Tildrakizumab

Introduction

Tildrakizumab is humanized monoclonal antibody to interleukin-23 that is used to treat moderate-to-severe plaque psoriasis. Tildrakizumab is associated with a low rate of transient and asymptomatic serum enzyme elevations during therapy, but has not been linked to cases of idiosyncratic, clinically apparent liver injury.

Background

Tildrakizumab (til" dra kiz' ue mab) is a humanized monoclonal IgG1 antibody to interleukin (IL)-23, a cytokine that is an important mediator of autoimmune reactions. IL-23 is found in the skin lesions of psoriasis and in the affected gastrointestinal mucosa of patients with inflammatory bowel disease. Among the monoclonal IL-23 inhibitors, tildrakizumab and guselkumab are directed to the p19 subunit of IL-23, whereas ustekinumab is directed at the p40 subunit which is a component shared by both IL-23 and IL-12. As a consequence, tildrakizumab and guselkumab have a more restricted activity in the Th17 immune pathways which are considered to play a major role in autoimmune reactions. Tildrakizumab has been shown to improve symptoms and signs of plaque psoriasis and was approved for this use in United States in 2017. While current indications are limited to moderate-to-severe plaque psoriasis, tildrakizumab is under active investigation as therapy of several other autoimmune diseases. Tildrakizumab is available in liquid solution in single use prefilled syringes of 100 mg/mL under the brand name Ilumya. The typical regimen is 100 mg subcutaneously initially, 4 weeks later and every 8 weeks thereafter. Side effects are uncommon and are usually mild, but may include injection site reactions, headache, diarrhea and minor infections such as upper respiratory infections. Less common, but potentially severe side effects include serious infections, hypersensitivity reactions and reactivation of tuberculosis.

Hepatotoxicity

Rates of serum aminotransferase elevations during tildrakizumab therapy have not been well defined, but rates of laboratory result abnormalities are said to be similar with tildrakizumab compared to placebo treatment. Neither during premarketing evaluation nor subsequently have there been case reports of clinically apparent, acute liver injury with symptoms or jaundice linked to tildrakizumab therapy, but experience with its use has been limited.

Tildrakizumab has immunosuppressive activity but has not been linked to instances of reactivation of hepatitis B or worsening of hepatitis C. However, patients at risk for these complications are often excluded from preregistration clinical trials, and ustekinumab, a similar biologic agent which is also active against IL-23 and is used to treat psoriasis, has been shown to cause reactivation of hepatitis B in postmarketing studies. HBV reactivation typically occurs in patients with preexisting HBsAg and relatively inactive disease. Reactivation causes acute hepatocellular injury that can be severe and lead to acute liver failure and death or need for emergency liver transplantation. Screening for hepatitis B before starting tildrakizumab is not recommended in the product label, but screening has been considered “advisable” in guidelines written by academic societies for many monoclonal antibodies used for psoriasis.

Likelihood score: E* (unlikely cause of clinically apparent liver injury but experience with its use has been limited).

Mechanism of Liver Injury

The mechanism of possible liver injury due to tildrakizumab is not known. Reactivation of hepatitis B appears to be due to a brisk immunological response to newly expressed viral antigens caused by suppression of the immune response to hepatitis B antigens. Injury generally arises between courses of immunosuppressive therapy.

Outcome and Management

Tildrakizumab has been linked to minor elevations in serum enzymes during therapy but not to clinically apparent liver injury or with reactivation of hepatitis B. The product label for tildrakizumab does not recommend routine screening for hepatitis B before initiation of therapy. However, guidelines prepared by some academic societies on the management of patients who are to receive biological agents similar to tildrakizumab have recommended routine screening before starting treatment. Screening should include tests for HBsAg and anti-HBc (and perhaps also anti-HBs as this may help in management). Prophylaxis with a potent oral, antiviral agent effective against hepatitis B is recommended for persons who have HBsAg in serum. An alternative approach is careful monitoring for HBV DNA during therapy and early institution of antiviral therapy if levels rise.

Drug Class: Dermatologic Agents, Psoriasis Agents; Monoclonal Antibodies