Drug Trials Snapshots: WAKIX

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 WAKIX Package Insert for complete information.

WAKIX (pitolisant)
way – kicks
Harmony Bioscience
Approval date: August 14, 2019

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

WAKIX is a drug used to treat excessive daytime sleepiness in adults with narcolepsy.

Narcolepsy is a sleep disorder with excessive daytime sleepiness. Some patients with narcolepsy also experience sudden loss of muscle tone (cataplexy).

How is this drug used?

WAKIX is a tablet taken by mouth once every day in the morning upon wakening.

What are the benefits of this drug?

Patients who received WAKIX had less daytime sleepiness in comparison to patients who received placebo.

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

The table below shows the efficacy assessment based on the change (from baseline to the final score) in the mean ESS scores for the patients in Trial 1 and Trial 2.

Table 2: Efficacy Results for Epworth Sleepiness Scale in Patients with Narcolepsy Trial 1 and Trial 2)

Trial	Treatment Group (N)	Baseline ESS Score Mean (SD)	Final ESS Scorec LS Mean at Week 8 (SE)	Placebo Subtracted Difference [95% CI] at Week 8d
Trial 1a	WAKIX (n=31)	17.8 (2.5)	12.4 (1.0)	-3.1* [-5.73; -0.5]
	Placebo (n=30)	18.9 (2.5)	15.5 (1.0)
Trial 2b	WAKIX (n=66)	18.3 (2.4)	13.3 (1.2)	-2.2* (-4.2; -0.2)
	Placebo (n=32)	18.2 (2.3)	15.5 (1.3)

SD = standard deviation; SE = standard error; LS = least-squares; CI = confidence interval
^aMaximum dose randomized to was 35.6 mg
^bMaximum dose randomized to was 17.8 mg
^cA lower score on the ESS represents improvement; scores range from 0 (no symptoms) to 24 (worst symptoms)
^dA negative value for the placebo subtracted difference represents improvement
* Statistically significant

WAKIX Prescribing Information

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

• Sex: WAKIX worked similarly in men and women.
• Race: The majority of patients were White. The number of patients of other races was limited; therefore, differences in how well WAKIX worked among races could not be determined.
• Age: The majority of patients were adults less than 65 years of age. The number of patients older than 65 years of age was limited; therefore, differences in how well WAKIX worked between patients younger and older than 65 years of age could not be determined.

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

The table below shows the subgroup analysis by sex for Trial 1. Subgroup analyses on race and age groups were not performed since the majority of patients were White and less than 65 years of age.

Table 3: Subgroup Analysis of Efficacy Results by Sex (Trial 1)

Sex	WAKIX N=31	Placebo N=30	WAKIX-Placebo 95% CI for Differences
	N LS Mean (SE) -Week 8
Men	20 12.3 (1.4)	13 13.4 (1.6)	-1.1; (-5.2, 3.0)
Women	11 11.9 (1.5)	17 17.6 (1.3)	-5.7; (-9.9, -1.6)

CI = confidence interval; LS = least-squares; LME = linear mixed effect model; SE = standard error

FDA Statistical review

What are the possible side effects?

WAKIX may cause heart rhythm problems (because of change in heart electrical activity called QT prolongation), especially in those who have underlying heart rhythm problems or who take drugs that alter the heart rhythm.

The most common side effects of WAKIX are difficulty sleeping, nausea, and feeling worried.

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

The table below summarizes the adverse reactions that occurred in the pooled population from 3 clinical trials.

Table 4: Adverse Reactions that Occurred in ≥2% of WAKIX-Treated Patients and More Frequently than in Placebo-treated Patients in Three Placebo-controlled Trials

Adverse Reaction	WAKIX (n = 152) %	Placebo (n = 114) %
Headache*	18	15
Insomnia*	6	2
Nausea	6	3
Upper respiratory tract infection*	5	3
Musculoskeletal pain*	5	3
Anxiety*	5	1
Heart rate increased*	3	0
Hallucinations*	3	0
Irritability	3	2
Abdominal pain*	3	1
Sleep disturbance*	3	2
Decreased appetite	3	0
Cataplexy	2	1
Dry mouth	2	1
Rash*	2	1

* The following terms were combined:
Abdominal pain includes: abdominal discomfort; abdominal pain; abdominal pain upper
Anxiety includes: anxiety; nervousness; stress; stress at work
Hallucinations includes:hallucination; hallucination visual; hypnagogic hallucination
Headache includes: cluster headache; headache; migraine; premenstrual headache; tension headache
Heart rate increased includes: heart rate increased; sinus tachycardia; tachycardia Insomnia includes: initial insomnia; insomnia; middle insomnia; poor quality sleep
Musculoskeletal pain includes: arthralgia; back pain; carpel tunnel syndrome; limb discomfort; musculoskeletal pain; myalgia; neck pain; osteoarthritis; pain in extremity; sciatica
Rash includes: eczema, erythema migrans, rash, urticaria
Sleep disturbance includes: dyssomnia; sleep disorder; sleep paralysis; sleep talking
Upper respiratory infection includes: pharyngitis; rhinitis; sinusitis; upper respiratory tract infection; upper respiratory tract inflammation; viral upper respiratory tract infection

WAKIX Prescribing Information

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

• Sex:The occurrence of side effects was similar between men and women.
• Race:The majority of patients were White. The number of patients of other races was limited; therefore, differences in side effects among races could not be determined
• Age:The majority of patients were adults less than 65 years of age. The number of patients older than 65 years was limited; therefore, differences in side effects between patients younger and older than 65 years of age 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 two most common adverse reactions, headache and insomnia, by sex. Subgroup analyses on race and age groups were not performed since the majority of patients were White and less than 65 years of age.

Table 5: Subgroup Analysis of Headache and Insomnia Adverse Reactions by Sex

	WAKIX (N = 152)		Placebo (N = 114)
	Men (n = 78) x (%)	Women (n=74) x (%)	Men (n = 56) x (%)	Women (n = 58) x (%)
Headache	11 (14%)	17 (23%)	6 (11%)	11 (19%)
Insomnia	5 (6%)	4 (5%)	1 (2%)	1 (2%)

FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved WAKIX for excessive daytime sleepiness in patients with narcolepsy based primarily on evidence from two trials (Trial 1/NCT 01067222, Trial 2/NCT 01638403). An additional trial (Trial 3/NCT01800045), in which patients with a different type of narcolepsy were exposed to the same dose of WAKIX, was used to add data for evaluation of side effects. The trials were conducted in Europe and South America.

Demographics of the patients who provided data on side effects (safety population) are presented below. The population that provided data for benefits of WAKIX (efficacy population) is presented in Table 7, under the MORE INFO section.

Figure 1 below summarizes how many men and women were in the clinical trials used to evaluate safety.

Figure 1. Demographics by Sex (safety population)

FDA Review

Figure 2 and Table 1 summarize the percentage of patients by race in the clinical trials used to evaluate safety.

Figure 2. Demographics by Race (safety population)

*Other includes one American Indian or Alaskan Native; the data for other 115 patients are missing or were not collected.

FDA Review

Table 1. Demographics of Safety Trials by Race

Race	Number of Patients	Percentage of Patients
White	146	55%
Black or African American	4	1%
American Indian or Alaskan Native	1	Less than 1 %
Not Collected or Missing*	115	43%

*Some data not collected per European regulatory authority

FDA Review

Figure 3 summarizes the percentage of patients by age group in the clinical trials used to evaluate safety.

Figure 3. Demographics by Age (safety population)

FDA Review

The tables below summarize the demographics for the safety and efficacy populations, respectively.

Table 6: Demographic Information for the Safety Population

                                       

Demographic Parameters	WAKIX (N= 152) n (%)	Placebo§ (N = 115) n (%)
Sex
Men	78 (51%)	57 (50%)
Women	74 (49%)	58 (50%)
Race
White	89 (59%)	57 (49%)
Black or African American	2 (1%)	2 (2%)
American Indian or Alaska Native	1 (< 1%)	0 (0%)
Not Collected or Missing*	60 (39%)	56 (49%)
Age Group
18 to 64 years	144 (95%)	107 (93%)
≥ 65 years	8 (5%)	8 (7%)
Ethnicity
Hispanic	0 (0%)	0 (0%)
Non-Hispanic	0 (0%)	0 (0%)
Not Collected*	152 (100%)	115 (100%)
Region
Eastern Europe	22 (15%)	19 (16%)
Western Europe	99 (65%)	72 (63%)
Other	31 (20%)	24 (21%)
United States	0 (0%)	0 (0%)

§includes 1 patient in placebo group of Trial 3 who withdrew before first treatment. *data not collected per European regulatory authority

FDA Review

Table 7: Demographics Information for the Efficacy Population

	WAKIX (N = 97) n (%)	Placebo (N = 62) n (%)
Sex
Men	52 (54%)	28 (45%)
Women	45 (46%)	34 (55%)
Race
White	89 (92%)	56 (90%)
Black or African American	2 (1%)	2 (3%)
American Indian or Alaskan Native	1 (1%)	0 (0%)
Missing	5 (5%)	4 (6%)
Age
18 to 64 years	89 (92%)	55 (89%)
≥ 65 years	8 (8%)	7 (11%)
Ethnicity
Not Hispanic or Latino	0 (0%)	0 (0%)
Hispanic or Latino	0 (0%)	0 (0%)
Not collected*	97 (100%)	62 (100%)
Region
Eastern Europe	23 (24%)	19 (31%)
Western Europe	64 (66%)	39 (63%)
South America	10 (10%)	4 (6%)
Other	0 (0%)	0 (0%)
United States	0 (0%)	0 (0%)

*data not collected per European regulatory authority

Adapted from FDA Review

How were the trials designed?

The benefits and side effects of WAKIX were primarily evaluated in two clinical trials.

Both trials enrolled adult patients with narcolepsy and excessive daytime sleepiness. Patients received WAKIX, placebo, or an approved drug for narcolepsy for 8 weeks. For patients receiving WAKIX, the dose could be increased during the first 3 weeks but had to remain the same for the next 5 weeks. Neither the patients nor the healthcare providers knew which treatment was being given during the trial.

The benefit of WAKIX was evaluated by comparing changes in daytime sleepiness during the trial between WAKIX- and placebo-treated patients. To measure the daytime sleepiness, the investigators used a scale called the Epworth Sleepiness Scale (ESS). The ESS asks patients to rate the likelihood that they would fall asleep while doing eight daily activities (such as sitting and reading or watching television). Patients rate each item from 0 (would never doze) to 3 (high chance of dozing).

Data from one additional trial were used to evaluate the side effects of WAKIX. This trial enrolled adult patients with different type of narcolepsy for which they also received WAKIX.

How were the trials designed?

The efficacy and safety of WAKIX in reducing excessive daytime sleepiness (EDS) in adult patients with narcolepsy were primarily evaluated in two multicenter, randomized, double-blind, placebo-and active-controlled trials (Trial1; NCT01067222 and Trial 2; NCT01638403). Patients ≥ 18 years of age with narcolepsy and who had an Epworth Sleepiness Scale (ESS) score ≥ 14 were eligible to enroll. EDS was assessed using the ESS, an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Items on the ESS are rated from 0 (would never doze) to 3 (high chance of dozing). The maximum score is 24. Trials included an 8-week treatment period, comprised of a 3-week dose titration phase and a 5-week stable dose phase. The primary endpoint was the difference between the mean ESS scores at the end of trial (adjusted for baseline differences) for WAKIX compared to placebo.

Additional safety data were collected from the trial in patients with narcolepsy with or without cataplexy.

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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