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  1. Development & Approval Process (Drugs)

Drug Trials Snapshots: Zinbryta

Drug Trials Snapshots: Zinbryta

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the ZINBRYTA Prescribing Information for complete information.

ZINBRYTA (daclizumab)
(zin-bry-tuh)
Biogen Inc
Approval date: May 27, 2016


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ZINBRYTA is a drug for the treatment of relapsing forms of multiple sclerosis (MS) in patients who have not responded adequately to at least 2 other treatments for MS.

How is this drug used?

ZINBRYTA is given once every month by injection under the skin (subcutaneous injection) of the thigh, belly, or back of the upper arm.

What are the benefits of this drug?

Patients treated with ZINBRYTA had fewer worsening episodes (relapses) of MS in one year.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes the efficacy results for Trial 1.

Table 2. Clinical and MRI Results of Trial 1

 

ZINBRYTA
15 0 mg SQ
Every 4 Weeks
N=919

AVONEX
3 0 mcg IM
Once Weekly
N=922
p-value
Clinical Results1
Annualized relapse rate
Relative reduction
Proportion Relapse Free
0.216
45%
67%

0.393

51%

<>
Proportion with 12-week confirmed disability progression16%20%0.16
MRI Results 2
Mean number of new or newly enlarging
T2 hyperintense lesions
Relative reduction

4.31
54%

9.44

<>

1Values refer to results up to 144 weeks
2MRI analysis used evaluable dataset and values reflect results at 96 weeks
ZINBRYTA Prescribing Information

Table 3. Clinical and MRI Results of Trial 2

 

ZINBRYTA
15 0 mg SQ
Every 4 Weeks
N=208

Placebo

N=204

p-value
Clinical Results1
Annualized relapse rate
Relative reduction
Proportion Relapse Free
0.211
54%
81%

0.458

64%

<>
Proportion with 12-week confirmed disability progression3
Relative risk reduction
6%
57%
13% 
MRI Results2
Mean number of new or newly enlarging
T2 hyperintense lesions1
Relative reduction


2.4
70%


8.1

<>
Mean number of new T1 Gd-enhancing lesions
Relative reduction
1.46
69%
4.79<>

1 Values refer to results at 52 weeks
2MRI analyses used evaluable dataset for each endpoint; T1 Gd-enhancing: MRI intensive population, between 8-24 weeks
3The proportion of patients with 12-week confirmed disability progression was an exploratory measure in Study 2. As the proportion of patients with 12-week confirmed disability was used as a key secondary outcome in Study 1, and is one of the main outcome measures in MS studies, the disability progression results are presented for Study 2. The nominal p value for that comparison, p=0.02, is not adjusted for multiple comparisons

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: ZINBRYTA worked similarly in men and women
  • Race: The majority of patients in the trials were white. Differences in response to ZINBRYTA among races could not be determined.
  • Age: All patients in the trials were below age 65. Differences in response to ZINBRYTA between patients above and below age 65 could not be determined.

Were there any differences in how well the drug worked in clinical trials among sex, race and age groups?

Subgroup differences in relapse rates in Trials 1 and 2 are presented in the tables below.

Table 3. Analysis of the Primary Endpoint by Demographic Subgroups (Trial 1)

 AvonexZINBRYTA
 N=919N= 922
Sex, Men
   n295294
   Adjusted annualized relapse rate0.4010.186
   Rate ratio (95% CI) 0.46 (0.35, 0.62)
Sex, Women
   n627625
   Adjusted annualized relapse rate0.3860.227
   Rate ratio (95% CI) 0.59 (0.49, 0.71)
Age, ≤ 35
   n449451
   Adjusted annualized relapse rate0.5050.205
   Rate ratio (95% CI) 0.41 (0.32, 0.51)
Age, > 35
   n473468
   Adjusted annualized relapse rate0.3150.233
   Rate ratio (95% CI) 0.74 (0.59, 0.92)
Race-White
   n828823
  Adjusted annualized relapse rate0.3940.213
  Rate ratio (95% CI) 0.54 (0.46, 0.64)
Race- non-White
   n9496
  Adjusted annualized relapse rate0.3770.241
  Rate ratio (95% CI) 0.64 (0.38, 1.08)

FDA Statistical review

Table 4. Analysis of the Primary Endpoint by Demographic Subgroups (Trial 2)

 PlaceboZINBRYTA
 N=196N=201         
Sex, Men
    n7365                                
   Adjusted annualized relapse rate0.430.13                             
   Rate ratio (95% CI) 0.22 (0.10, 0.48)
Sex, Women
    n123136
   Adjusted annualized relapse rate0.320.22                             
   Rate ratio (95% CI) 0.66 (0.40, 1.07)          
Age <=>
   n9099                                
  Adjusted annualized relapse rate0.460.18                           
   Rate ratio (95% CI) 0.32 (0.18, 0.56)
Age > 35
   n106102                              
   Adjusted annualized relapse rate0.280.20                             
   Rate ratio (95% CI) 0.68 (0.38, 1.20)          
Race-White
   n189195                              
   Adjusted annualized relapse rate0.4300.208                             
   Rate ratio (95% CI) 0.48 (0.33, 0.71)          
Race-non-White
   n76                             
   Adjusted annualized relapse rate1.1750.364                             
   Rate ratio (95% CI) 0.31 (0.06, 1.67)          

FDA Statistical review

What are the possible side effects?

ZINBRYTA may cause serious and life threatening liver injury, immune-mediated disorders including allergic reactions, infections, and depression and suicide.

The most common side effects of ZINBRYTA are nasopharyngitis, upper respiratory tract infection and rash.

ZINBRYTA may cause serious adverse reactions including

  • severe liver injury, including life-threatening and fatal events, liver failure, and autoimmune hepatitis
  • Immune mediated disorders including skin reactions, lymphadenopathy, non-infectious colitis , sarcoidosis
  • Hypersensitivity reactions (anaphylaxis and angioedema) increased risk of infection and depression and/or suicidal ideation

The tables below summarize the adverse reactions that occurred at least 2% more frequently in patients treated with ZINBRYTA in Trials 1 and 2.

Table 5. Adverse Reactions in Adults With RMS That Occurred at least 2% More Frequently for ZINBRYTA Than AVONEX (Trial 1)

Adverse ReactionZINBRYTA
150 mg SQ Every 4
Weeks
N=919
%
AVONEX
30 mcg IM
Once Weekly
N=922

%
Nasopharyngitis2521
Upper respiratory tract infection11714
Rash2114
Influenza96
Dermatitis392
Oropharyngeal pain84
Bronchitis75
Eczema452
Lymphadenopathy5<>
Tonsillitis42
Acne3<>

1 includes upper respiratory tract infection and viral upper respiratory tract infection
2 includes erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, and vesicular rash
3 includes allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis, and seborrheic dermatitis
4 includes dyshidrotic eczema, eczema, and nummular eczema
ZINBRYTA Prescribing Information

Table 6. Adverse Reactions in Adults with RMS That Occurred at least 2% More Frequently for ZINBRYTA than Placebo (Trial 2)

Adverse ReactionZINBRYTA
150 mg SQ
Every 4 Weeks

N=208
%
Placebo

N=204
%
Upper Respiratory Tract Infection97
Depression172
Rash273
Pharyngitis64
Increased ALT52
Rhinitis41
Anemia3<>
Pyrexia3<>
Increased AST3<>
Dermatitis33<>

1 includes depressed mood and depression
2 includes erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, and vesicular rash
3 includes allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis, and seborrheic dermatitis
ZINBRYTA Prescribing Information

Were there any differences in side effects among sex, race and age?

  • Sex: The rate of side effects was similar in men and women.
  • Race: The majority of patients in the trials were white. Differences in side effects among races could not be determined.
  • Age: All of the patients in the trials were below age 65. Differences in side effects between patients above and below age 65 could not be determined.

Were there any differences in side effects of the clinical trials among sex, race and age groups?

The table below summarizes the most common adverse reaction that occurred in both trials (upper respiratory tract infection) by subgroup

Table 7. Upper Respiratory Tract Infection by Subgroups in ZINBRYTA treated Participants

Demographic
Parameters
ZINBRYTA
(N=1127)
Avonex
(N=922)
Placebo
(N=204)
Patients with AR*
n/N (%)
Patients with AR*
n/N (%)
Patients with AR*
n/N (%)
Sex
   Men45/362 (12)40/295(14)1/76 (1)
   Women122/765 (16)84/627(13)14/128 (11)
Age Group
   <40>104/704 (15)78/579 (13)9/126 (7)
   40 years and older63/423 (15)46/343(13)6/78 (7)
Race
   White157/1025 (15)118/828 (14)15/197(3)
   All Other10/102 (10)6/94(6)0/7(0)

* Adverse Reaction: Upper Respiratory Tract Infection
Clinical trial data


WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA based the approval of ZINBRYTA on evidence from 2 clinical trials with 2253 patients with relapsing multiple sclerosis. The patients lived in the United States, Canada, Europe, Asia and South America.

Figure 1 summarizes how many men and women volunteered to be in the clinical trials.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trials of the drug Zinbryta. In total, 733 men (33%) and 1520 women (67%) participated in the clinical trials.

Clinical trial data

Figure 2 summarizes the percentage of patients by race in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race in the ZINBRYTA clinical trials. In total, 2050 Whites (91%), 25 Blacks (1%), 68 Asians (3%), 56 Other (3%), and 54  patients where race was not reported (2%) participated in the clinical trials.

Clinical trial data

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage
White205091%
Black or African American251%
Asian683%
All Other563%
Not reported542%

Clinical trial data

Figure 3. Baseline Demographics by Age

Pie charts summarizing how many individuals of certain age groups were in the ZINBRYTA clinical trials.  All 2253  patients  (100%) were  between 18 and 56 years old.

Clinical trial data

Who participated in the trials?

The table below summarizes demographics of patients in clinical Trials 1 and 2 combined.

Table 8. Baseline Demographics

Demographic ParametersZINBRYTA
(N=1127)
Avonex
(N=922)
Placebo
(N=204)
Total
(N=2253)
Sex 
  Men362 (32%)295 (32%)76 (37%)733 (33%)
  Women765 (68%)627 (68%)128 (63%)1520 (67%)
Age 
  Median (years)36363736
  Min, Max (years)18, 5618, 5619, 5518, 56
Age Group 
  18-39 years704 (62%)579 (63%)126 (62%)1409 (63%)
  40-56 years423(38%)343 (37%)78 (38%)844 (37%)
Race 
  White1025 (91%)828 (90%)197 (97%)2050 (91%)
  African American or Black13 (1%)12 (1%)025(1%)
  Asian33 (3%)28 (3%)7   (3%)68 (3%)
  American Indian or Alaska   
Native
01 (<>01 (<>
  Other27(3%)28 (3%)055 (2%)
 Race not reported29 (3)25 (3)054 (2%)
Region  
  United States and Canada118(10%)118 (13%)0236 (10%)
  Other*1109 (90%)604 (87%)204 (100%)1917 (90%)

*From countries in Europe, Asia and South America.
Clinical trial data

How were the trials designed?

There were two trials that evaluated the benefits and side effects of ZINBRYTA.

In Trial 1, which was 96 weeks in duration, patients had injections with ZINBRYTA injections every four weeks or with an approved drug for MS called Avonex every week. In Trial 2, which was 52 weeks in duration, patients had injections with ZINBRYTA or a similar inactive drug every four weeks.

Neither the patients nor the health care providers knew for sure which treatment was being given until after the trials were completed. The trials counted the number of episodes when the patients' symptoms became worse ( MS relapses) each year and compared the number for ZINBRYTA to the numbers for Avonex and placebo.

How were the trials designed?

ZINBRYTA trials include 2 double-blind, randomized trials.

In Trial 1, ZINBRYTA given SC every 4 weeks was compared to AVONEX 30 mcg IM weekly. The treatment lasted 96 weeks and the primary endpoint was the annualized relapse rate (ARR).

In Trial 2, ZINBRYTA given SC every 4 weeks was compared to placebo. The treatment lasted 52 weeks and the primary endpoint was the annualized relapse rate (ARR) at week 52.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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