IXEKIZUMAB

Introduction

T h17 helper T cells are a distinct lineage from either Th1 or Th2 helper T cells that produce a unique set of
pro inflammatory cytokines in response to antigen-specific activation. In fact, Th17 cells are defined by
their ability to produce interleukin (IL)-17 in addition to other cytokines. The IL-17 cytokine family is made
up of six cytokines (IL-17A to IL-17F) and five receptors (IL-17RA to IL-17RE).

When Th17 cell activation occurs, there is a rapid initiation of this unique inflammatory response dominated
by neutrophils. Activation of the Th17 immune response is particularly important at epithelial and mucosal
surfaces where Th17 host protection is induced by a number of infectious pathogens. However, if the Th17
response becomes unregulated, it contributes to a large IL-17 burden that is associated with chronic
inflammation and immunopathology.

The initial differentiation of naïve T lymphocytes to Th17 cells is mediated by tumor growth factor (TGF)-
β, IL-6, and IL-1β, but IL-23 is essential for the activation and maintenance of Th17 cells to secrete IL-17.

IL-17 is associated with multiple chronic pro inflammatory diseases like rheumatoid arthritis, multiple
sclerosis, and inflammatory bowel disease (IBD). It is also involved in the pathogenesis of psoriasis. Levels
of IL-17 are elevated in both the serum and skin of those affected with psoriasis; and these levels are
correlated with disease severity.

IL-17 is one of the cytokines that contributes to the activation of aberrant keratinocyte activity, immune
cells, and other inflammatory cytokines. This abnormal differentiation and hyperproliferation causes the
hyperkeratosis, epidermal acanthosis, and diffuse hyperplasia characteristic of the phenotype of plaque
psoriasis.

In psoriatic arthritis (PsA), synovial tissue levels of IL-17 and the receptor IL-17RA are elevated. The IL-
17RA is active, leading to the abnormal regulation of matrix metalloproteinases and other cytokines
(namely IL-6 and IL-8) underlying the disease process of PsA. Additionally, it has been proposed that IL-17
also contributes to the bony changes characteristic of PsA.

In rheumatoid arthritis, IL-17 is implicated in osteoclast activation and bone erosion30 by upregulation of
receptor activator of nuclear factor κ-B ligand (RANKL) signaling. Since there are elevated numbers of
osteoclasts in both PsA in rheumatoid arthritis, there may be a shared pathogenicity in this feature of both
diseases mediated by the Th17 pathway and IL-17.

The discovery of the Th17 inflammatory axis and the key upstream and downstream cyokines has led to
important therapeutic implications for the treatment of psoriasis. Therapies directed against these key
cytokines are both safe and effective for treating plaque psoriasis and psoriatic arthritis. IL-17 is one of
these targets. There are currently three drugs in this class available for the treatment of moderate-to-severe
psoriasis: secukinumab, ixekizumab, and brodalumab.

Ixekizumab

Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds and neutralizes IL-17A,
inhibiting its interaction with IL-17 receptors.
 Indications

Plaque Psoriasis

The safety and efficacy of ixekizumab were evaluated in three randomized, double-blind, placebo-controlled
clinical trials ( UNCOVER1,2,3 studies)

All patients were at least 18 years old with moderate-to-severe plaque psoriasis and were candidates for
systemic or phototherapy. They had at least 10% BSA, PASI of ≥12, and a Static Physicians Global
Assessment (sPGA) of 3 or more. In all studies, patients were randomized to receive placebo or ixekizumab
(160 mg week 0 and then 80 mg q2w or 80 mg q4w) until week 12.

Overall, two of the three studies also compared ixekizumab with etanercept (50 mg twice weekly). The
proportion of patients achieving PASI-75 and the proportion of patients achieving sPGA of 0 or 1 with at
least a 2-point improvement at week 12 were the common primary endpoints.

UNCOVER-1 compared ixekizumab treatment in 1296 patients with psoriasis. Researchers randomly assigned
patients to one of three groups. The two-week group received a 160 mg starting dose at week zero and 80 mg every
two weeks for 12 weeks. The four-week group received 160 mg starting dose at week zero, 80 mg every four weeks
for 12 weeks. The placebo group received a placebo for 12 weeks. The measurement of therapeutic efficacy was via
the psoriasis area and severity index (PASI) score. A psoriasis area and severity index (PASI) score of 90 indicates
a 90% reduction in the psoriasis skin lesion area. At the end of 12 weeks, the two-week, four-week, and placebo
groups had the following psoriasis area and severity index (PASI) 90 scores: 70.9%, 64.6%, and 0.5%, respectively,
which were statistically significant when researchers compared the two treatment groups to placebo.
UNCOVER-2 compared ixekizumab treatment in 1224 patients with psoriasis. The same UNCOVER-1 treatment
regimens were used, with the additional treatment group receiving etanercept 50 mg twice a week for 12 weeks. At
the end of 12 weeks, the two-week, four-week, etanercept, and placebo groups had the following psoriasis area and
severity index (PASI) 90 scores: 70.7%, 59.7%, 18.7%, and 0.6%, respectively, which were statistically significant
when researchers compared the ixekizumab treatment groups to etanercept and placebo.[14]
UNCOVER-3 compared ixekizumab treatment in 1346 patients with psoriasis. The study used the same treatment
regimens as in UNCOVER-2. At the end of 12 weeks, the two-week, four-week, etanercept, and placebo groups
had the following psoriasis area and severity index (PASI) 90 scores: 68.1%, 65.3%, 25.7%, and 3.1%,
respectively, which were statistically significant when researchers compared the ixekizumab treatment groups to
etanercept and placebo.

Psoriatic Arthritis

The safety and efficacy of ixekizumab for PsA were evaluated in two clinical trials of ixekizumab 80 mg
q2w or q4w after a 160-mg loading dose. One of the studies required patients to be biologic-naïve and also
had an adalimumab arm. The other study required prior failure of a tumor necrosis factor inhibitor (TNRi).

The common primary endpoint was the proportion of patients achieving ACR-20 at week 24. In both
studies, significantly more patients achieved ACR-20 at week 24 on ixekizumab q4w (53%–57.9%) and
q2w (48%–62.1%) versus placebo (20%–30.2%). Significantly more subjects achieved ACR-20 on
ixekizumab than adalimumab and the results were maintained through week 52.

Off-Label/Other Dermatologic Uses

Administration & Storage

Storage should be at 2 to 8 degrees Celsius (36 to 46 degrees Fahrenheit). The ixekizumab dosage form
should not be frozen, and it requires protection from light.

Remove ixekizumab from the refrigerator and let it warm to room temperature, which will take
approximately 30 minutes. Next, visually inspect the ixekizumab liquid, which should be free of particles
and a clear to slightly yellow color. Should not shake the autoinjector or prefilled syringe.

Ixekizumab administration is subcutaneous.

Recommended injection sites are the thighs, upper arms, or abdomen, which should be rotated to prevent
damage to the skin. Avoid injecting sites that are affected by psoriasis, are bruised, or are damaged.

Dosing

The recommended dosing is the following (all doses administered subcutaneously).

For moderate to severe plaque psoriasis:

Ÿ 160 mg once on week 0, then 80 mg every 2 weeks for 12 weeks

Ÿ 80 mg every four weeks thereafter

For psoriatic arthritis or ankylosing spondylitis:

Ÿ 160 mg once on week 0, then 80 mg every four weeks

For non-radiographic axial spondyloarthritis:

Ÿ 80 mg SQ every 4 weeks

There are no documented maximum doses for indicated use. There are no studies for dose adjustment in
patients with renal or hepatic impairment.

Adverse Effects

Commonly observed (over 10%) adverse drug reactions in patients who have treatment with ixekizumab
are: neutropenia, hypersensitivity reactions, e.g., urticaria and angioedema, infections, injection site
reactions, e.g., pain.

Less commonly observed (less than 10%), adverse drug reactions are fungal skin infections (tinea), nausea,
thrombocytopenia, and antibody development. Antibody development can decrease the concentrations of
ixekizumab and decrease drug efficacy.

Less than 1% of observed adverse drug reactions are Crohn disease, ulcerative colitis, oral candidiasis
(Candida albicans infection), influenza, conjunctivitis, and rhinitis. Crohn disease and ulcerative colitis
include exacerbations in susceptible patients.
Miller J. et al. conducted research from several clinical trials on the safety and efficacy of ixekizumab in
treating psoriatic arthritis. Ixekizumab caused greater injection site reactions when compared to placebo or
adalimumab. Ixekizumab had fewer serious adverse events when compared to adalimumab. Ixekizumab was
efficacious in treating psoriatic arthritic disease and slowed radiographic disease progression.

Romozzi M. et al. reported that a 28-year-old man with psoriatic arthritis developed cervical myelitis during
ixekizumab treatment. A T2 hyperintense lesion was noted on a spinal MRI at the C4-C5 level. However,
the brain MRI was unspecific. Ixekizumab re-exposure caused similar neurological effects.

Contraindications

Contraindications include a severe hypersensitivity reaction, for example, anaphylaxis resulting from
ixekizumab itself or any excipients in the dosage form.[25] Contraindications also include active infection,
particularly with TB, and IBD.