Zinbryta - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Zinbryta 150 mg solution for injection in pre-filled syringe

Zinbryta 150 mg solution for injection in pre-filled pen

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 150 mg of daclizumab beta in 1 mL solution for injection.

Each pre-filled pen contains a pre-filled syringe, containing 150 mg of daclizumab beta in\ 1 mL solution for injection.

Daclizumab beta is produced in a mammalian cell line (NS0) by recombinant DNA technology.

For the full list of excipients, see section 6.1.

4 4r r4 „

3. PHARMACEUTICAL FORM

Solution for injection (injection).

Colourless to slightly yellow, clear to slightly opalescent liquid with pH 6.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Zinbryta is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) who have had an inadequate response to at least two disease modifying therapies (DMTs) and for whom treatment with any other DMT is contraindicated or otherwise unsuitable (see section 4.4).

4.2 Posology and method of administration

Treatment should be initiated by a physician experienced in the management of multiple sclerosis.

Posologyy^

The recommended dose of Zinbryta is 150 mg injected subcutaneously once a month.

In case a dose is missed and it is within 2 weeks of the missed dose, patients should be instructed to inject without delay their missed dose and then remain on their original monthly dosing schedule.

If a dose is missed and it is more than 2 weeks from the missed dose, patients should skip the missed dose, wait until their next scheduled dose, and then remain on their original monthly dosing schedule.

Only one dose should be administered at a time to make up for a missed dose.

Special populations

Elderly population

There was limited exposure in patients over 55 years of age in clinical studies with daclizumab beta. It has not been determined whether these patients respond differently compared with younger patients.

Renal impairment

Daclizumab beta has not been studied in patients with renal impairment. As renal excretion is not a major route of elimination, no dose adjustments are considered necessary (see section 5.2).

Hepatic impairment

Daclizumab beta has not been studied in patients with hepatic impairment. Zinbryta is contraindicated in patients with pre-existing hepatic impairment (see sections 4.3 and 4.4).

Paediatric population

The safety and efficacy of Zinbryta in children and adolescents below 18 years have not been established. No data are available.

Method of administration

Zinbryta is for subcutaneous use.

It is recommended that patients should be trained in the proper technique for self-administering subcutaneous injection using the pre-filled syringe/pre-filled pen. The usual sites for subcutaneous injection include the thigh, abdomen, and back of the upper arm.

Zinbryta is provided with the needle pre-attached. Pre-filled syringes/Pre-filled pens contain a single dose only and should be discarded after use.

Precautions to be taken before handling or administering the medicinal product

Once removed from the refrigerator, Zinbryta should be allowed to warm to room temperature (20°C-30°C) (about 30 minutes) prior to injection. External heat sources such as hot water must not be used to warm Zinbryta.

• This medicinal product should • not be used if:
• • the syringe/pen is cra- cked or broken
• • the solution is cloudy or you can see particles floating in it
• • the solution is a ny other colour than colourless to slightly yellow
• • the pen has been dropped or is visibly damaged.

4.3 Contraindications

Zinbryta is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylaxis or anaphylactoid reactions) to all forms of daclizumab or to any of the excipients in Zinbryta (see section

Pre-existing hepatic disease or hepatic impairment (see section 4.4).

4.4 Special warnings and precautions for use

Hepatic injury

Due to the risk of hepatic injury, the use of Zinbryta is restricted (see section 4.1).

Serious hepatic injury including elevations of serum transaminases and fatal cases of autoimmune hepatitis and fulminant liver failure have occurred in patients treated with Zinbryta (see section 4.8). Cases occurred early after treatment initiation, in patients having received repeated treatment courses and several months after discontinuation.

Prior to treatment initiation with Zinbryta, serum transaminases (ALT and AST) and total bilirubin levels should be obtained, and patients should be screened for Hepatitis B (HBV) and C (HCV). Treatment initiation is not recommended in patients with ALT or AST > 2 times the upper limit of normal (ULN) and is contraindicated in patients with pre-existing hepatic impairment (see section 4.3). For patients who test positive for HBV or HCV infection, consultation with a physician with expertise in the treatment of HBV or HCV is recommended. Treatment initiation is not recommended in patients with history of concurrent autoimmune conditions other than multiple sclerosis.

Patient serum transaminase and total bilirubin levels should be monitored at least monthly and as close as possible before each administration, and more frequently as clinically indicated during treatment and up to 6 months after the last dose of Zinbryta. Treatment discontinuation is recommended in patients who reach ALT or AST >3 times the ULN regardless of bilirubin levels.

Patients should be informed about the risk of hepatic injury, the need for periodic monitoring and warned about signs or symptoms suggestive of hepatic dysfunction. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g. unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), it is recommended to promptly measure serum transaminases, discontinue treatment with Zinbryta, as appropriate, and promptly refer the patient to a hepatologist.

Treatment discontinuation should be considered if an adequate response has not been achieved or the patient fails to follow the requirement for scheduled liver test monitoring.

inistering medicinal products of known hepatotoxic potential, herbal supplements, concomitantly with Zinbryta (see section

cational Guidance’, for details of the Hepatic Risk Management Guide for that are recommended for use with this medicine.

Educational gu ida nce

All physicians who intend to prescribe Zinbryta must ensure they are familiar with the Hepatic Risk Management Guide for Physicians for this medicinal product.

The physician should discuss the risk of hepatic injury with patients and provide them with a Patient

The Card informs patients of the risk of serious hepatic injury, and its possible symptoms, so that they are aware of situations in which they should contact a healthcare professional in a timely manner. In addition, the Card explains the need for monitoring of liver function and educates the patient on the importance of adherence to their monthly blood tests.

Skin reactions

Skin reactions, some serious (e.g. exfoliative rash or dermatitis, toxic skin eruption), have been reported with Zinbryta. Skin reactions generally resolved with standard care, including treatment with topical or systemic steroids. If a patient develops a diffuse or highly inflammatory rash, referral to a dermatologist and discontinuation of Zinbryta may be required (see section 4.8).

Depression

Zinbryta should be administered with caution to patients with previous or current depressive disorders.

Patients treated with Zinbryta should be advised to report any symptoms of new or worsening depression, and/or suicidal ideation immediately to the prescribing physician. If a patient develops severe depression, and/or suicidal ideation, discontinuation of Zinbryta should be considered (see section 4.8).

Infections

Infections, some serious (e.g. pneumonia and bronchitis), have been reported with Zinbryta. If serious infection develops, it could be necessary to withhold treatment with Zinbryta until the infection resolves.

Tuberculosis infections have been reported in patients treated with Zinbryta. In patients who have had tuberculosis or who live in endemic areas of the disease, screening for active tuberculosis should be performed before starting treatment, and patients should be monitored during treatment.

In patients with severe active infection, a delay in initiation of Zinbryta therapy should be considered (see section 4.8).

Zinbryta has not been studied in patients with immunodeficiency syndrome

Autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia has been reported in patients treated with Zinbryta which resolved with standard treatment and discontinuation of Zinbryta.

If a patient develops signs or symptoms of autoimmune haemolytic anaemia (e.g. pallor, fatigue, dark urine, jaundice, shortness of breath), consider referring to a specialist and discontinuing Zinbryta (see section 4.8).

Gastrointestinal disorders

Colitis has been reported with Zinbryta. The colitis improved with discontinuation of Zinbryta and standard treatment. Referring patients who develop symptoms of colitis (e.g. abdominal pain, fever, prolonged diarrhoea) to a specialist is advisable (see section 4.8).

Lymphopenia

When observed during Zinbryta clinical studies, lymphopenia was mostly mild to moderate (> 500/mm3). Sustained severe lymphopenia (< 500/mm3), was not observed in clinical studies with Zinbryta. However, as a precaution, monitoring of complete blood count is recommended every 3 months.

The risk of Progressive Multifocal Leukoencephalopathy (PML) associated to the treatment with Zinbryta has not been established.

Excipi ent related considerations

edicinal product contains 0.14 mmol sodium per dose. It is essentially ‘sodium-free’ and can be used by patients on a sodium-restricted diet.

4.5 Interaction with other medicinal products and other forms of interaction

Zinbryta is not expected to undergo metabolism by hepatic enzymes or renal elimination. There is limited data on concomitant use of Zinbryta with MS symptomatic therapies.

Hepatic injury

Cases of hepatic injury have occurred in patients taking Zinbryta with other hepatotoxic drugs, although the role of these medicinal products is uncertain. Caution is recommended when administering medicinal products of known hepatotoxic potential including non-prescription products and herbal supplements concomitantly with Zinbryta (see section 4.4).

Immunisations

The safety of immunisation with live viral vaccines during treatment with Zinbryta has not been studied. Vaccination with live vaccines is not advised during treatment and up to 4 months after discontinuation.

In a clinical study, patients (n=90) on long-term treatment with Zinbryta mounted appropriate immune responses to an inactivated trivalent seasonal influenza vaccine. The magnitude of the immune response to the seasonal influenza vaccine, and proportion of patients with seroconversion and seroprotection were consistent with those observed in healthy volunteer populations. Patients on Zinbryta may receive non-live vaccines.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of Zinbryta in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reprotoxicity (see section 5.3).

Zinbryta should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

Available toxicology data in lactating cynomolgus monkeys have shown excretion of daclizumab beta in milk (for details see section 5.3). It is not known whether Zinbryta is secreted in human milk. Although human IgG is secreted into human milk, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. A risk to newborns/infants cannot be excluded.

If a woman wishes to breast-feed during treatment with Zinbryta, the benefit of breast-feeding to the child and of therapy to the woman should be considered.

Fertility

No impact on male or female fertility as assessed by fertility indices was detected in animal studies (see section 5.3). There are no data on the effects of Zinbryta on human fertility.

4.7 Effects on ability to drive and use machines

Zinbryta has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

S umm^ry of the safety profile

In the placebo-controlled study (the SELECT study), 417 patients received Zinbryta (150 mg, n=208; 300 mg, n=209; every 4 weeks) for up to 1 year. In the active-controlled study (the DECIDE study), 919 patients received Zinbryta (150 mg, every 4 weeks) and 922 patients received interferon beta-1a intramuscular, (30 microgram weekly) for a minimum of 2 years and up to 3 years.

The most commonly reported adverse reactions leading to discontinuation in patients treated with Zinbryta were hepatic reactions, including elevations of serum transaminases (5%), and cutaneous reactions (4%) (see section 4.4).

The most common adverse reactions reported for Zinbryta were rash, increased alanine aminotransferase (ALT), depression, nasopharyngitis, upper respiratory tract infection, influenza, oropharyngeal pain, and lymphadenopathy.

Tabulated list of adverse reactions

The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Order Class by frequency and incidence. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The incidence of the adverse reactions is expressed according to the following categories:

• • Very common (> 1/10)
• • Common (>1/100 to <1/10)
• • Uncommon (>1/1,000 to <1/100)
• • Rare (>1/10, 000 to <1/1,000)
• • Very rare (<1/10,000)
• • Not known (cannot be estimated from the available data)

Table 1: Adverse reactions reported for Zinbryta 150mg

System Organ Class	Adverse reaction	Frequency
Infections and infestations	Upper respiratory tract infection^	Very Common
	Nasopharyngitisf	Very Common
	Pneumonia	Common
	Respiratory tract infection	Common
	Bronchitis	Common
	Viral infection	Common
	Influenzaf	Common
	Laryngitis	Common
	Tonsillitis^	Common
	Pharyngitis	Common
	Folliculitis	Common
	Rhinitis*	Common
Blood and lymphatic system disorders	Lymphadenopathyf	Common
	Lymphadenitis	Common
	Anaemia*	Common
	Autoimmune haemolytic anaemia	Uncommon
l/V Immune system disorders	Sarcoidosis	Uncommon
Psychiatric disorders	Depression*	Common
Respiratory, thoraci: and mediastinal disorders	Oropharyngeal paint	Common
Gastrointestinal disorders	Diarrhoea	Common
	Colitis	Common
Skin and subcutaneous tissue disorders	Dermatitis	Common
	Dermatitis allergic	Common
	Eczemat	Common
	Psoriasis	Common
	Seborrhoeic dermatitisf	Common
	Skin exfoliation	Common
	Rash*f	Common
	Rash maculopapular	Common
	Acnef	Common
	Erythema	Common
	Pruritus	Common
	Dry skin	Common

	Exfoliative rash	Uncommon
	Toxic skin eruption	Uncommon
	Eczema nummular	Uncommon
General disorders and administration site conditions	Pyrexia*	Common
Hepatobiliary disorders	Transaminases increased	Very common
	Autoimmune hepatitis	Uncommon
	Fulminant hepatitis	Not known
Investigations	Liver function test abnormal	Very common
	Lymphocyte count decreased	Common

Observed with a >2% higher incidence than placebo

^Observed with a >2% higher incidence than interferon beta-1a (intramuscular)

Description of selected adverse reactions 

Hepatic injury

Serious hepatic injury, including fatal cases of autoimmune hepatitis and fulminant liver failure have occurred in patients treated with Zinbryta. Serious reactions, including autoimmune hepatitis, hepatitis and jaundice, were observed in 1.7% of patients in clinical trials.

In clinical studies, serum transaminase elevations occurred at any time during treatment and up to 6 months after the last dose of Zinbryta. Most patients had mild elevations that were below or up to 3 x ULN and resolved spontaneously. In clinical trials, an increased incidence of elevations of ALT or AST was reported more frequently in Zinbryta-treated patients compared to placebo or interferon beta-1a (intramuscular). The incidence of discontinuation due to medicine related hepatic disorders was 5% in Zinbryta-treated patients and 4% in interferon beta-1a (intramuscular).

Table 2. Cumulative incidences of peak AL t or aST increase (based on laboratory data) observed in clinical trials

	Daclizumab 150 mg (N=1943)	Interferon beta-1a (N=922)	Placebo (N=204)
Total exposure (subject-years)	7011	1884	210
> 3 x ULN	13.6%	8.5%	3.4%
> 5 x ULN	9.0%	3.4%	0.5%
> 10 x ULN	4.3%	1.3%	0.0%
> 20 x ULN	1.4%	0.4%	0.0%
A ST or aLT > 3 x ULN AND total bilirubin > x 2 ULN	0.77%	0.1%	0.5%

Skin reactions

In clinical studies Zinbryta increased the incidence of skin reactions [18% vs 13% (placebo); 37% vs 19% (interferon beta-1a (intramuscular))] and serious skin reactions [<1% vs 0% (placebo); 2% vs <1% (interferon beta-1a (intramuscular))] compared to placebo and interferon beta-1a (intramuscular).

The most common skin reactions were rash, dermatitis, and eczema. The majority of patients had skin reactions that were mild or moderate in severity. Discontinuation due to skin reactions was 4% in Zinbryta-treated patients.

Depression

In clinical studies, Zinbryta increased the incidence of depression [5% vs 1% (placebo); 8% vs 6% (interferon beta-1a (intramuscular))]; the incidence of serious reactions of depression was <1% with Zinbryta.

Infections

In clinical studies, Zinbryta increased the incidence of infections [50% vs 44% (placebo) and 65% vs 57% (interferon beta-1a (intramuscular))] and serious infections [3% vs 0% (placebo); 4% vs 2% (interferon beta-1a (intramuscular))] compared to placebo and interferon beta-1a (intramuscular). The most common types of infections were upper respiratory tract infections and viral infections. The median duration was similar between the treatment groups. The rate of infections and serious infections did not increase over time. The majority of patients with infections continued on treatment with Zinbryta. Discontinuation of Zinbryta due to infections was <1%.

Autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia was reported in < 1% of patients treated with Zinbryta in clinical studies.

Gastrointestinal disorders

An increased incidence of serious colitis (<1%) was reported in patients treated with Zinbryta in clinical studies.

t 7 a

Lymphadenopathy

In clinical studies, Zinbryta increased the incidence of lymphadenopathy, with onset occurring throughout the treatment period. Discontinuation due to lymphadenopathy was <1% in Zinbryta-treated patients. The majority of patients with lymphadenopathy continued on treatment with Zinbryta, and the majority of cases resolved within 3 months.

Immunogenicity W

In the DECIDE study (see section 5.1), patients were tested for anti-drug (daclizumab beta) antibodies at week 4 and approximately every 3 months thereafter. Treatment-emergent anti-drug antibodies and neutralising antibodies were observed in 19% (175/913) and 8% (71/913) of study patients, respectively. The majority of the treatment-emergent anti-drug antibodies responses were transient (12% [110/913]) and the remaining minority (7% [65/913]) were persistent. Among the evaluable patients, the majority of treatment-emergent neutralising antibody responses were transient (6% [56 of 913]) and 2% of patients (15 of 913) had persistent responses. Treatment-emergent anti-drug antibodies and neutralising antibodies responses predominantly occurred during the first year of treatment and their frequency declined with continued Zinbryta treatment.

In patients with neutralising antibodies, daclizumab beta clearance was increased on average by 19% (see section 5.2). There was no apparent correlation of anti-drug antibodies or neutralising antibodies development to clinical response, adverse reactions, or pharmacodynamic profile of daclizumab beta.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

Reported experience with overdose is limited. The safety of doses above 300 mg administered subcutaneously and 400 mg intravenously have not been evaluated. Doses up to this level were well tolerated with no evidence of acute toxicity. Potential adverse reactions beyond this level are expected to be consistent with the safety profile for daclizumab beta in MS patients.

Management

In case of overdose, patients may require medical attention and appropriate supportive treatment should be given.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressants, interleukin inhibitors, ATC code: L04AC01

Mechanism of action                          |

Daclizumab beta is a humanised IgG1 monoclonal antibody that binds to CD25 (IL-2Ra), andH 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 CD56bright 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 progressio

Pharmacodynamic effects

In clinical studies, the pharmacodynamic effects of Zinbryta j 50 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 CD56bright NK cells and a decrease in regulatory T-cells (defined as CD4+CDj27lowFoxP3+ T-cells) was observed within 2 weeks after the first dose, with a sustained 5-fold increase in CD56bright 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-j2 weeks after the last dose of Zinbryta (j50mg). Total lymphocyte counts <0.8×j09 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-ja (intramuscular)-treated and 8% of Zinbryta-treated patients in the DECIDE study. Total NK cell counts increased approximately j.5-fold as a result of the change in CD56bright NK cells.

Clinical e fficacy 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

Study name	SELECT	DECIDE
Study design
Treatment	52 weeks	96 to 144 weeks
Disease history	Patients with RMS, at least 1 relapse (clinical and/or MRI) during the year prior to randomisation, and had an EDSS score between 0 to 5.0. For DECIDE, at least 2 relapses (one of which was a clinical relapse) within the prior 3 years was also required
Baseline characteristics
Mean age (years)	35.7	36.3          _|
Mean disease duration (years)	4.1	4.2
Mean number of relapses within 12 months prior to study	1.4	6
Median EDSS score	2.5
Percent with EDSS > 3.5	36%	3 0%
Percent with > 1 Gd enhancing lesion (mean)	44% (1.8)	46% (2.1)
Percent > 2 relapses in the year prior to study	31%	46%
Percent prior DMT use (% )	20%         >      41%

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)

	Placebo	Zinbryta 150 mg	p-value
Clinical endpoints
Number of patients	196	201
Annualised relapse rate Rate ratio [95% CI]	0.458	0.211 0.461 [0.318, 0.668]	p<0.0001
Percentage of patients relapse-free Hazard ratio* [95% CI]	64%	81% 0.45 [0.30, 0.67]	p<0.0001
Percentage with 24 weeks confirmed disability progression Hazard ratio [95% CI]	11%	2.6% 0.24 [0.09, 0.63]	p=0.0037
Percentage with 12 weeks confirmed disability progression Hazard ratio [95% CI]	13% r	6% 0.43 [0.21, 0.88]	p=0.0211
Mean change in MSIS-29 physical score	3.0 point worsening	1.0 point improvement	p=0.0008
MRI endpoints#
Mean number of new or newly enlarging T2 hyperintense lesions Lesion mean ratio [95% CI]	8 13	2.4 0.30 [0.22, 0.40]	p<0.0001
Mean number of new T1 Gd-enhancing lesions between 8 and 24 weeks (on monthly MRI scans) Lesion mean ratio [95% CI]	4.79	1.46 0.31 [0.20, 0.48]	p<0.0001

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 patient-reported 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.)

	Interferon beta-1a (intramuscular) 30 micrograms	Zinbryta 150 mg	p-value
Clinical endpoints
Number of patients	922	919
Annualised relapse rate Rate ratio* [95% CI]	0.393	0.216 0.550 [0.469, 0.645]	p<0.0001
Percentage of patients relapse-free Hazard ratio# * [95% CI]	59%	73% 0.59 [0.50, 0.69]	p<0.0001
Percentage with 24 weeks confirmed disability progression Hazard ratio* [95% CI]	12%	9% 0.73 [0.55, 0.98]	p=0.03
Percentage with 12 weeks confirmed disability progression Hazard ratio* [95% CI]	14% ~\C	1,% 0.84 [0.66, 1.07]	p=0.16
Percentage of patients with clinically meaningful worsening in MSIS-29 physical score (>7.5 point) Odds ratio [95% CI]	23%	19% 0.76 [0.60, 0.95]	p=0.018
MRI endpoints f
Mean number of new or newly enlarging T2 hyperintense lesions Lesion mean ratio [95% CI]	9.44	4.31 0.46 [0.39, 0.53]	p<0.0001
Mean number of new T1 Gd-enhancing lesions Odds r atio [95% CI]	1.0	0.4 0.25 [0.20, 0.32]	p<0.0001
Mean number of new T1 hypointense lesions Lesion mean ratio [95% CI]	4.43	2.13 0.48 [0.42, 0.55]	p<0.0001

* Rates and risk reductions/en­dpoints are calculated over the treatment period up to 144 weeks.

# Hazard ratio for the risk of relapse.

t 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 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).

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).

5.2 Pharmacokinetic properties

Daclizumab beta pharmacokinetics are well described by a two-compartment model with first-order absorption and elimination.

Absorption

Following subcutaneous administration of daclizumab beta, the median time to reach maximum serum concentrations (Tmax) ranged from 5 to 7 days. The absolute bioavailability of daclizumab beta 150 mg subcutaneously administered was approximately 90% based on a cross-study population pharmacokinetic analysis of subcutaneous and intravenous dosing.

Distribution

Following subcutaneous administration of daclizumab beta 150 mg every 4 weeks, steady-state serum daclizumab beta concentrations were achieved by the 4th dose and daclizumab beta accumulated to a level approximately 2.5-fold compared to a single dose. At steady state, daclizumab beta mean maximum serum concentration (Cmax), minimum serum concentration (Cmin) and area under the serum concentration-time curve over the dosing interval (AUCtau) values were approximately

30 micrograms/mL, 15 micrograms/mL and 640 day*micro­grams/mL, respectively, with inter-patient variability (% CV) of approximately 40%.

Based on the cross-study population pharmacokinetic analysis, the steady-state volume of distribution of daclizumab beta is 6.34 L in a patient with a body weight of 68 kg (approximate median of evaluated patients). This small volume of distribution indicates that daclizumab beta is primarily confined to the vascular and interstitial spaces.

Biotransformation

The exact metabolic pathway for daclizumab beta has not been characterised. As an IgG1 monoclonal antibody, daclizumab beta is expected to undergo catabolism to peptides and amino acids in the same manner as endogenous IgG. Daclizumab beta is not expected to undergo metabolism by hepatic enzymes such as CYP isoenzymes (see section 4.5).

Elimination

As an IgG1 monoclonal antibody, daclizumab beta is not expected to undergo renal elimination.

yjCS

Based on the cross-study population pharmacokinetic analysis, the clearance of daclizumab beta is 0.212 L/day with a terminal half-life value of approximately 21 days. Daclizumab beta clearance in patients who developed neutralising antibodies was, on average, 19% higher (see section 4.8 Immunogeni­city).

Linearity/non-line' '.rity

Consistent with results from individual studies, a cross-study population pharmacokinetic analysis indicated that daclizumab beta exposure is more than dose-proportional in the 50 mg to 100 mg subcutaneous dose range and is dose proportional in the 100 mg to 300 mg subcutaneous dose range.

Pharm acokinetic/phar­macodynamic relationship(s)

Within the studied regimens of daclizumab beta 150 mg and 300 mg administered subcutaneous every 4 weeks in MS patients, there was no clear relationship between daclizumab beta exposure and clinical efficacy endpoints (ARR, T2 lesions and Gd-enhancing lesions) or safety endpoints of interest (serious infection status, moderate or severe cutaneous adverse reaction, and AST/ALT > 5 times the ULN).

Special populations

Renal or hepatic impairment

No studies were conducted to evaluate daclizumab beta pharmacokinetics in patients with renal or hepatic impairment. Daclizumab beta is not expected to undergo renal elimination or metabolism by hepatic enzymes (see section 4.2).

Weight

Based on the cross-study population pharmacokinetic analysis, body weight accounted for less than 40% of the inter-patient variability in daclizumab beta clearance. No meaningful differences in clinical efficacy or safety were observed among the subgroups of MS patients by weight quartile in the DECIDE study.

Age and gender

Based on the cross-study population pharmacokinetic analysis, daclizumab beta pharmacokinetics were not influenced by age (range: 18 to 66 years; n=1670) or gender (n = 567 males and 1103 females).

Race

No pharmacokinetic differences were observed between Japanese and Caucasian healthy volunteers.

5.3 Preclinical safety data

Preclinical safety studies were conducted in cynomolgus monkeys due to species specificity of daclizumab beta binding only to human or primate CD25.

Carcinogenesis

Carcinogenicity studies with daclizumab beta have not been conducted. In two 9 month studies in monkeys there were no pre-neoplastic or neoplastic tissue observed.

Mutagenesis

Genotoxicity studies have not been conducted.

Reproductive toxicity

Daclizumab beta did not affect reproductive capacity in female and male cynomolgus monkeys (AUC in females and males up to 85 and 100times higher than the exposure at the clinical dose respectively). There was no effect on foetal development and no evidence of teratogenicity. Daclizumab beta had no effect on peri- and post-natal development from birth to up to 6 months in the offspring. Exposures (AUC) in these studies ranged from 55 to 140 times that observed with the clinical

dose. Daclizumab beta was detected in the milk of 11/14 lactating monkeys at levels that were

• <0.122% of the maternal serum levels, with no adverse reactions observed in the off-spring.

Toxicology

In two 9 month studies conducted in cynomolgus monkeys daclizumab beta was subcutaneously administered at bi-weekly doses of 10–200 mg/kg.

Chronic administration of daclizumab beta at all doses increased the incidence of skin findings (compared to those observed in control animals). These findings (dry, red raised patchy areas of the skin, as compared to controls, that correlated microscopically with acanthosis/hy­perkeratosis and subacute to chronic inflammation) were characterised predominantly as mild to moderate, with one case assessed as severe.

A dose dependent increase in incidence of microglial aggregates above background was observed in the brain and spinal cord of monkeys treated with >35 mg/kg, (AUC 27 times higher than the clinical dose). Following a recovery period of up to 12 weeks, there was evidence of reversibility. Microglial aggregates in monkeys did not increase in incidence or severity with increased duration of dosing and were not associated with neuronal damage or neurobehavioral effects. A small subset of microglial aggregates were associated with microhaemorrhage but with no evident functional sequelae in monkeys.

In vitro investigative studies suggest that microglial aggregates are not due to a direct effect of daclizumab beta on microglial cells but are likely to be attributable to an increase in local IL-2 bioavailability.

The clinical relevance of microglial aggregates is unknown, however no deleterious neurologic effects attributed to the microscopic change have been observed in monkeys.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sodium succinate Succinic acid

Sodium chloride

Polysorbate 80 Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product should not be mixed with other products.

6.3 Shelf life

• 3 years.

Zinbryta can be stored at room temperature (up to 30oC) in the original pack for 30 days.

Do not place Zinbryta back into the refrigerator after warming to room temperature.

If Zinbryta has been outside of the refrigerator for more than a total of 30 days or if you are not sure how long Zinbryta has been at room temperature, it should be discarded.

6.4 Special precautions for storage

oo

Store in a refrigerator (2oC-8oC).

Do not freeze.

Store in the original package in order to protect from light.

For additional information on storage at room temperature, see section 6.3.

6.5 Nature and contents of container

♦

Pre-filled syringe made of glass (Type 1) with a rubber stopper and thermoplastic rigid needle shield containing 1 mL of solution. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe.

Pack sizes:

• – Pack containing one 150 mg pre-filled syringe.

• – 3 month multipack containing three 150 mg pre-filled syringes (3 boxes containing 1 syringe each).

A pre-filled syringe of Zinbryta is contained within a spring-powered pen injector called Zinbryta Pen. The syringe inside the pen is a pre-filled syringe made of glass (Type 1) with a rubber stopper and thermoplastic rigid needle shield, containing 1 mL of solution. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe.

Pack sizes:

• – Pack containing one 150 mg pre-filled pen.

• – 3 month multipack containing three 150 mg pre-filled pens (3 boxes containing 1 pen each).

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

BIOGEN IDEC Limited

Innovation House

70 Norden Road

Maidenhead

Berkshire

EU/1/16/1107/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 01 July 2016