ZINBRYTA Solution for injection Ref.[8979] Active ingredients: Daclizumab

Pharmacotherapeutic group: immunosuppressants, interleukin inhibitors
ATC code: L04AC01

Mechanism of action

Daclizumab beta is a humanised IgG1 monoclonal antibody that binds to CD25 (IL-2Rα), and prevents IL-2 binding to CD25. Daclizumab beta modulates IL-2 signalling by blocking CD25-dependent, high-affinity IL-2 receptor signalling, resulting in higher levels of IL-2 available for signalling through the intermediate-affinity IL-2 receptor. Key effects of this IL-2 pathway modulation potentially related to the therapeutic effects of daclizumab beta in MS include selective antagonism of activated T-cell responses, and expansion of immunoregulatory CD56^bright natural killer (NK) cells, which have been shown to selectively decrease activated T-cells. Together, these immunomodulatory effects of daclizumab beta are believed to reduce CNS pathology in MS and thereby reduce the occurrence of relapses and disability progression.

Pharmacodynamic effects

In clinical studies, the pharmacodynamic effects of Zinbryta 150 mg administered subcutaneously every 4 weeks were consistent with modulation of IL-2 signalling as evidenced by the rapid and sustained saturation of the target CD25 receptors on circulating T-cells and a sustained approximately 2-fold increase in serum IL-2 concentration. In addition, an increase in CD56^bright NK cells and a decrease in regulatory T-cells (defined as CD4+ CD127lowFoxP3+ T-cells) was observed within 2 weeks after the first dose, with a sustained 5-fold increase in CD56^bright NK cells above baseline and an approximately 60% decrease in regulatory T-cells in the treatment phase, with a return to baseline levels approximately 20-24 weeks after the last dose. During Zinbryta treatment, mean cell counts for the major immune subsets (T, B, and NK cells) remained within normal ranges; total lymphocyte, T and B cell counts decreased on average ≤10% from baseline during the first year of treatment. Total lymphocyte counts returned to baseline levels approximately 8-12 weeks after the last dose of Zinbryta (150mg). Total lymphocyte counts <0.8x109 cells/L ([Common Terminology Criteria for Adverse Events – CTCAE] Grade 2; at least one measurement) occurred in 4% of placebo-treated and 5% of Zinbryta-treated patients in the SELECT study, and 9% of the interferon beta-1a (intramuscular)-treated and 8% of Zinbryta-treated patients in the DECIDE study. Total NK cell counts increased approximately 1.5-fold as a result of the change in CD56^bright NK cells.

Clinical efficacy and safety

The efficacy of Zinbryta was demonstrated in two studies (SELECT and DECIDE) in patients with RMS. The SELECT study was double-blind, randomised, placebo-controlled, with either Zinbryta 150 mg (n=208), or 300 mg (n=209) versus placebo (n=204) every 4 weeks for 52 weeks. The DECIDE study was double-blind, randomised, parallel-group, active-controlled with Zinbryta 150 mg every 4 weeks (n=919) versus interferon beta-1a (intramuscular) 30 micrograms weekly (n=922), for a minimum of 2 to a maximum of 3 years (96 to 144 weeks). The study designs and baseline characteristics are presented in Table 3.

Table 3. Study design and baseline characteristics for SELECT study and DECIDE study:

Results for the SELECT study are shown in Table 4. Treatment with Zinbryta 150 mg every 4 weeks versus placebo significantly reduced the annualised relapse rate (ARR) and risk of relapse compared to placebo. In addition, there was a statistically significant effect on 24 week confirmed disability progression in Zinbryta treated patients with a hazard ratio 0.24 [95% CI: 0.09, 0.63]. The 300 mg dose did not provide additional benefit over the 150 mg dose.

Table 4. SELECT study clinical and MRI results (at 52 weeks):

* Hazard ratio for the risk of relapse
^# MRI analyses used evaluable dataset for each endpoint; T1 Gd-enhancing: MRI intensive population

Table 5 and Figures 1-2 show the results for the DECIDE study. Zinbryta significantly reduced the ARR and the risk of relapse, compared to interferon beta-1a (intramuscular)-treated patients. In addition, there was a statistically significant effect on 24 week confirmed disability progression in Zinbryta treated patients with a hazard ratio 0.73 [95% CI: 0.55, 0.98]. At week 96, Zinbryta demonstrated a statistically significant reduction in the number of new or newly enlarging T2 hyperintense lesions, the number of new T1 Gd-enhancing lesions and the mean number of new T1 hypointense lesions. In addition, Zinbryta reduced clinically meaningful worsening in the patientreported physical impact of MS (≥7.5 point worsening from baseline to week 96 in the MSIS-29 physical score) compared to interferon beta-1a (intramuscular).

Table 5. DECIDE study clinical and MRI results (96 to 144 weeks) (Values refer to results at 96 weeks, unless otherwise indicated):

* Rates and risk reductions/endpoints are calculated over the treatment period up to 144 weeks.
^# Hazard ratio for the risk of relapse.
^† MRI analyses used evaluable dataset for each MRI endpoint.

Subgroup analyses of the SELECT and DECIDE studies demonstrated a consistent effect of Zinbryta compared to placebo and interferon beta-1a (intramuscular) across subgroups defined by demographic and MS disease characteristics. In the DECIDE study subgroup analysis, there was a statistically significant reduction observed compared to interferon beta-1a (intramuscular) on ARR and the number of new or newly enlarging T2 hyperintense lesions across subgroups (gender, age, prior MS DMT therapy, and disease activity levels).

Although the effect on disability progression was mainly seen in patients with baseline EDSS <3.5, evidence of efficacy was shown in patients with relapsing secondary progressive MS (SPMS) as defined by baseline EDSS ≥3.5 and at least one of the three: confirmed 24 week worsening of EDSS, or ≥20% decline on Timed 25-foot Walk (T25FW), or, ≥20% decline on 9-Hole Peg Test (9-HPT).

Efficacy in patients with highly active disease

Highly active disease was defined as follows:

• Patients with 2 or more relapses in 1 year, and with 1 or more Gd-enhancing lesions on brain MRI, or
• Patients who had failed to respond to a full and adequate course (at least 1 year) of prior DMT treatment, having had at least 1 relapse in the previous year while on therapy, and at least 9 T2 hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or having an unchanged or increased relapse rate in the prior year as compared to the previous 2 years.

Clinical trial data from the DECIDE study demonstrated consistent treatment effects in the highly active disease subgroup. Compared with interferon beta-1a intramuscular (n=440), Zinbryta (n=404) led to reductions on ARR (rate ratio 0.52 [95% CI: 0.42, 0.64], p<0.0001), number of new or newly enlarging T2 hyperintense lesions (lesion mean ratio 0.46 [95% CI: 0.37, 0.57], p<0.0001), and 24 weeks confirmed disability progression (hazard ratio 0.60 [95% CI: 0.40, 0.89], p=0.012).

Figure 1. Percentage of patients relapse-free (DECIDE study):

Figure 2. Proportion of patients with 24 week confirmed disability (DECIDE study):

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Zinbryta in one or more subsets of the paediatric population in treatment of multiple sclerosis (see section 4.2 for information on paediatric use).