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  1. Development & Approval Process (Drugs)

Drug Trials Snapshots: SYMDEKO

Drug Trials Snapshots: SYMDEKO

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 SYMDEKO Package Insert for complete information.

SYMDEKO (tezacaftor/ivacaftor)
{sim-DECK-oh}
Vertex Pharmaceuticals
Approval date: February 12, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

SYMDEKO is a drug for the treatment of cystic fibrosis (CF) in patients 12 years and older, who have specific gene mutations.

CF is a serious genetic disorder that results in the formation of thick mucus that builds up in the lungs and other parts of the body. This can lead to severe breathing problems.

How is this drug used?

SYMDEKO is packaged as two tablets. One tablet, a combination of two drugs (tezacaftor and ivacaftor) is taken by mouth in the morning. The second tablet (ivacaftor) is taken by mouth, in the evening.

What are the benefits of this drug?

SYMDEKO improved lung function by allowing air to move easier. The amount of air that can be forcibly blown out in one second [percent predicted forced expiratory volume (ppFEV1)] was increased.

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

The figures below summarize the primary endpoint results for the trials. The population represents randomized patients who were treated, intent to treat (ITT).

Figure 4: Trial 1- Absolute Change from Baseline in Percent Predicted FEV1 at Each Visit

Graph summarizes efficacy results for Trial 1.

Figure 4 additional text SYMDEKO


LS = least squares

The primary efficacy endpoint was change from baseline in absolute ppFEV1 through Week 24.

SYMDEKO Prescribing Information

Trial 2: Patients with CF Who Were Heterozygous for the F508del Mutation and a Second Mutation Predicted to be Responsive to SYMDEKO

The primary efficacy endpoint was change in lung function as determined by the mean absolute change from baseline in ppFEV1 averaged at weeks 4 and 8 of treatment. For the overall population in Trial 2, treatment with SYMDEKO compared to placebo resulted in significant improvement in ppFEV1 [6.8 percentage points (95% CI: 5.7, 7.8); P<0.0001]. treatment="" difference="" for="" ppfev1="" between="" ivacaftor="" and="" placebo="" treated="" patients="" was="" 4.7="" percentage="" points="" (95%="" ci:="" 3.7,="" 5.8;=""><0.0001) and="" 2.1="" percentage="" points="" (95%="" ci:="" 1.2,="" 2.9;=""><0.0001) between="" symdeko="" and="" ivacaftor="" treated="" patients,="" which="" were="" statistically="">

SYMDEKO Prescribing Information

Trial 3: Patients with CF Who Were Heterozygous for the F508del Mutation and a Second Mutation Not Predicted to be Responsive to Tezacaftor/Ivacaftor

The primary efficacy endpoint was change from baseline in absolute ppFEV1 through Week 12. The overall treatment difference between SYMDEKO and placebo for the mean absolute change in ppFEV1 from baseline through Week 12 was 1.2 percentage points (95% CI: -0.3, 2.6).

SYMDEKO Prescribing Information

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

  • Sex: SYMDEKO worked similarly in males and females.
  • Race: Most of the patients were White. Differences in how well the drug worked among races could not be determined because of the small number of patients in other races.
  • Age: SYMDEKO worked similarly in patients younger and older than 18 years of age.

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

The figures below summarize the primary endpoint, the change in ppFEV1, results by age and sex subgroup for Trials 1 and 2. Race differences were not assessed because of the small number of patients in races other than White. Trial 3 was not assessed for subgroup difference. This trial was terminated early, because treatment did not show a benefit.

Figure 5. Subgroup Analyses on Primary Endpoint of Change from Baseline of ppFEV1 Through Week 24 (Trial 1 SYMDEKO vs Placebo)

Figure summarizes efficacy results by subgroup for Trial 1.

Diff = difference
LCL = lower confidence limit
UCL = upper confidence limit

FDA Review

Figure 6. Subgroup Analyses on Primary Endpoint of Absolute Change from Study Baseline in ppFEV1 to the Average of Week 4 and Week 8 Measurements (Trial 2 SYMDEKO vs Placebo)

Figure summarizes efficacy results by subgroup for Trial 2.

Diff = difference
LCL = lower confidence limit
UCL = upper confidence limit

FDA Review

What are the possible side effects?

SYMDEKO may cause serious side effects including increased liver enzymes and clouding of the lens in the eye (cataracts).

The most commonly reported side effects associated with SYMDEKO are headache, nasopharyngitis, nausea, sinus congestion, and dizziness.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes common adverse reactions for safety population from Trials 1 and 3. Demographics of this population (safety population) is presented in Table 9 under MORE INFO section.

Table 2. Incidence of Adverse Drug Reactions in ≥3% of SYMDEKO- Treated Patients and Greater than Placebo (safety population)

Adverse Reactions
(Preferred Term)
SYMDEKO
N=334
n (%)
Placebo
N=343
n (%)
Headache49 (15)44 (13)
Nausea29 (9)24 (7)
Sinus congestion13 (4)6 (2)
Dizziness12 (4)8 (2)

The safety profile for the CF patients enrolled in Trial 2 who were heterozygous for the F508del mutation and had a second mutation predicted to be responsive to SYMDEKO was similar to that observed in Trials 1 and 3.

Adapted from SYMDEKO Prescribing Information

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

  • Sex: The risk of side effects was similar in males and females.
  • Race: Most of the patients in the trials were White. Differences in the occurrence of side effects among races could not be determined, because of the small number of patients in other races.
  • Age: The risk of side effects was similar in patients less than and older than 18 years of age.

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

The tables below summarize the most common adverse reactions -headache and nausea by subgroup.

Table 3. Subgroup Analysis of Headache (safety population)

Demographic ParametersSYMDEKO
n/N (%)
Placebo
n/N (%)
Sex
Male23/174 (13.2%)31/168 (18.5%)
Female41/160 (25.6%)40/175 (22.9%)
Race
White62/326 (19.0%)70/332 (21.1%)
Black or African American1/2 (50%)0/2 (0%)
Asian0/0 (0%)0/2 (0%)
Other1/2 (50%)0/3 (0%)
Not reported10/4 (0%)1/4 (25%)
Age Group
< 18="" years="" of="">18/77 (23.4%)23/77 (29.9%)
≥18 years of age46/257 (17.9%)48/226 (21.2%)

1Data for race was not collected due to local regulations

Clinical Trial Data

Table 4. Subgroup Analysis of Nausea (safety population)

Demographic ParametersSYMDEKO
n/N (%)
Placebo
n/N (%)
Sex
Male9/174 (5.2%)9/168 (5.4%)
Female23/160 (14.4%)19/175 (10.9%)
Race
White31/326 (9.5%)27/332 (8.1%)
Black or African American0/2 (0%)0/2 (0%)
Asian0/0 (0%)0/2 (0%)
Other1/2 (50%)1/3 (33.3%)
Not reported10/4 (0%)0/4 (0%)
Age Group
< 18="" years="" of="">6/77 (7.8%)9/77 (11.7%)
≥18 years of age26/257 (10.1%)19/266 (7.1%)

1Data for race was not collected due to local regulations

Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved SYMDEKO based on evidence from 3 clinical trials of 916 patients with cystic fibrosis.

Trial 1 (NCT02347657) was conducted in CF patients, who have two copies of the F508del mutation. This trial was conducted at 91 sites in the following 12 countries: Canada, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland, and the United Kingdom.

Trial 2 (NCT02392234) was conducted in CF patients, who have the F508del mutation and a second mutation that is predicted to respond to tezacaftor and/or ivacaftor therapy. This trial was conducted at 81 sites in the following 10 countries: Australia, Belgium, Canada, Germany, France, Israel, Italy, Netherlands, and the United Kingdom.

Trial 3 (NCT02516410) was conducted in CF patients, who have the F508del mutation and a second mutation that is predicted to be unresponsive to tezacaftor and/or ivacaftor therapy. This trial was conducted 38 sites in the following 7 countries: Australia, Austria, Canada, France, Israel, and Spain.

Figures 1 – 3 below summarize by sex, race and age how many patients participated in the combined clinical trials.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many males and females were in the clinical trials. In total, 455 males (50%) and 461 women (50%) participated in the clinical trials.

FDA Review

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race in the clinical trials. In total, 891 White (97%), 7 Black or African American (1%), and 16 Other (2%) participated in the clinical trials.

FDA Review

Table 1. Demographics of Efficacy Trials by Race

RaceNumber of PatientsPercentage of Patients
White89197%
Black or African American71%
Asian2less than 1%
Other71%
Not reported*91%

*Data for race was not collected due to local regulations

FDA Review

Figure 3. Baseline Demographics by Age

Pie chart summarizes how many individuals of certain age groups were in the clinical trials. In total, 187 patients were 12 to 17 years old (20%) and 729 patients were 18 years and older (80%).

FDA Review

Who participated in the trials?

The table below summarizes patients who participated in the combined 3 trials.

Table 5. Baseline Demographics for Patients in SYMDEKO Trials

 Placebo
N = 421
Ivacaftor
N = 81
SYMDEKO
N = 414
Total
N = 916
Sex
Male208 (49.4)41 (50.6)206 (49.8)455 (49.7)
Female213 (50.6)40 (49.4)208 (50.2)461 (50.3)
Race
White407 (96.7)81 (100)403 (97.3)891 (97.3)
Black or African American3 (1.2)04 (1.0)7 (0.8)
Asian2 (0.8)002 (0.2)
Other4 (1.0)03 (1.0)7 (0.8)
Not reported15 (1.2)04 (1.0)9 (1.0)
Age (yrs)
<>87 (22.7)12 (23.4)88 (23.0)187 (20.4)
≥18334 (77.3)69 (76.6)326 (77.0)729 (79.6)
Mean (SD)28.1 (10.7)36.3 (15.2)29.6 (11.4)31.3 (12.4)
Ethnic Group
Hispanic or Latino12 (2.9)4 (4.9)11 (2.7)27 (2.9)
Not Hispanic or Latino401 (95.2)77 (95.1)394 (95.2)872 (95.2)
Not reported18 (1.9)09 (2.1)17 (1.9)
Geographic Region
North America158 (37.5)36 (44.4)146 (35.3)340 (37.1)
Europe242 (57.5)45 (55.6)248 (59.9)535 (58.4)
Asia14 (3.3)010 (2.4)24 (2.6)
Australia7 (1.7)010 (2.4)17 (1.9)

1Data was not collected due to local regulations

FDA Review

The table below summarizes the safety population of patients with cystic fibrosis, who participated in 2 pooled placebo-controlled trials-Trials 1 and 3, and formed the safety population.

Table 6. Baseline Demographics for Safety Population

 Placebo
N = 343
SYMDEKO
N = 334
Total
N = 677
Sex
Male168(36.4)174 (51.2)342 (51.2)
Female175(48.8)160 (48.8)335 (48.8)
Race
White332 (96.8)326 (97.6)658 (97.2)
Black or African American2 (0.6)2 (0.6)4 (0.6)
Asian2 (0.6)02 (0.3)
Other3 (0.9)2 (0.6)5 (0.7)
Not reported4 (1.1)4 (1.2)8 (1.2)
Age (yrs)
<>77 (22.7)77 (23.4)154 (23.0)
≥18266 (77.3)257 (76.6)523 (77.0)
Mean (SD)25.9 (9.2)26.6 (10.4)26.3 (9.8)
Ethnic Group
Hispanic or Latino8 (1.2)10 (3.6)18 (2.4)
Not Hispanic or Latino328 (97.7)315 (94.4)643 (96.0)
Not reported17 (1.2)9 (2.0)16 (1.6)
Geographic region
North America119 (34.7)101 (30.2)220 (32.5)
Europe203 (59.2)213 (63.8)416 (61.4)
Asia14 (4.1)10 (3.0)24 (3.5)
Australia7 (2.0)10 (3.0)17 (2.5)

1Data was not collected due to local regulations

FDA Review

How were the trials designed?

The benefit and side effects of SYMDEKO were evaluated in three trials. Each trial had a different design and treatment duration.

Trial 1: Patients were randomly assigned to receive SYMDEKO, or placebo twice daily. The SYMDEKO morning dose was one table containing tezacaftor and ivacaftor; and the evening dose was one tablet containing ivacaftor only. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed. ppFEV1, the amount of air that can be forcibly blown out in one second, was measured after 24 weeks of treatment. SYMDEKO was compared to placebo.

Trial 2: Patients were randomly assigned to one of three treatments. Treatment one was SYMDEKO, in the morning and evening. The SYMDEKO morning dose was one table containing tezacaftor and ivacaftor; and the evening dose was one tablet containing ivacaftor only. Treatment two was ivacaftor twice daily. Treatment three was placebo twice daily. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed. In this trial, the benefit of SYMDEKO was assessed by taking the average of week 4 and week 8 measurements of ppFEV1 and compared to placebo and ivacaftor.

Trial 3: Patients were randomly assigned to receive SYMDEKO or placebo twice daily. The SYMDEKO morning dose was one table containing tezacaftor and ivacaftor; and the evening dose was one tablet containing ivacaftor only. Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed. ppFEV1 was measured after 12 weeks of treatment. SYMDEKO was compared to placebo. This trial also had pre-planned analysis of some data, before the trial was completed.

How were the trials designed?

The efficacy of SYMDEKO in patients with cystic fibrosis (CF) was evaluated in three clinical trials (Trials 1, 2, and 3).

Trial 1 evaluated SYMDEKO in patients, who are homozygous for the F508del mutation on the CFTR gene. This trial was a randomized, double-blind, placebo-controlled, parallel-group trial. The primary efficacy endpoint was change in lung function as determined by absolute change from baseline in ppFEV1 at week 24.

Trial 2 evaluated ivacaftor monotherapy and SYMDEKO in patients, who are heterozygous for the F508del mutation on the CFTR gene. This trial was a randomized, double-blind, placebo-controlled, 2-period, 3-treatment crossover trial with 2 eight- week treatment periods. Treatment period 1 was followed by an eight-week washout period. The primary efficacy endpoint was change in lung function as determined by the mean absolute change from baseline in ppFEV1 averaged at weeks 4 and 8 of treatment.

Trial 3 evaluated SYMDEKO in patients, who are heterozygous for the F508del mutation on the CFTR gene and have a second mutation that is predicted to be unresponsive to tezacaftor and/or ivacaftor therapy. This trial was a randomized, double-blind, placebo-controlled, parallel-group trial. The primary efficacy endpoint was change in lung function as determined by absolute change from baseline in ppFEV1 at week 12. Trial 3 had a planned interim analysis and was terminated after pre-specified futility criteria were met.

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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