Ixekizumab

Medical uses

Ixekizumab is used for the treatment of moderate to severe plaque psoriasis in adults.

In studies, the drug reduced the Psoriasis Area and Severity Index by at least 75% (PASI75) in 82–89% of patients during the first three months of treatment (depending on the dosing scheme), and 40% of patients experienced a complete absence of psoriasis symptoms (PASI100). In the placebo group, PASI75 was reached in 4% of patients, and PASI100 in none; in the group of patients receiving etanercept, an older anti-psoriasis drug, PASI75 was reached in 48%. Until the 60th study week, 11–44% of ixekizumab treated patients relapsed (again, depending on the dosing scheme), as compared to 84% under placebo.

Contraindications

The drug is contraindicated for patients with certain infections such as active tuberculosis.

Adverse effects

In studies, ixekizumab increased the rate of infections (27% of ixekizumab treated patients, compared to 23% under placebo), including severe ones (0.6% versus 0.4% under placebo). Other common side effects included injection site pain (13–17% versus 3%), oropharyngeal pain (1%) and nausea (1–2%).

Overdose

Up to fourfold doses have been given in studies without causing serious side effects.

Interactions

No interaction studies have been done. Ixekizumab and interleukin 17 are not known to interact with cytochrome P450 (CYP) liver enzymes. Since inflammation suppresses CYP activity, it is theorized that ixekizumab could neutralize this effect and lower blood plasma concentrations of drugs that are metabolized by CYP enzymes, such as warfarin.

Mechanism of action

Ixekizumab binds to interleukin 17 (IL-17), a pro-inflammatory cytokine, and blocks its action. Among other things, IL-17 stimulates proliferation and activation of keratinocytes in the skin. This mechanism is similar to that of another anti-psoriasis antibody, brodalumab, which binds to the interleukin-17 receptor.

The antibody has affinity to the homodimer IL-17A and the heterodimer IL-17A/F, but not to other members of the interleukin 17 family.

Pharmacokinetics

After subcutaneous injection, ixekizumab has a bioavailability of 54–90%. Highest blood plasma concentrations are reached after four to seven days after a single dose. With the usual dosing scheme (loading plus a dose every two weeks), steady state concentrations are reached in the eighth week on average.

Like other antibodies, ixekizumab is probably degraded by proteolysis. Its elimination half-life is 13 days.

Chemistry

Ixekizumab is a complete monoclonal antibody of the subclass IgG₄, consisting of two light chains and two heavy chains linked by disulfide bridges. Both heavy chains are glycosylated at the asparagine in position 296. In the hinge region, a serine is replaced by a proline to reduce formation of half-antibodies and heterodimers in the manufacturing process. The terminal lysine found in wild-type IgG₄ is removed. The antibody is produced in Chinese hamster ovary cells.

History

Clinical trials included a Phase II trial of patients with moderate to severe psoriasis, and a Phase III open-label trial. The drug was approved by the FDA on 22 March 2016 for the treatment of plaque psoriasis, under the trade name Taltz, and by the European Medicines Agency on 25 April 2016 under the same trade name.

The drug was launched in the US on 16 April 2016 and has been approved for use in the UK and is expected to launch on 1 July 2016.

Research

As of 2016, ixekizumab is in Phase III clinical trials for the treatment of active psoriatic arthritis.