Recommendation
Midazolam	CYP3A4	No clinically significant change	Not reported as significant	No action required
Dextromethorphan	CYP2D6	Modest increase in AUC	~20% increase in AUCinf	Unlikely to require dose adjustment for CYP2D6 substrates
Caffeine	CYP1A2	No clinically significant change	Not reported as significant	No action required
Warfarin	CYP2C9	No clinically significant change	Not reported as significant	No action required
Omeprazole	CYP2C19	No clinically significant change	Not reported as significant	No action required

Live vaccines: As an immunomodulatory biologic, concomitant use of live vaccines is contraindicated. No formal DDI study with vaccines; based on pharmacological class effect.

Mechanism of Action

§5.7

Tildrakizumab is a humanized recombinant IgG1/κ monoclonal antibody that selectively binds the p19 subunit of human IL-23 with a dissociation constant (Kd) of approximately 297 pM. The epitope is primarily on the p19 subunit with limited interaction with the p40 subunit, preserving IL-12 activity. Binding prevents IL-23 from engaging its receptor (IL-23R), blocking JAK2-mediated phosphorylation of STAT3. This abrogates STAT3 homodimerisation, nuclear translocation, and transcription of pro-inflammatory cytokines including IL-17A, IL-17F, and IL-22, which drive keratinocyte hyperproliferation, epidermal thickening, and dermal inflammation in psoriasis. Tildrakizumab does not bind human IL-12 (confirmed by surface plasmon resonance and indirect ELISA), nor does it bind murine or rat IL-23.

Pharmacodynamics

§5.8

In vitro neutralisation of IL-23 biological activity demonstrated IC₅₀ values of 59–187 pM across three orthogonal cell-based assay platforms (BAF/3 transfected cells, primary human splenocytes, KIT225 T-cell line). Tildrakizumab binds cynomolgus monkey IL-23 with higher affinity (Kd ~47 pM). Exposure–response analyses (population PK/PD) demonstrated a positive correlation between tildrakizumab trough concentrations and efficacy (PASI 75 and PGA 0/1 response rates) at Week 12, supporting the selected dosing regimen. Subjects with neutralising anti-drug antibodies had lower serum tildrakizumab concentrations and reduced clinical response, consistent with PK-mediated immunogenicity impact.

Source: FDA Medical Review BLA 761067 (Ref ID 4233639), §6 (Clinical Pharmacology), §5 (Nonclinical Pharmacology). PK parameters from Clinical Pharmacology review included in Multi-Disciplinary Review. DDI data from Trial P009.

Dosing & Contraindications

§6

Approved Dose

100 mg SC

Per single-dose prefilled syringe

Route

Subcutaneous

HCP-administered (no self-injection approved at launch)

Frequency

Wk 0, 4, Q12W

Initial loading at Wk 0 and Wk 4; maintenance Q12W

Duration

Continuous

No defined treatment limit; reassess periodically

Standard Dosing

100 mg SC at Week 0 (initial dose)
100 mg SC at Week 4 (loading dose)
100 mg SC every 12 weeks (Q12W) thereafter
No approved dose above 100 mg for plaque psoriasis
200 mg dose not approved (higher AE burden without superior efficacy at label)

Dose Modifications

Renal impairment: no dose adjustment (no dedicated PK study; mAb catabolism)
Hepatic impairment: no dose adjustment (no dedicated PK study)
Elderly (≥65 yr): no dose adjustment
Body weight: no weight-based dosing (flat dosing regimen)
No dose reduction criteria defined in PI

Preparation & Administration

Remove from refrigerator; allow 30 min to reach room temperature
Inspect visually: clear to slightly opalescent, colourless to slightly yellow; discard if discoloured, cloudy, or contains particles
Administer SC only: abdomen, thighs, or upper arm
Avoid 2 inches around navel; avoid tender/bruised/erythematous/indurated skin
Avoid psoriasis-affected skin, scars, stretch marks
Rotate injection sites; do not inject into same site twice in a row
Do not shake the syringe

Missed Dose

Administer as soon as possible if a dose is missed
Resume Q12W schedule from the date of the missed dose administration
Do not double-dose
No specific bridging required unless extended interruption due to serious infection

Storage & Handling

§6.2

Condition	Specification
Refrigerated storage	2°C–8°C (36°F–46°F); keep in original carton; protect from light
Room temperature	Stable up to 30 days at ≤25°C (77°F); once removed from refrigerator, do not return
Dating period (drug product)	36 months at 2–8°C
Do not	Freeze; shake; expose to light without carton

Contraindications

§6.3

Contraindication (PI §4): Prior serious hypersensitivity reaction to tildrakizumab or to any of the excipients of ILUMYA. Excipients: L-histidine, L-histidine hydrochloride monohydrate, sucrose 7%, polysorbate 80 0.05%, Water for Injection.

Warnings Relevant to Dosing

§6.4

TB screening required before first dose: Evaluate all patients for latent and active TB. Initiate treatment of latent TB prior to initiating tildrakizumab.
Immunisations before initiating: Complete all age-appropriate immunisations per current guidelines before first dose. Avoid live vaccines during treatment.
Active infection: Do not initiate tildrakizumab in patients with any clinically important active infection until resolved or adequately treated.

Drug Interactions Affecting Dosing

§6.5

Interacting Drug/Class	Mechanism	Recommendation
Live vaccines	Immunosuppression — potential vaccine failure or disease transmission	Contraindicated; avoid during treatment
CYP2D6 substrates (narrow TI)	Modest (~20%) CYP2D6 AUC increase with 200 mg; effect at 100 mg unknown but likely smaller	Clinical significance uncertain; no dose adjustment requirement identified
CYP3A4, 1A2, 2C9, 2C19 substrates	No clinically significant interaction detected at 200 mg	No dose adjustment required

Administration Instructions

§6.6

Parameter	Recommendation
Injection technique	Pinch skin and insert needle at 45–90° angle; inject full 1 mL volume; apply pressure after withdrawal
Needle guard activation	Passive safety device activates automatically on needle withdrawal; do not recap
Site rotation	Rotate across abdomen, thigh, and upper arm; document prior sites
Disposal	Dispose of used prefilled syringe immediately in an appropriate sharps container
Caregiver training	HCP should train patient/caregiver on SC injection technique before any self-administration

Source: ILUMYA Prescribing Information (original approval March 2018); FDA Medical Review BLA 761067 (Ref ID 4233639), §10 (Labelling Recommendations).

Regulatory History

§7

BLA Key Facts

§7.1

Parameter	Detail
Application Number	BLA 761067
Application Type	BLA 351(a), Public Health Service Act — Original BLA (not a biosimilar or supplement)
Applicant	Merck Sharp and Dohme Corp.
Original Developer	Schering-Plough (acquired by Merck 2009); developed as SCH 900222 / MK-3222
Submission Date	March 23, 2017
PDUFA Goal Date	March 23, 2018
Actual Approval Date	March 2018 (review completed March 13, 2018)
Review Division	Division of Dermatology and Dental Products (DDDP), Office of Drug Evaluation III (ODE III)
Review Type	Standard Review
Breakthrough Therapy Designation	Not designated
Fast Track Designation	Not designated
Orphan Drug Designation	Not applicable
Advisory Committee	Not convened (no advisory committee meeting held for this application)
Medical Review Ref ID	4233639 (Multi-Disciplinary Review and Evaluation)
Statistical Review Ref ID	4237390
CDTL Review Ref ID	4236563
Review Team	Clinical: Melinda McCord MD, Kevin Clark MD; CDTL: Gordana Diglisic MD; Statistics: Matthew Guerra PhD, Mohamed Alosh PhD; Project Manager: Dawn Williams

Regulatory Timeline

§7.2

APRIL 1, 2008

Pre-IND Meeting

Initial FDA meeting prior to IND filing to discuss development programme for SCH 900222 / MK-3222.

SEPTEMBER 8, 2008

IND 101389 Opened

IND opened for tildrakizumab (code names SCH 900222 and MK-3222) under development by Schering-Plough/Merck.

JUNE 1, 2011

Guidance Meeting

FDA advised applicant on need to characterise PK of to-be-marketed prefilled syringe formulation and on optimal PK/immunogenicity sampling timepoints for Phase 3 trials. Human factors study for PFS recommended.

APRIL 11, 2012

End-of-Phase 2 (EOP2) Meeting

Applicant and Agency agreed to co-primary endpoints: PASI 75 and PGA 0/1 (≥2-grade improvement) at Week 12. Agency provided guidance on multiplicity control, randomisation stratification, missing data handling (NRI primary), and MACE adjudication. Three Phase 3 protocols (P010, P011, P012) proposed.

JUNE 8 – JULY 18, 2012

Special Protocol Assessments (SPA)

SPAs submitted for Trials P010, P011, and P012. Agreement letters issued July 18, 2012. Agency reiterated comments on multiplicity, placebo arm continuity to Week 28 in P011/P012, and ITT population use.

NOVEMBER 24, 2015

Amended Protocols — PASI 90/100 Added; P012 Dropped

Applicant amended P010/P011 protocols to add PASI 90 and PASI 100 as key secondary endpoints with sequential gatekeeping. Applicant confirmed abandonment of Trial P012 and withdrawal of comparative efficacy claim versus etanercept. FDA concurred with amendments in advice letter December 29, 2015.

DECEMBER 2015 – MAY 2016

Agreed Initial Paediatric Study Plan (iPSP)

iPSP submitted December 11, 2015; agreed iPSP May 20, 2016. Partial waiver granted for <6 yr (low prevalence); deferral granted for 6–18 yr until adult approval.

MARCH 23, 2017

BLA 761067 Submitted

Original BLA submitted in eCTD format by Merck Sharp & Dohme Corp. Standard review designation. Two pivotal Phase 3 trials (P010, P011) plus Phase 2 data (P003) and 6 Phase 1 trials submitted.

OCTOBER 2, 2017

120-Day Safety Update Report (SUR) Received

Updated mean treatment duration 108.1 weeks; total exposure 4,130.24 subject-years (base + extension).

MARCH 13, 2018

Multi-Disciplinary Review Signed (Ref ID 4233639)

All reviewers recommended approval. CDTL (Gordana Diglisic MD) and clinical team (Melinda McCord MD, Kevin Clark MD) concluded data support approval. Statistical reviewer (Matthew Guerra PhD) confirmed statistical analysis of efficacy supports approval.

MARCH 2018

FDA Approval — BLA 761067

Approved indication: ILUMYA (tildrakizumab-asmn) injection 100 mg/mL for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. U.S. License No. 0002. Drug Product manufactured at MSD Ireland, Dublin Road, Carlow, Ireland. Dating period: 36 months at 2–8°C.

Key Review Issues Raised and Resolved

§7.3

Statistical Multiplicity — Phase 3 Protocol Agency initially identified that the applicant’s proposed stepwise multiplicity control method did not fully control the Type I error rate (noted at EOP2). Resolved by adoption of a sequential gatekeeping approach covering both doses and both co-primary endpoints (PASI 75 → PGA 0/1 → PASI 90 → PASI 100), agreed via SPA process and confirmed in December 2015 advice letter.

Missing Data Handling Agency required justification for LOCF as a sensitivity analysis (cited limited evidence base for LOCF). Resolved: applicant retained NRI as primary method and added multiple imputation (MI) as second sensitivity; FDA statistical reviewer added worst-case scenario analysis which confirmed superiority under all imputation frameworks.

Trial P012 Discontinuation Agency recommended placebo arm in P012 through Week 28 to avoid interpretation difficulties. Applicant cancelled P012 and withdrew comparative efficacy claim against etanercept entirely. FDA accepted this in April 2015 guidance meeting; Trial P011 data still included etanercept as active comparator through Wk 28 without a regulatory comparative claim.

TB Case & Safety Signal One drug-related vertebral TB case (tildrakizumab 200 mg) required labelled precaution. The TB screening requirement and monitoring language were added to PI §5.3. The 100 mg approved dose had no TB cases among the 55 latent TB subjects receiving concurrent prophylaxis during trials.

Neoplasm Signal — Ongoing Monitoring Malignancies (including melanoma, bladder cancer, breast cancer, haematologic) assessed as possibly related to treatment necessitated inclusion of immunogenicity risk context in labelling and post-marketing surveillance plan. No increase in total malignancy rate relative to background psoriasis population risk was concluded.

Paediatric Assessment Agency required agreed iPSP per PREA requirements. Partial waiver granted for <6 yr (extremely low prevalence of severe psoriasis); paediatric studies deferred for 6–18 yr pending adult approval. Studies remain outstanding as post-marketing paediatric commitments.

Postmarketing Requirements & Commitments

§7.4

PMC summary: No CMC-specific postmarketing commitments (PMCs) from the CMC review team. Stability protocols approved for annual assessment and for extending expiration dating (21 CFR 601.12). Product is exempt from lot release per 21 CFR 601.2(a). Paediatric study requirements outstanding per iPSP agreement.

PMR/PMC	Study Type	Objective	Key Design Elements
Paediatric deferral (iPSP)	Efficacy & safety trial(s)	Evaluate tildrakizumab in paediatric plaque psoriasis ages 6–<18 yr	Deferred until adult approval confirmed; design TBD; partial waiver for <6 yr
Annual stability protocols	Drug Substance & Drug Product stability	Extend expiration dating; trend release results	Annual stability per approved protocol; 21 CFR 601.12 compliance
None (CMC)	—	No additional CMC PMCs identified by CMC review team	N/A

Regulatory Notes

§7.5

Domain	Note
Benefit-risk conclusion	Available safety and efficacy data support approval. Both pivotal trials met all co-primary and key secondary endpoints. Safety profile acceptable for target population with appropriate labelling of TB, infection, and hypersensitivity risks.
Approved dose selection	100 mg approved; 200 mg dose not approved — no meaningful efficacy advantage over 100 mg with higher SAE burden (particularly musculoskeletal and infection SAEs) at 200 mg.
Immunogenicity labelling	ADA incidence (6.5%) and nAb impact (reduced PK and efficacy) required labelling per FDA biologics guidance. Included in PI §6.1.
REMS	No Risk Evaluation and Mitigation Strategy (REMS) required. No safety issues identified that could not be managed through routine labelling.
Advisory Committee	None convened. Application reviewed entirely through normal DDDP/ODE III clinical review process.
Lot release exemption	ILUMYA exempted from lot release per 601.2(a) as a specified product. U.S. License No. 0002.
Source document Ref IDs	Multi-Disciplinary Review: Ref ID 4233639 \| Statistical Review Memo: Ref ID 4237390 \| CDTL Memo: Ref ID 4236563

Source: FDA BLA 761067 Multi-Disciplinary Review and Evaluation (Ref ID 4233639); Statistical Review and Evaluation Memo (Ref ID 4237390); CDTL Memorandum (Ref ID 4236563). ILUMYA Prescribing Information, original March 2018 approval. All values extracted directly from FDA source documents; no interpolation or estimation applied. For post-approval label updates, refer to current labelling at Drugs@FDA BLA 761067.