sábado, 7 de mayo de 2016

Clinical Pharmacology Corner: FDA approves TALTZ (ixekizumab)

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FDA approves TALTZ (ixekizumab) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy
On March 22, 2016, the U.S. Food and Drug Administration (FDA) approved TALTZ™ (ixekizumab) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Approved Recommended TALTZ Dosage and Administration
  • TALTZ is administered by subcutaneous (SC) injection. The approved recommended dosage is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks. 
  • Evaluate patients for tuberculosis (TB) infection prior to initiating treatment. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering TALTZ. Consider completion of all age appropriate immunizations prior to initiating therapy with TALTZ. Avoid use of live vaccines in patients treated with TALTZ.
Mechanism of Action (MOA) and Pharmacokinetics (PK) of Ixekizumab
  • MOA: Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. 
  • Dose linearity: Ixekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 5 mg (0.06 times the approved recommended dosage) to 160 mg following subcutaneous administration.
  • Bioavailability: Ranged from 60% to 81% following SC injection in subjects with plaque psoriasis. Thigh SC injection achieved a higher bioavailability relative to other potential injection sites including the arm and abdomen.
  • Time to steady-state concentrations (mean (standard deviation)): Steady-state concentrations (trough: 9.3 (5.3) mcg/mL) were achieved by week 8 following the 160 mg starting dose and 80 mg every 2 weeks (80 mg Q2W) dosing regimen and approximately 10 weeks after switching from the 80 mg Q2W to an 80 mg Q4W dosing regimen at Week 12 (trough: 3.5 (2.5) mcg/mL).
  • Clearance and half-life (mean (geometric CV%)): Systemic clearance was 0.39 L/day (37%) and half-life was 13 days (40%) in subjects with plaque psoriasis.
Drug Interaction Potential
  • The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, TALTZ, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes. Therefore, upon initiation or discontinuation of TALTZ in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.
  • As with all therapeutic proteins there is the potential for immunogenicity with TALTZ. Approximately 9% of subjects treated with TALTZ every 2 weeks developed antibodies to ixekizumab by Week 12. Approximately 22% of subjects treated with TALTZ at the approved recommended dosage developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response. 
  • Of the subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with TALTZ at the recommended dosing regimen, had antibodies that were classified as neutralizing. However, the assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy.
Safety and Efficacy
The efficacy and safety of TALTZ were established in three clinical trials. Changes from baseline to Week 12 were assessed in the two co-primary endpoints: (1) Psoriasis Area and Severity Index (PASI) 75 and (2) static Physician Global Assessment (sPGA) of 0 (clear) or 1 (minimal). The TALTZ 80 mg Q2W dosing regimen demonstrated superiority over placebo in the proportion of subjects who achieved PASI 75 and in the proportion of subjects who achieved sPGA of 0 or 1 at Week 12. Among subjects enrolled at US sites, TALTZ also demonstrated superiority to U.S. approved etanercept on sPGA and PASI scores during the 12 week treatment period.
The common adverse reactions were injection site reactions, upper respiratory tract infections, nausea, and tinea infections. Serious infections and allergic reactions have occurred.

Full prescribing information is available at http://go.usa.gov/cuUg4 
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/cuUgG).
We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.
This burst was prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov

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