Ixekizumab


Ixekizumab, sold under the brand name Taltz, is an injectable drug for the treatment of autoimmune diseases. Chemically, it is a form of a humanized monoclonal antibody. The substance acts by binding interleukin 17A and neutralizing it, reducing inflammation.
The drug was developed by Eli Lilly and Co. and is approved for the treatment of plaque psoriasis in Europe and the US.

Medical uses

In the United States, ixekizumab is approved for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, active psoriatic arthritis, and active ankylosing spondylitis. In Europe it is approved for the treatment of moderate-to-severe plaque psoriasis and as a second-line therapy for active psoriatic arthritis.
In studies, the drug reduced the Psoriasis Area and Severity Index by at least 75% in 82–89% of patients during the first three months of treatment, and 40% of patients experienced a complete absence of psoriasis symptoms. 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, as compared to 84% under placebo.
In December 2017, the US Food and Drug Administration approved it for active psoriatic arthritis.

Contraindications

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

Adverse effects

In studies, ixekizumab increased the rate of infections, including severe ones. Other common side effects included injection site pain, oropharyngeal pain and nausea.

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 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.

Pharmacology

Mechanism of action

Ixekizumab binds to interleukin 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, 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

s 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 US Food and Drug Administration on March 22, 2016 for the treatment of plaque psoriasis, under the trade name Taltz, and by the European Medicines Agency on April 25, 2016 under the same trade name.
The drug was launched in the US on April 16, 2016, and was approved for use in the UK in the same year.